Determining Structurally Identifiable Parameter Combinations Using Subset Profiling

Identifiability is a necessary condition for successful parameter estimation of dynamic system models. A major component of identifiability analysis is determining the identifiable parameter combinations, the functional forms for the dependencies between unidentifiable parameters. Identifiable combinations can help in model reparameterization and also in determining which parameters may be experimentally measured to recover model identifiability. Several numerical approaches to determining identifiability of differential equation models have been developed, however the question of determining identifiable combinations remains incompletely addressed. In this paper, we present a new approach which uses parameter subset selection methods based on the Fisher Information Matrix, together with the profile likelihood, to effectively estimate identifiable combinations. We demonstrate this approach on several example models in pharmacokinetics, cellular biology, and physiology

The Association Between Pelvic Discomfort and Erectile Dysfunction in Adult Male Bicyclists.

BackgroundBicycle riding's impact on erectile function remains a topic of great interest given cycling's popularity as a mode of transportation and exercise.AimWe evaluated risk factors for sexual dysfunction in male cyclists with the primary intention of determining if genital/pelvic pain and numbness are associated with erectile dysfunction (ED).MethodsWe surveyed male cyclists using an online anonymous questionnaire. Cyclists were queried on their demographics, cycling experience, and sexual function using the Sexual Health Inventory for Men (SHIM). ED was diagnosed when a completed SHIM score was <22. Regression analysis was used to evaluate the risk of ED in men with genital/pelvic pain or numbness after riding. The survey was designed in the United States.OutcomesQuantitative characterization of cycling habits, onset and timing of genital pain and numbness, and SHIM score.ResultsA total of 1635 participants completed the survey. A majority of men were over the age of 50 (58%, 934/1,607), Caucasian (88%, 1,437/1,635), had been active cyclists for over 10 years (63%, 1,025/1,635) and used road bikes (97%, 1,578/1,635). Overall, 22%, 30%, and 57% of men reported ED, genital pain, and genital numbness, respectively. While controlling for cohort demographics, body mass index, cycling intensity and equipment, and medical comorbidities, no saddle characteristics were associated with the risk of developing genital numbness. However, men reporting penile numbness were at higher risk of reporting ED (odds ratio [OR] = 1.453, P = .048). In addition, quicker onset of numbness and resolution of numbness within a day was associated with impaired erectile function. For example, numbness occurring less than 1 hour after cycling had greater odds of leading to ED than numbness after 5 hours (OR = 2.002, P = .032). Similarly, genital pain occurring less than 1 hour (OR = 2.466, P = .031) after cycling was associated with higher ED risk.Strengths & limitationsStrengths include a large sample size of high-intensity cyclists and validated questionnaire use. Limitations include reliance on anonymous self-reported survey data and minimal inquiry into the riding preferences and terrain traversed by cyclists.ConclusionsPelvic pain and numbness are common complaints among male riders in the United States. Men with such complaints are more likely to also report ED especially if it occurs earlier in the ride. Although direction of causality and temporality are uncertain, alleviation of factors resulting in pelvic discomfort may reduce cycling's impact on sexual function. Such interventions are critical given that cycling for both active travel and aerobic exercise confers numerous health benefits. Balasubramanian A, Yu J, Breyer BN, et al. The Association Between Pelvic Discomfort and Erectile Dysfunction in Adult Male Bicyclists. J Sex Med 2020;17:919-929

Linking Decision Theory and Quantitative Microbial Risk Assessment: Tradeoffs Between Compliance and Efficacy for Waterborne Disease Interventions

Achieving health gains from the U.N. Sustainable Development Goals of universal coverage for water and sanitation will require interventions that can be widely adopted and maintained. Effectiveness—how an intervention performs based on actual use—as opposed to efficacy will therefore be central to evaluations of new and existing interventions. Incomplete compliance—when people do not always use the intervention and are therefore exposed to contamination—is thought to be responsible for the lower‐than‐expected risk reductions observed from water, sanitation, and hygiene interventions based on their efficacy at removing pathogens. We explicitly incorporated decision theory into a quantitative microbial risk assessment model. Specifically, we assume that the usability of household water treatment (HWT) devices (filters and chlorine) decreases as they become more efficacious due to issues such as taste or flow rates. Simulations were run to examine the tradeoff between device efficacy and usability. For most situations, HWT interventions that trade lower efficacy (i.e., remove less pathogens) for higher compliance (i.e., better usability) contribute substantial reductions in diarrheal disease risk compared to devices meeting current World Health Organization efficacy guidelines. Recommendations that take into account both the behavioral and microbiological properties of treatment devices are likely to be more effective at reducing the burden of diarrheal disease than current standards that only consider efficacy.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151809/1/risa13381.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151809/2/risa13381-sup-0001-Appendix.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151809/3/risa13381_am.pd

The Decision to Award Punitive Damages: An Empirical Study

Empirical studies have consistently shown that punitive damages are rarely awarded, with rates of about 3 to 5 percent of plaintiff trial wins. Using the 2005 data from the Bureau of Justice Statistics Civil Justice Survey, this article shows that knowing in which cases plaintiffs sought punitive damages transforms the picture of punitive damages. Not accounting for whether punitive damages were sought obscures the meaningful punitive damages rate, the rate of awards in cases in which they were sought, by a factor of nearly 10, and obfuscates a more explicable pattern of awards than has been reported. Punitive damages were surprisingly infrequently sought, with requests found in about 10 percent of tried cases that plaintiffs won. State laws restricting access to punitive damages were significantly associated with rates of seeking punitive damages. Punitive damages were awarded in about 30 percent of the plaintiff trial wins in which they were sought. Awards were most frequent in cases of intentional tort, with a punitive award rate of over 60 percent. Greater harm corresponded to a greater probability of an award: the size of the compensatory award was significantly associated with whether punitive damages were awarded, with a rate of approximately 60 percent for cases with compensatory awards of $1 million or more. Regression models correctly classify about 70 percent or more of the punitive award request outcomes. Judge-jury differences in the rate of awards exist, with judges awarding punitive damages at a higher rate in personal injury cases and juries awarding them at a higher rate in nonpersonal injury cases. These puzzling adjudicator differences may be a consequence of the routing of different cases to judges and juries

Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain.

Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation of amyloid fibrils in patients' tissues. Excess light chains are in equilibrium between dimers and less stable monomers which can undergo irreversible aggregation to the amyloid state. The dimers therefore must disassociate into monomers prior to forming amyloid fibrils. Here we identify ligands that inhibit amyloid formation by stabilizing the Mcg light chain variable domain dimer and shifting the equilibrium away from the amyloid-prone monomer

Genital Pain and Numbness and Female Sexual Dysfunction in Adult Bicyclists.

IntroductionBicycle seat pressure on the perineum may impair arousal and clitoral erection, likely contributing to genital pain and numbness experienced by female cyclists.AimWe aimed to identify the association between genital pain and numbness experienced by female cyclists and female sexual dysfunction (FSD).MethodsFemale cyclists were recruited to complete an online survey using the Female Sexual Function Index (FSFI), a validated questionnaire to assess FSD. Cyclist demographics, experience, preferred riding style, use of ergonomic cycle modifications, and genital discomfort while riding were also queried. Multivariate logistic regression analysis was used to evaluate risk factors of FSD.Main outcome measuresThe main outcome was FSFI score, which is used to diagnose FSD when the FSFI score is <26.55.ResultsOf the survey respondents, 178 (53.1%) completed the survey and FSFI questionnaire. Mean age was 48.1 years (±0.8 standard error [SE]), and the average riding experience was 17.1 years (±0.9 SE). Overall, 53.9% of female cyclists had FSD, 58.1% reported genital numbness, and 69.1% reported genital pain. After adjusting for age, body mass index, relationship status, smoking history, comorbidities, and average time spent cycling per week, females who reported experiencing genital numbness half the time or more were more likely to have FSD (adjusted odds ratio [aOR], 6.0; 95% CI, 1.5-23.6; P = .01), especially if localized to the clitoris (aOR, 2.5; 95% CI, 1.2-5.5; P = .02). Females that reported genital pain half the time or more while cycling also were more likely to have FSD (aOR, 3.6; 95% CI, 1.2-11.1; P = .02). Cyclists experiencing genital pain within the first hour of their ride were more likely to have FSD (aOR, 12.6; 95% CI, 2.5-63.1; P = .002). Frequency and duration of cycling were not associated with FSD. Analysis of FSFI domains found that the frequency of numbness was correlated with decreased arousal, orgasm, and satisfaction during intercourse, whereas the frequency of pain significantly reduced arousal, orgasm, and genital lubrication.Clinical implicationsFemale cyclists that experience numbness and/or pain have higher odds of reporting FSD.Strengths & limitationsOur study includes a validated questionnaire to assess FSD and queries specific characteristics and symptoms of genital pain and genital numbness; however, the study is limited by its cross-sectional survey design.ConclusionThis study highlights the need for cyclists to address genital pain and numbness experienced while cycling, and future studies are required to determine if alleviating these symptoms can reduce the impact of cycling on female sexual function. Greenberg GR, Khandwala YS, Breyer BN, et al. Genital Pain and Numbness and Female Sexual Dysfunction in Adult Bicyclists. J Sex Med 2019; 16:1381-1389

Informing Policy: Mapping Information Literacy Research to Education Policy

Information literacy, defined as the skills and stages of successful information problem-solving, is often cited as a goal of education efforts at every level, pre-kindergarten through higher education. For these efforts to be effective, they must be guided by empirical research on information literacy. This study sought to determine the extent to which evidence of how students develop information literacy skills gleaned from empirical research is explicitly represented in a high-profile education policy initiative, the Common Core State Standards. Results reveal that not all stages of the information problem-solving process are represented in these standards, and that the crucial stage of Task Definition is not explicitly represented at all. Implications and directions for future research are presented.publishedye

Judges, Juries, and Punitive Damages: Empirical Analyses Using the Civil Justice Survey of State Courts 1992, 1996, and 2001 Data

We analyze thousands of trials from a substantial fraction of the nation\u27s most populous counties. Evidence across ten years and three major datasets suggests that: (1) juries and judges award punitive damages in approximately the same ratio to compensatory damages, (2) the level of punitive damages awards has not increased, and (3) juries\u27 and judges\u27 tendencies to award punitive damages differ in bodily injury and no-bodily-injury cases. Jury trials are associated with a greater rate of punitive damages awards in financial injury cases. Judge trials are associated with a greater rate of punitive damages awards in bodily injury cases

Structure-based inhibitors of amyloid beta core suggest a common interface with tau.

Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline