Board elects two members, honors three life trustees – University of Rochester

May 26, 2020

At a virtual May meeting, the University of Rochester Board of Trustees elected two new board members and recognized three individuals who become life trustees.

I am thrilled to welcome Betsy Ward and Martin Sanders to the board, said Board Chair Rich Handler 83. Its during an unprecedented time in the Universitys history that they are joining us, and their expertise and commitment to the University are needed now more than ever. I also want to express my gratitude to our new life trustees for their distinguished service over many years. We look forward to their continued engagement with the University.

University President Sarah Mangelsdorf said, I wish to welcome our newly elected members to the board and thank them in advance for their commitment. Im also very grateful to our newest life trustees, all of whom have made invaluable contributions to the University and provided wise counsel and support to me in my first year as president.

With current circumstances resulting from the COVID-19 pandemic, both new and life trustees will be recognized in person at a later date.

Martin Sanders is cofounder and CEO of Io Therapeutics, Inc., a privately held company based in Santa Ana, California, that develops treatments for Parkinsons disease, Alzheimers disease, multiple sclerosis, and various cancers. He is also the executive chairman of the companys board of directors.

Sanders, a medical doctor, has had a long career in clinical medicine, basic laboratory research in immunology, drug discovery research, pharmaceutical product development, patient care, venture capital investment, and serial company formation in the life sciences. He holds many patents, including one that was granted in March 2020 for treating nervous system disorders. Dedicated to bringing new treatments to people suffering from Parkinsons disease, cancer, migraines, and blindness, he has served as an advisor to more than 50 biopharmaceutical companies in the areas of preclinical and clinical product development since 1992.

Sanders is a passionate supporter of the arts and believes that art and music play a role in good health. In 2018, he and his wife, Corazon, established the Martin E. and Corazon D. Sanders Professorship in Voice at the Eastman School of Music in appreciation of their daughter, Lauras, voice teacher. Laura earned her bachelors degree in 2016 and a masters degree in 2018 in voice and opera from Eastman. Through the Sanderss generosity, Eastman celebrated the first installation of a performance faculty member into an endowed position. In addition, Martin Sanders is a member of the Eastman School of Music National Council and the University of Rochester Volunteer Task Force.

He received his medical degree from the University of Chicago; served as an intern and resident in internal medicine at Washington University Medical Center in St. Louis; and completed three postdoctoral fellowships in allergy/clinical immunology at the National Institute of Allergy and Infectious Diseases, in rheumatology at Johns Hopkins Medical School, and in cancer immunology at the immunology branch of the National Cancer Institute. He is board certified in internal medicine and in subspecialties allergy/clinical immunology and rheumatology.

Elizabeth (Betsy) Ward 86 is the chief financial officer at MassMutual, leading the finance department at the nearly 170-year-old life insurance company into a new era, with a focus on connecting finance to broader strategic planning. Before becoming CFO in 2016, she held several prominent positions at the Springfield, Massachusettsbased company, including chief enterprise risk officer and managing director at a couple of their subsidiary asset management firms.

Ward serves on the US Department of the Treasurys Federal Advisory Committee on Insurance and has been a member of the American Academy of Actuaries and the Fellow Society of Actuaries since the early 1990s. She has been a key contributor to global risk management through her work leading various industry groups. She has also served on federal committees on supervisory requirements and research, focusing on the effective groupwide supervision of insurance groups and seeking to narrow the gaps among global regulatory regimes.

Ward earned a bachelors degree in economics and Spanish from the University, while also studying flute through lessons at the Eastman School of Music. Music continues to play an important role in her life. She serves on the board of directors of the Community Music School of Springfield and continues to perform on flute in local classical ensembles, and as an alto singer with chamber choirs and chorales in Connecticut and Massachusetts.

In November 2019, Ward was the keynote speaker at the Universitys Simon Womens Conference. In 2012, she was named by Diversity Journal as a Woman Worth Watching in Financial Services, and in 2014, she was cited by Insurance Risk magazine as CRO of the Year.

At the May meeting, the board approved the transition of three individuals to life trustee status. Together the individuals have provided years of distinguished service to the board and their philanthropy has supported the creation of new facilities, scholarships, professorships, and other initiatives throughout the University.

Kathleen Murray 77 has been a board member since 2010, serving at different times on the Academic Affairs, Audit and Risk Assessment, Executive, Facilities, Human Resources, and Nominations and Board Practices committees. In her role as trustee, she has lent her business expertise to assist leadership in complex strategic, financial, and managerial issues, as well as supported key University goals through service on the Diversity Advisory Council, the NY Metro Women Steering Committee (for which she is chair emeritus), River Campus Libraries National Council, and Meliora Campaign Cabinet Chair.

In Arts, Sciences & Engineering, she established the Kathleen McMorran Murray 74 Endowed Scholarship Fund and Rochester Annual Fund. She has also exemplified generosity to other units of the University, particularly to the College Annual Fund, Diversity Program Fund, and the River Campus Libraries Annual Fund.

Francis Price 74, 75S (MBA) has provided business, financial and strategic advice to the University since he joined the Board in 1995. He has served on the Academic Affairs, Executive, Executive Alternate, Financial Planning (now Strategic and Financial Planning), Health Affairs, Nominations and Board Practices, and Student Affairs (now Student Life) committees during his tenure.

Price has additionally served on the Memorial Art Gallery Board of Managers, Diversity Initiative Campaign Committee; Hajim School of Engineering Visiting Committee; Los Angeles Regional Cabinet; and the Multicultural Alumni Advisory Council Executive Committee. In 2016, he volunteered his time to serve as the inaugural chair of the Public Safety Review Board.

He has generously supported the David T. Kearns Center, African-American Institute Gift Account, and the College Annual Fund.

E. Philip Saunders has provided distinguished service to the University as a member of the Board of Trustees since 2015. He has encouraged valuable discussions and principled engagement in a wide range of issues affecting the University. He has served with distinction on the Health Boards Affairs Committee, and served as Rochester Philanthropy Council chair; Medical Center Campaign Cabinet cochair; Medical Center Meliora Campaign vice-chair; and George Eastman Circle Rochester Leadership Council chair.

Saunders has provided extraordinary philanthropic support to the University. In 2011, he contributed $10 million to the University of Rochester Medical Center to support neuromuscular disease and translational research. The Saunders Research Building, home to the Clinical and Translational Science Institute, clinical research programs, and academic departments, was named in his honor. His gift also supports the Saunders Family Distinguished Professorship in Neuromuscular Research and the E. Philip and Carole Saunders Professorship in Neuromuscular Research. He served as a cochair of the Medical Centers campaign in support of The Meliora Challenge and honorary chair of the George Eastman Circle Rochester Leadership Council. He greatly influenced and encouraged philanthropy with the creation of the highly successful George Eastman Circle Plus One outreach concept, inspiring other units of the University to adopt the concept to increase engagement.

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Board elects two members, honors three life trustees - University of Rochester

Learning how the coronavirus affects the body offers clues to fight COVID-19 – CBC.ca

This is an excerpt fromSecond Opinion, aweeklyroundup of eclectic and under-the-radar health and medical science news emailed to subscribers every Saturday morning.If you haven't subscribed yet, you can do that byclicking here.

The devastating damage that the novel coronavirus inflicts on the human body can set off inflammatory havoc. As we learn more, doctors are gaining clues to hopefully prevent deaths and improve treatment.

Last December, COVID-19 entered the world stage as a flu-like illness causing fever, dry cough and a sore throat.

Since then, the list of how the illness can present has expanded, and expanded again, to include gastrointestinal symptoms like diarrhea, general aches, loss of taste and smell and serious blood-clotting problems, among others.

Of the more than five million infections globally so far, 2.4 million have recovered.

Most infected people have so few symptoms they are better off at home. The minority of serious infections in patients mainly those over 65, though no age group is left unscathed can confound health professionals caring for them.

The illness can worsen to a severe stage called Acute Respiratory Distress Syndrome, which includes severe lung inflammation and damage. These are often the patients who are admitted to intensive care units and need life support such as ventilation.

Dr. Lynora Saxinger, an infectious disease physician at the University of Alberta, co-chairs a provincial scientific advisory board reviewing how COVID-19 manifests and what it means for reducing transmission and extending treatment beyond current care measures.

"The landscape shifts really quickly," Saxinger said. "We just want to make sure that we're not missing [what] could be spreading, because that's where we're going to run into trouble."

As initial anecdotes about inflammatory-like effects such as blood-clotting complications mounted into a clearer signal for caution, clinicians adapted their care while scientists worked to understand why it happens.

Now, Saxinger said there's more evidence of clotting damage in both large and small blood vessels."This virus is doing different things in the body."

Experts say some of these inflammatory effects look to be unique to this particular coronavirus, which is known asSARS CoV-2.

Dr. Zain Chagla, an associate professor of infectious disease at McMaster University in Hamilton, Ont., said the wide extent of clotting with this virusdiffers from other infections, including from the deadly SARS and MERS coronaviruses.WithCOVID-19, the clots occur in veins in the legs and lungs, as well as in arterial ones that cause strokes and can lead surgeons to resort to amputating a patient's limbs.

Medical researchers have also found tiny clots that damaged tissue throughout the body in hospitalized patients and in autopsies.

Chagla said this means that "from a therapeutic standpoint," it might be better to give patients a low dose of heparin,an anticoagulant or blood thinner. It's often used before surgery and in a variety of medical conditions to prevent and treat clots.

Clinical trial researchers are also exploring the use of high-dose anti-coagulants in carefully selected patients, Chagla said.

This week, Health Minister Patty Hajdu announced an accelerated path for clinical trials to help find answers to urgent COVID-19 diagnosis, treatment, mitigation or prevention questions while keeping patients safe.

On Friday, Montserrat Puig of the U.S. Food and Drug Administration and her team published what they called a road map for effective treatment of COVID-19, based on both repurposing existing approved drugs as well as those still under development.

The review, published in Frontiers in Immunology, unravels factors leading to the "cytokine storm" that can rampage in people with severe COVID-19. Cytokines are small molecules released by the body's immune system to co-ordinate response against an infection or injury, ranging from a mild fever to suspected deaths in the 1918 flu pandemic.

Scientists are still working to understand the key events in cells, tissues and the body's immune system that tips the balance from a normal, protective, "hey, come help" call for reinforcements to an unnecessary, four-alarmcall that leads to a life-threatening overreaction.

Puig wrote that potential drugs include those that could block the virus from entering our cells in the first place, antivirals to stop the virus from making copies of itselfand therapies called monoclonal antibodies that dampen the haywire response from cytokines.

People who develop symptoms of COVID-19 do so within 14 days, and it mostly occurs about five days after exposure.

Saxinger said when patients struggle with congested lungs and poor blood pressure control, it's often a manifestation of lung inflammation in response to the infection.

She said there's also an arc to the story of how the disease marches through the body from initial infection to damage to recovery or death.

"The initial infection triggersthis body-wide response that is devastating," Saxinger said. "Then, when the infection itself might be coming under control, it's almost like you unleash this storm of immune reactivity and inflammation."

Once the storm is set off, doctors say treating the infection itself is unlikely to help much.

So, what could help? As physicians report more symptoms, scientists working in parallel are exploring why and how the virus replicates in some tissues and organs so well.

Matthew Miller, an associate professor of infectious disease and immunology at McMaster, is following the scientific advances.

The virus seems to use a receptor called ACE2 to enter human cells. Miller said many groups of researchers are working to understand what cells in our body have active proteins where the virus might be able to replicate and cause disease.

"Knowing what cells a virus is capable of infecting is really important, because it can help us anticipate what types of diseases or what types of symptoms it might cause," Miller said.

It's thought that the infectious dose a person is exposed to,as well as minute, genetic differences in the individual and whether theyhave underlying health conditions (like heart disease or diabetes)all play a role in how COVID-19 manifests.

For now, medical researchers are exploring how ramping up a beneficial aspect of the immune response that cells normally use to kill off a virus could be complemented with "immune modulators" to tamp down overreactions. It's a delicate balance and timing is key.

Miller said as we learn more about the unique features of SARS-CoV-2, governments and public health officials have been forced to "learn on the fly" and adapt pandemic plans built for a different respiratory infection:influenza, commonly called flu.

"One of the areas that this pandemic has really brought to light is that there's not enough focus on prevention control measures," he said.

Countries imposed and eased lockdowns without a firm grasp on what measures work best for this particular virus, leading to differences across the globe and shifting recommendations on wearing masks or physical distancing.

"I think we're all learning that we don't understand nearly as well as we should," Miller said.

WATCH | Why we should expect waves of COVID-19:

Public health basics like staying home when sick, handwashing and cough etiquette apply to all respiratory pathogens. It's the specifics that are still a work in progress.

For Saxinger, these knowledge gaps mean that understanding COVID-19 will be a long-term effort.

"It's not just going to be a one, we're done," Saxinger said. "We are all going to have to figure out the best way to manage people and try to give them the best outcomes possible."

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Learning how the coronavirus affects the body offers clues to fight COVID-19 - CBC.ca

Study reveals factors influencing outcomes in kidney cancer treated with immunotherapy – Science Codex

BOSTON - By analyzing tumors from patients treated with immunotherapy for advanced kidney cancer in three clinical trials, Dana-Farber Cancer Institute scientists have identified several features of the tumors that influence their response to immune checkpoint inhibitor drugs.

The research was presented during the Clinical Science Symposium at the American Society of Clinical Oncology (ASCO) Annual Meeting and published simultaneously in Nature Medicine. The researchers say the study provides important clues about kidney cancer genetics and its interaction with the immune system that may prove to be vital in our ability to predict which patients are likely to benefit from immunotherapy drugs, which have been approved for first- and second-line treatment in the disease, but which don't work in all patients. The study showed that features that are typically linked to immunotherapy response or resistance in other types of cancer don't work the same way in advanced clear cell renal cell cancer (ccRCC).

"Kidney cancer breaks all those rules," said David Braun, MD, PhD, a Dana-Farber kidney cancer specialist and first author of the report. Co-senior authors are Toni Choueiri, MD, Catherine J. Wu, MD, Sachet A. Shukla, PhD, and Sabina Signoretti, MD all of Dana-Farber. Other authors are from the Broad Institute of MIT and Harvard, Bristol Myers Squibb, and Brigham and Women's Hospital.

Clear cell renal cell cancer is the most common form of kidney cancer. There are about 74,000 new cases of kidney cancer in the United States each year, and about 15,000 deaths. Checkpoint inhibitor immunotherapy drugs such as pembrolizumab (Keytruda) and nivolumab (Opdivo) used in advanced kidney cancer work by blocking PD-1, a protein on immune T cells that normally keep these cells from attacking other cells in the body. By blocking PD-1, these drugs boost the immune response against kidney cancer cells.

PD-1 checkpoint inhibitors have brought a powerful new weapon to bear on advanced kidney cancer, which generally doesn't respond to standard chemotherapy. In cancers such as melanoma and lung cancer, checkpoint inhibitors - drugs like pembrolizumab (Keytruda) and nivolumab (Opdivo) - tend to be more effective against tumors with a "high mutational burden," that is, their DNA is riddled with many mutations. Advanced clear cell renal cell cancer, by contrast, has a moderate number of mutations yet is relatively responsive to checkpoint inhibitors - and scientists don't know why that is. Another puzzling difference is that in melanoma and some other cancers, tumors that are infiltrated with large numbers of immune CD8 T cells, creating what's termed an inflamed or "hot" environment within the tumor, respond better to PD-1 blockade. But the reverse is true in advanced kidney cancer - high infiltration by CD8 T cells is associated with a worse outcome.

In this study, the scientists analyzed 592 tumors collected from patients with advanced kidney cancer who were enrolled in clinical trials of PD-1 blocking drugs. They used whole-exome and RNA sequencing and other methods to uncover the genomic changes and other factors that were associated with how the patients' tumors responded to the drugs - specifically, the patients' progression-free survival and overall survival.

The study was aimed at determining what features of advanced kidney cancer cells were associated with their response or resistance to PD-1 inhibitors. In analyzing the tumors from advanced ccRCC patients treated with PD-1 inhibitors, the investigators looked for biomarkers - genetic changes, mutations, copy number alterations, and so forth - in the genomes of the kidney cancer cells that might be correlated with patient outcomes - such as progression-free survival and overall survival.

Braun said that some of the most interesting findings were characteristics of the kidney tumors that - unlike with other types of cancer - did not influence responsiveness to PD-1 inhibitor drugs. For example, tumors containing a large number of neoantigens - proteins made by cancer-related DNA mutations that may make the tumors more responsive to immunotherapy, but this proved not to be true of the kidney tumors. Also, even though the kidney tumors were heavily infiltrated by CD8 immune T cells - which causes other kinds of cancer to provoke a strong immune attack against the tumors - this actually led to no difference in outcome for these kidney cancer patients. "To our surprise, the immunologically 'hot' tumors did not respond any better than the 'cold' tumors," said Braun.

Another factor that affects responsiveness in some types of cancer - the specific HLA molecules inherited by individuals that present antigens to the immune system - didn't affect the immune response to advanced kidney tumors. "That surprised us," said Dr. Wu, chief of Division of Stem Cell Transplantation and Cellular Therapies. "We reasonably hypothesized that the potential of the patient's immune system to present and react to a greater diversity of antigens may be associated with better outcomes, but clearly kidney cancer does not fit the standard mold," noted Wu.

"However, we did uncover some factors that may explain the unexpected observations," said Dr. Shukla who leads the computational group at the Dana-Farber Translational Immunogenomics Laboratory. The study uncovered that advanced kidney tumors heavily infiltrated with CD8 T cells did not respond well to immune checkpoint blockers even though they were immunologically "hot" tumors. The scientists, with their comprehensive analysis of changes in the kidney tumors' genomes, found that the tumors were depleted of mutated PBRM1 genes - which are correlated with improved survival with PD-1 blockade therapy - and also had an abundance of deletions of a chromosomal segment known as 9p21.3, which is associated with worse outcomes with PD-1 blockade. "We believe that these two factors may explain why CD8 T cell infiltration of the tumors did not make them responsive to checkpoint blocker therapy," explained Shukla, "while other types of cancer that exhibited CD8 T cell infiltration but did not have those chromosomal changes did respond."

"Our work highlights the importance of integrating genomic data with immunopathologic data generated through painstaking review by expert pathologists," said Dr. Signoretti, professor of pathology at Harvard Medical School. "Our findings reveal that interactions between immune T cell infiltration and alterations in the tumor DNA (such as inactivation of the PBRM1 gene and the abundance of 9p21.3 deletions) can be important influences on tumors' response to PD-1 blockade - perhaps not only in kidney cancer but in other types of tumors as well."

"The current study provides critical insights into immunogenomic mechanisms contributing to response and resistance to immunotherapy in clear cell renal cell cancer," said Dr. Choueiri, director of the Lank Center for Genitourinary Oncology and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School. "The detailed clinical, genomic, transcriptomic, and immunopathology data produced by this study will serve as a valuable resource for the cancer immunology community. This work, therefore, will be important for ongoing research in precision medicine and immuno-oncology, helping to identify which patients are likely to respond to current therapies, and providing fundamental information to aid in development of rational combination therapies to overcome resistance in the future."

"One notable thing," said Choueiri, "is the collaboration between multiple disciplines and stakeholders: Immunology, pathology, genetics, computational and clinical expertise all converged on one tumor, while involving academic and industry stakeholders."

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Study reveals factors influencing outcomes in kidney cancer treated with immunotherapy - Science Codex

Indira IVF to resume in-vitro fertilisation services – Express Healthcare

All safety protocols directed by authorities will be followed to ensure safety of patients, doctors, working staff

In March, the Human Fertilisation and Embryology Authority (HFEA) ordered to pause the IVF treatment procedures in the UK. After the massive Coronavirus hit,IVFclinics were asked to postpone its services amidst the lockdown. There has been too much fear about the patients contracting the virus and they are taking all the measures to curb it. Recently, European Society of Human Reproduction and Embryology, The American Society for Reproductive Medicine and Indian health department have asked clinics to start essential services in a phased manner with all necessary safety measures.

Working as per the guidelines provided by the authorities, Indira IVF has taken a decision to restart its in-vitro fertilisation (IVF) services. All 89 clinics are open for patients who are seeking treatment with all the precautionary measures as per the guidelines provided by the Government of India.

With the current number of cases increasing aggressively, hospitals and clinics are advised to remain vigilant in the safety protocols and take all the required safety measures. Relentless adherence to safety protocols is a must.

Keeping into consideration the current COVID-19 condition, Indira IVF is following all safety protocols directed by the authorities to ensure the safety of patients, doctors and the working staff.

To ensure a safe and clean environment, the company has come up with precautions including:

Mandatory checking of temperature for all who enter the premises

Self-declaration form by the patients to identify the high-risk patients

Proper precautionary measure should be taken by the patients, doctors, and staff like gloves, masks, and others

Regular disinfection of the hospital facility

Strict sanitisation protocols

Social distancing and entry only by prior appointment

Speaking about the same, Nitiz Murdia, Marketing Director, Indira IVFsaid In this difficult time, we are keeping our focus to minimise visits a patient makes to the clinic for IVF treatment by offering tele-consultation with the treating fertility specialist. We are also taking special precaution at all our 88 clinics across pan India to strictly follow health and hygiene guidelines issued by the government for the safety of our staff and our patients. To live with COVID-19 virus is now the new way to live life hence its our collective responsibility to take all the necessary precautions to safeguard our-self as well as our family members from this virus.

Fertility clinics have shut down its services since March after the lockdown was announced. But today, fertility hospitals are trying to resume their operations.The reopening is happening in phases with new safety measures being put in place.

Speaking about the present scenario,Dr Kshitiz Murdia, Chief Operating Officer, Indira IVFsaid The impact of Coronavirus has greatly affected infertile couples who have planned to undergo treatment in summers; due to lockdown conditions in the city, couples had to postpone their treatment. The good news is that now they will be able to re-start their treatment at Indira IVF clinics. To tackle the previous load of the IVF patients, we are giving priority to patients whose embryos were frozen with us but due to lockdown they couldnt undergo embryo transfer procedure followed by other patients.

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Indira IVF to resume in-vitro fertilisation services - Express Healthcare

Reconstructing the time since death using noninvasive thermometry and numerical analysis – Science Advances

Abstract

The early postmortem interval (PMI), i.e., the time shortly after death, can aid in the temporal reconstruction of a suspected crime and therefore provides crucial information in forensic investigations. Currently, this information is often derived from an empirical model (Henssges nomogram) describing posthumous body cooling under standard conditions. However, nonstandard conditions necessitate the use of subjective correction factors or preclude the use of Henssges nomogram altogether. To address this, we developed a powerful method for early PMI reconstruction using skin thermometry in conjunction with a comprehensive thermodynamic finite-difference model, which we validated using deceased human bodies. PMIs reconstructed using this approach, on average, deviated no more than 38 minutes from their corresponding true PMIs (which ranged from 5 to 50 hours), significantly improving on the 3 to 7 hours uncertainty of the gold standard. Together, these aspects render this approach a widely applicable, i.e., forensically relevant, method for thermometric early PMI reconstruction.

The early postmortem interval (PMI), i.e., the time shortly after death, plays a key role in forensic investigations, as it aids in the temporal reconstruction of events. Consequently, the development of a method to determine the PMI remains one of the most important challenges in forensic medicine to date (1). In its pursuit, many pathophysiological changes have been investigated as potential measures of the PMI. These measures can be divided into two groups. The first relies on sampling of tissue or bodily fluids (2), followed by laboratory examinations to quantify, e.g., nucleic acid degradation (3), changes in the ocular potassium concentration (4, 5), and microbial (6) and metabolomic (7) changes. In contrast, the second group involves probing optical, mechanical, or thermal changes in human tissue (812). This latter group does not require any sample extraction or laboratory examinations; these pathophysiological changes can therefore be quantified directly at the crime scene.

Of these measures, the change in body temperature is most frequently probed to determine the PMI in the early postmortem period. Thermometric PMI determination was first introduced in the 19th century (13), and since then, many models have been developed aiming to map postmortem body temperature to time since death (1316). The current gold standard in forensic practice is a model by Henssge (1719), relating rectal (core) temperature to PMI. Usually presented in the form of a nomogram, this model is based on a limited set of measurements and the underlying assumption that the postmortem rectal temperature of any given human body follows a typical cooling curve. In Henssges model, this typical cooling curve is described by a double exponential decay, the exponents of which are derived empirically and related to the victims body weight, its coverage, and surface contact. While this approach is widely used, it is subject to substantial limitations. First, the underlying dataset was acquired under standardized conditions; deviations from these standard conditions necessitate the use of subjective correction factors or preclude the use of Henssges nomogram altogether. Moreover, use of this model requires an invasive measurement of the victims rectal temperature, risking contamination, and destruction of other traces. Last, the model classifies human bodies only by weight, thereby introducing a consequential thermodynamic degree of freedom: under identical circumstances, two bodies of equal weight but different stature or body composition (body fat percentage) will cool at different rates. As a result, the uncertainties of PMIs determined using Henssges nomogram vary broadly from 3 to 7 hours on a 20-hour time scale.

More rigorous, i.e., nonsubjective, approaches to thermometric early PMI determination have been developed (2024). In these approaches, the thermodynamic processes governing body cooling are modeled using numerical methods, e.g., finite elements. While these efforts expand the applicability of thermometric PMI determination in theory, in practice, they are subject to considerable limitations. First, some require computed tomography (CT) data, which are not commonly available in forensic case work. Second, their computational implementation necessitates highly specialized technical expertise. Last, and perhaps most importantly, none of these approaches have been validated using human bodies. Consequently, there is a clear need to develop and validate a numerical approach to early PMI reconstruction straddling the divide between model complexity and usability in forensic practice.

To address this, we developed an approach that overcomes the above limitations by using a simplified but versatile numerical (finite difference) model. Body posture, stature, and composition as well as (time-dependent) environmental variables such as contact surface, (partial) submersion in water, and (partial) coverage by clothes are all readily integrated in our model (including environmental changes before and after discovery of the body), rendering it applicable in a wide variety of forensic cases. Furthermore, it allows computation of the body temperature at external body locations, in turn, enabling a noninvasive experimental protocol. We validated and benchmarked our approach using deceased human bodies. To this end, we recorded time-resolved skin temperature curves, at several body locations, on deceased human subjects and then evaluated the performance (accuracy and precision) of PMI reconstruction using our model. To determine the accuracy, we compared measured abdominal skin temperatures of four deceased subjects to their corresponding numerical predictions to reconstruct a wide range of PMIs, ranging from 5 to 50 hours since death. Next, we determined the variability in these PMI reconstructions resulting from uncertainty in the model input parameters. The outcome of this evaluation has important practical implications, as in forensic practice, some of these parameters will only be known within parameter-specific margins of error.

To reconstruct the PMI from a measured body temperature, we developed a finite difference model (see Materials and Methods and section S1) allowing time- and spatially resolved simulation of the body temperature following death. To this end, the model uses a discretized three-dimensional representation of the body and its surroundings to calculate the heat exchange between the involved materials. By repeating this calculation for consecutive time intervals, the change in body temperature can be simulated. The sum of the necessary computational repetitions required to reach a location-specific measured reference temperature then corresponds to the numerically reconstructed PMI.

To determine the model accuracy, we first tested our finite difference model on a simple system for which an analytical solution exists. To this end, we solved the problem of a solid sphere cooling in air using our finite difference algorithm. The resulting numerical solution was then compared to the analytical solution (25) at different spatial positions on the sphere as well as different points in time (Fig. 1). The numerical simulations are in close agreement with the analytical solution demonstrating the accuracy of the computational implementation.

Evolution of the temperature distribution of a solid sphere (radius = 30 cm) with a thermal conductivity of 0.55 Wm1 K1 cooling in air (20C). The blue lines correspond to the analytical solutions, while the red lines represent the numerical solutions yielded by our model. (A) Sphere temperature as a function of time at two locations: in the center and on the surface. (B) The sphere temperature as a function of radial distance at five distinct time points.

Next, we evaluated the capacity of our model to describe the change in skin temperature for recently deceased human subjects. To this end, we recorded skin cooling curves for four deceased subjects lying on a medical dissection table and stored at 2 to 4C. These measurements were performed at specific body locations (abdomen, chest, forehead, and thigh) and compared with the corresponding model predictions. These results are presented as a function of PMI in Fig. 2. The change in environmental temperature following storage in the mortuary refrigeration unit is included in the computation and manifests as a change in cooling rate, i.e., as an inflection point, in all simulated temperature curves.

Measured and simulated skin temperature as a function of PMI of different locations of a deceased (A) 79-year-old male, (B) 60-year-old male, (C) 94-year-old female, and a (D) 61-year-old female body in the AMC morgue. The blue solid lines correspond to the measured data, while the red dashed lines denote the simulated data. The inflection point in the simulated curves corresponds to the change in environmental temperature upon storage of the body in the mortuary refrigeration unit.

Figure 2A shows numerical and experimental data of a 79-year-old male weighing 64.5 kg, with a body length of 169 cm and with a calculated fat percentage of 29% wearing a shirt and a diaper. The body was additionally covered with a sheet, and the subjects head was resting on a pillow. This case-specific coverage and surface contact were included in the simulations by assigning the thermal conductivities of the clothes and the pillow to the appropriate locations in the grid. Skin temperatures were recorded between 6 and 30 hours postmortem. All numerically derived temperature curves are in excellent agreement with the measured cooling curves. Figure 2B depicts simulated and measured data of a 60-year-old male with a body weight of 99 kg, a body length of 181 cm, and a calculated body fat percentage of 29%. Besides a long-sleeved shirt and a diaper, the subject also had long and facial hair; all coverage was included in the simulations by adjusting the thermal properties of the corresponding grid elements accordingly. Skin temperatures were measured between 21 and 43 hours after death. While simulation and experiment are in close agreement for the abdomen and the forehead, the measured temperatures of the chest and the thigh exceed the simulated ones at these locations. The subject of the experiment summarized in Fig. 2C was a 94-year-old female and weighed 39 kg with a body length of 159 cm and a computed fat percentage of 21%. Skin temperatures were measured between 24 and 45 hours postmortem during which the subject was naked. Despite the progressed cooling state upon arrival, the simulated temperatures are still in close agreement with the measured temperatures. Only the simulated temperatures of the chest and the thigh exhibit moderate deviations from the measured data. Last, Fig. 2D depicts the measured and simulated location-specific skin cooling curves of a 61-year-old female with a body weight of 87 kg, a body length of 157 cm, and an estimated fat percentage of 34%. This subject also wore a shirt and a diaper; however, no sheet or a pillow was present. Again, the clothes were incorporated by assigning the respective thermal conductivities to the appropriate locations within the grid. Thermal measurements took place at PMIs ranging from 26 to 50 hours. The simulated cooling curves are generally in good agreement with the measured curves. For three of the four measurement locations, however, small deviations are visible: While the time-dependent temperatures are underestimated for the forehead, they are overestimated for the thigh and the chest. Notwithstanding, all simulated decay rates accurately model those of the measured temperatures.

Using both the measured and simulated abdominal data shown in Fig. 2, we reconstructed PMIs for each measurement time point of all subjects. By comparing these reconstructed PMIs to their corresponding true values (which ranged from 5 to 50 hours), we determined the accuracy of our method for PMI reconstruction. Figure 3A shows the numerically reconstructed PMIs as a function of the true PMI. The absolute errors of the PMI reconstructions (PMI) are shown in Fig. 3B. All reconstructed PMIs lie within at least 3.2 hours of the true PMI, while the average PMI is 38 min. Moreover, 83.3% of the reconstructed PMIs deviate no more than 1 hour from their corresponding true PMI. Next, we investigated the extent to which this error depends on the uncertainty in the model input parameters. To this end, we chose a specific set of input parameters as a starting point, yielding a reference PMI. We then systematically and sequentially varied these input parameters and compared the resulting reconstructed PMIs to this reference PMI. The results of this parameter sensitivity analysis are summarized in Fig. 4 and fig. S2. Both figures show the maximum error of the reconstructed PMI as a function of the variation in five model input parameters: initial body temperature (Fig. 4A), body fat percentage (Fig. 4B), thermal conductivity of the clothes (Fig. 4C), thermal conductivity of adipose tissue (fig. S2A), and thermal conductivity of nonadipose tissue (fig. S2B). The black stars denote the values for the reference dataset. Of these parameters, variation in the thermal conductivity of the clothes induces the largest variation in reconstructed PMI. On average, the reconstructed PMIs deviate no more than 2 hours from the reference PMI. Moreover, the deviation in reconstructed PMI induced by uncertainty in the thermal conductivity of the clothes, adipose tissue, and nonadipose tissue or the body fat percentage is independent of the environmental temperature. In contrast, the extent to which uncertainty in the initial body temperature induces deviation in the reconstructed PMI depends on the environmental temperature. Together, these results demonstrate that the accuracy of our method surpasses that of the gold standard even in cases where input parameters are known only within a margin of uncertainty.

(A) Comparison of true versus reconstructed PMIs using the abdominal reference measurements of four different bodies (each indicated by a different marker color). (B) Absolute error, i.e., difference, between the reconstructed and correspdoning true PMIs shown in (A).

Effect of uncertainty in the model input parameters (A) initial body temperature, (B) body fat percentage, and (C) thermal conductivity of the clothes on the estimated PMIs. Circles and upward pointing triangles denote results for the parameter variations at environmental temperature (ET) values of 10 and 20C, respectively. Negative values of the PMI deviation correspond to an underestimation of the true PMI, while positive values indicate overestimation.

In this study, we developed and validated an advanced approach to describe postmortem body cooling. Computational robustness and numerical accuracy of this approach were established by solving the heat exchange problem for a simple geometry both analytically and numerically and demonstrating close agreement of these solutions. Overall, we found the predicted cooling curves of (partially) clothed human bodies to be in close agreement with the measured temperatures (mean deviation of 1C) of subjects spanning large ranges in age (60 to 94 years), weight (39 to 99 kg), body length (157 to 181 cm), and fat percentage (21 to 34%) showcasing the broad applicability of the model. To demonstrate the feasibility of PMI reconstruction, we used our model in conjunction with measured abdominal temperature curves of four subjects to reconstruct PMIs ranging from 5 to 50 hours. We found the maximum and average error of these reconstructed PMIs to be as low as 3.2 hours and 38 min, respectively. Moreover, 83.3% of the reconstructed PMIs deviate no more than 1 hour from their corresponding true PMIs. Parameter sensitivity analysis revealed the extent to which these errors depend on uncertainties in the studied model input parameters. Errors of the reconstructed PMIs induced by parameter-specific uncertainties remain within 2.5 hours for true PMIs ranging from 6 to 40 hours. While the errors induced by uncertainty in the thermal conductivity of the clothes and the body fat percentage are independent of the environmental temperature, the effect of uncertainty in the initial body temperature clearly is not. This latter finding is in agreement with the results of a similar study (26). The initial body temperature determines the temperature gradient between the body and its surroundings; this gradient, in turn, is the fundamental property underlying and driving the heat exchange process. Therefore, uncertainty in the initial body temperature plays a bigger role at higher environmental temperatures. Notwithstanding, these results represent a notable improvement over the current gold standard (Henssges nomogram) where uncertainties range from 3 to 7 hours.

In some of the subjects, there is an observable discrepancy between the simulated and measured temperatures of the chest. The deviation of the temperature of the chest may be a result of placing the temperature sensor on the sternum. Our model does not include the location of bones within the body. This, in turn, may lead to measured temperatures exceeding simulated ones: The higher thermal conductivity of bone will transport core body heat to the skin more efficiently than accounted for in the model (see fig. S1). This deviation can therefore easily be avoided in the future by placing the sensor next to the sternum. While we successfully validated our approach on cooling human bodies, all experimental work was conducted in a standardized environment (hospital morgue), significantly reducing the variability of many environmental parameters. Consequently, performance evaluation of the approach in forensic fieldwork is paramount in determining its added value to forensic practice. The parameter most likely to vary considerably in most cases will be the posture of the victim. Currently, our approach implements the body in a straight configuration (see Fig. 5). The required individualization of the virtual body posture could be addressed using photogrammetric image processing techniques, e.g., Structure from Motion (SfM). SfM allows noncontact measurement of the three-dimensional shapes of objects from two-dimensional images (27); this information (the dimensions and the posture of the body) could then serve to render the virtual body in a straightforward way. Furthermore, spatial coregistration of measured and simulated skin temperatures can be achieved through the addition of coded imaging targets, increasing modeling accuracy and potentially allowing the integration of thermal imaging. Similarly useful to the individualization of the virtual body could be the inclusion of postmortem CT scans (22): Besides improving the assignment of the different tissue types (28), this tomographic information would also allow both the inclusion of cavities filled with air (or other materials) and the locations of bones in the model, the latter addressing issues such as that of the sternum mentioned earlier. While integration of these data could potentially increase model accuracy, it may hamper practical applicability of the approach by the same token: The increased model complexity would manifest as a higher computational workload, larger datasets, and decreased ease of use. However, postmortem CT scans are increasingly performed in forensic practice, rendering the required information available for a larger number of cases.

(A) Material assignment of adipose tissue and nonadipose tissue as well as virtual probe locations (for the forehead, chest, abdomen, and thigh) within the model. The numbered red bars within the frontal cross sections indicate the location of the corresponding horizontal cross sections (above). (B) Simulated spatial temperature distributions (in C) of the body shown in (A) cooling in air: frontal cross sections of the computed temperature distributions at distinct time points (0, 5, 10, and 25 hours postmortem).

Improving the error margin in our PMI estimates necessitates the reduction of the uncertainty in the model input parameters. It would therefore also be desirable to measure the thermal properties, e.g., thermal conductivity, of the materials, which are in contact with the body, and hence relevant to the heat exchange problem, directly at the crime scene.

Last, another varying environmental parameter is the ambient temperature. An unknown ambient temperature significantly increases the uncertainty in the time of death estimate (23). However, in many situations, this information may be available as thermostat or meteorological data, in which case they could be easily included in the thermodynamic computations. Moreover, a general strength of our model is that multiple scenarios can be simulated to reconstruct a range of possible PMIs, the maximum and minimum of which can be reported as the most likely time frame for the PMI. While other numerical descriptions of the postmortem body cooling process exist, they lack either geometric accuracy (20) or experimental validation using deceased human bodies (20, 24). Moreover, currently, none of these approaches include modeling of (partial) clothing, (partial) contact with surfaces, or submersion in water. To our knowledge, we are the first to validate a numerical description of postmortem skin cooling with realistic and noninvasive measurements on deceased human bodies. Last, multiple (simultaneous) skin temperature measurements may reduce uncertainty in the PMI calculation by increasing the number of independent measurements. Together, these aspects render this study a considerable advance in the pursuit of a widely applicable, and hence forensically relevant, method for temperature-based PMI estimation.

Thermometric PMI reconstruction using the numerical approach outlined in the theory section (see section S1) requires modeling (discretization) of the body and its environment. Here, a discretized three-dimensional representation of the body and its surroundings is obtained as follows. First, the individual body parts are approximated as cones (e.g., arms and legs), ellipsoids (e.g., head), and cylinders (e.g., neck and torso), the proportions of which are dictated by standardized anatomical measurements (e.g., length of the arms and legs and the circumference of the head, torso, upper arms, and wrists). Second, these individual body parts are then assembled to form the entire body. Third, this simplified model of the body is placed within an isotropic cubic mesh (which is generated automatically based on the body dimensions) of desired cube size (in this study, 1 cm3) where it then serves to determine material (i.e., thermal properties) assignments on a cube-by-cube basis (see Fig. 5A). Similarly, to obtain spatially resolved temperature data for different time points, it is necessary to discretize the time before equilibrium into finite time intervals t, in our case 60 s (matching the sampling period of our temperature measurements). This, in turn, determines the number of computational iterations needed to simulate the heat exchange process: e.g., for a period of 24 hours, a t of 60 s corresponds to 1440 iterations.

Besides modeling the geometry of the body and its surroundings, it is crucial that the material composition of the computational representation (i.e., the cube-wise assignment of the thermal properties) closely resembles reality to ensure accurate simulation of the body temperature change. Important factors therefore include body fat percentage, coverage by clothes, and contact area with other surfaces, such as the floor or water. The bodys adipose tissue is modeled as an outer layer surrounding the individual body parts. To accurately model the layer thickness, we estimate the fat percentage using the U.S. Navy circumference method (see Fig. 5A) (29).

The thermal conductivities of the nonadipose tissue, adipose tissue, and the clothes (in our case cotton) were set to 0.55, 0.2, and 0.03 Wm1 K1, respectively (30, 31). For the emissivity , we used the emissivity of human skin, namely, 0.96 (32), while for the characteristic length of the convective heat transfer, we chose the characteristic length of a cylinder approximated by the width and depth of the torso of the virtual body (33). Last, the specific heat capacities of nonadipose tissue, adipose tissue, skin, and clothing were chosen as 4.5, 1.96, 3.77, and 4 JK1 cm3, respectively (30, 3436). All simulations and data analyses were carried out using custom-made scripts written in MATLAB (The MathWorks Inc., Natick, Massachusetts, USA) and executed on a laptop with 8 GB RAM and an Intel Core i5-8250U CPU operating at 1.6 GHz. Typically encountered runtimes of our simulations are on the order of 10 s to 20 s.

The accuracy of the finite difference model was validated by numerically solving the problem of a solid sphere (radius = 30 cm) of nonadipose tissue (thermal conductivity = 0.55 Wm1 K1) in air over a period of 50 hours. The spatial and temporal changes of the temperature distribution of the sphere were then compared to the corresponding analytical solutions (25).

Our finite difference approach yields spatially and temporally resolved computations of the postmortem body temperature (see Fig. 5B). This, in turn, allows for the temperature measurements to be performed on the surface (i.e., the skin) of the body rather than rectally as required for the use of Henssges nomogram. To validate this approach, we conducted postmortem skin temperature measurements on deceased subjects available through the body donation program of the Department of Medical Biology, Section Clinical Anatomy and Embryology, of the Amsterdam University Medical Centers [location Academic Medical Center (AMC)] in The Netherlands. The donation of these bodies to science occurred in accordance with Dutch legislation and the regulations of the medical ethical committee of the Amsterdam UMC, location AMC. Bodies were included if they were suitably warm to ensure a measurable change in skin temperature. All measurements were performed in the AMC morgue using small ( = 16 mm) contact temperature sensors (DS1922L iButtons, Thermochron, USA) attached to the bodies using adhesive tape. Using this approach, skin cooling datasets were gathered from four deceased subjects, two males and two females, aged between 60 and 94 years. The body weights, body lengths, and calculated fat percentages of the subjects ranged from 39 to 99 kg, 157 and 181 cm, and from 21 to 34%, respectively. The amount of clothing and surface contact with insulating materials as well as the PMI at the beginning of the measurements varied between experiments. As all of these are input parameters in our model, their variation between experiments was accounted for by adjusting them accordingly in the respective calculations.

Reconstruction of the time since death, using our model, comprises computation of the heat exchange until a measured location-specific reference temperature is reached. The sum of the necessary computational time steps, i.e., n*t, required to reach the measured temperature then corresponds to the numerically reconstructed PMI (see section S1). The accuracy of this numerical PMI reconstruction was evaluated using abdominal skin temperatures of four deceased subjects comprising 96 measurement time points, i.e., true PMIs, between 5 and 50 hours with the corresponding measured abdominal reference temperatures ranging from 28 to 5C.

Our computational approach requires the values of several physical quantities (model parameters): the initial body temperature, the environmental temperature, the body fat percentage, and, if applicable, the thermal conductivity of the clothes and the floor, the floor temperature, as well as the flow speed of the surrounding medium (e.g., air). The extent to which uncertainty in these input parameters generates variation in our PMI predictions was evaluated by simulating the cooling of a body for 13 different sets of model input parameters at two different environmental temperatures (10 and 20C) yielding a total of 26 set-specific simulations. These 26 parameter sets were generated as follows: For both environmental temperatures, an original set of input parameters was chosen (see Table 1). Subsequently, we assigned physiologically and physically reasonable parameter ranges for three of the seven parameters, namely, initial body temperature, thermal conductivity of the clothes, and fat percentage of the body (see Table 1). This particular choice of parameters to investigate was motivated by their likelihood of being unknown and/or exhibit most variation in forensic casework. Next, for each of these three parameters, four (equidistant) values were chosen within their respective parameter ranges. Together with the original set of input parameters, this yields 13 separate sets of model parameters (see table S1) for each environmental temperature, i.e., 26 separate cooling simulations in total. For each of the two environmental temperatures, skin temperatures (of the abdomen, chest, upper arm, and thigh) simulated using the original parameter set served as a reference in the calculation of the deviation in predicted PMIs. The reference temperature ranged from 34.7 to 10.6C (environmental temperature = 10C) and 35.6 to 20.4C (environmental temperature = 20C) corresponding to true PMIs between 6 and 40 hours. Deviations from these true PMIs were then calculated for each of the four body locations for all 12 parameter sets for both environmental temperatures. Last, we determined the maximum deviation in reconstructed PMI (over all reference temperatures, i.e., reference PMIs, and body locations) for every parameter set for both environmental temperatures yielding a total of 24 data points. In addition, we investigated the parameter sensitivity of our model with respect to two more model parameters: the thermal conductivities of adipose and nonadipose tissue. Here, we chose two equidistant values on either side of the original parameter value within their respective parameter ranges (see Table 1) and calculated the maximum deviation in PMI at two environmental temperatures (10 and 20C). The results are summarized in fig. S2.

Parameters used in the parameter sensitivity study. Model input parameters and, where applicable, chosen parameter ranges. N.A., not applicable.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

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Acknowledgments: We thank M. Clerkx, R.-J. Oostra, H. Boesveld, J. Woertman, M. van den Born, and B. F. L. Oude Grotebevelsburg for help in carrying out measurements and improving the algorithm. Funding: Ministerie van Veiligheid en Justitie, Innovatieproject ronde 2019 Therminus. Author contributions: L.S.W. developed software, performed measurements, and analyzed data. R.J.M.H., G.J.E., and H.V. performed measurements. H.J.J.H. partly developed the theoretical framework. S.S. developed software. M.C.G.A. performed measurements, partly developed the theoretical framework, and conceived and supervised the project. All authors contributed to planning, design of experiments, discussion of results, and writing of the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Reconstructing the time since death using noninvasive thermometry and numerical analysis - Science Advances

Genetic genealogy companies Ancestry, 23andMe begin COVID-19 research – Detroit Free Press

Ancestry and 23andMe offer direct-to-consumer DNA tests.(Photo: Reviewed.com/Jackson Ruckar)

It's a question that has vexed researchers from the beginning of the coronavirus outbreak: Why do some people get severely ill and die from COVID-19, while others have mild symptoms or none at all?

Now, scientists at two direct-to-consumer genealogy DNA companies hope to use the genomesthey've collected from millions of people over the years to see if they can find a genetic explanation toanswer that question.

Both 23andMe and Ancestry have launched COVID-19 studies, asking U.S. adult customers who've already submitted DNA samples to answer online questions about how the virus affected or didn't affect them.

"From the early days ... I think it was clear to all of us that some people were getting very, very sick when they were affected with coronavirus, and some people had hardly any symptoms at all," said Dr. Catherine Ball,chief scientific officer at Utah-based Ancestry."It turns out that there are plenty of people who have no symptoms. The spectrum of human response to the same pathogen is unusual.

"And even with a bunch of comorbidities and other problems, it's still remarkably divergent in different people, even if they have the same age and have the same overall health. And soto geneticists, that looks like there's a genetic factor in whether people become infected in the first placeor have serious or mild symptoms."

With 16 million people who've already spit in vials and sent them to Ancestryfor genetic testing to find blood relatives who might be closely or distantly related or learn how much of their DNA suggests their relatives came from Africa or Asia or were Native American or European, Ball said the companyknew it had a potentially useful data pool to tap for COVID-19 research.

"We clearly want to take the opportunity to unleash that power to be able to see if there are genetic signals, and be able to help researchers and people making drugs and therapeutics and vaccines dosmarter work faster," she said.

Dr. Catherine Ball, chief scientific officer for Utah-based Ancestry.(Photo: Ancestry)

Of those 16 million DNA customers through Ancestry, so far about 500,000people have already taken an online survey to participate in the company'scoronavirus research.

At 23andMe, principal scientist Adam Auton said the California-based company's COVID-19 genome-wide association study launched in April.

About 10 million of itsgenotype customers are eligible for the study, he said.Of them, about 80%have consented to participate in research, and600,000 customers have opted into the COVID-19 study.

"It is a really quite tremendous response to the study and I think shows that people really do want to try and contribute to help understand and fight this disease," said Auton.

Both Ancestry and 23andMeacknowledge that the bigger the sample size, the better their research will be.

"Never ask a scientisthow much data she needsbecause she always needs more," Ball said. "We're really hoping to get a minimum of a million respondentsbecause we need to have a decent number of people who have tested positive to give us a statistical signal."

So far, about9,000 people in 23andMe'sCOVID-19 study reported that theytested positive for coronavirus.

"That's a pretty substantial number," Auton said. "However, it's the nature of genetic studies that we really need very large numbers of people to be able to draw connections between the genetic information and people's health information."

A worker at 23andMe performs DNA testing on samples provided by customers.(Photo: 23andMe)

Since the pandemic began,about 1.6million people in the United States, a country of 330 million, have tested positive for COVID-19. As the virus continues to spread,and more people get coronavirus diagnoses, the companies suspect that the number of people who will go on to enroll in their studies also is likely to rise.

"We understand this is an evolving situation," Ball said. "And while we can't shelter in place forever, at some point, as we're opening up our cities and states, more people will start contracting the virus."

Anyone who may have already filled out anonline COVID-19 survey on Ancestry.com or 23andMe.com, saying they had not yet had the virus, can go back and revise their answers later to reflect that they've contracted it.

To expand its research of people who've had COVID-19 even more, Auton said 23andMeis now offering tomail a free DNA test kit to any U.S adult who was hospitalized with COVID-19, but has not yet submitted a DNA sample to the company.

"We are essentially asking if people have been hospitalized with COVID-19, and they have recovered, if they would like to participate inour research. They can come to our website and we'll offer them a free kit,"Auton said.

The contents of a 23andMe kit.(Photo: 23andMe)

"We're very much interested in trying to get the word out so that people to hear about this because really every data point is going to be pretty valuable."

23andMe has emailed customers in areas hardest hit so far in the pandemic including those in Michiganto let them know about its study, Auton said.

"The best thing that we can do to make a difference for COVID is to really publish the results that we find and make them available to the research and scientific communities," he said.

23andMe haspublishedmore than 150 studies in peer-reviewed scientific journals, "the majority of which come from collaboration with the broader academic and the scientific community," Auton said,since it launched in 2006with its direct-to-consumer DNA kit.

But the company ran afoul of the U.S. Food and Drug Administration in 2013, when the agency ordered 23andMeto halt the release of genetic health information to customers, saying the company had yet to prove its tests were"analytically or clinically validated."

After revamping, the company passed FDA muster in 2017, and got authorization tooffergenetic healthreports that outlinedrisk for 10conditions, including late-onset Alzheimers disease andParkinsons disease.

Ancestry is new to the health genetics business. It launched AncestryHealth in 2019, with the disclaimer that its tests are physician-ordered and not diagnostic, but offer "health insights" into whether a person might be a carrier for cystic fibrosis or sickle cell anemia or whether there's a genetic variant associated with a higher risk for breast cancer or colon cancer.

Ball said Ancestry also will seek to publish its COVID-19 research findings, too.

"We will be doing our very best to publish our findings as quickly as possible, and making them as useful to clinicians and other researchers as quickly as possible," she said.

Ancestry DNA(Photo: Melissa Rorech)

Both companies are looking for research partners for the coronavirus studies. Ancestry has had nibbles from universities, biotech and pharmaceutical companies, but Ball said, right now, the focus is on safeguarding the privacy of its customers.

"We typically do not share data out with third parties," Ball said. "That's an unusual activity for us.

"We will not be sharingpersonal data. Everything will be de-identified. So names, email addresses, your address, your ZIP code, your phone number, all that stuff will be stripped and will not be shared. We do want to still be very conservative because it is people's genetic data."

At 23andMe, individual-level data is never shared with a third party "without explicit additional consent from participants," Auton said.

"The information that we're talking about here, where we would be working with the academic community, is all aggregated at a very high level. So it's really just information about whether a specific genetic variant is associated with the disease. It doesn't contain any information about the individuals in the study."

Ball urged people to consider participating in this research for the common good.

"The people who came to AncestryDNA were interested in finding out about their ancestors, their past and their history," she said."This is our chancein this moment of history ... to take 5-10 minutes ... and do our best to help our community of friends or familyand the people who we don't even know who will be coming along later.

"It's our chance to contribute to the benefit of everybody. And I think right now, it'san opportunity that resonates with a lot of people."

Auton said the research could lead to therapies or treatments for people sickened by COVID-19.

"Hopefully, that can make a difference," he said.

Contact Kristen Jordan Shamus: 313-222-5997 or kshamus@freepress.com. Follow her on Twitter @kristenshamus.

Read or Share this story: https://www.freep.com/story/news/health/2020/05/26/genes-dna-ancestry-23-andme-coronavirus-covid-19/5223568002/

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Genetic genealogy companies Ancestry, 23andMe begin COVID-19 research - Detroit Free Press

Seattle Genetics Announces Positive Results from Exploratory Analyses of HER2CLIMB for TUKYSA (tucatinib) in Brain Metastases Patients With…

BOTHELL, Wash.--(BUSINESS WIRE)--Seattle Genetics, Inc. today announced positive results from exploratory analyses of intracranial efficacy, including survival, in patients with HER2-positive metastatic breast cancer (MBC) who had stable or active brain metastases in the HER2CLIMB pivotal trial of TUKYSA (tucatinib). HER2CLIMB compared TUKYSA in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with unresectable, locally advanced or metastatic HER2-positive breast cancer with or without brain metastases. Of the patients enrolled in the trial, 48 percent had a presence or history of brain metastases. Results demonstrated that the addition of TUKYSA to trastuzumab and capecitabine in patients with brain metastases delayed progression in the brain, doubled the intracranial response rate (tumor shrinkage in the brain) and reduced the overall risk of death by nearly half. The data were consistent across patients who had either stable or active brain metastases. Results were presented in an oral presentation in the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the Journal of Clinical Oncology.

TUKYSA in combination with trastuzumab and capecitabine was approved by the U.S. Food and Drug Administration (FDA) in April 2020 for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. Primary results from HER2CLIMB were first presented at the San Antonio Breast Cancer Symposium in December 2019 and published in the New England Journal of Medicine.

It is immensely gratifying to see for the first time, results for patients with stable or active brain metastases who are not typically included in clinical trials, especially when you consider that nearly half of patients with HER2-positive metastatic breast cancer experience disease progression to the brain, said Nancy U. Lin, M.D., director of the Metastatic Breast Cancer Program in the Susan F. Smith Center for Womens Cancers at Dana-Farber in Boston, MA. These additional analyses provide further evidence that TUKYSA improves survival and delays cancer progression in the brain for patients with HER2-positive metastatic breast cancer who have brain metastases.

These additional analyses, together with the primary analysis of HER2CLIMB, show TUKYSA is active for patients with and without disease that has spread to the brain, said Roger Dansey, M.D., Chief Medical Officer of Seattle Genetics. We continue to be encouraged by the remarkable clinical activity of TUKYSA in combination with trastuzumab and capecitabine and look forward to evaluating its potential in additional treatment settings and tumor types through our ongoing clinical program.

The new data that further examine TUKYSAs effect in the brain include exploratory analyses for central nervous system progression-free survival (CNS-PFS), overall survival (OS), intracranial objective response rate (ORR-IC) and duration of response in HER2-positive metastatic breast cancer patients whose disease had spread to the brain.

The exploratory analyses demonstrated that patients with brain metastases who received the TUKYSA combination versus trastuzumab and capecitabine alone had:

Endpoint

TUKYSA Arm (TUKYSA + trastuzumab + capecitabine)

Control Arm (Placebo + trastuzumab + capecitabine)

OS Benefit in All Patients with Brain Metastases

N=198

N=93

Risk Reduction

42% (Hazard Ratio [HR]=0.58 [95% Confidence Interval (CI): 0.40, 0.85]; p=0.005)

One-Year OS

70.1% (95% CI: 62.1, 76.7)

46.7% (95% CI: 33.9, 58.4)

Median OS

18.1 months (95% CI: 15.5, not estimable)

12 months (95% CI: 11.2, 15.2)

CNS-PFS Benefit in All Patients with Brain Metastases

N=198

N=93

Risk Reduction

68% (HR=0.32 [95% CI: 0.22, 0.48]; p<0.0001)

One-year CNS-PFS

40.2% (95% CI: 29.5, 50.6)

0%

Median CNS-PFS

9.9 months (95% CI: 8.0, 13.9)

4.2 months (95% CI: 3.6, 5.7)

Intracranial Objective Response Rate (ORR-IC) in Patients with Active Brain Metastases and Measurable Intracranial Lesions at Baseline

N=55

N=20

Complete Response (CR)

3 (5.5%)

1 (5.0%)

Partial Response (PR)

23 (41.8%)

3 (15.0%)

Stable Disease

24 (43.6%)

16 (80.0%)

Progressive Disease

2 (3.6%)

0

Not Available

3 (5.5%)

0

ORR-IC (CR+PR)

26 (47%) (95% CI: 34, 61)

4 (20%) (95% CI: 6, 44)

Duration of Response-IC

6.8 months (95% CI: 5.5, 16.4)

3 months (95% CI: 3.0, 10.3)

About HER2CLIMB

HER2CLIMB is a multinational randomized (2:1), double-blind, placebo-controlled, active comparator, pivotal clinical trial comparing TUKYSA in combination with trastuzumab and capecitabine compared with trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab and T-DM1. The primary endpoint of the trial was PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent central review (BICR) in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including OS, PFS per BICR in patients with brain metastases at baseline and confirmed ORR.1

Results of Primary Analysis of HER2CLIMB

Control Arm (Placebo + trastuzumab + capecitabine)

PFS by BICR in the first 480 patients

46% reduction in risk of progression or death (HR=0.54 [95% CI: 0.42, 0.71]; p<0.00001; N=480)

OS

34% reduction in risk of death (HR=0.66 [95% CI: 0.50, 0.87]; p=0.0048; N=612)

PFS* by BICR in patients with brain metastases

52% reduction in risk of progression or death (HR=0.48 [95% CI: 0.34, 0.69]; p<.0.00001; N=291)

One-Year PFS

25% (95% CI: 17, 34)

0%

Median PFS

7.6 months (95% CI: 6.2, 9.5)

5.4 months (95% CI: 4.1, 5.7)

*standard RECIST, includes brain and body

In HER2CLIMB, serious adverse reactions occurred in 26 percent of patients who received TUKYSA. Serious adverse reactions occurring in 2 percent or more of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea, abdominal pain, and seizure (2% each). The most common adverse reactions occurring in 20 percent or more of patients who received TUKYSA were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash. Adverse reactions leading to treatment discontinuation occurred in 6 percent of patients who received TUKYSA; adverse reactions leading to treatment discontinuation of TUKYSA (in 1 percent or more of patients) were hepatotoxicity (1.5%) and diarrhea (1%).1

About HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. An estimated 279,100 new cases of breast cancer will be diagnosed in the U.S. in 2020.2 Between 15 and 20 percent of breast cancer cases are HER2-positive.3 Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.3,4,5 Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time. 6,7,8

About TUKYSA (tucatinib)

TUKYSA is an oral, small molecule tyrosine kinase inhibitor (TKI) of HER2, a protein that contributes to cancer cell growth.1,9 In vitro (in lab studies), TUKYSA inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell growth (proliferation), and showed anti-tumor activity in HER2-expressing tumor cells. In vivo (in living organisms), TUKYSA inhibited the growth of HER2-expressing tumors. The combination of TUKYSA and the anti-HER2 antibody trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone.1

Important Safety Information

Warnings and Precautions

If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

Adverse Reactions

Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in 2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.

Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; those occurring in 1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; those occurring in 2% of patients were hepatotoxicity (8%) and diarrhea (6%).

The most common adverse reactions in patients who received TUKYSA (20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

Lab Abnormalities

In HER2CLIMB, Grade 3 laboratory abnormalities reported in 5% of patients who received TUKYSA were: decreased phosphate, increased ALT, decreased potassium, and increased AST. The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

Drug Interactions

Use in Specific Populations

For more information, please see the full Prescribing Information for TUKYSA here.

About Seattle Genetics

Seattle Genetics, Inc. is a global biotechnology company that discovers, develops and commercializes transformative medicines targeting cancer to make a meaningful difference in peoples lives. The company is headquartered in the Seattle, Washington area, and has offices in California, Switzerland and the European Union. For more information on our robust pipeline, visit http://www.seattlegenetics.com and follow @SeattleGenetics on Twitter.

Forward Looking Statements

Certain statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of TUKYSA including its efficacy, safety and therapeutic uses, including its use in combination with trastuzumab and capecitabine to treat patients with HER2-positive metastatic breast cancer with brain metastases who have received one or more previous anti-HER2 therapies, and its potential use in additional treatment settings and tumor types. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the difficulty and uncertainty of pharmaceutical product development; the possibility that adverse events or safety signals may occur; that utilization and adoption of TUKYSA by prescribing physicians may be limited due to impacts related to the COVID-19 pandemic, availability and extent of reimbursement or other factors; and that adverse regulatory actions may occur. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption Risk Factors included in the companys Quarterly Report on Form 10-Q for the quarter ended March 31, 2020 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

1 TUKYSA [package insert]. Bothell, WA: Seattle Genetics, Inc.2 Cancer Facts & Figures 2020. American Cancer Society website. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Accessed May 28, 2020.3 Loibli S, Gianni L. HER2-positive breast cancer. Lancet. 2017; 389(10087): 2415-29.4 Slamon D, Clark G, Wong S, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235(4785): 177-82.5 Breast Cancer HER2 Status. American Cancer Society website. http://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html. Accessed May 28, 2020.6 Freedman RA, Gelman RS, Anders CK, et al. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2019;37:1081-1089.7 Olson EM, Najita JS, Sohl J, et al. Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast. 2013;22:525-531.8 Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97:2972-2977.9 Anita Kulukian, Patrice Lee, Janelle Taylor, et al. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol Cancer Ther 2020;19:976-987.

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Seattle Genetics Announces Positive Results from Exploratory Analyses of HER2CLIMB for TUKYSA (tucatinib) in Brain Metastases Patients With...

BRIEF-Seattle Genetics Announces Positive Results From Exploratory Analyses Of Her2climb For Tukysa – Reuters

May 29 (Reuters) - Seattle Genetics Inc:

* SEATTLE GENETICS ANNOUNCES POSITIVE RESULTS FROM EXPLORATORY ANALYSES OF HER2CLIMB FOR TUKYSA (TUCATINIB) IN BRAIN METASTASES PATIENTS WITH HER2-POSITIVE BREAST CANCER

* SEATTLE GENETICS INC - TUKYSA COMBINATION REDUCED RISK OF CANCER PROGRESSION IN BRAIN OR DEATH BY TWO-THIRDS

* SEATTLE GENETICS -RESULTS DEMONSTRATED ADDITION OF TUKYSA TO TRASTUZUMAB,CAPECITABINE IN PATIENTS WITH BRAIN METASTASES DELAYED PROGRESSION IN BRAIN Source text for Eikon: Further company coverage:

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BRIEF-Seattle Genetics Announces Positive Results From Exploratory Analyses Of Her2climb For Tukysa - Reuters

How to know your risk factors for hypertension and whether high blood pressure is genetic – Insider – INSIDER

Hypertension is the medical term for high blood pressure. It can cause serious health problems, like heart disease or stroke, if left untreated.

There are many risk factors that make it more likely for someone to develop hypertension. These include genetic factors, age, race, medical conditions, and unhealthy lifestyle choices.

Here's what you need to know about what increases the risk of high blood pressure.

Overall, one or more of these factors are most likely to cause high blood pressure:

One of the biggest culprits is smoking, which can double or triple the risk of developing hypertension. That's because smoking damages blood vessels and can reduce blood flow to the heart.

But these factors won't always cause hypertension alone genetics and medical conditions can also increase your risk.

"I would say the simplest answer to this is, yes, there is a genetic component," says Joshua Shatzkes, MD, a cardiologist at Mt. Sinai Hospital.

If your parents have hypertension, you are at an increased risk for high blood pressure.

A 2018 study involving over a million people identified 500 genes that influence blood pressure. Some of these genes influence the cells lining blood vessels, causing them to be abnormally constricted and raise blood pressure.

Other genes can cause high cholesterol, especially in a condition known as hypercholesterolemia, which can also increase blood pressure.

In addition, genetic factors often combine with other adverse lifestyle choices, which can further increase the risk of hypertension.

For example, when you're growing up, if your family eats an unhealthy diet high in sodium, creates a high stress environment, smokes too many cigarettes, and doesn't exercise often, then you're more likely to inherit those behaviors and more likely to develop hypertension.

While there's no universal way to describe obesity, it's often considered a condition where someone has a high body mass index (BMI). A BMI over 40 can double or triple your likelihood of developing obesity-related illnesses.

"When someone is obese, it simply takes more work for the heart to pump blood throughout the whole body," says Christopher Granger, MD, a cardiologist at Duke Health. "And when it has to pump blood throughout the whole body, it has to generate a higher kind of pressure to do so."

In fact, a study from 2015 suggests that excess body fat accounts for 65% to 75% of hypertension cases. Moreover, a 2017 study found that childhood obesity increased the rate of developing adult hypertension by 65%.

Diabetes is a condition where your body doesn't react to high blood sugar properly, which may cause it to be too high or too low longer than normal. Insulin is the hormone designed to take glucose (sugar) from the blood to the cells, but if there's not enough insulin, glucose stays in the blood, elevating blood sugar levels.

Over time, high blood sugar can cause plaque to build up in your blood vessels, which narrows the vessel and increases blood pressure.

Granger explains that high blood sugar can cause the arteries to stiffen because it can increase the production of free radicals tiny particles that damage cells and reduce nitrous oxide, a chemical that dilates blood vessels.

As a result, 30% of people with type 1 diabetes develop hypertension. Those with type 2 diabetes are 2.5 times more likely to develop hypertension and 50% to 80% will develop hypertension. However, diabetics who carefully control their blood sugar levels can effectively decrease the risk of developing hypertension.

The American Heart Association has found that over 40% of non-Hispanic African-Americans have high blood pressure, and that it can develop earlier in their lives and become more severe.

Overall, black Americans are twice as likely to develop hypertension by the age of 55 compared to white Americans. Systemic issues could explain this increase in blood pressure.

There's an association between racism and higher blood pressure in African-American men, according to the CDC. Black Americans are also exposed to more factors that can increase chronic stress such as discrimination and lower socioeconomic status which may contribute to high blood pressure.

Older people are more likely to develop hypertension because the arteries stiffen as we age. This process is called atherosclerosis, and it describes plaque build-up in blood vessels.

According to Granger, young people's arteries are able to expand and more effectively accommodate the pulse of blood flow.

Overall, your lifetime risk for developing hypertension is 90%, according to Johns Hopkins Medicine. Even if you have heart-healthy habits, you'll still most likely develop hypertension, according to the National Institute on Aging.

However, certain lifestyle changes, such as exercising every day, sleeping adequately, and avoiding smoking, can lower the risk of developing high blood pressure.

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How to know your risk factors for hypertension and whether high blood pressure is genetic - Insider - INSIDER