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Naval aviation bridges medicine, engineering to advance aerospace tech – The Southern Maryland Chronicle

NAVAL AIR WARFARE CENTER AIRCRAFT DIVISION, (Patuxent River, Md.) The Naval Air Warfare Center Aircraft Division (NAWCAD) is advancing its human systems technology by combining best practices from the medical and engineering communities.

The warfare center recently stood up the Aeromedical Monitoring and Analysis branch comprised of licensed medical military officers bridging their perspective with engineering disciplines to improve operational capabilities like night vision technology, hearing protection, mission planning software, and more.

Medicine and engineering seldom wholly come together, said NAWCAD Aeromedical Monitoring and Analysis branch head Cmdr. Matthew Doubrava, a Navy Flight Surgeon board certified in Aerospace Medicine and Occupational Medicine. Our team of biomedical scientists looks forward to bringing human oriented science and a medical perspective to enhance our Navys advanced technology.

The uniformed medical specialists have a broad range of academic expertise including aerospace and occupation medicine, optometry and vision science, audiology, research and aviation physiology, and experimental psychology. With these skillsets, they will work directly alongside NAWCAD engineers, testers, and aviators to enhance their research, development, tests, and evaluation to advance aerospace technology. Adding this expertise will help create technology more relevant to human capability, and fill knowledge gaps where technical professionals typically hold little experience.

The Navys challenge with physiological episodes showed us how critically important a medical perspective can be, said Doubrava. Were working to stay ahead of the curve what is the next physiological episode on the horizon and how can we prevent it?

NAWCADs lineup of clinical scientists completed health care professional and graduate school, and entered the Navy to receive specialized training as aeromedical and research professionals. Most attended the six-month Aeromedical Officer Course that consists of a specialized flight school syllabus and clinical training in Pensacola, Florida. As an aeromedical officer, they hold a Navy aeronautical rating that requires a monthly minimum of aircrew flight time making them uniquely qualified as aeromedical professionals. While their primary mission is medical research, they are required to accrue flight time with fleet aviators for continued understanding of naval aviations evolving systems.

NAWCAD advances capability and operational readiness for naval aviation and our warfighters. The warfare center is where naval aviation takes flight through research, development, test, evaluation, and sustainment of both fielded and not-yet fielded naval platforms and technologies that ensure Americas Sailors and Marines always go into conflict with significant advantage. With sites in Patuxent River, Maryland, Lakehurst, New Jersey, and Orlando, Florida, the command is the Navys largest warfare center with a diverse force of military, civilians, and contractors building the Navy of today, the Navy of tomorrow, and the Navy after next.

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Naval aviation bridges medicine, engineering to advance aerospace tech - The Southern Maryland Chronicle

Physiology

Gene therapy for overactive bladder | TCRM – Dove Medical Press

Introduction

Overactive bladder (OAB) is a disorder characterized by urgency and frequency with and without urinary incontinence. It affects 15% to 25% of the general population older than 40 years of age.15 Current guidelines recommend non-subtypeselective oral antimuscarinics or 3-adrenergic receptor agonists as primary pharmacotherapy.68 Although these agents modulate the neurotransmitter-mediated signals that cause OAB-related symptoms,9 some, such as anticholinergics, are associated with challenging adverse effects that limit compliance, and they may not be effective in all patients.611 Chemodenervation agents may improve symptoms with similar or even greater efficacy compared with oral agents; however, treatment with botulinum toxin may result in unwanted post-procedural outcomes such as urinary retention and urinary tract infections. Other treatments for OAB are limited by cost and invasiveness, require general anesthesia (eg, sacral neuromodulation), or have limited efficacy and require inconvenient weekly treatment sessions (eg, percutaneous tibial nerve stimulation).12 Thus, while bladder-targeted treatments are available, there remains an unmet need for locally administered interventions to treat OAB.

The large-conductance, voltage- and calcium-activated K+ channel, known as the big potassium (BK) or Maxi-K channel, is highly expressed on urinary bladder smooth muscle cells and regulates bladder detrusor muscle function.13 BK channel activation reduces smooth muscle cell excitability, and therefore modulation of this channels activity by the introduction of a locally instilled plasmid expressing the BK channel is a potential novel approach to OAB treatment. This article reviews the physiological importance and regulation of the BK channel in the bladder, as well as the potential of BK channel modulation with gene therapy in the management of OAB.

When functioning normally, the bladder has a change in internal volume from nearly zero to >400 mL during its filling cycle.14 During voluntary or involuntary voiding, the detrusor smooth muscle cells go from a state of low tension to a rapid contraction in order to empty the bladder. Detrusor smooth muscle is organized in contractile units in a syncytium connected by gap junctions that facilitate the spread of contractile function throughout the detrusor muscle tissue.15 These contractile units show spontaneous depolarizations leading to uncoordinated contractile activity that has little effect on intravesical pressure but is essential for maintaining tone of the bladder wall.16 The spontaneous activity in turn generates afferent nerve activity and the sensation of bladder filling.17,18 Increases in the spontaneous activity leading to increased afferent nerve activity have been considered important in the generation of OAB symptoms.

In order to produce an emptying contraction, coordination of the activity of the muscle units is necessary, and this is provided by excitatory input from the parasympathetic system.17 Bladder emptying contraction is initiated by a massive release of acetylcholine from the pelvic nerve, which stimulates muscarinic (M3) receptors on the detrusor smooth muscle cell, and triggers an intracellular signaling cascade that leads to simultaneous membrane depolarization of all detrusor muscle cells. This results in the opening of voltage-dependent Ca2+ channels at the cell surface and a massive influx of extracellular calcium. High intracellular Ca2+ is sensed by calmodulin, an intracellular messenger protein, which leads to the activation of myosin light chain kinase and muscle contraction.17

Relaxation of detrusor smooth muscle cells is mediated, at least in part, when K+ channels open to allow the efflux of K+ ions, and hyperpolarization of the cell membrane is produced, leading to diminished intracellular calcium levels and reduction of the spontaneous activity and thus reduced detrusor muscle tone.13 This mechanism operates during the filling phase, when OAB symptoms are experienced, and has no effect on the emptying contraction. Thus, restoration/maintenance of the endogenous ionic mechanisms that govern smooth muscle cell tone, through targeted gene therapy, is an attractive approach to the treatment of any disease or disorder characterized by altered smooth muscle cell physiologyincluding OAB. The BK or Maxi-K channel is the K channel subtype most responsible for creating and maintaining the cells resting membrane potential.

Gene therapy can be used to treat diseases and conditions such as OAB. Specifically, we suggest that tissue or organ-specific overexpression of key modulators of smooth muscle function can mitigate pathophysiological features of diseases as diverse as hypertension, asthma, irritable bowel, erectile dysfunction, and OAB. The explicit scientific rationale, in the case of the bladder, is driven by the supposition that targeted, locally delivered, gene therapy can address the pathophysiological changes in molecular and biochemical pathways that result in dysfunctional control of detrusor smooth muscle tone, which in turn, manifests as OAB.

In this scenario, gene therapy can be used to restore, reduce, or enhance the expression of the normal gene products that control key cellular actions.19 Aging and disease can modify normal gene expression, for example, by elaboration of splice variants whose downstream products alter normal cellular physiology to result in dysfunctional bladder control. The introduction of carefully selected genes into a significant fraction of affected cells can return the cells and organs to more normal physiology and function.

The bladder is notably amenable to such an approach for 3 main reasons. First, the bladder is readily accessible via the urethra for delivery of therapeutic genes to the urothelium, neural network, and/or underlying detrusor myocytes.20,21 Second, therapeutic administration is local, and thus the main part of the corresponding activity should be confined to the bladder. In fact, these 2 points have recently been demonstrated in pilot clinical studies of naked DNA gene therapies for OAB, which have produced no evidence of systemic effects.22 Third, relatively modest transfection efficiency can be therapeutically tolerated, as the bladders myocytes communicate with each other through intercellular channels, referred to as gap junctions. This latter mechanism leverages the important role that gap junctions play in the coordinated contractile responses mediated by the extant syncytial smooth muscle cell network to ensure complete bladder emptying upon appropriate parasympathetic activation.15,20 More specifically, although only a small proportion of myocytes might incorporate and express the therapeutic naked DNA gene, the presence of an intercellular network of gap junctions allows corrective changes in gene expression to facilitate passage of current-carrying ions and secondary messenger molecules from cell to cell throughout the bladder wall.23

Again, it appears that the large-conductance, voltage- and calcium-activated BK (Maxi-K) channel is the K channel subtype most responsible for creating and maintaining the cells resting membrane potential.13 The BK channel consists of a tetramer of pore-forming -subunits that are typically surrounded by modulatory -subunits.24,25 The -subunit is encoded by a single gene called Slo or KCNMA1 that is located on the long arm of chromosome 10.26 Activation by either membrane depolarization or increased intracellular Ca2+ increases the permeability of the BK channel permitting outward K+ efflux across the cell membrane down the electrochemical gradient, resulting in hyperpolarization and reduced cellular excitability (Figure 1). Since increased myogenic activity may contribute to bladder overactivity, increasing the number of BK channels (via gene transfer) has a rational scientific basis.

Figure 1 Schematic depiction of the central role of the BK channel in regulation of myogenic tone in bladder smooth muscle. As shown, detrusor smooth muscle exhibits spontaneous myogenic contractile activity (spikes) associated with depolarizations. The depolarizations are associated with Ca2+ influx via voltage-dependent calcium channels (VDCCs). Ca2+-induced Ca2+ release from the sarcoplasmic reticulum activates BK channels via sparks, but BK channels are also activated via more global increases in intracellular calcium, and eventually the cell is repolarized. The repolarization closes (temporarily) the VDCC, and spike activity is reduced.

Overall, the BK channels in bladder smooth muscle act to promote detrusor relaxation and limit the amplitude and duration of spontaneous or nerve-induced detrusor contraction.13 Several lines of evidence suggest the importance of BK channels for modulating and sustaining the bladders resting state. In normal detrusor smooth muscle, the BK channel is expressed at high levels.27,28 In fact, the conductance of the BK channelthat is, the rate of K+ ions passing through the channelis an order of magnitude greater than the conductance of other K+ channels.29 The BK channel is therefore unique among K+ channels in its responsiveness either to membrane depolarization or a rise in intracellular calcium, enabling it to integrate these contraction-governing signals.13 Consistent with these electrophysiological properties, in mice, for example, knockout of BK channel -subunits is associated with increased detrusor contractility and urination frequency.30 In mouse bladder myocytes, deletion of the BK -subunit or pharmacologic blockade of transient BK currents is sufficient to depolarize the cell membrane.31,32

Ion channel dysfunction, often referred to as channelopathy, is often associated with disorders of smooth muscle.33 In the case of the BK channel, mutations, splice variants, or low levels of channel expression in bladder myocytes would be expected to lead to increased intracellular Ca2+ levels and abnormal responsiveness to cholinergic signaling.13,34 Using detrusor smooth muscle tissue samples obtained from 33 patients during open bladder surgeries, neurogenic detrusor overactivity was associated with decreased BK channel expression and function, leading to increased detrusor smooth muscle excitability and contractility.35 BK channel dysfunction may also heighten the responsiveness of the central nervous system to sensory signals from the bladder, a phenomenon called central sensitization, which appears to occur in illnesses such as irritable bowel syndrome and fibromyalgia.36 High levels of gap junction expression would likewise be expected to make the bladder smooth muscle cells hypersensitive to cholinergic stimulation, presumably due to excessive diffusion of Ca2+ ions among detrusor coupled myocytes.15,3739 Indeed, upregulation of connexin 43, a predominant connexin protein expressed in human bladder gap junctions, has been identified in patients with urgency incontinence.32

The use of gene therapy to treat bladder dysfunction may have intrinsic advantages over conventional pharmacotherapies when the therapeutic target is subject to epigenetic modification. It was recently demonstrated that diabetes results in epigenetic changes in the methylation pattern of the detrusor genome which are mostly, but not entirely, normalized with glycemic control.40 This phenomenon is known as hyperglycemic memory and would likely contribute to the persistence of bladder dysfunction even in diabetic patients that achieve glycemic control. The KCNMA1 gene (encoding the BK channel, -subunit) was identified in the subset of genes encoded by genomic loci that had modulated methylation patterns with diabetes that were not reversed with glycemic control. The changes in methylation pattern correlated with expression of the BK channel -subunit protein; its expression was downregulated with diabetes that was not reversed with insulin treatment. Although decreased expression and activity of KCNMA1 in the diabetic bladder has been reported (and used to support targeting BK channel activity to treat diabetic bladder dysfunction), expression was previously not known to be subject to hyperglycemic memory. Gene therapy overcomes hyperglycemic memory by introducing exogenous DNA into the bladder that has not been subject to epigenetic modification, restoring BK channel activity. In contrast, pharmacologic approaches to increase BK channel activity in the bladder of diabetic patients, even patients who have achieved glycemic control, would have no target to act on, or have such low levels of expression that activation is insufficient for physiological effect. Therefore, the strategy of increasing BK channel activity to treat patients with bladder dysfunction involving epigenetic modification will be more effective using gene therapy (which overexpress the KCNMA1 gene) than the use of pharmacologic agents (which may have no or little target to activate).

Gene therapies are often designed for the purpose of gene augmentation or the introduction of a functional gene into a cell with deficient expression of the desired gene product.19 To ensure sufficient expression, the gene delivery system must permit uptake by the targeted cells, protect the exogenous nucleic acid from degradation by host-cell nuclease enzymes, and ensure intracellular transport of the gene to the cell nucleus. To these ends, viral vectors have often been used. However, viral-based gene therapy has been associated with severe adverse events and risk of mortality, leading to increased investigations of non-viral vectors.19,41,42

Naked plasmid DNA (pDNA) is one such non-viral vector option. Naked pDNA is significantly less immunogenic relative to viral and retroviral vectors.43 Further, naked pDNA has less potential for integration into the host cells genome, thereby reducing the risk of adverse events associated with insertional mutagenesis, position-effect variegation, or inflammatory immune responses.41,44 However, gene transfer via naked pDNA is also limited by low transfection efficiency and transient expression of the transgene, necessitating the administration of large quantities of the vector.41 Organs and systems successfully targeted by naked pDNA in preclinical and clinical studies have included the heart, central nervous system, pancreas, penis, and skeletal muscle.41,4547

URO-902 is a 6880-base-pair naked pDNA incorporating a DNA sequence synthesized from the messenger RNA (mRNA) that encodes the human BK channel -subunit (Figure 2).21,48 To ensure robust expression of the encoded protein in eukaryotic cells, the -subunit code is flanked at its upstream end by a CMV promoter (from cytomegalovirus) to initiate DNA transcription and at its downstream end by a polyadenylation signal (from the bovine growth hormone gene) to terminate transcription and protect the transcript from enzymatic degradation. In addition, the plasmid incorporates sequences that are frequently used in plasmid construction to facilitate its selection and replication in Escherichia coli cultures. None of the modules enable the plasmid to replicate in eukaryotic cells, thereby confining the treatment to targeted cells transfected with the plasmid.

Figure 2 The URO-902 plasmid construct. For further construct details, see Melman et al.48 BGH, bovine growth hormone; CMV, cytomegalovirus.

Within targeted cells, URO-902 enters the cell presumably via endocytosis and then transits the cell nucleus through a nuclear pore. The type of plasmid promoter driving BK expression determines which cells will express the protein. URO-902 uses a CMV promoter, which is a nonspecific promoter that is active in all cells. Smooth muscle cellspecific promoters, such as the smooth muscle -actin (SMAA) promoter, also have been incorporated into the plasmid backbone and were shown to be physiologically active.49,50 In the nucleus, pDNA for the BK -subunit is transcribed by the host cell into an mRNA, which is translated into protein in the cytoplasm. The expressed BK -subunit channels are then inserted into the cell membrane via the cells endogenous machinery. Reverse transcription polymerase chain reaction (RT-PCR) measures show that the gene is expressed in erectile smooth muscle for up to 6 months.51 The hypothesis underlying the development of URO-902 as a gene therapy for OAB is that increased expression of BK channels in bladder myocytes may enhance the cellular capacity to expel K+ ions, promoting membrane hyperpolarization and reducing excitability (Figure 1). The resulting smooth muscle relaxation would be expected to reduce the symptoms associated with OAB.

Transfer of DNA encoding the BK channel -subunit was first tested as a potential treatment for erectile dysfunction.21 In 2 rat models, intracavernosal injection of a plasmid incorporating the -subunit gene yielded improvement in the ratio of intracavernous pressure to systemic arterial blood pressure.5153 A dose-dependent effect on erectile response to cavernous nerve stimulation was seen for up to 6 months. Improvement in erectile function also was identified in atherosclerotic male cynomolgus monkeys, where intracorporal BK channel gene transfer also enhanced sexual behaviorimplying that erectile function per se may lead to increased sexual function.49

In a phase 1 safety study, 11 men with severe erectile dysfunction who were unresponsive to pharmacotherapy but otherwise in good health were treated with open-label URO-902 administered as a single dose by intracavernosal injection.47,48 The tested dose levels were 0.5, 1, 5, and 7.5 mg. Patients were monitored for 6 months with annual follow-up for 2 years. The therapy was well tolerated, with no adverse events considered to be gene-transfer-related and no clinically significant changes in physical, laboratory, or electrocardiographic parameters. Semen samples obtained up to 4 weeks after URO-902 dosing showed no evidence of the plasmid. At the 2 highest doses, a clinical response persisted throughout the 6-month study period. A phase 2 study in 26 men confirmed the tolerability of URO-902, with all events being mild and considered not related to study drug.54

To evaluate potential use in OAB, preclinical research established the ability of bladder instillation of pDNA encoding the BK -subunit to ameliorate the bladder overactivity observed in rats following partial urethral obstruction.55 These studies were followed by phase 1 safety studies of female patients with OAB.22 In each of 2 such trials, the participants were otherwise healthy, non-fertile women with non-neurogenic (idiopathic) OAB and associated detrusor overactivity of at least 6-month duration (Table 1). Moreover, study participants were required to document at least 8 micturitions per day and at least 5 urgency urinary incontinence episodes per week at baseline, without clinically significant stress incontinence. Each woman received a single double-blind dose of URO-902 or placebo administered by intravesical instillation in one trial (ION-02 [NCT00495053]) and by direct detrusor injection in another trial (ION-03 [NCT01870037]). For instilled URO-902, the tested dose levels were 5 and 10 mg. For injected URO-902, dose levels were 16 and 24 mg divided among 20 to 30 injection sites. Patients were assessed and monitored for 6 months with periodic follow-up for an additional 18 months.

Table 1 Baseline Characteristics by Study Drug Treatment in Women Participating in Phase 1 URO-902 Trials

In ION-02 (intravesical installation), the 90-mL dose of URO-902 was instilled through a small-diameter catheter into the lumen of the bladder, and patients were requested to retain the solution in the bladder for at least 2 hours.22 In ION-03 (direct injection), URO-902 was injected approximately 2 mm into the detrusor muscle with a BoNee needle through a rigid cystoscope, without general or regional anesthesia, and 20 injections of either 0.2 mL (16-mg dose) or 30 injections of 0.2 mL (24-mg dose) each were spaced approximately 1 cm apart.22 Prior to direct injection, 40 mL of 2% lidocaine was instilled into the bladder, and 10 mL of 2% xylocaine gel was instilled into the urethra.

In both studies, few treatment-related adverse events were noted. Of 34 participants in both studies, only 3 had treatment-related adverse events, and 1 of those patients received placebo. Furthermore, there were no adverse events leading to an early withdrawal from the study (Tables 2 and 3).22 One serious adverse event was reported in ION-03: exacerbation of pre-existing asthma in a patient treated with 16 mg URO-902. This event was not considered related to the investigational agent. Across both trials, no patients experienced urinary retention as a reported adverse event.22

Table 2 Reported Adverse Events by Study Drug Treatment Among Women Participating in the Phase 1 ION-02 URO-902 Trial

Table 3 Reported Adverse Events by Study Drug Treatment Among Women Participating in the Phase 1 ION-03 URO-902 Trial

Among the 16 women receiving URO-902 by instillation, post-dose urine samples showed no evidence of the plasmid.22 Among the 9 women receiving URO-902 by injection, post-dose samples obtained after dosing detected the plasmid in the urine of 4 patients and in the blood of 1 patient 15 minutes after dosing. There was no evidence of the plasmid in later samples.22

In both ION-02 and ION-03, the efficacy of URO-902 for the treatment of OAB was assessed by several endpoints.22 In ION-02, patients receiving URO-902 by intravesical instillation exhibited no significant changes in the mean number of voids or urgency incontinence episodes at either dose. Nevertheless, several efficacy signals were detected. Across URO-902 recipients, the mean reduction in detrusor contractions from baseline to week 24 was trending toward significance (P<0.0508). At week 8, the 5-mg subgroup showed a >40% mean reduction in urgency incontinence episodes.22

In ION-03, URO-902 administered by direct detrusor injection showed greater efficacy compared with results of ION-02.22 Improvement of OAB manifestations included a dose-dependent reduction in the mean number of micturitions and urgency episodes per day, with statistical significance versus placebo for the 24-mg dose at post-dose time points including weeks 12 and 24 (Figure 3A and B). These improvements were accompanied by a decrease in urgency incontinence episodes per day, with dose dependence observed at week 24 (Figure 3C). For micturitions per day and urgency episodes per day, the mean improvement at both URO-902 doses was statistically significant versus placebo at week 1, whereas placebo recipients showed no improvement throughout the trial. In future trials, these higher doses of URO-902 may lead to further improved response. URO-902 recipients also reported improvements versus baseline in quality of life (QoL) as measured by the Kings Health Questionnaire, a healthrelated QoL instrument specific for urinary incontinence. At multiple post-dose visits, statistically significant improvements were reported in domain scores measuring impact on life, physical limitations, role limitations, social limitations, and sleep/energy.22

Figure 3 Mean changes from baseline in (A) micturitions, (B) urgency episodes, and (C) UUI episodes by treatment group during the ION-03 study of URO-902.22 Data on file from Dr. Melman. *P<0.05 versus placebo. P values are derived from a linear mixed model with the number of urgency episodes or number of voids as dependent variables, treatments, time point, and interaction of time and treatment.

Abbreviations: BL, baseline; SE, standard error; UUI, urge urinary incontinence.

It has been demonstrated that large molecular weight proteins, such as nerve growth factor, botulinum toxin,56 and wheat germ agglutinin conjugated to horseradish peroxidase,57 are capable of retrograde transport to dorsal root ganglia from intradetrusor injection sites. A similar transport of the injected plasmid in ION-03 is possible, and, provided that this is the case, a contribution to the lack of dose dependence in toxicity and in efficacy cannot be excluded. However, in a recently published study,58 it was the absence of the BK channel and not increased expression that resulted in decreased neuromuscular transmission. Additionally, because URO-902 uses a nonspecific promoter, it is possible that there may be an effect on neurons in the bladder.

As different injection techniques and doses were used for delivery of URO-902 in ION-02 and ION-03, results from these studies cannot be compared. At present, it is not known whether direct detrusor injection or intravesical instillation will yield the best gene expression in patients with OAB, nor is it established which technique may ultimately be more effective at reducing the symptoms of OAB. As long-term animal studies may pose challenges with multiple survival surgeries, further in-human studies are required to optimize and refine the use of URO-902.

Among transmembrane ion channels in bladder smooth muscle cells, the BK channel has a particularly crucial role in modulating smooth muscle excitability and thus detrusor tone and contraction. The rationale for URO-902 as a gene therapy for OAB is that enhanced expression of BK channel -subunits in bladder myocytes may decrease detrusor smooth muscle cell excitability leading to decreased afferent activity. In turn, this leads to decreased urgency, urinary frequency, and urge urinary incontinence. In preclinical research, gene transfer via naked pDNA encoding the BK channel -subunit led to improvement in animal models of detrusor overactivity. In adult female patients with OAB, secondary analyses of efficacy endpoints suggested sustained benefits through 24 weeks of post-dose monitoring, especially with direct detrusor injection of the gene therapy, which were accompanied by improvements in QoL. These findings warrant continued investigation of URO-902 in larger-scale clinical studies.

Medical writing and editorial support was provided to the authors by The Curry Rockefeller Group, LLC, Tarrytown, NY, and was funded by Urovant Sciences.

ION-03 was supported in part by National Institute on Aging grant R44DK093279. Urovant Sciences provided funding for medical writing and editorial support, which was provided by The Curry Rockefeller Group, LLC.

K-EA has nothing to disclose. GJC is co-founder, director, and shareholder of Ion Channel Innovations, LLC, and has a US Patent Application Appl. No. 16/612286; 371(c) Date: November 8, 2019 (US National Phase of Intl Appl. No. PCT/US2018/032574; Intl Filing Date: May 14, 2018) For: Compositions And Methods For Treating Idiopathic Overactive Bladder Syndrome And Detrusor Overactivity, pending to Urovant. KD is a shareholder of Ion Channel Innovations, LLC, and received research funds from Urovant. ER reports relationships with Ion Channel Innovations, LLC, during the conduct of the study and with Urovant in the form of consulting honoraria. AM reports an NIH grant for Ion Channel Innovations, LLC, and consultant relationship with Urovant; he was co-founder of Ion Channel Innovations, LLC.

1. Abrams P, Artibani W, Cardozo L, et al. Reviewing the ICS 2002 terminology report: the ongoing debate. Neurourol Urodyn. 2009;28(4):287. doi:10.1002/nau.20737

2. Van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardization of terminology in nocturia: report from the standardization subcommittee of the International Continence Society. BJU Int. 2002;90(suppl 3):1115. doi:10.1046/j.1464-410X.90.s3.3.x

3. Reynolds WS, Fowke J, Dmochowski R. The burden of overactive bladder on US public health. Curr Bladder Dysfunct Rep. 2016;11(1):813. doi:10.1007/s11884-016-0344-9

4. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20(6):327336. doi:10.1007/s00345-002-0301-4

5. Irwin DE, Kopp ZS, Agatep B, Milsom I, Abrams P. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int. 2011;108(7):11321138. doi:10.1111/j.1464-410X.2010.09993.x

6. Gormley EA, Lightner DJ, Burgio KL, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. J Urol. 2012;188(6 Suppl):24552463.doi:10.1016/j.juro.2012.09.079

7. Lightner DJ, Gomelsky A, Souter L, Vasavada SP. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment 2019. J Urol. 2019;202(3):558563. doi:10.1097/ju.0000000000000309

8. Maman K, Aballea S, Nazir J, et al. Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison. Eur Urol. 2014;65(4):755765.doi:10.1016/j.eururo.2013.11.010

9. Yamada S, Ito Y, Nishijima S, Kadekawa K, Sugaya K. Basic and clinical aspects of antimuscarinic agents used to treat overactive bladder. Pharmacol Ther. 2018;189:130148.doi:10.1016/j.pharmthera.2018.04.010

10. Yeowell G, Smith P, Nazir J, Hakimi Z, Siddiqui E, Fatoye F. Real-world persistence and adherence to oral antimuscarinics and mirabegron in patients with overactive bladder (OAB): a systematic literature review. BMJ Open. 2018;8(11):e021889. doi:10.1136/bmjopen-2018-021889

11. Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J. Anticholinergic drug exposure and the risk of dementia: a nested case-control study. JAMA Intern Med. 2019;179(8):10841093. doi:10.1001/jamainternmed.2019.0677

12. Lo C-W, Wu M-Y, Yang SS-D, Jaw F-S, Chang S-J. Comparing the efficacy of onabotulinumtoxinA, sacral neuromodulation, and peripheral tibial nerve stimulation as third line treatment for the management of overactive bladder symptoms in adults: systematic review and network meta-analysis. Toxins. 2020;12(2):128. doi:10.3390/toxins12020128

13. Petkov GV. Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology. Am J Physiol Regul Integr Comp Physiol. 2014;307(6):R571584. doi:10.1152/ajpregu.00142.2014

14. Lukacz ES, Sampselle C, Gray M, et al. A healthy bladder: a consensus statement. Int J Clin Pract. 2011;65(10):10261036. doi:10.1111/j.1742-1241.2011.02763.x

15. Wang H-Z, Brink PR, Christ GJ. Gap junction channel activity in short-term cultured human detrusor myocyte cell pairs: gating and unitary conductances. Am J Physiol Cell Physiol. 2006;291(6):C13661376. doi:10.1152/ajpcell.00027.2006

16. Andersson K-E. Detrusor myocyte activity and afferent signaling. Neurourol Urodyn. 2010;29(1):97106. doi:10.1002/nau.20784

17. Andersson K-E, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev. 2004;84(3):935986. doi:10.1152/physrev.00038.2003

18. Chakrabarty B, Bijos DA, Vahabi B, et al. Modulation of bladder wall micromotions alters intravesical pressure activity in the isolated bladder. Front Physiol. 2019;9:1937. doi:10.3389/fphys.2018.01937

19. Anguela XM, High KA. Entering the modern era of gene therapy. Annu Rev Med. 2019;70(1):273288. doi:10.1146/annurev-med-012017-043332

20. Christ GJ, Hodges S. Molecular mechanisms of detrusor and corporal myocyte contraction: identifying targets for pharmacotherapy of bladder and erectile dysfunction. Br J Pharmacol. 2006;147(Suppl S2):S4155. doi:10.1038/sj.bjp.0706627

21. Melman A, Davies K. Gene therapy for erectile dysfunction: what is the future? Curr Urol Rep. 2010;11(6):421426. doi:10.1007/s11934-010-0145-1

22. Rovner E, Chai TC, Jacobs S, et al. Evaluating the safety and potential activity of URO-902 (hMaxi-K) gene transfer by intravesical instillation or direct injection into the bladder wall in female participants with idiopathic (non-neurogenic) overactive bladder syndrome and detrusor overactivity from two double-blind, imbalanced, placebo-controlled randomized phase 1 trials. Neurourol Urodyn. 2020;39(2):744753. doi:10.1002/nau.24272

23. Campos de Carvalho AC, Roy C, Moreno AP, et al. Gap junctions formed of connexin43 are found between smooth muscle cells of human corpus cavernosum. J Urol. 1993;149(6):15681575. doi:10.1016/S0022-5347(17)36455-8

24. Knaus HG, Garcia-Calvo M, Kaczorowski GJ, Garcia ML. Subunit composition of the high conductance calcium-activated potassium channel from smooth muscle, a representative of the mSlo and slowpoke family of potassium channels. J Biol Chem. 1994;269(6):39213924. doi:10.1016/S0021-9258(17)41720-0

25. Latorre R, Castillo K, Carrasquel-Ursulaez W, et al. Molecular determinants of BK channel functional diversity and functioning. Physiol Rev. 2017;97(1):3987. doi:10.1152/physrev.00001.2016

26. Tseng-Crank J, Foster CD, Krause JD, et al. Cloning, expression, and distribution of functionally distinct Ca2+-activated K+ channel isoforms from human brain. Neuron. 1994;13(6):13151330. doi:10.1016/0896-6273(94)90418-9

27. Petkov GV, Bonev AD, Heppner TJ, Brenner R, Aldrich RW, Nelson MT. 1-Subunit of the Ca2+-activated K+ channel regulates contractile activity of mouse urinary bladder smooth muscle. J Physiol. 2001;537:443452. doi:10.1111/j.1469-7793.2001.00443.x

28. Ohi Y, Yamamura H, Nagano N, et al. Local Ca2+ transients and distribution of BK channels and ryanodine receptors in smooth muscle cells of guinea-pig vas deferens and urinary bladder. J Physiol. 2001;534:313326. doi:10.1111/j.1469-7793.2001.t01-3-00313.x

29. Latorre R, Miller C. Conduction and selectivity in potassium channels. J Membr Biol. 1983;71(12):1130. doi:10.1007/BF01870671

30. Meredith AL, Thorneloe KS, Werner ME, Nelson MT, Aldrich RW. Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel. J Biol Chem. 2004;279(35):3674636752. doi:10.1074/jbc.M405621200

31. Mimata H, Nomura Y, Emoto A, Latifpour J, Wheeler M, Weiss RM. Muscarinic receptor subtypes and receptor-coupled phosphatidylinositol hydrolysis in rat bladder smooth muscle. Int J Urol. 1997;4(6):591596. doi:10.1111/j.1442-2042.1997.tb00315.x

32. Neuhaus J, Pfeiffer F, Wolburg H, Horn L-C, Dorschner W. Alterations in connexin expression in the bladder of patients with urge symptoms. BJU International. 2005;96(4):670676. doi:10.1111/j.1464-410X.2005.05703.x

33. Bailey CS, Moldenhauer HJ, Park SM, Keros S, Meredith AL. KCNMA1-linked channelopathy. J Gen Physiol. 2019;151(10):11731189. doi:10.1085/jgp.201912457

34. Davies KP, Zhao W, Tar M, et al. Diabetes-induced changes in the alternative splicing of the slo gene in corporal tissue. Eur Urol. 2007;52(4):12291237. doi:10.1016/j.eururo.2006.11.028

35. Hristov KL, Afeli SAY, Parajuli SP, Cheng Q, Rovner ES, Petkov GV. Neurogenic detrusor overactivity is associated with decreased expression and function of the large conductance voltage- and Ca2+-activated K+ channels. PLoS One. 2013;8(7):e68052. doi:10.1371/journal.pone.0068052

36. Reynolds WS, Dmochowski R, Wein A, Bruehl S. Does central sensitization help explain idiopathic overactive bladder? Nat Rev Urol. 2016;13(8):481491.doi:10.1038/nrurol.2016.95

37. Zhou F, Li H, Zhou C, et al. Structural and functional changes in gap junctional intercellular communication in a rat model of overactive bladder syndrome induced by partial bladder outlet obstruction. Exp Ther Med. 2016;11(6):21392146.doi:10.3892/etm.2016.3246

38. Okinami T, Imamura M, Nishikawa N, et al. Altered detrusor gap junction communications induce storage symptoms in bladder inflammation: a mouse cyclophosphamide-induced model of cystitis. PLoS One. 2014;9(8):e104216.doi:10.1371/journal.pone.0104216

39. Imamura M, Negoro H, Kanematsu A, et al. Basic fibroblast growth factor causes urinary bladder overactivity through gap junction generation in the smooth muscle. Am J Physiol Renal Physiol. 2009;297(1):F4654.doi:10.1152/ajprenal.90207.2008

40. Wang Y, Tar MT, Davies KP. Hyperglycemic memory in the rat bladder detrusor is associated with a persistent hypomethylated state. Physiol Rep. 2020;8:e14614.doi:10.14814/phy2.14614

41. Jayant RD, Sosa D, Kaushik A, et al. Current status of non-viral gene therapy for CNS disorders. Expert Opin Drug Deliv. 2016;13(10):14331445.doi:10.1080/17425247.2016.1188802

42. Chira S, Jackson CS, Oprea I, et al. Progresses towards safe and efficient gene therapy vectors. Oncotarget. 2015;6(31):3067530703.doi:10.18632/oncotarget.5169

43. Hardee CL, Arvalo-Soliz LM, Hornstein BD, Zechiedrich L. Advances in non-viral DNA vectors for gene therapy. Genes. 2017;8(2):65. doi:10.3390/genes8020065

44. Athanasopoulos T, Munye MM, Yanez-Munoz RJ. Nonintegrating gene therapy vectors. Hematol Oncol Clin North Am. 2017;31(5):753770.doi:10.1016/j.hoc.2017.06.007

45. Hagstrom JE, Hegge J, Zhang G, et al. A facile nonviral method for delivering genes and siRNAs to skeletal muscle of mammalian limbs. Mol Ther. 2004;10(2):386398. doi:10.1016/j.ymthe.2004.05.004

46. Yamada Y, Tabata M, Abe J, Nomura M, Harashima H. In vivo transgene expression in the pancreas by the intraductal injection of naked plasmid DNA. J Pharm Sci. 2018;107(2):647653.doi:10.1016/j.xphs.2017.09.021

47. Melman A, Bar-Chama N, McCullough A, Davies K, Christ G. hMaxi-K gene transfer in males with erectile dysfunction: results of the first human trial. Hum Gene Ther. 2006;17(12):11651176.doi:10.1089/hum.2006.17.1165

48. Melman A, Bar-Chama N, McCullough A, Davies K, Christ G. The first human trial for gene transfer therapy for the treatment of erectile dysfunction: preliminary results. Eur Urol. 2005;48(2):314318.doi:10.1016/j.eururo.2005.05.005

49. Christ GJ, Andersson KE, Williams K, et al. Smooth-muscle-specific gene transfer with the human maxi-K channel improves erectile function and enhances sexual behavior in atherosclerotic cynomolgus monkeys. Eur Urol. 2009;56(6):10551066.doi:10.1016/j.eururo.2008.12.016

50. Melman A, Biggs G, Davies K, Zhao W, Tar MT, Christ GJ. Gene transfer with a vector expressing Maxi-K from a smooth muscle-specific promoter restores erectile function in the aging rat. Gene Ther. 2008;15(5):364370.doi:10.1038/sj.gt.3303093

51. Melman A, Zhao W, Davies KP, Bakal R, Christ GJ. The successful long-term treatment of age related erectile dysfunction with hSlo cDNA in rats in vivo. J Urol. 2003;170(1):285290.doi:10.1097/01.ju.0000063375.12512.6e

52. Christ GJ, Day N, Santizo C, et al. Intracorporal injection of hSlo cDNA restores erectile capacity in STZ-diabetic F-344 rats in vivo. Am J Physiol Heart Circ Physiol. 2004;287(4):H15441553.doi:10.1152/ajpheart.00792.2003

53. Christ GJ, Rehman J, Day N, et al. Intracorporal injection of hSlo cDNA in rats produces physiologically relevant alterations in penile function. Am J Physiol. 1998;275(2):H600608.doi:10.1152/ajpheart.1998.275.2.H600

54. Arun N. Treatment of erectile dysfunction with hMaxi-K gene transfer: safety report from phase IIA study. Eur Urol. 2018;12(2):e1706.

55. Christ GJ, Day NS, Day M, et al. Bladder injection of naked hSlo/pcDNA3 ameliorates detrusor hyperactivity in obstructed rats in vivo. Am J Physiol Regul Integr Comp Physiol. 2001;281(5):R16991709.doi:10.1152/ajpregu.2001.281.5.R1699

56. Papagiannopoulou D, Vardouli L, Dimitriadis F, Apostolidis A. Retrograde transport of radiolabelled botulinum neurotoxin type A to the CNS after intradetrusor injection in rats. BJU Int. 2016;117(4):697704.doi:10.1111/bju.13163

57. Kruse MN, Erdman SL, Puri G, de Groat WC. Differences in Fluorogold and wheat germ agglutinin-horseradish peroxidase labelling of bladder afferent neurons. Brain Res. 1993;613(2):352356.doi:10.1016/0006-8993(93)90926-e

58. Wang X, Burke SRA, Talmadge RJ, Voss AA, Rich MM. Depressed neuromuscular transmission causes weakness in mice lacking BK potassium channels. J Gen Physiol. 2020;152(5):e201912526. doi:10.1085/jgp.201912526

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Gene therapy for overactive bladder | TCRM - Dove Medical Press

Human Behavior

China’s 2022 Olympics a chance to press Beijing on human rights -Canada – Reuters

People wearing face masks following the coronavirus disease (COVID-19) outbreak are seen near the lit-up Olympic rings at top of the Olympic Tower, a year ahead of the opening of the 2022 Winter Olympic Games, in Beijing, China February 4, 2021. REUTERS/Tingshu Wang/File Photo

Beijings hosting of the 2022 Winter Olympics offers concerned nations the chance to press China on its human rights record, Canadian Prime Minister Justin Trudeau said on Friday.

Trudeau said China would only change its behavior if faced with a united front, adding he would raise the matter at a Group of Seven leaders' summit next week.

"The pressure on China right now from the international community ... is significantly acute, particularly with the Winter Olympics coming up in China next year," Trudeau told the Toronto Star in a video interview.

"It would be easy for China ... to shrug off what any one country, including just the United States alone, says. But when the global community comes together, that starts to shape their own calculations."

Canada, locked in a major diplomatic and trade dispute with China for more than two years, is one of the world's leading winter sports nations.

Trudeau did not raise the question of athletes staying away from the Games. The Canadian Olympic Committee opposes a boycott, saying it would not force a change to Chinas human rights record.

U.S. House of Representatives Speaker Nancy Pelosi last month called for a U.S. diplomatic boycott of the Games next year, citing the State Departments conclusion that a genocide of Uyghurs and other ethnic minorities is taking place in China.

Canada's parliament passed a nonbinding motion in February saying China's treatment of the Uyghurs in the Xinjiang region constitutes genocide. read more

Our Standards: The Thomson Reuters Trust Principles.

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Human Behavior

Column: Coming together to overcome loneliness and isolation – The Salem News

Call your grandparent, visit an elderly neighbor, volunteer at your local senior center, enlist older individuals to join your workforce as expertsand -- most importantly -- dont forget how lonely, isolated and disconnected you felt this past year.

Humans crave connection. We develop from cells connected to another person. We are born into a world full of people and we thrive when we are held, touched, caressed, fed and loved. Somehow, as we grow older, our craving for connection changes. Toddlers rant and shout get away, teenagers duck the hug from a parent and adults move from hugs to handshakes. This past year has been a lesson and awakening to many about our primal need for connection.

Unforgettable may be the word to describe this pandemic year. However, as a psychologist, I understand how human behavior will propel us in another direction. We will remember the losses, the quarantineand the home schooling but time will soften the edges of those negative memories and some will fade completely as we begin to socialize, hug our friends and go back to a way of living that is happily familiar. Most individuals will move forward in their life slowly and steadily but others may struggle to do so because before the pandemic; there was already an invisible epidemic that unfortunately may continue to go unseen -- loneliness.

If you are someone who was spared from the detrimental impact of the physical and social disconnection during this past year, you are lucky. Most of us experienced some form of disconnection and felt the loss. However, many of us had resources, skills and needed technology to adapt and find a new way to connect. We started zooming dinner parties, telephoning old college friends and hosting work happy hours and virtual game nights. Some of us even podded with other individuals/families/groups to reduce some of the consequences we were experiencing from the required restrictions placed upon us. As we go back to our lives, remember that our communities are filled with people that have and will continue to suffer from the impact of physical and social disconnection.

An especially hard hit group during and before the pandemic are older adults and the elderly. Loneliness and disconnection or feelings of isolation can create a mental health crisis in individuals. Research has detailed health consequences that include premature mortality.

Lacking social connection carries a risk that is comparable, and in many cases, exceeds that of other well-accepted risk factors, including smoking up to 15 cigarettes per day, obesity, physical inactivity, and air pollution (Holt-Lunstad et al., 2010). This research article, titled, Social Relationships and Mortality Risk: A Meta-analytic Review, was published back in 2010 and indicates that social connection has a direct impact on not only mental health but also physical health.

In a more recent 2017 article, J. Lubben states, Strong social relationships are essential for a good life. The consequences of neglecting this fact become especially apparent in old age. Thus it is urgent that more attention be given to social isolation as a potent killer.

Human beings need connection for their physical and emotional well-being. We are created to connect and be connected with others. Social connection is a protective factor to cognitive decline, heart disease, depression and much more.

Social connection does not equal company. Loneliness can occur even when people are among others. You can be alone and not feel lonely and vice versa. With a growing adult population who are increasingly living alone, the risk of loneliness is growing larger and the impact to our communities greater.

A task force, Salem for all Ages, was created to support the work of the World Health Organization and AARPs sponsored campaign to combat loneliness. When the task force was first established five years ago, isolation was the top item respondents listed as an issue on a survey. In Salem, North Shore Community Health Center partnered with the Council on Aging prior to the pandemic to provide counseling to older adults. When everything shut down, individuals were reluctant to have virtual counseling. Thankfully, this has changed recently and North Shore Community Health behavioral health clinicians are using the Community Life Center to provide counseling to those 55 and older in the community.

While the pandemic has created widespread misfortune one positive outcome may be the reduction in stigma surrounding mental health as well as an increase in access to individuals needing support.

If you are one of those individuals or someonewho wants to support an older adult here are some things that can mediate the risks associated with loneliness:

Reach out and connect. This can be volunteering, working for a social cause or purpose, or joining a group that shares a like or hobby.

Check in on older adults in your community: neighbors, relatives, the person you see every week sitting alone in the coffee shop.

Furry interactions offer great benefits. Visit a dog park. If you are a relative of an older adult and have a pet, bring them along on your visit.

If you are feeling lonely or believe loneliness is impacting a loved one, reach out for help. Contact their primary care physician, their religious or spiritual leader, a counselor or other family members to make a plan and take action.

Dr. Angela Parente is a clinical psychologist and the director of behavioral health at North Shore Community Health Center. She is also the primary caretaker of her 94-yeat-old aunt who enjoys weekly visits with Chiara the cat. This column was produced in cooperation with the Salem for All Ages Task Force.

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Column: Coming together to overcome loneliness and isolation - The Salem News

Human Behavior

The Anatomy of a Great Pitch | Inc.com – Inc.com

In an elevator pitch, you have approximately 60seconds to get the recipient's attention. With an email pitch, even if you get someone to open your email, you have just 30. Here's what you need to include in those precious few seconds.

Research for attention

Attention is a scarce, expensive currency nowadays. Not everything grabs our attention anymore--what really hooks usare only those things that speak to our interest and appeal to our style/tone.

Researching what the other side thinks and likes, and how they speak, is crucial to your pitch being successful. When pitching a business, learn its pain and goals. If you're pitching a VC firm, use the same language that businesses in your niche used during a successful funding round. Above all, study the voice of the customer. It's what keeps any business running, both B2B and B2C. In the end, it's really B2P -- business to people -- and each target audience is different.

I asked Drayton Bird, former vice chairman and global creative director at Ogilvy how he successfully pitched Bentley. His response:

I worked with more than eight brands in the car business, and everyone I knew started out by selling cars. So, I just asked Bentley if the language they use when selling a car to a prospect is the same language used in the meeting with me today.

They said yes, and I suggested that's the tone we should use in your copy, and that got me the business. I won Bentley by asking a question I already knew the answer to because I've done my research.

Be clear

A clear message will always triumph over a complex pitch filled with jargon.

Skill to work on: Communication

Communication is fundamental because the next three skills will have less impact without it.Warren Buffett said it best: "If you can't communicate, it's like winking at a girl in the dark, nothing happens."

Benefits alone (emotions like relief, status, or desire) can get the job done most of the time, as people buy (and accept pitches) for two reasons: to move away from pain, or get closer to desire. As humans, we justify emotional decisions with logic, and in general, emotions are stronger than logic in behavioral economics.

Pitching a content strategy promising great writing is a feature. The same pitch focusing on promising the buyer they'll become an authority in their space is a desire-driven-benefit (status).

Focus on selling the benefits, not the features, to increase desire. Also, to increase connection between seller and buyer in your pitches, use personal language like "you" and "you're,"and avoid "I" and "we" as much as possible.

Skill to work on: Psychology

Educating yourself on human behavior, consumer psychology, and behavioral economics will maximize your ability to influence, persuade, and pitch successfully.

Here are three books that helped me:

Thinking, Fast and Slow by Daniel Kahneman

Influence by Robert Cialdini

Emotion will help drive prospects to allocate mental bandwidth into calculating the deal logically.But logic is necessary for an air-tight pitch. You sell certainty in an uncertain world. People don't necessarily accept the best pitches. They say yes to those they deem least risky.

People buy from people. You're pitching (selling) an idea, but what you're truly selling is "yourself."Even if the proposition is great, the pitch won't sell if the seller isn't trusted.To bypass the logical barrier, present a pitch with strong case studies, proven business models, and social proof like:

Celebrity endorsements

Media coverage

Loan approvals

Testimonials

LOI letters

Skill to work on: Sales

It shouldn't surprise you that the number one job billionaires and multimillionaires held before they accumulated wealth is in sales.

I've held a commission-only sales job for three years in my mid-20s, and I attest that it's the single most important skill I learned -- and it directly affected my copywriting business pitches.

Skill to work on: Negotiation

Improving this skill will make your pitches better, both verbally and in a written format. I recommend the book Getting to Yesby William Uri, and the wonderful Harvard Program On Negotiation.

Communication, sales, negotiation, and psychology are four pillars that helped me better implement attention, clarity, emotion, and logic in my pitches - landing nine-figure clients through cold emails and over Zoom. Use these tips to land your next big contract.

The opinions expressed here by Inc.com columnists are their own, not those of Inc.com.

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Human Behavior

Bad bear behavior in the Smokies is most often caused by people – WBIR.com

Despite signs reminding visitors not to feed or get close to animals, there are always those who break the rules. Experts are teaching bears to avoid humans.

GATLINBURG, Tenn. In the Great Smoky Mountains National Park, there are millions of visitors each year. Many of them are looking for a chance to see a bear, but most are oblivious to a phrase often repeated in the Smokies: "A fed bear is a dead bear."

"Bears are a novelty," wildlife technician Ryan Williamson said. "A lot of people come to this area to see bears and to view bears."

NPS said human/bear interactions typically peak around late-May or June. Despite numerous signs reminding visitors not to feed or get too close to the wildlife, there are always those who break the rules.

"It's a really simple message that people have a really hard time following," Williamson said. "They think that by feeding them or getting them close that they're doing the bear a favor... the bear usually loses when it comes to that scenario."

If people won't listen, the park hopes bears will. Wildlife experts use a variety of adverse conditioning techniques for their own safety.

"We really try to maintain that sense of fear that bears naturally have for people," Williamson said. "When bear start showing up around humans, their lifespan's cut in half."

Those techniques include shooting them with paintballs, creating loud noises and setting off firecrackers to discourage them from going too close the road or in areas that people like to congregate.

They also sweep picnic areas and campgrounds to make sure bears won't find any leftover food.

"Once a bear learns to do something one time, it learns that behavior," Williamson said. "We never want them to get that one opportunity."

Those strategies don't always work, which is why the park also uses ear tags to track the bears and their behavior.

"There's many bears in this park that have been handled almost 10 times and released on site," Williamson said. "That's just because every year or so they just need a reminder that people are bad for them."

Every year, the park anesthetizes and ear tags between 50 and 70 bears. Of those, only about 10 are relocated.

"The preference is once we handle a bear, we never want to handle that bear again," Williamson said. "We prefer them to live naturally and do what bears normally do."

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Bad bear behavior in the Smokies is most often caused by people - WBIR.com

Human Behavior

Social Anxiety and Work – Harvard Business Review

June 01, 2021

The Covid-19 pandemic changed how many of us interact and feel about people. Some of us experienced more social anxiety in the past year and may be feeling it even now, in the aftermath of the pandemic.

How do we listen to ourselves and know when to address our social anxiety, especially when it comes into play with colleagues? Host Morra Aarons-Mele speaks with Stefan Hofmann, a clinical psychologist at Boston University about social anxietys deep roots in natural human behavior and how we can address it now.

HBR Presents is a network of podcasts curated by HBR editors, bringing you the best business ideas from the leading minds in management. The views and opinions expressed are solely those of the authors and do not necessarily reflect the official policy or position of Harvard Business Review or its affiliates.

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Social Anxiety and Work - Harvard Business Review

Human Behavior

Bear Sightings In CT On The Rise: Town-By-Town Updates – Patch.com

CONNECTICUT Black bears can be found throughout the state, and their population is on the rise, according to the latest data released by the Department of Energy and Environmental Protection.

"That means there is going to be more encounters between bears and humans, and those encounters can take many forms," said DEEP wildlife biologist Paul Rego.

Those can range from spying one from a distance during a nature walk to hitting one on a highway through having one break into your home looking for breakfast.

Residents interested in minimizing the number of those last kinds of encounters would do well to stow their bird feeders, according to Rego. Not only do they attract bears, but reward them for coming close to your home. That same guidance applies to trash cans that aren't tightly covered.

It's not that the bears have become hungrier or more desperate, it's just that they have become more habituated to man-made structures and human behavior.

"Almost all of a bear's life revolves around food," Rego said. "So when they break into a home it means they have overcome any fear of humans."

On those infrequent but memorable occasions when you encounter a bear in your kitchen, Rego says the important thing to remember is to not corner it.

"Often once a bear detects a human inside the home, it will try to leave, most often through the same route that it entered." So, make sure you're not in the way.

It's less rare to find a bear along your hiking trail. Now that hiking season is in full throttle, Rego recommends you start making some noise, and maybe bring a noisy group along for the romp.

"The most dangerous thing you can do involving bears is to surprise one," the biologist said.

The second, related, rule is to keep your dog on a leash. Bears "generally have no interest in pursuing humans as meals," but they'll happily break a sweat for your off-leash dog. When your canine friend inevitably leads the bear back to you, everybody gets caught off-guard by the surprise, and nobody has a good day.

If you're camping, it's important to keep a clean campsite, and make sure the food is not available to bears. Some campgrounds provide a big metal "bear box," Rego said. Otherwise, he recommends storing the burger patties and s'mores fixings in your car.

Connecticut is currently at the height of bear activity. Late May to early July is their breeding season, and the time of year that young bears born 18 months earlier start flexing on their own. DEEP will receive relatively few reports of sightings from December to March. Outside of those times, the state is Bear World, and humans just live in it.

"They come out of winter hibernation and start getting active as early as March, and most are out of hibernation by late April, and then they're wandering around looking for food," Rego told Patch.

See Also: Bobcat Sightings In CT Rise: Town-By-Town Updates

The DEEP biologists have a good handle on our ursine neighbors' comings and goings because they have been studying their habits for decades. Each year technicians will tag the ears of the beasts with a different color code (we're currently in the "pink" season) and track the animals' migration.

The system also allows DEEP to keep an eye on the troublemakers, or as Rego more politely phrased it, "identify a bear that is involved in repeat conflicts."

Ten years ago, DEEP was able to identify a bear as one who "had taken a liking to killing goats and sheep," Rego said. Their tracking system informed the biologists that it was just one bad bear going on a tear, and not a new trend of the whole population.

If you need to protect your goats and sheep from bear clutches, Rego says electric fencing, "one with pretty good power to it," is the way to go. Anything else won't cut it.

"An 8-foot chain link fence with barbed wire stretched across the top is nothing for a bear to climb up and go over,"the wildlife expert said.

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Bear Sightings In CT On The Rise: Town-By-Town Updates - Patch.com

Human Behavior

Janie Funk | Nevada Center for Excellence in Disabilities | College of Education and Human Development – Nevada Today

Janie Funk serves as a Licensed Behavior Analyst for the Positive Behavior Support of Nevada System of Care Project.

Funk has provided behavior-analytic services in Northern Nevada since 2012.She became a Board-Certified Behavior Analyst in 2016, graduated from NvLEND in 2017, andearned her doctoral degree in 2020 from the University of Nevada, Reno. Her clinical expertise includes providing assessment, direct services, and consultation for families and caretakers of children and adults with developmental and intellectual disabilities with co-occurring mental health disorders. She also has experience with statewide program evaluation and developing behavioral services policies for state agencies.

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Janie Funk | Nevada Center for Excellence in Disabilities | College of Education and Human Development - Nevada Today