Physiology

Risk of ICU Admission and Related Mortality in Patients… : Critical … – LWW Journals

KEY POINTS

Questions: The efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors on clinical outcomes related to burden of critical illness has not been examined.

Findings: In this retrospective cohort study, 10,308 SGLT2 inhibitors users and 17,664 dipeptidyl peptidase-4 (DPP-4) inhibitors users were included in analysis after 1:2 propensity score matching. The use of SGLT2 inhibitors compared with DPP-4 inhibitors was significantly associated with lower rates of ICU admission (286 [2.8%] vs 645 [3.7%]) and all-cause mortality (315 [3.1%] vs 1,327 [7.5%]).

Meanings: SGLT2 inhibitors may be associated with benefits in clinical efficacy and cost-benefit ratios in the critical care setting that remains to be confirmed in prospective trials.

The global burden of critical illness has steadily increased especially with an aging population in the developed world (1). Despite modern advances in life support, mortality rates in the ICU has remained persistently high at over 15%, and even higher for patients admitted with sepsis (2,3). However, recent clinical trials have failed to identify therapies that effectively moderate overall ICU and sepsis-related mortality (4,5). In large cohort studies, patients with diabetes contribute more than 15% of intensive care admissions and are at increased risks of adverse outcomes after intensive care (6).

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the occurrence rate of major adverse cardiovascular events (MACE) and adverse renal events among patients with type 2 diabetes in randomized controlled trials (711). At the same time, certain safety endpoints were more frequently observed in the groups assigned to SGLT2 inhibitors, including urinary tract infection, diabetic ketoacidosis (DKA), hypotension, volume depletion, and amputation (79,12). While there have been preliminary data on the reduced risks of pneumonia and sepsis-related morbidities with use of SGLT2 inhibitors (13,14), the effect on the overall burden of critical illnesses and their efficacy in reducing ICU-related mortality have not been studied.

The objective of the study was to determine whether SGLT2 inhibitors had any benefit to the overall burden of critical illness. We hypothesized that the use of SGLT2 inhibitors is associated with decreased risks of ICU admission and all-cause mortality. We compared the risks and causes of admission to the ICU, severity of illness, and mortality associated with the incidental use of SGLT2 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with type 2 diabetes.

Data on new users of SGLT2 inhibitors or DPP-4 inhibitors between January 1, 2015, and December 31, 2019, from all public hospitals in Hong Kong were reviewed. Patients baseline characteristics, clinical information, and outcomes were retrieved from the Clinical Data and Analysis Reporting System of the Hospital Authority in Hong Kong. We included all adult patients (18 yr old or older) with type 2 diabetes who received SGLT2 inhibitors or DPP-4 inhibitors for the first time or had not received these drugs within 12 months prior to the index date. Type 2 diabetes was defined as having an International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code starting with 250, except those indicating type 1 diabetes; or having baseline hemoglobin A1c (HbA1c) greater than or equal to 6.5%; or using any anti-diabetic medications (i.e., insulins, glucagon-like peptide-1 [GLP-1] agonists, or oral hypoglycemic agents). Patients who received SGLT2 inhibitors or DPP-4 inhibitors for other indications and did not have diabetes were not included. Exclusion criteria were patients with estimated glomerular filtration rate (eGFR) less than 25mL/min/1.73 m2 or patients who were started on both SGLT2 inhibitors and DPP-4 inhibitors on the index date. This study was approved by the Institutional Review Board of The University of Hong Kong/Hospital Authority of Hong Kong West Cluster with a waiver of informed consent on July 28, 2022 (Institutional Review Board reference number: UW 22-561, study title Association of SGLT2 Inhibitors and ICU Outcomes In a Territory Wide Longitudinal Cohort). All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki Declaration of 1975 and its later amendments.

We defined the index date as the first date of dispensing SGLT2 inhibitors or DPP-4 inhibitors. SGLT2 inhibitors included canagliflozin, dapagliflozin, and empagliflozin. DPP-4 inhibitors included alogliptin, linagliptin, linagliptin/metformin, saxagliptin, sitagliptin, sitagliptin/metformin, vildagliptin, and vildagliptin/metformin. Patients were assigned to either the SGLT2 inhibitors group or DPP-4 inhibitors group and followed up according to their assigned drug group. Patients who were prescribed medication from the alternative drug group were censored on the dispense date of the alternative drug.

The co-primary outcomes were any admission to the ICU and all-cause mortality. Secondary outcomes were duration of ICU stay, severity of illness upon ICU admission, mortality due to cardiovascular, renal, and infectious causes, any emergent ICU admission, and any nonoperative ICU admission. The severity of illness upon ICU admission was measured by the Acute Physiology and Chronic Health Evaluation (APACHE) IV-predicted mortality (15). Safety outcomes including DKA, lower limb amputation, new requirement for dialysis, acute pulmonary edema, and urinary tract infection were also examined. DKA was defined using ICD-9-CM code or an elevated beta-hydroxybutyrate level. All outcome events were recorded until the date of censoring or death, or the data cutoff date of March 31, 2022, whichever occurred first. Detailed ICD-9-CM codes for clinical outcomes are listed in eTable 1 (https://links.lww.com/CCM/H330).

Patients baseline characteristics including age, sex, HbA1c, eGFR, comorbidities, and previous ICU admissions were collected. Detailed ICD-9-CM codes for comorbidities, that is, malignancy, hypertension, cerebrovascular disease, coronary artery disease, and congestive heart failure (CHF) are listed in the eTable 1 (https://links.lww.com/CCM/H330). Concomitant cardiovascular medications, including aspirin, statins, beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs); laboratory results were also obtained. Baseline laboratory results were defined as results closest to the index date.

All analyses were performed with prespecified outcome and statistical methods. Based on data in published literature and biological plausibility, we constructed a logistic regression model that predicted the likelihood of receiving SGLT2 inhibitors or DPP-4 inhibitors. These included age, sex, baseline HbA1c, duration of diabetes, eGFR, previous ICU admission, underlying malignancy, hypertension, cerebrovascular disease, coronary artery disease, CHF, use of metformin, insulins, sulfonylureas, GLP-1 agonists, thiazolidinedione, ACEIs or ARBs, beta-blockers, statins and ezetimibe, calendar year of index medication initiation, risk for amputation, risk for fractures, and risk for genitourinary infections. Risk for amputation was defined using history of peripheral vascular disease or lower limb amputation. Risk for fractures was defined using history of osteoporosis or fractures, and risk for genitourinary infections was defined using history of urinary tract infections or positive urine cultures. The final study cohort consisted of two comparison groupsSGLT2 inhibitors and DPP-4 inhibitorsgenerated by 1:2 propensity score matching using a caliper of 0.2 times sd of the logit of propensity score.

Unadjusted analyses were made using chi-square tests for categorical variables and Student t test or Wilcoxon rank-sum tests for continuous variables. Cox proportional hazards regression was performed to evaluate the relationship between use of SGLT2 inhibitors or DPP-4 inhibitors and clinical outcomes in a time-to-first-event analysis.

First, we performed sensitivity analysis by including all complete cases before propensity score matching. A multivariable Cox proportional hazards model adjusting for the same variables in the propensity score model was used to examine the association between study groups and the co-primary outcomes. Next, we repeated the analysis in all complete cases before propensity score matching using inverse probability treatment weighting to adjust for the same set of confounders. An on-treatment analysis was performed to account for possible differences in treatment duration.

Since the complete case method was adopted to address missing data in the primary statistical analysis, we tested the robustness of our results by repeating the multivariable Cox regression analysis with the entire cohort using the technique of multiple imputations by chained equations to account for missing data. We calculated E-values to quantify the association that a confounder would need to have with clinical outcomes to nullify the primary analyses (16). Finally, to better ensure that the observed association between medication groups and clinical outcomes was not due to some underlying cause unrelated to the mechanistic hypothesis, falsification testing was performed with two clinical outcomes, trauma and acute cholecystitis. These outcomes were selected based on unlikely causal relationships with the medication groups, and detailed ICD-9-CM codes are listed in eTable 1 (https://links.lww.com/CCM/H330).

Subgroup analyses were performed according to the following seven dichotomized subgroups: age greater than 65 years, sex, HbA1c greater than 8%, eGFR less than 60mL/min/1.73 m2, previous heart failure, number of oral hypoglycemic agents greater than or equal to 2, and index medication initiation during or after 2018.

All analyses were performed using Stata MP software, Version 16.1 (StataCorp, College Station, TX). A two-tailed p value of less than 0.05 was considered statistically significant.

Between January 2015 and December 2019, a total of 73,111 patients were considered for inclusion: 4,053 (5.5%) were excluded after application of exclusion criteria. Of the remaining 69,058 patients, a total of 6,674 (9.7%) were excluded from complete case analysis due to missing values in any of the variables used in the propensity score matching model. After 1:2 propensity score matching, a total of 10,308 SGLT2 inhibitors users and 17,664 DPP-4 inhibitors users were included in the final analysis, representing 44.8% of the complete case cohort (eFig. 1, https://links.lww.com/CCM/H330). The mean age of the cohort was 5911 years, and 17,416 (62.3%) were male. Baseline characteristics and medications prescribed of the propensity score matched cohort and the complete case cohort are shown in Table 1 and eTable 2 (https://links.lww.com/CCM/H330), respectively. All variables in Table 1 were included in the propensity score model, and apart from certain oral anti-diabetic agents were well-balanced between groups with standardized difference less than 0.1. The median follow-up period was 2.9 years (2.34.0 yr).

aLipid-lowering medications included atorvastatin, fluvastatin, rosuvastatin, simvastatin, and ezetimibe.

bRisk for amputation was defined using history of peripheral vascular disease or lower limb amputation.

cRisk for fractures was defined using history of osteoporosis or fractures.

dRisk for genitourinary infections was defined using history of urinary tract infections or positive urine cultures.

All results were presented with frequency (percentage) or mean sd.

Table 2 describes the primary and secondary outcomes in SGLT2 inhibitors users and DPP-4 inhibitors users. Critical illness requiring ICU admission occurred in 286 patients (2.8%) in the SGLT2 inhibitor group and 645 patients (3.7%) in the DPP-4 inhibitor group. The risk of ICU admission was lower in SGLT2 inhibitors users compared with DPP-4 inhibitors users (hazard ratio [HR], 0.79; 95% CI, 0.690.91; p = 0.001), translating to an absolute between-group difference of 0.9 percentage points (95% CI, 0.51.3) and a number needed to treat of 114. The severity of illness upon ICU admission was lower in SGLT2 inhibitors users compared with DPP-4 inhibitors users (median APACHE IV-predicted risk of death 0.08 [0.030.25] vs 0.14 [0.050.36]; p < 0.001). The ICU length of stay was similar between the two groups. The risk of emergency ICU admission was lower in SGLT2 inhibitors users (208 [2.0%] vs 496 [2.8%]; HR, 0.75; 95% CI, 0.640.89; p = 0.001), as was the risk of nonoperative ICU admission (151 [1.5%] vs 415 [2.4%]; HR, 0.66; 95% CI, 0.540.79; p < 0.001). Kaplan-Meier survival curves showed that the use of SGLT2 inhibitors was associated with lower risks of critical illness requiring any ICU admission, emergent ICU admission, and nonoperative ICU admission (Fig. 1). Admissions for sepsis were fewer in SGLT2 inhibitors users compared with DPP-4 inhibitors users (45 [0.4%] vs 134 [0.8%]; HR, 0.61; 95% CI, 0.430.85; p = 0.004). Data for other causes of ICU admission are presented in eTable 3 (https://links.lww.com/CCM/H330).

DPP-4 = dipeptidyl peptidase-4, SGLT2 = sodium-glucose cotransporter 2.

aResults are presented as rate per 100 patient year (95% CI).

bResults are presented as median (interquartile range).

cAmong 931 people required ICU admission, two patients (0.2%) had missing Acute Physiology and Chronic Health Evaluation IV predicted values, therefore, n = 929.

Estimated probabilities of ICU admission stratified by sodium-glucose cotransporter 2 (SGLT2) inhibitor group and dipeptidyl peptidase-4 (DPP-4) inhibitor group. Use of SGLT2 inhibitors was associated with lower risks of critical illness requiring any ICU admission (hazard ratio [HR], 0.79; 95% CI, 0.690.91; p = 0.001) (A), emergent ICU admission (HR, 0.75; 95% CI, 0.640.89; p = 0.001) (B), and nonoperative ICU admission (HR, 0.66; 95% CI, 0.540.79; p < 0.001) (C) compared with use of DPP-4 inhibitors.

The co-primary outcome of all-cause mortality occurred in 315 patients (3.1%) in the SGLT2 inhibitor group and 1,327 patients (7.5%) in the DPP-4 inhibitor group. The risk of death was lower in SGLT2 inhibitors users compared with DPP-4 inhibitors users (HR, 0.44; 95% CI, 0.380.49; p < 0.001), translating to an absolute between-group difference of 4.5 percentage points (95% CI, 3.95.0) and a number needed to treat of 22 (Table 2). The risk of mortality due to infectious causes was lower in SGLT2 inhibitors users compared with DPP-4 inhibitors users (59 [0.6%] vs 414 [2.3%]; HR, 0.26; 95% CI, 0.200.34; p < 0.001). The risk of cardiovascular death was lower in SGLT2 inhibitors users (105 [1.0%] vs 332 [1.9%]; HR, 0.58; 95% CI, 0.460.72; p < 0.001), as was the risk of renal-related mortality (3 [0.03%] vs 25 [0.14%]; HR, 0.22; 95% CI, 0.070.73; p = 0.014). Kaplan-Meier survival curves demonstrated that the use of SGLT2 inhibitors was associated with lower risks of all-cause mortality, mortality due to infectious, cardiovascular, and renal causes, compared with use of DPP-4 inhibitors (Fig. 2).

Estimated probabilities of all-cause mortality stratified by sodium-glucose cotransporter 2 (SGLT2) inhibitor group and dipeptidyl peptidase-4 (DPP-4) inhibitor group. Use of SGLT2 inhibitors was associated with lower risks of all-cause mortality (hazard ratio [HR], 0.44; 95% CI, 0.380.49; p < 0.001) (A), mortality due to infectious causes (HR, 0.26; 95% CI, 0.200.34; p < 0.001) (B), cardiovascular mortality (HR, 0.58; 95% CI, 0.460.72; p < 0.001) (C), and renal mortality (HR, 0.22; 95% CI, 0.070.73; p = 0.014) (D) compared with use of DPP-4 inhibitors.

After adjustment by multivariable Cox regression, the risk of ICU admission was lower in SGLT2 inhibitors users compared with DPP-4 inhibitors users (HR, 0.85; 95% CI, 0.740.97; p = 0.016) in the complete case cohort (n = 62,384), as was the risk of all-cause mortality (HR, 0.53; 95% CI, 0.470.60; p < 0.001), which were consistent with the primary analysis. These associations remained significant after adjustment by inverse probability treatment weighting as determined by the propensity score (ICU admission: HR, 0.76; 95% CI, 0.710.81; p < 0.001 and all-cause mortality: HR, 0.43; 95% CI, 0.410.45; p < 0.001). The median duration of treatment were similar in the two medication groups (SGLT2 inhibitors: 953 d [4031,367 d] and DPP-4 inhibitors: 967 d [4001,351 d]; p = 0.70), and results in the on-treatment analysis were similar to the intention-to-treat analysis.

A total of two variables, baseline HbA1c and eGFR, in the propensity score model had missing data. Multiple imputation was conducted, and the imputed cohort included all 6,674 patients (9.7%) who were excluded due to missing values in any of the variables used in the propensity score model. The association between SGLT2 inhibitors and ICU admission in the imputed dataset remained significant (adjusted HR, 0.79; 95% CI, 0.69 to 0.90; p < 0.001), as was the association with all-cause mortality (adjusted HR, 0.52; 95% CI, 0.460.58; p < 0.001). The E-value for the HR for new ICU admission is 1.63, while the E-value for the HR for all-cause mortality is 2.94, suggesting that for an unmeasured confounder to render the primary results statistically insignificant, it would need to be very strongly associated with ICU admission and all-cause mortality (> 60% difference in prevalence between SGLT2 inhibitors users and DPP-4 inhibitors users, and a HR > 1.6 or < 0.6 on ICU admission). Finally, falsification testing showed that the clinical outcomes of trauma and acute cholecystitis were not significantly associated with medication group. Detailed results of sensitivity analyses are presented in Table 2.

The effect of SGLT2 inhibitors on the outcomes of ICU admission and all-cause mortality was modified by eGFR (p for interaction < 0.001 and 0.004, respectively), with patients with eGFR less than 60mL/min/1.73 m2 deriving more clinical benefit than those with eGFR greater than or equal to 60mL/min/1.73 m2. The benefit of SGLT2 inhibitors on ICU admission was greater in patients on less than two oral hypoglycemic agents (p for interaction = 0.042) and the benefit of SGLT2 inhibitors on all-cause mortality was greater in patients who were initiated on index medication before 2018 (p for interaction = 0.025). The associations between SGLT2 inhibitors and outcomes were not modified by age, sex, HbA1c level, or previous CHF (p for interaction > 0.05 for all) (eTable 4, https://links.lww.com/CCM/H330; and Fig. 3).

Forest plots for subgroups analyses. The effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the outcomes of ICU admission and all-cause mortality was modified by estimated glomerular filtration rate (eGFR) (p for interaction < 0.001 and 0.004, respectively). Patients who were on less than two oral hypoglycemic agents and patients who were initiated on index medication before 2018 also derived greater clinical benefit. There was no effect modification in other predefined subgroups for the two co-primary outcomescritical illness requiring any ICU admission (A) and all-cause mortality (B). DDP4i = dipeptidyl peptidase-4 inhibitor, HbA1c = hemoglobin A1c.

Safety outcomes are reported in Table 3. The risks of lower limb amputation, new requirement for dialysis, acute pulmonary edema, and urinary tract infection were significantly lower in SGLT2 inhibitors users compared with DPP-4 inhibitors users (p < 0.05 for all). The risk of DKA was similar between the SGLT2 inhibitor users and DPP-4 inhibitor users (160 [1.6%] vs 297 [1.7%]; p = 0.41).

aDiabetic ketoacidosis was defined as using International Classification of Diseases, 9th Revision, Clinical Modification code or an elevated beta-hydroxybutyrate level.

bNew requirement for dialysis refers to patients who were started and maintained on dialysis with no record of receiving dialysis prior to the index date.

In this cohort of 69,058 adult patients with type 2 diabetes, initiation of SGLT2 inhibitors compared with DPP-4 inhibitors were associated with lower risks of critical illness, decreased disease severity, and lower all-cause mortality over a median follow-up of 2.9 years. We identified that infections- and sepsis-related admissions to ICU and mortality were concurrently mitigated by the use of SGLT2 inhibitors. The beneficial effects of SGLT2 inhibitors were seen across various subgroups of age and underlying comorbid conditions, and the protection appeared to be more pronounced in patients with chronic renal impairment.

SGLT2 inhibitors have been shown to effectively reduce MACE and renal events among patients with type 2 diabetes (710). Since hospitalizations secondary to decompensated heart failure and decline in renal function are clearly reduced with the use of SGLT2 inhibitors, it would be reasonable to extrapolate a reduction in burden of critical illnesses and admissions to ICU. However, SGLT2 inhibitors have been associated with a two- to 10-fold risk of DKA (8,17), along with other safety concerns including a doubling in risk of severe urinary tract infection (18), hospital admission for infections (19), volume depletion (8,20), hypotension (21), or even amputation (9). Taken together, the net effect of SGLT2 inhibitors on critical illness and the utilization of ICU resources remains to be clarified. To our knowledge, this topic has never been evaluated in any randomized trials or observational studies.

In the current study including a large representative cohort of patients with type 2 diabetes, we observed that the risk of critical illness requiring admission to ICU was reduced by approximately 20% with the use of SGLT2 inhibitors. The biological mechanisms underlying the protective effects of SGLT2 inhibitors against critical illnesses are multidimensional, among which benefits in cardiac and renal function are two of the most important. SGLT2 inhibitors can improve cell life programming (22), arterial stiffness (23), cardiac structure and function (24,25), and reduce cardiorenal effects and albuminuria (26,27); hence, the strong cardiorenal efficacy observed in clinical trials (28). In our cohort, the absolute differences in mortality due to cardiovascular and renal causes were 0.9% and 0.1%, respectively.

More specific to acute and critical illnesses, SGLT2 inhibitors have been associated with protective effects against pneumonia, sepsis, and infection-related mortality (13). This may be related to the anti-inflammatory properties of SGLT2 inhibitors, mediated through down-regulation of cytokine production by macrophages and inflammasomes (29). Alternative mechanisms such as counteracting lipopolysaccharide (LPS)-induced vascular hyperpermeability and improving intestinal barrier function have also been demonstrated in animal models (30,31). The beneficial effects of SGLT2 inhibitors were observed across all categories of ICU admission but were most evident in reducing nonoperative ICU admissions, which in our cohort referred to emergency admissions due to nonsurgical causes. When further stratified by disease category, the reduction in ICU admission due to sepsis was the most striking, with a 40% reduction in risk for SGLT2 inhibitors users. The milder severity of illness upon ICU admission may be partially explained by pathophysiological mechanisms such as damping of LPS-induced acute renal injury in animal models (14), possibly undermining the greater benefit derived in patients with renal impairment and eGFR less than 60mL/min/1.73 m2. The reduction of sepsis-related complications in chronic users of SGLT2 inhibitors, if confirmed in follow-up prospective trials, could have significant implications for the population with diabetes, to whom up to 6% of infection-related hospitalizations and 12% of infection-related deaths had been attributed (32). It remains to be examined whether users of SGLT2 inhibitors for reasons other than diabetes would derive similar clinical benefits.

The significant reduction in all-cause mortality of SGLT2 inhibitors that has been demonstrated in randomized trials was further validated in our cohort (9,11), as were reductions in death due to cardiovascular, renal, and infection-related causes, with a number needed to treat of 22. Recent studies have shown that the clinical benefit derived from SGLT2 inhibitors begins to manifest as early as 13 days (33). The potential cost-efficiency of SGLT2 inhibitors in decreasing healthcare utilization and morbidities across broad populations of patients with cardiovascular risk factors, risks for progressive renal injury, and even immunosuppressed or infection-prone individuals could amount to significant cost-benefit ratios across hospital intensive care systems (34).

The current study had some limitations. First, the observational nature of the study conferred risks of unmeasured confounding and bias, but the large cohort size with complete longitudinal electronic healthcare records and incident new user design minimized selection, information, and recall biases (35). We used rigorous propensity score matching, and the findings were consistent in many sensitivity analyses. The utilization of an active comparator of DPP-4 inhibitors allowed evaluation of SGLT2 inhibitors in a typical decision bifurcation during escalation of diabetes care. Second, we only collected prescription data and could not ascertain drug adherence, which could have biased the results toward the null. Third, patients were censored if they crossed over to or added on the other drug class, and the effect of continuing both drug classes is unclear.

In conclusion, we showed that patients with type 2 diabetes who were on SGLT2 inhibitors were independently associated with reduction in admission to the ICU, milder disease severity, and lower all-cause mortality compared with patients on DPP-4 inhibitors. The use of SGLT2 inhibitors in the critical care setting remains to be clarified in future prospective trials.

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Physiology

Phi Beta Kappa Selects New Members at UW | News – University of Wyoming News

April 7, 2023

The Alpha Chapter of Wyoming at the University of Wyoming has selected 36 new members for the prestigious Phi Beta Kappa honor society. Among the new inductees are four juniors who have been awarded $1,000 scholarships for their academic achievements.

Each year, 290 national chapters select new members into Phi Beta Kappa. Fewer than 1 percent of U.S. college graduates are chosen. Members have included 17 U.S. presidents and 42 U.S. Supreme Court justices. There are nearly 100 faculty and staff resident members in UWs chapter. The students who are selected for this honor at UW are usually in the top 3 to 4 percent of their classes.

A committee of Phi Beta Kappa members selects the eligible students based on liberal arts hours, foreign language hours and GPA, says Joy Landeira, professor, chair of the Department of Modern and Classical Languages and Alpha Chapter president. Phi Beta Kappa is one of the most respected honor societies in the United States.

The four juniors who have earned the Louise A. Lee Johnson Memorial Scholarships, listed by hometown, are:

Casper -- Joenon Sulzen, a Kelly Walsh High School graduate, who is studying English with honors and creative writing minors; and Samantha Veauthier, also a graduate of Kelly Walsh High School, who is studying zoology with an honors minor.

Cheyenne -- Dillon McLean, a graduate of Cheyenne Central High School, who is studying chemistry.

Diamond Point, N.Y. -- Morgan Miller, who is studying international studies with an honors minor.

The induction ceremony for the new members will take place Friday, April 28, at 4 p.m. in Room 506 of Coe Library. The event will be attended by family, friends and faculty members.

In addition to the scholarship recipients, 26 new seniors and six December graduates also have been elected to Phi Beta Kappa. Those newly elected members, listed by hometowns and majors, are:

Arvada, Colo. -- Madison Singh, gender and womens studies.

Bandera, Texas -- Kyla Ditges, English.

Boise, Idaho -- Larissa Rutz, history.

Broomfield, Colo. -- Elena Rae Stewart, English.

Casper -- Benjamin Radosevich, a Natrona County High School graduate, molecular biology.

Chattanooga, Tenn. -- Abby Worlen, B.A. in English (December 2022).

Cheyenne -- Val Herd Jr., a Cheyenne Central High School graduate, history; Christopher Hood, also a Cheyenne Central graduate, international studies and French; Maeve Knepper, a Cheyenne East High School graduate, economics and international studies; and Fox Glenn Nelson, also a Cheyenne East graduate, anthropology.

Douglas -- William Trimnal, a Douglas High School graduate, international studies.

Eagle River, Alaska -- Ashton Love, political science.

Fort Collins, Colo. -- Kaytlyn Vander Meer, chemical engineering and Spanish; and Frank Richard Wright, geography, and environment and natural resources with minors in Spanish and honors.

Gering, Neb. -- Brock Parker, astronomy and astrophysics.

Jackson -- Samantha Smith, a Jackson Hole High School graduate, B.A. in criminal justice, sociology and English (December 2022).

Lakewood, Colo. -- Lydia Ellefsen, environmental systems science, and environment and natural resources.

Lander -- Emma Jo Comstock, a Lander Valley High School graduate, B.A. in history (December 2022).

Laramie -- Hailey Hysong, a Laramie High School graduate, international studies; Sai Kit Ng, also a Laramie High graduate, microbiology and molecular biology with minors in music and physiology; and Lander Stone, also a Laramie High graduate, environmental systems science and religious studies.

McLean, Va. -- Anna Spear, environmental studies and environmental politics.

Midvale, Utah -- Shannon Fassler, English, and art and art history.

Monument, Colo. -- Makayla Kocher, English with minors in anthropology and museum studies.

Norway -- Irja Smith Sandvik, anthropology, and environment and natural resources.

Parker, Colo. -- Mckenna Egolf, history.

Phoenix, Ariz. -- Rebecca DeCero, history.

Pine Bluffs -- Harper Pachel, a Pine Bluffs High School graduate, B.A. in history (December 2022).

Powell -- Abigail Saville, a Powell High School graduate, B.S. in biology (December 2022).

Reno, Nev. -- Erin Schwalbe, microbiology.

St. Joseph, Mo. -- Ruby Jenco, environment and natural resources, and wildlife biology and management.

Torrington -- Maryssa Lira, a Torrington High School graduate, B.S. in microbiology (December 2022).

The Alpha Chapter of Wyoming was established in 1940. It sponsors lectures, scholarships and other academic activities. For more information about the Phi Beta Kappa honor society or UWs Alpha Chapter, visit http://www.uwyo.edu/pbk.

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Phi Beta Kappa Selects New Members at UW | News - University of Wyoming News

Dermatology

How, where to get medical records from closed Myrtle Beach dermatology office – wpde.com

MYRTLE BEACH, S.C. (WPDE)

Thousands of local dermatology patients are one step closer to getting their medical records back after Dermatology and Skin Cancer Center SC closed without warning in February.

It has now been more than 40 days that patients haven't been able to access their records, and many of these patients have cancer.

ABC15 first broke the story afterseveral patients reached out to us to investigate the unexpected closure.

READ MORE: Patients say MB dermatology office closes, fails to disclose medical records, requests

The office abruptly closed without warning to either employees, and patients, on February 17, and never reopened.

Initially, ABC15reached out to the South Carolina Department of Labor Licensing and Regulationin March to askhow patients could get their records back.

Now, alongside the state Board of Medical Examiners, they have officially enacted a petition appointing another doctor as the custodian for these records.

Dermatology and Skin Cancer Center SC Myrtle Beach office (Credit: Emma Parkhouse/WPDE)

Here's how to do it.

The Board confirmed the associated medical offices were closed down after a transfer of ownership fell through.

The initial owner, Dr. Joseph Masessa, died in 2019.

His practice was taken over by his brother, Jeffery Masessa, who is not a licensed physician in South Carolina.

According to the Board, Jeffery never reached out to the state's labor department or the Board about the closure; or made any arrangements for record retrieval.

SUGGESTED: Patients can retrieve records after Myrtle Beach dermatology office unexpectedly closed

The board determined while Jeffery Masessa may have once been considered a "responsible party at one point in time", he no longer is.

In addition, because Dr. Joseph Masessa is deceased, the Board has the legal authority to appoint a custodian of the records.

Board-certified surgeon and dermatologist, Dr. Brandon Coakley at Waccamaw Dermatology has been selected as that custodian.

"Patients have been panicked. There's patients that went into the doctor's office and were told, 'hey, you have a spot that's suspicious for cancer'; a biopsy was taken, and then there was no answer," said Coakley.

Waccamaw Dermatology office in Myrtle Beach (Credit: Emma Parkhouse/WPDE)

Dr. Coakley told ABC15 according to the closed office's former manager,Dermatology and Skin Cancer Center SC in Myrtle Beach had roughly 36,000 patient visits in 2022.

Even if those patients attended the office multiple times throughout the year, Coakley says there will be at least 10,000 patients impacted by this.

He's still waiting to hear back about a confirmed number of patient files.

While he's not sure exactly how many thousands of records there are at the moment, Dr. Coakley is sure that he wants to help these patients in anyway he can.

"We will be contacting, as per the medical board's order, contacting every patient to let them know that we have the records," said Coakley. "I don't know the state of the paper records. My plan is to contact everybody who had an email on file electronically because that's faster and easier, but we will go through the process of organizing the paper records and notifying those people by regular first class mail."

Dr. Coakley and his office staff at Waccamaw Dermatology will be receiving all of the paper and digital records from Dermatology and Skin Cancer Center SC over the next couple of days.

Waccamaw Dermatology andDermatology and Skin Cancer Center SC are not associated or affiliated with each other.

NEW: Trump surrenders at Manhattan courthouse ahead of arraignment in hush money case

ABC15 got ahold of Jeffery Masessa Tuesday afternoon.

Over the phone, our reporter asked him if he was available for an interview to talk about the closing of the dermatology offices he owns in South Carolina.

He agreed to an interview and said he would call back after a meeting to set it up. Since then, he has not returned any phone calls or texts.

The Board and the state LLR have stated they have still not heard from, or been able to get in contact, with Jeffery Masessa.

Dr. Coakley says he and his team will be working as quickly as possible to obtain and organize the records as they prepare to directly contact everyone whose been affected.

Updates on obtaining medical records for former patients ofDermatology and Skin Cancer Center SC will be posted here.

His office is located at 5046 Highway 17 Bypass South, in Suite 200.

This is a developing story. Stay with ABC15 News for updates.

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How, where to get medical records from closed Myrtle Beach dermatology office - wpde.com

Dermatology

Dermatology Month in Review: Highlights from March 2023 – MD Magazine

This past month on HCPLive, several important topics were covered as part of our dermatology content from March.

The list includes new trial data on psoriasis, atopic dermatitis (AD), hidradenitis suppurativa (HS), and prurigo nodularis (PN) treatment options.

The following list is a summary of these major breakthroughs covered in March in the dermatology space, with more news and updated content on these topics available on the HCPLive main news page.

1. Positive Phase 3 Trial Results for Tapinarof Cream on Atopic Dermatitis

In this HCPLive article, phase 3 data from the ADORING 2 trial indicated that about of half of AD patients treated with tapinarof, 1% showed improvement on the Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-ADTM).

The investigators noted that tapinarof may be potential two-in-one first-line topical treatment for both atopic dermatitis and plaque psoriasis, as the new trial found the cream to be both safe and tolerable for all age groups down to 2 years.

The study results were announced by biopharmaceutical company Dermavant Sciences.

2. Positive Trial Results for Hand, Foot Eczema Patients Treated with Dupilumab

This late-breaking data was shown at the American Academy of Dermatology (AAD) 2023 conference, showing that about 40% of uncontrolled moderate-to-severe hand and foot AD patients achieved clear or almost clear skin compared to 17% with placebo.

The researchers saw improvements as early as 1 week, noting that there were substantial improvements in measures of sleep, skin pain, as well as hand eczema-related life quality. They noted that the drug was the first biologic evaluated for this particular patient population.

The data was presented by Eric Simpson, MD, the studys principal trial investigator.

3. Nemolizumab Treatment Led to Improved Skin Lesions, Itch for Prurigo Nodularis Patients

Phase 3 data from the OLYMPIA 2 trial, presented at AAD, showed that nemolizumab monotherapy improved skin lesions, itch, and sleep disturbances in adults with moderate-to-severe prurigo nodularis (PN).

The investigators reported that nemolizumab, a first-in-class, interleukin-31 receptor alpha antagonist, met all of the studys primary and key secondary endpoints.

The late-breaking results were presented by Shawn Kwatra, MD, from Johns Hopkins University School of Medicine.

4. Once Daily Roflumilast Improved Symptoms of Atopic Dermatitis in Phase 3 Trials

This late-breaking data, presented at AAD, showed that roflumilast 0.15% once-daily improved AD across multiple efficacy endpoints and produced favorable safety and tolerability in patients.

The results showed that adverse events (AEs) were reported in less than 3.5% of patients, and application site pain incidence was low. The data resulted from the INTEGUMENT-1 and INTEGUMENT-2 studies.

The results were presented by Lawrence Eichenfield, MD, from Rady Children's Hospital.

5. Phase 3 Trial Data on Bimekizumab for Patients with Hidradenitis Suppurativa

This data, also presented at AAD, indicated that a greater percentage of HS patients achieved HiSCR50 for those treated with bimekizumab compared to placebo at week 16 of the study.

The results came from the BE HEARD I and II trials investigating the selective inhibition of IL-17F and IL-17A by bimekizumb, a monoclonal IgG1 antibody.

The research was presented at the conference by lead investigator Alexa B. Kimball, MD, from Beth Israel Deaconess Medical Center.

6. Oral Roflumilast Effective, Safe in Treating Plaque Psoriasis Over 24 Weeks

In this study, oral roflumilast treatment was found to lead to significant Psoriasis Area and Severity Index (PASI) score, with 34.8% of their treatment group reached PASI75 compared to 0.0% in given placebo by week 12.

The late-breaking data on oral roflumilast, a targeted phosphodiesterase (PDE)-4 inhibitor, was presented at AAD 2023. The research team also stated that roflumilast may become a cheap alternative treatment to other psoriasis drugs with more research.

The findings were presented by Alexander Egeberg, MD, PhD, from the University of Copenhagen and Bispebjerg Hospital.

7. Oral TYK2 Inhibitor Led to Significant Skin Clearance Improvement in Psoriasis

These results showed that treatment with TAK-279 (formerly NDI-034858), an oral tyrosine kinase 2 (TYK2) inhibitor, led to significant skin clearance improvement for moderate-to-severe psoriasis patients compared to placebo, especially at a once-daily, 5 mg dose.

The phase 2b clinical trial data was shown at AAD, and the investigators demonstrated that at the highest dose of TAK-279, 33% of study participants reached complete skin clearance by week 12.

The data was presented at the conference by April W. Armstrong, MD, MPH, from USCs Keck School of Medicine.

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Dermatology Month in Review: Highlights from March 2023 - MD Magazine

Dermatology

Pure Dermatology will bring skin care, treatments to South Austin – Community Impact Newspaper

Pure Dermatology is coming in May to South Austin and promises to bring skin checks, treatments and more at 8701 Hwy. 71, Ste. 101, Austin.

Opening day will be May 16, said co-owner Dr. Christopher Chu. His wife, Dr. Chelsey Straight, will also be a partner in the dermatology practice. Both are board-certified dermatologists. Chu is also a board-certified dermatopathologist, while Straight is also a board-certified micrographic surgeon.

Services provided will include skin checks, skin cancer treatments including surgical excision and micrographic surgery, treatment of common skin conditions such as acne, rosacea, eczema, psoriasis, warts, etc., hair loss consultations and treatments, and cosmetic treatments including Botox/Dysport, injectable fillers and chemical peels.

For more information, call 512-766-2610 or visit http://www.puredermtx.com in May.

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Pure Dermatology will bring skin care, treatments to South Austin - Community Impact Newspaper

Dermatology

Fatty Liver More Frequent in Alopecia Universalis and Patchy … – Dermatology Times

Nadya Kolobova/AdobeStock

A recent study published in the Journal of Cosmetic Dermatology examined the frequency of fatty liver in patients with alopecia areata subtypes, including alopecia universalis (AU) and patchy alopecia areata (PAA).1 After reviewing data from patients with AU and PAA referred to a dermatology clinic from September 23, 2019, to September 23, 2020, study investigators determined that fatty liver was more frequent in patients with AU and PAA compared to a control group, but without statistically significant differences.

Patients without hair loss disorders who attended the same clinic were selected as the control group. Additionally, patients with known liver diseases were excluded from the case-control study. The study investigators began collecting data from the AU and PAA patient groups, including age, sex, weight, and waist circumference. Disease duration and the Severity of Alopecia Tool (SALT) score were also documented among the AU and PAA patient groups.

Overall, 32 patients were included in each study group: AU, PAA, and control. Age, sex, weight, height, BMI, and waist circumference were comparable across all 3 groups. The study investigators found that the frequency of hyperlipidemia was the highest in AU patients (31.3%), followed by PAA patients (15.6%), but the difference was not statistically significant among the groups (p=0.131). Abnormal liver enzymes were recorded in 9.4% of AU patients, 12.5% of PAA patients, and 3.1% of controls (p=0.524). Statin use was also the highest in AU patients (28.1%), with no statistically significant difference among the 3 groups. Finally, disease duration and SALT score were significantly higher in the AU patient group than in the PAA patient group (p=0.009 andp<0.001, respectively).

The study investigators noted that The higher frequency of fatty liver in AU patients compared with the PAA group can be attributed to the longer disease duration and the higher SALT score in this group. To the best of our knowledge, in previous studies, fatty liver has not been evaluated in patients with AA. Still, recently the replacement of nonalcoholic fatty liver disease (NAFLD) with metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed, highlighting the association between fatty liver and metabolic syndrome.

The investigators also noted that the higher frequency of fatty liver in AA patients may be related to an oxidant/antioxidant imbalance, which was reported in the studys patients. Overall, the study suggests that there may be an association between fatty liver and the AU subtype, but larger studies are needed to confirm the correlation.

Reference

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Fatty Liver More Frequent in Alopecia Universalis and Patchy ... - Dermatology Times

Dermatology

Dermatologist Jessie Cheung on How to Make Your Penis Bigger – Men’s Health

NO SURPRISE TO anyone whos been living on planet Earth, but a lot of men want to have a bigger penis. The thing is, we cant go to the gym, do three sets of dumbbell penis reps, and get a larger schlong. If it were that easy, nearly every guy would be walking around with a snake in his pants.

Still, there actually are some things you can do to get a bigger penis, but many of these procedures are not cheap and come with some serious health risks. Nevertheless, we know you're probably curious about the wild world of penis enlargement, which is why we reached out to Jessie Cheung, M.D., a board-certified dermatologist who specializes in some of these techniques. Cheung has been a dermatologist for nearly 20 years, and six years ago, she moved from doing medical dermatology to focusing exclusively on cosmetic and sexual dermatology.

In addition to standard facial cosmetic procedures, Cheungwho's based in Manhattan and Chicagoperforms a slew of penis procedures, including fillers, fat injections, Bocox (that's Botox for your cock, FYI), and Emsella (a form of electromagnetic therapy that helps with premature ejaculation and erection strength.)

We interviewed Cheung about her dermatological methods for making patients' penises bigger, longer, and even capable of lasting longer during sex.

This interview has been lightly edited and condensed for clarity.

I dont want to brag, but a lot, hundreds. As a dermatologist, I'm used to looking at skin everywhere, including the penis, anus, scrotum, and perineum, and dealing with warts, hemorrhoids, and fissures. I stopped doing medical dermatology years ago and now focus on cosmetics, hormones, and sexual health. So that brings in men who need help with their erectile function, libido, premature ejaculation, and men who have purely cosmetic issues. The big one, of course, is increasing their penis size.

Actually, I see more men who complain about erectile dysfunction instead of size, but they always say that even if they are happy with their size, they wouldn't mind more length or girth.

I give them statistics: Numbers are facts. Interestingly, many of my men who want bigger penises have above-average length and girth. I think porn makes them lose touch with reality, just like we're seeing social media distort our perception of beauty.

Penis length must be 2.5 standard deviations below the average for that age to be considered a micropenis. For adults, that is 9.3 cm when stretched or 3.6 inches. In my office, I consider it a micropenis if they are too short to penetrate their partner.

Not that often. I would say my whole career, probably two that were so small they couldn't penetrateand that's really short. When its that small, they may want surgical intervention, and I dont do penis surgeries. So because of that, I don't see many men with a proper micropenis.

Yeah, so I perform filler injections. I also perform P-shots, which are designed to treat ED but have the additional benefit of increasing size, specifically girth. P-shots involve injecting biological substances such as Platelet-rich plasma (PRP). PRP is a source of growth factors for blood vessels and tissue, so activating the hibernating stem cells in the arteries and nerves stimulates repair and the production of healthy tissue.

P-shots start at $1800 and increase depending on the protocol used.

Ill try not to be too technical, but we draw your blood in these special tubes. We spin it down on the centrifuge, and on the top coat, there's a layer that's kinda yellowy, that's very rich with platelets, which contains eight to ten growth factors that are good for your blood vessels, collagen, and stem cell activation. So we inject that into places where you want to turn on stem cells, whether into your scalp to grow hair, your skin to help with wound healing, or the penis to activate stem cells to make blood vessels and nerves again. That said, PRP is about 10 to 15 years old. I prefer to use exomes.

So, I perform a topical infusion of exosomes, which really is the cutting edge of regenerative medicine. Exosomes are basically little email packets of information that your stem cells secrete to turn each other on and talk to each other. And they're filled with RNA, proteins, and peptides. Exomes have hundreds of more growth factors than PRP. They're also anti-inflammatory. So I use exosomes the exact same way I use P-shots, to help with ED, functionality, and size.

Anti-inflammation helps prevent tissue from aging. So in the case of penises, this will help you retain your functionality and erection strength as you age.

Fat is a great filler, and since fat is full of stem cells, I recommend fat for improving size and restoring erectile function. You will see increased girth and can regain lost length, both flaccid and erect.

A fat transfer to the penis is very straightforward. The injection technique is similar to how we inject the penis with regular fillers, but we are harvesting your own fat with gentle liposuction and processing the fat with PRP or exomes. I like to take fat from the pubic mound, which helps to expose more of the base of the penis to create more visible length. I call it pulling the turtle out of the shell.

Fat is a very cost-effective filler, and since fat functions as a natural implant, it lasts much longer than other fillers. The most significant benefit of using fat is the improvement of functionality, as the wound-healing activation of stem cells will target nerves and blood vessels to improve sensitivity and circulation. I like to transfer at least 20 mL of fat, which starts at $8,000.

There are risks associated with any injection! But understanding the anatomy and potential complications will mitigate those risks. For example, you don't want any material getting into large arteries, which can cause tissue to die. You also have to respect the layers and boundaries of the penis to avoid migration of the filler (i.e., the filler all moving to one place and sitting there). Bruising, swelling, uneven appearance, and infection are potential complications that I warn my patients about.

No, I have never had a patient who asked for a smaller penis. But penises do shrink over time, as testosterone levels fall and there is a decrease in blood flow. The blood vessels and tissue scar down and get stiff, so they can't stretch and fill up with blood for a full erection. As a result, men will notice their penis looking smaller while flaccid and erect and report softer erections.

Typically men in their fifties and sixties, though Ive seen men coming and seeking help for their shrinkage in their thirties.

Staying healthy [and] keeping your hormone levels optimized. [And you do that by] having a good quality of sleep, a healthy diet, keeping stress levels low, and not smoking. So things that are generally thought of as bad for you will negatively affect your penis size as you age.

Yes, my patients love Bocox! It helps with size and erections. Botulinum toxin works by relaxing the smooth muscle in the blood vessels of the penis. This means the blood vessels are more dilated and filled with blood at rest, so the penis hangs longer and thicker when flaccid. So its great if youre a grower and not a shower. But even with an erection, the penis is even more full of blood than usual, so it is harder and may be thicker. Bocox is a relatively safe treatment. It's usually two pokes after the application of a topical numbing cream. Risks include mild bruising and swelling.

So it's electromagnetic therapy. Basically, you're sitting on a chair, and a powerful magnet is at the chair's base. That magnet makes your pelvic floor muscles activate. So essentially, you're doing kegel exercises, whether it be for the penis, the vagina, or the anus. For the penis, that can help with premature ejaculation, but also erection strength and even size because of the increased blood flow. We have men who do Emsella for the anus, specifically sphincter control. There's a statistic that you complete over 11,000 Kegel exercises in 28 minutes on the Emsella chair. So it's very legit, and I love using it on my patients.

I will refuse to treat a patient who has unrealistic expectations. Beyond that, everyone has their own desired aesthetic, so I won't judge a man if he wants to have a huge penis. To each their own!

Social media and porn have created unrealistic expectations for bodies, faces, and genitalia. It's difficult to maintain a smooth, pink anus or vagina or penis or even nipples as we age, and sexual confidence is at an all-time low. Sex is excellent for your physical and mental health and appearance, so a therapeutic procedure that encourages sexual wellness and confidence is not really up to public judgment. It's a private health issue.

I had a patient who had filler injections done elsewhere. He had 15 syringes done in one session, and all the filler clumped up at the head of his penis. It was this huge blob. It looked like a golf ball.

So he came after it was botched to get it fixed. But didnt want to get the filler removed. So what I did was add more filler at the shaft and base, essentially to blend it in better.

Aside from the usual wows, what's memorable are the stories I hear when my patients return: sex multiple times a day, getting propositioned on Snapchat, video parties, and underground fame. My patients are definitely more confident. I had one patient who was too short to penetrate his partner, and after a combination of hormones, a P-shot, and fat transfer, he was finally able to have penetrative sex!

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Dermatologist Jessie Cheung on How to Make Your Penis Bigger - Men's Health

Dermatology

Dr. Arvinder Singh Awarded As Father Of Cosmetic Dermatology In The International Fame Award – Zee News

Dr. Arvinder Singh has been bestowed with the prestigious International Fame Award by the famous Bollywood Actress Shilpa Shetty Kundra. He has been awarded as Father of Cosmetic Dermatology for his contribution to the field of Cosmetic Dermatology, Clinical Cosmetology, Medical Aesthetics, and Medical LASERS.

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As the CEO and MD of the Arth Group of Companies and a cosmetic dermatologist who holds the world record in this field, Dr. Arvinder Singh is well-known for his expertise in chemical peels, botox, and dermal fillers. He is a Rajasthan-based, internationally board-certified cosmetic dermatologist with a specialization in facial aesthetics and clinical cosmetics, including Botox, fillers, LASERS, and thread lifts.

The International Board of Cosmetic Dermatology (IBCD) was founded in London by Dr. Arvinder Singh. The board consists of Dermatologists, Plastic Surgeons, Clinical Cosmetologists and Aesthetic Dentistists. The board was established with the goal of giving medical professionals, such as MBBS, Postgraduate doctors, dentists, and Aayush (BHMS, BAMS, BUMS), high-quality education and career opportunities in the fields of Cosmetic Dermatology, Clinical Cosmetology, Medical Aesthetics, and Medical LASERS.

His Academy, Institute of Aesthetic Medicine, Cosmetology, and LASERS (IAMCL), located in India, has been training non-medical students and professionals also who want to pursue careers in cosmetology and aesthetics and become accredited clinical cosmetologists in the vicinity of aesthetic medicine.

Additionally accredited by the UK and registered in the USA, the IAMCL provides course materials in both Hindi and English languages.

Along with this, Dr. Arvinder Singh also established what is thought to be India's first clinical fitness and cosmetology centre in Udaipur and Jaipur, Rajasthan, which has been accredited by the Quality Accreditation Institute (QAI).

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Dr. Arvinder Singh Awarded As Father Of Cosmetic Dermatology In The International Fame Award - Zee News

Dermatology

The Future of Immunotherapy Targets – Dermatology Times

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Immunotherapy, in the form of immune checkpoint inhibitors (ICI), has been a recent breakthrough in the management of both early and late-stage melanoma. With the advent of immunotherapy, the 1-year survival rate for patients with metastatic disease has increased from 25% to 50%.1 ICIs have contributed to improved outcomes of treatment and prognosis of patients with different malignancies and are now served as a standard treatment for advanced melanoma.2

Recent study results revealed that treatment with combined anti-CTLA-4/anti-PD-1 results in median overall survival and a significant durability response, which is superior to that of nivolumab monotherapy and ipilimumab monotherapy.3 Also, the benefits of combined treatment were similar for patients, irrespective of their BRAFV600 mutational and PD-L1 expression status. ICIs provide a significant response in patients with brain metastasis, particularly those who are asymptomatic of malignant infiltration at the time of presentation.4 Study results also revealed that intracranial responses of combined ipilimumab/nivolumab were more than 50% in patients whose metastases have not been treated with brain radiotherapy.5 Another study found that ipilimumab/nivolumab was significantly superior to nivolumab monotherapy with a 5-year survival rate of 51% in patients with asymptomatic disease.6 In the therapeutic field of melanoma, prior immunostimulatory treatments such as interleukin-2 (IL-2) were superseded by ICIs. For high-risk, early-stage melanoma, ipilimumab was found to increase the 3-year recurrence-free rate by more than 10%.6

While surgical excision is the primary treatment for non-melanoma skin cancers (NMSCs), immunotherapy has emerged as a promising treatment option in recent years.7 In the case of NMSCs, ICIs are the most commonly used immunotherapy drugs. These drugs block proteins in cancer cells, preventing the immune system from recognizing and attacking them.8 Clinical trials have shown that ICIs such as pembrolizumab and nivolumab have high response rates and durable responses in patients with advanced NMSCs.9 These drugs have been approved by the US Food and Drug Administration for the treatment of metastatic or locally advanced squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), which cannot be treated with surgery or radiation. Other types of immunotherapies for NMSCs include topical immunomodulators such as imiquimod and ingenol mebutate, which stimulate the immune system to attack cancer cells locally.10 Intralesional immunotherapy, which involves injecting an immune-stimulating substance directly into the tumor, is also being investigated as a potential treatment option. For the treatment of cutaneous SCC (cSCC), pembrolizumab and cemiplimab, two single-agent anti-PD-1 inhibitors, exhibited an overall response rate of 42% and 52% in recurrent/metastatic disease and locally advanced disease, respectively, when used as frontline, first-line treatment for advanced or metastatic cSCC that is not responsive to surgery or radiation.11 Both medications had long-lasting effects with manageable side effects. Merkle cell carcinoma (MCC), like cSCC, is a very immunogenic illness and a promising target for immunotherapy based on ICI. In pre-treated patients with advanced MCC, the JAVELIN Merkel 200 study showed that avelumab resulted in a 33.0% overall response rate and a median duration of response of 40.5 months.12 In comparison to cSCC, BCCs are at least two times more prevalent. The metastatic rate for BCCs is less than 1%, which is substantially lower than that for cSCCs and MCCs. Moreover, cemiplimab has been shown to generate a strong antitumor response in patients with locally advanced BCC.13

Biomarkers of response to immunotherapy in melanoma have been studied to help identify patients most likely to benefit from treatment and develop new therapeutic strategies. Programmed death-ligand 1 (PD-L1) is a protein expressed on the surface of some cancer cells, including melanoma.14 It interacts with the programmed death-1 (PD-1) receptor on T cells, inhibiting their activity and preventing the immune system from attacking cancer cells. Tumors with high levels of PD-L1 expression are more likely to respond to PD-1/PD-L1 checkpoint inhibitors. Tumor mutational burden (TMB) measures the number of mutations present in a tumor's DNA. High TMB is associated with an increased likelihood of response to ICIs, as these mutations may generate new tumor antigens that can be recognized by the immune system.15 TMB is naturally elevated in melanoma and correlates with better responses toimmune checkpoint inhibition depending on the severity of cancer. However, it is not regularly used as a predictor of ICI response. Melanoma responds exceedingly well to ICI; hence, a biomarker of ICI resistance may be more important than a biomarker of response in clinical care. Tumor-infiltrating lymphocytes (TILs) are immune cells that have migrated into the tumor microenvironment. Tumors with high levels of TILs are more likely to respond to immunotherapy, as they indicate an ongoing immune response against the tumor.16 The biomarkers of immunotherapy response in melanoma also include immune gene expression profiling and the gut microbiome. Gene expression profiling can be used to assess the activity of immune-related genes within the tumor microenvironment.17 Certain gene signatures have been associated with response to immunotherapy in melanoma. The composition of the gut microbiome has been shown to affect the efficacy of immune checkpoint inhibitors.18 Studies suggest that a more diverse gut microbiome is associated with a better response to immunotherapy.

Biomarkers that can help predict immunotherapy response or resistance in non-melanoma skin cancers include Interferon-gamma (IFN-) signature, Immunoscore, and Circulating tumor DNA (ctDNA). Interferon-gamma (IFN-) signature is a cytokine that plays a vital role in activating the immune system.19 Tumors with a high IFN- signature may be more likely to respond to immunotherapy. The Immunoscore is a measure of the immune cell infiltration and activation within a tumor. A higher Immunoscore may indicate a better response to immunotherapy.20 Circulating tumor DNA (ctDNA) refers to small fragments of DNA that are shed by tumor cells into the bloodstream. The presence of ctDNA may indicate the presence of residual disease, and monitoring ctDNA levels may help predict response to immunotherapy.21

Immunotherapy has revolutionized the treatment of melanoma and non-melanoma skin cancers, and research is ongoing to identify new targets and improve existing therapies. Now considered the gold standard for treating advanced melanoma, immune checkpoint inhibitors (ICIs) have helped improve the treatment and prognosis of patients with a variety of cancers. Median overall survival and a substantial, durable response are achieved with anti-CTLA-4/anti-PD-1 combination therapy. Previous immunostimulatory therapies, such as interleukin-2 (IL-2), have been replaced by immune checkpoint inhibitors in the therapeutic field of melanoma. Patients with advanced NMSCs have shown both a high response rate and long-lasting responses to immune checkpoint inhibitors like pembrolizumab and nivolumab, according to clinical trials. Immunotherapy has been shown to be effective against melanoma, and researchers have been looking at biomarkers of response to better target treatment towards patients suffering from skin cancers. PD-L1 expression, TMB, MSI, TILs, and HPV status have all been identified as potential biomarkers of response to immunotherapy in melanoma and non-melanoma skin cancers. However, additional research is needed to better understand the complex interplay between the tumor microenvironment and the immune system.

References

1. Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: Clinical impact and mechanisms of response and resistance.Annual Review of Pathology: Mechanisms of Disease. 2021;16(1):223-249. doi:https://doi.org/10.1146/annurev-pathol-042020-042741

2. Kostine M, Rouxel L, Barnetche T, et al. Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancerclinical aspects and relationship with tumour response: a single-centre prospective cohort study.Annals of the Rheumatic Diseases. 2017;77(3):393-398. doi:https://doi.org/10.1136/annrheumdis-2017-212257

3. Hwang JK, Hong J, Yun CO. Oncolytic viruses and immune checkpoint inhibitors: Preclinical developments to clinical trials.International Journal of Molecular Sciences. 2020;21(22):8627. doi:https://doi.org/10.3390/ijms21228627

4. Bence C, Hofman V, Chamorey E, et al. Association of combined PD L1 expression and tumourinfiltrating lymphocyte features with survival and treatment outcomes in patients with metastatic melanoma.Journal of the European Academy of Dermatology and Venereology. 2019;34(5):984-994. doi:https://doi.org/10.1111/jdv.16016

5. Suda K. Recent Advances in cancer immunotherapy.Biomolecules. 2021;11(2):335. doi:https://doi.org/10.3390/biom11020335

6. Zimmer L, Livingstone E, Hassel JC, et al. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial.The Lancet. 2020;395(10236):1558-1568. doi:https://doi.org/10.1016/s0140-6736(20)30417-7

7. Shalhout SZ, Emerick KS, Kaufman HL, Miller DM. Immunotherapy for non-melanoma skin cancer.Current Oncology Reports. 2021;23(11). doi:https://doi.org/10.1007/s11912-021-01120-z

8. Zelin E, Maronese CA, Dri A, et al. Identifying candidates for immunotherapy among patients with non-melanoma skin cancer: A review of the potential predictors of response.Journal of Clinical Medicine. 2022;11(12):3364. doi:https://doi.org/10.3390/jcm11123364

9. Fahradyan A, Howell AC, Wolfswinkel EM, Tsuha M, Sheth P, Wong AK. Updates on the management of non-melanoma skin cancer (NMSC).Healthcare. 2017;5(4). doi:https://doi.org/10.3390/healthcare5040082

10. Cives M, Mannavola F, Lospalluti L, et al. Non-melanoma skin cancers: Biological and clinical features.International Journal of Molecular Sciences. 2020;21(15). doi:https://doi.org/10.3390/ijms21155394

11. Ascierto PA, Schadendorf D. Immunotherapy in non-melanoma skin cancer: Updates and new perspectives.Drugs in Context. 2019;8:1-6. doi:https://doi.org/10.7573/dic.212583

12. Shalhout SZ, Emerick KS, Kaufman HL, Miller DM. Immunotherapy for non-melanoma skin cancer.Current Oncology Reports. 2021;23(11). doi:https://doi.org/10.1007/s11912-021-01120-z

13. Stratigos AJ, Sekulic A, Peris K, et al. Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial.The Lancet Oncology. 2021;22(6):848-857. doi:https://doi.org/10.1016/s1470-2045(21)00126-1

14. Berghoff AS, Ricken G, Widhalm G, et al. Tumour-infiltrating lymphocytes and expression of programmed death ligand 1 (PD-L1) in melanoma brain metastases.Histopathology. 2014;66(2):289-299. doi:https://doi.org/10.1111/his.12537

15. Jardim DL, Goodman A, de Melo Gagliato D, Kurzrock R. The challenges of tumor mutational burden as an immunotherapy biomarker.Cancer Cell. 2021;39(2):154-173. doi:https://doi.org/10.1016/j.ccell.2020.10.001

16. Paijens ST, Vledder A, de Bruyn M, Nijman HW. Tumor-infiltrating lymphocytes in the immunotherapy era.Cellular & Molecular Immunology. Published online November 2, 2020:1-18. doi:https://doi.org/10.1038/s41423-020-00565-9

17. Farberg AS, Marson JW, Glazer A, et al. Expert consensus on the use of prognostic gene expression profiling tests for the management of cutaneous melanoma: Consensus from the skin cancer prevention working group.Dermatology and Therapy. 2022;12(4):807-823. doi:https://doi.org/10.1007/s13555-022-00709-x

18. Rezasoltani S, Yadegar A, Asadzadeh Aghdaei H, Reza Zali M. Modulatory effects of gut microbiome in cancer immunotherapy: A novel paradigm for blockade of immune checkpoint inhibitors.Cancer Medicine. 2020;10(3):1141-1154. doi:https://doi.org/10.1002/cam4.3694

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The Future of Immunotherapy Targets - Dermatology Times