Examining Diversity in Digital Therapeutics Clinical Trials: Descriptive Analysis.

BACKGROUND: Digital therapeutics (DTx) are an emerging class of software-based medical therapies helping to improve care access and delivery. As we leverage these digital health therapies broadly in clinical care, it is important to consider sociodemographic representation underlying clinical trials data to ensure broad application to all groups. OBJECTIVE: We review current sociodemographic representation in DTx clinical trials using data from the Digital Therapeutics Alliance Product Library database. METHODS: We conducted a descriptive analysis of DTx products. We analyzed 15 manuscripts associated with 13 DTx products. Sociodemographic information was retrieved and compared with the US population's demographic distribution. RESULTS: The median study size and age of participants were 252 and 43.3 years, respectively. Of the 15 studies applicable to this study, 10 (67%) reported that females made up 65% or greater of the study cohort. A total of 14 studies reported race data with Black or African American and Asian American individuals underrepresented in 9 and 11 studies, respectively. In 7 studies that reported ethnicity, Hispanics were underrepresented in all 7 studies. Furthermore, 8 studies reported education levels, with 5 studies reporting populations in which 70% or greater had at least some college education. Only 3 studies reported health insurance information, each reporting a study cohort in which 100% of members were privately insured. CONCLUSIONS: Our findings indicate opportunities for improved sociodemographic representation in DTx clinical trials, especially for underserved populations typically underrepresented in clinical trials. This review is a step in examining sociodemographic representation in DTx clinical trials to help inform the path forward for DTx development and testing.

Return to Sport After Operative Fixation of Midshaft Clavicle Fractures in Professional Jockeys.

OBJECTIVE: Clavicle fractures are the most commonly observed fracture sustained in professional horse racing. This study is the first to report on time lost from injury and functional recovery after surgical fixation of midshaft clavicle fractures in professional jockeys. DESIGN: Retrospective cohort study. SETTING: Professional Horse Racing Ireland; Patients (or Participants): Professional Jockeys in Ireland with midshaft clavicular fractures managed with Open Reduction Internal Fixation. Interventions (or Assessment of Risk Factors or Independent Variables): Operative fixation with Open Reduction Internal Fixation. MAIN OUTCOME MEASURES: Assessment of postoperative Quick Disabilities of Arm Shoulder and Hand (QuickDASH) score and Patient Reported Outcome Measures assessing for associated complications and time to return to competition among professional athletes. RESULTS: Between 07/06/2013 and 29/09/2022, 22 patients met the predetermined inclusion criteria. Ninety-five percent of patients returned to competition at their preinjury level, one patient failed to return to competition for reasons unrelated to his injury. The mean time for return to competition was 68.14 days postinjury. Few complications were reported, whereas functional recovery was excellent across the cohort, with an average QuickDASH score of 0.85 (0.0-2.3). CONCLUSIONS: Plate fixation of midshaft clavicle fractures is effective and safe in the setting of professional horse racing. Ninety-five percent of patients can be expected to return within 14 weeks of injury. Patients returning at less than 7 weeks after injury had no adverse outcomes, suggesting a potential role for more aggressive rehabilitation postoperatively and ultimately, a quicker return to competition.

A comparison of the effects of resistant starch types on glycemic response in individuals with type 2 diabetes or prediabetes: A systematic review and meta-analysis.

Background: Type 2 diabetes (T2D) diagnoses are predicted to reach 643 million by 2030, increasing incidences of cardiovascular disease and other comorbidities. Rapidly digestible starch elevates postprandial glycemia and impinges glycemic homeostasis, elevating the risk of developing T2D. Starch can escape digestion by endogenous enzymes in the small intestine when protected by intact plant cell walls (resistant starch type 1), when there is a high concentration of amylose (resistant starch type 2) and when the molecule undergoes retrogradation (resistant starch type 3) or chemical modification (resistant starch type 4). Dietary interventions using resistant starch may improve glucose metabolism and insulin sensitivity. However, few studies have explored the differential effects of resistant starch type. This systematic review and meta-analysis aims to compare the effects of the resistant starch from intact plant cell structures (resistant starch type 1) and resistant starch from modified starch molecules (resistant starch types 2-5) on fasting and postprandial glycemia in subjects with T2D and prediabetes. Methods: Databases (PubMed, SCOPUS, Ovid MEDLINE, Cochrane, and Web of Science) were systematically searched for randomized controlled trials. Standard mean difference (SMD) with 95% confidence intervals (CI) were determined using random-effects models. Sub-group analyses were conducted between subjects with T2D versus prediabetes and types of resistant starch. Results: The search identified 36 randomized controlled trials (n = 982), 31 of which could be included in the meta-analysis. Resistant starch type 1 and type 2 lowered acute postprandial blood glucose [SMD (95% CI) = -0.54 (-1.0, -0.07)] and [-0.96 (-1.61, -0.31)]. Resistant starch type 2 improved acute postprandial insulin response [-0.71 (-1.31, -0.11)]. In chronic studies, resistant starch type 1 and 2 lowered postprandial glucose [-0.38 (-0.73, -0.02), -0.29 (-0.53, -0.04), respectively] and resistant starch type 2 intake improved fasting glucose [-0.39 (-0.66, -0.13)] and insulin [-0.40 (-0.60, -0.21)]. Conclusion: Resistant starch types 1 and 2 may influence glucose homeostasis via discrete mechanisms, as they appear to influence glycemia differently. Further research into resistant starch types 3, 4, and 5 is required to elucidate their effect on glucose metabolism. The addition of resistant starch as a dietary intervention for those with T2D or prediabetes may prevent further deterioration of glycemic control.

The effects of SCFAs on glycemic control in humans: a systematic review and meta-analysis.

BACKGROUND: Noncommunicable disease development is related to impairments in glycemic and insulinemic responses, which can be modulated by fiber intake. Fiber's beneficial effects upon metabolic health can be partially attributed to the production of SCFAs via microbial fermentation of fiber in the gastrointestinal tract. OBJECTIVES: We aimed to determine the effects of SCFAs, acetate, propionate, and butyrate on glycemic control in humans. METHODS: The CENTRAL, Embase, PubMed, Scopus, and Web of Science databases were searched from inception to 7 December 2021. Papers were included if they reported a randomized controlled trial measuring glucose and/or insulin compared to a placebo in adults. Studies were categorized by the type of SCFA and intervention duration. Random-effects meta-analyses were performed for glucose and insulin for those subject categories with ≥3 studies, or a narrative review was performed. RESULTS: We identified 43 eligible papers, with 46 studies within those records (n = 913), and 44 studies were included in the meta-analysis. Vinegar intake decreased the acute glucose response [standard mean difference (SMD), -0.53; 95% CI, -0.92 to -0.14; n = 67] in individuals with impaired glucose tolerance or type 2 diabetes and in healthy volunteers (SMD, -0.27; 95% CI, -0.54 to 0.00; n = 186). The meta-analyses for acute acetate, as well as acute and chronic propionate studies, showed no significant effect. CONCLUSIONS: Vinegar decreased the glucose response acutely in healthy and metabolically unhealthy individuals. Acetate, propionate, butyrate, and mixed SCFAs had no effect on blood glucose and insulin in humans. Significant heterogeneity, risks of bias, and publication biases were identified in several study categories, including the acute vinegar glucose response. As evidence was very uncertain, caution is urged when interpreting these results. Further high-quality research is required to determine the effects of SCFAs on glycemic control.

Body Composition and Bone Health Status of Jockeys: Current Findings, Assessment Methods and Classification Criteria.

Jockeys are unlike other weight-making athletes as the sport of horse racing requires strict weight management to meet the racing stipulations, protracted working hours and an extended racing season with limited downtime. Several studies have reported on the body composition and bone status of male and female professional and retired jockeys, yet the variety of assessment techniques, lack of standardised testing protocols and classification inconsistency make interpretation and comparison between studies problematic. This review aimed to appraise the existing body composition and bone health evidence in jockeys and evaluate the assessment methods and classification criteria used. Dual-energy X-ray absorptiometry (DXA) has been used most frequently in jockey research to assess body composition and bone status, while various generic skinfold equations have been used to predict body fat percentage. Evidence indicates flat jockeys are now taller and heavier than the data reported in earlier studies. Absolute fat mass has steadily increased in male jockeys in the last decade. The bone status of male jockeys remains a concern as constant low bone density (BMD) is evident in a large percentage of young and experienced professional jockeys. Due to limited studies and variations in assessment methods, further research is required to investigate bone turnover markers in male and female jockeys. A standardised testing protocol using internationally recognised assessment guidelines is critical for the accurate interpretation and evaluation of body composition and bone health measurements. Furthermore, establishing jockey-specific BMD and bone turnover reference ranges should be considered using existing and future data.

Physical and Lifestyle Factors Influencing Bone Density in Jockeys: A Comprehensive Update of the Bone Density Status of Irish Jockeys.

Compromised bone density in jockeys has previously been identified as an important health and safety concern in horseracing. Despite this, no update on the bone density status in Irish jockeys has been provided in the past decade. The study aimed to conduct a comprehensive update of the current bone density status in professional Irish jockeys and identify possible contributory physical and lifestyle factors. Eighty-five professional male jockeys (flat n = 39; national hunt (NH) n = 46) completed a dual-energy X-ray absorptiometry (DXA) scan for the assessment of body composition and bone mineral density (BMD) at the lumbar spine (LS), femoral neck (FN) and hip, 24-hour food recall, bone-specific physical activity questionnaire (BPAQ) and lifestyle questionnaire on weight making practices and injury history. Z-scores were interpreted to assess current bone density status. Correlation analysis was used to identify physical and lifestyle factors associated with bone mineral apparent density (BMAD). Results revealed a high prevalence of low BMD (Z-score < - 1.0) at the LS (44%), FN (15%) and hip (29%) in Irish jockeys. Analysis of jockeys physical characteristics found a positive relationship with the LS but not FN BMAD. Riding experience and timing of weight cut in NH and the practice of cutting weight in flat jockeys negatively influenced BMAD sites, while supplement use in flat jockeys displayed a positive effect on LS BMAD. Findings indicate the need for targeted individualised support strategies. Further investigation is required into jockey-specific intervention strategies that promote the development of optimal bone health in professional jockeys.

Mental health difficulties among professional jockeys: a narrative review.

INTRODUCTION: Emerging academic literature and high-profile disclosures of mental health difficulties and mental illness from current and former professional jockeys suggest that further exploration of the mental health of jockeys is required. To date, a comprehensive review of jockeys' mental health has yet to be conducted. OBJECTIVES: To examine the existing literature related to jockeys' mental health, including the prevalence of symptoms associated with mental health difficulties and help-seeking. DESIGN: A narrative review of the literature was conducted with articles screened from inception until January 2021. RESULTS: Sixteen studies were included in the narrative review. Studies covered a range of mental health difficulties which included mood (depression), anxiety, distress, disordered eating and substance misuse. Rates of help-seeking among jockeys were also explored. Results indicated that jockeys reported higher levels of depressive and anxiety symptoms compared with other elite athletes. Substance misuse, in particular adverse alcohol use, also appears greater among jockeys than other elite athletes. Distress symptoms appear comparable with other elite athletes. Risk factors for mental health difficulties included injury, perceived stress, athlete burnout, career dissatisfaction and the contemplation of retirement. Weight-making negatively impacts jockeys' mood and attitudes towards eating, with lower competitive riding weights associated with more disordered eating attitudes. Moreover, help-seeking from mental health professionals appears low. CONCLUSION: The review identifies a high prevalence of symptoms of mental health difficulties among professional jockeys. Applied recommendations and future research considerations are proposed throughout the review article.

The impact of starchy food structure on postprandial glycemic response and appetite: a systematic review with meta-analysis of randomized crossover trials.

BACKGROUND: Starchy foods can have a profound effect on metabolism. The structural properties of starchy foods can affect their digestibility and postprandial metabolic responses, which in the long term may be associated with the risk of type 2 diabetes and obesity. OBJECTIVES: This systematic review sought to evaluate the clinical evidence regarding the impact of the microstructures within starchy foods on postprandial glucose and insulin responses alongside appetite regulation. METHODS: A systematic search was performed in the PUBMED, Ovid Medicine, EMBASE, and Google Scholar databases for data published up to 18 January 2021. Data were extracted by 3 independent reviewers from randomized crossover trials (RCTs) that investigated the effect of microstructural factors on postprandial glucose, insulin, appetite-regulating hormone responses, and subjective satiety scores in healthy participants. RESULTS: We identified 745 potential articles, and 25 RCTs (n = 369 participants) met our inclusion criteria: 6 evaluated the amylose-to-amylopectin ratio, 6 evaluated the degree of starch gelatinization, 2 evaluated the degree of starch retrogradation, 1 studied starch-protein interactions, and 12 investigated cell and tissue structures. Meta-analyses showed that significant reductions in postprandial glucose and insulin levels was caused by starch with a high amylose content [standardized mean difference (SMD) = -0.64 mmol/L*min (95% CI: -0.83 to -0.46) and SMD = -0.81 pmol/L*min (95% CI: -1.07 to -0.55), respectively], less-gelatinized starch [SMD = -0.54 mmol/L*min (95% CI: -0.75 to -0.34) and SMD = -0.48 pmol/L*min (95% CI: -0.75 to -0.21), respectively], retrograded starch (for glucose incremental AUC; SMD = -0.46 pmol/L*min; 95% CI: -0.80 to -0.12), and intact and large particles [SMD = -0.43 mmol/L*min (95% CI: -0.58 to -0.28) and SMD = -0.63 pmol/L*min (95% CI: -0.86 to -0.40), respectively]. All analyses showed minor or moderate heterogeneity (I2 < 50%). Sufficient evidence was not found to suggest how these structural factors influence appetite. CONCLUSIONS: The manipulation of microstructures in starchy food may be an effective way to improve postprandial glycemia and insulinemia in the healthy population. The protocol for this systematic review and meta-analysis was registered in the international prospective register of systematic reviews (PROSPERO) as CRD42020190873.

Racehorse Trainer Mental Health: Prevalence and Risk Factors.

Racehorse trainers play an important role within the horseracing industry. Despite this, scarce empirical information exists regarding the mental health of this population. Thus, the purpose of the present study was to explore the prevalence of symptoms related to common mental disorders (CMDs) and their associations with specific risk factors for CMD. Participants completed an anonymous online questionnaire. CMDs were assessed including distress, depression, generalized anxiety and adverse alcohol use. The risk factors examined included career dissatisfaction, social support and financial difficulties. 124 participants (28% response rate) completed the questionnaire. In total, 45% met the threshold indicative of at least one CMD. Specifically, prevalence of symptoms associated with depression (41%), adverse alcohol use (38%), psychological distress (26%), and generalized anxiety (18%) was observed. Career dissatisfaction (28%) and financial difficulties (64%) were identified. Career dissatisfaction, lower levels of social support and financial difficulties all increased the likelihood of trainers meeting the criteria for at least one of distress, depression or generalized anxiety. The study was the first to highlight prevalence rates of symptoms associated with CMDs among racehorse trainers in Ireland and identify certain risk factors which may increase the likelihood of racehorse trainers meeting the criteria for a CMD. Assessment of risk factors can aid early identification of CMDs among racehorse trainers. Such benefits may include early diagnosis or signposting to professional support. Further research is required in examining other occupational stressors experienced by trainers and the impact these may have on symptoms of CMDs.

Skin tapes and tissue adhesive vs. either method alone for laceration repair in a porcine model.

STUDY OBJECTIVE: To determine whether the combination of skin tapes and tissue adhesive is superior to either method alone for laceration repair. METHODS: This was a prospective, longitudinal experiment on six anesthetized swine. Thirty-six full-thickness linear wounds were created using a metal template, then closed using one of three methods: skin tapes over benzoin, tissue adhesive, or a combination of both. The study was done in two parts. Group 1 (immediate excision) animals were euthanized at day zero for skin excision and tensile strength testing following wound repair. Group 2 (delayed excision) had initial wound repair; animals were euthanized at day 35 for skin excision and tensile strength testing. RESULTS: In Group 1, the combination of skin tapes and tissue adhesive provided the strongest immediate wound closure. Average mean force for disruption immediately after wound repair was 19.9 lbs. for the tapes and tissue adhesive group compared to 9.6 lbs. for adhesive alone and 8.9 lbs. for tapes alone. The difference in mean force for combination repair vs. tapes alone was 10.3 lbs. (95% CI 4.1, 16.7), and combination vs. adhesive alone was 10.9 lbs. (95% CI 4.7, 17.3). In Group 2, the mean force required for laceration disruption for those repaired with both tape and tissue adhesive was 188.9 lbs. The mean force until wound disruption for tape only was 165.6 lbs., and the mean force until wound disruption for tissue adhesive alone was 118.9 lbs. The difference in mean force required for wound disruption for those repaired with adhesive alone vs. combination repair is 66.5 lbs. (95% CI 21.2, 111.9). The difference in mean force required for wound disruption between the other two groups was not statistically significant. CONCLUSIONS: This study demonstrates that the combination of skin tapes and tissue adhesive provides superior immediate wound closure strength to either of these methods alone in a porcine model.

Injuries outside of horseracing: is it time to focus on injury prevention of jockeys outside of races?

Objectives: Falls and injuries are frequent in professional horseracing. However, professional jockeys spend a large part of their week in horse-related activities outside of racing such as schooling, exercise riding, and yard-related activities. The injury risk related to these activities remains largely unknown internationally. This study aimed to identify the injury prevalence and injury profile of flat and jump jockeys during non-racing activities. Methods: In total 45.6% and 38.5% of all licensed Irish professional flat and jump jockeys completed a cross-sectional self-recall questionnaire examining injuries that occurred outside of racing during 2018. Injury proportion, repeat incidence proportion, and descriptive statistics were calculated. Results: Fifteen percent of professional jockeys sustained an injury outside of a race, half of those injured receiving at least another injury in 2018 and 66.52 injuries per 1,000 falls were noted. Injuries frequently occurred to the upper limb (36.67%), with fractures common (32.00%). Most injuries occurred due to a fall (60.00%) and 77.27% occurred in the gallops. Half of injuries resulted in the jockey missing racing, with 31.00 ± 47.18 (4-180) days lost on average. Twenty-three percent of jockeys attended hospital and 16.67% required surgery due to injury. Interestingly, just under a third did not report their injury to anyone. Conclusion: Injuries to professional jockeys, whilst not as frequent outside of racing, tend to be serious and can affect jockeys financially and impact their availability to ride. Prioritizing injury prevention strategies to maximize availability of jockeys to race is important. Education on the importance of reporting all injuries regardless of where they occur is important to ensure their management and rehabilitation.

Physiological Demands of Professional Flat and Jump Horse Racing.

Kiely, M, Warrington, GD, McGoldrick, A, Pugh, J, and Cullen, S. Physiological demands of professional flat and jump horse racing. J Strength Cond Res 34(8): 2173-2177, 2020-No information is currently available on the effect of race distance on the physiological demands of jockeys. This study aimed to quantify the respective demands of short and long flat and jump race distances. Twenty professional jockeys (10 flat and 10 jump) participated in the study. The subjects initially performed a graded incremental exercise test to volitional exhaustion on a treadmill to determine the peak heart rate (HR) and blood lactate concentrations. Two competitive races (short and long) were then monitored on 2 separate occasions for each jockey type to obtain hydration, HR, blood lactate concentration, and rating of perceived exertion data. Mean distances for the 4 races were: 1,247.2 ± 184.7 m (short flat race), 2,313.4 ± 142.2 m (long flat race), 3,480.2 ± 355.3 m (short jump race), and 4,546.4 ± 194.3 m (long jump race). The mean HR for the long flat race was 151 ± 19 b·min (79 ± 11% of HRpeak), which was significantly lower than all other race distances (p = 0.000, effect size [ES] = 0.469). A longer jump race resulted in a significantly higher reported rate of perceived exertion (RPE) (14 ± 2.8) than the short jump race (11.0 ± 1.5) (p = 0.009, ES = 0.271), whereas no significant difference was revealed between peak HR responses or blood lactate concentrations when comparing other race distances (p < 0.05). The finding of this study supports previous limited research, which suggests that horse racing is a high-intensity sport, whereas RPE and mean HR fluctuate according to the race distance.

Calcineurin inhibitor (CNI)-associated skin cancers: New insights on exploring mechanisms by which CNIs downregulate DNA repair machinery.

The use of the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus remains a cornerstone in post-transplantation immunosuppression. Although these immunosuppressive agents have revolutionized the field of transplantation medicine, its increased skin cancer risk poses a major concern. A key contributor to this phenomenon is a reduced capacity to repair DNA damage caused by exposure to ultraviolet (UV) wavelengths of sunlight. CNIs decrease DNA repair by mechanisms that remain to be fully explored. Though CsA is known to decrease the abundance of key DNA repair enzymes, less is known about how tacrolimus yields this effect. CNIs hold the capacity to inhibit both of the main catalytic calcineurin isoforms (CnAα and CnAß). However, it is unknown which isoform regulates UV-induced DNA repair, which is the focus of this review. It is with hope that this insight spurs investigative efforts that conclusively addresses these gaps in knowledge. Additionally, this research also raises the possibility that newer CNIs can be developed that effectively blunt the immune response while mitigating the incidence of skin cancers with immunosuppression.

Estimation of Body Fat Percentage in Jockeys: Implications for a Weight Category Sport.

The assessment of body composition in horse racing, a unique weight-restricted sport, provides an important health and performance indicator. The accuracy of skinfold prediction equations at estimating % body fat (% BF) was compared with dual-energy X-ray absorptiometry (DXA) data in a group of professional Irish jockeys (age 27.5 ± 7.7 years). Body composition was assessed in seventy-two male professional jockeys (flat n=35 and national hunt n=37) using standardised guidelines for skinfold thickness at 8 sites and DXA body fat assessment. Hydration status was assessed using urine specific gravity (Usg) to determine if participants were euhydrated and male specific prediction equations (Durnin and Womersley, Evans, Lohman, Reilly, Withers and Zemski) were selected to estimate % BF. Jockey-group specific equations were developed using the collected dataset. The selected equations underestimated % BF with variability between equations ranging from 7% to 10% compared to the DXA % BF of 15%. Flat jockeys were significantly lighter and shorter (p < 0.05) compared to national hunt jockeys resulting in the need for individual jockey-specific equations. The Flat and National Hunt Jockey specific equations demonstrated overall agreement accounting for 84% and 83% variance, respectively. Caution must be taken when using existing prediction equations due to the variability of % BF relative to DXA. Jockey-specific equations offer an alternative method for interpreting estimated body fat %.

Concussion Guidelines in National and International Professional and Elite Sports.

The Berlin statement on sport-related concussion was published in 2017 using evidence-based recommendations. We aimed to examine (1) the implementation of, distribution and education based on the Berlin recommendations, and the development of sport-specific protocols/guidelines among professional and elite sports, (2) the implementation of guidelines at the community level, (3) translation of guidelines into different languages, and (4) research activities. Senior medical advisers and chief medical officers from Australian Football League, All Japan Judo Federation, British Horseracing Authority, Cricket Australia, Fédération Equestre Internationale, Football Association, Gaelic Athletic Association, International Boxing Association, Irish Horseracing Regulatory Board, Major League Baseball, National Football League, National Hockey League, National Rugby League, and World Rugby completed a questionnaire. The results demonstrated that all 14 sporting organizations have published concussion protocols/guidelines based on the Berlin recommendations, including Recognize, Removal from play, Re-evaluation, Rest, Recovery, and Return to play. There is variable inclusion of Prolonged symptoms. Prevention and Risk reduction and Long-term effects are addressed in the guidelines, rules and regulations, and/or sport-specific research. There is variability in education programs, monitoring compliance with guidelines, and publication in other languages. All sporting bodies are actively involved in concussion research. We conclude that the Berlin recommendations have been included in concussion protocols/guidelines by all the sporting bodies, with consistency in the essential components of the recommendations, whilst also allowing for sport- and regional-specific variations. Education at the elite, community, and junior levels remains an ongoing challenge, and future iterations of guidelines may consider multiple language versions, and community- and junior-level guidelines.

Use of Big Data to Estimate Prevalence of Defective DNA Repair Variants in the US Population.

Importance: Wide use of genomic sequencing to diagnose disease has raised concern about the extent of genotype-phenotype correlations. Objective: To correlate disease-associated allele frequencies with expected and reported prevalence of clinical disease. Design, Setting, and Participants: Xeroderma pigmentosum (XP), a recessive, cancer-prone, neurocutaneous disorder, was used as a model for this study. From January 1, 2017, to May 4, 2018, the Human Gene Mutation Database and a cohort of patients at the National Institutes of Health were searched and screened to identify reported mutations associated with XP. The clinical phenotype of these patients was confirmed from reports in the literature and National Institutes of Health medical records. The genetically predicted prevalence of disease based on frequency of known pathogenic mutations was compared with the prevalence of patients clinically diagnosed with phenotypic XP. Exome sequencing of more than 200 000 alleles from the Genome Aggregation Database, the National Cancer Institute Division of Cancer Epidemiology and Genetics database of healthy controls, and an Inova Hospital Study database was used to investigate the frequencies of these mutations in the general population. Main Outcomes and Measures: Listing of all reported mutations associated with XP, their frequencies in 3 large exome sequence databases, determination of the number of patients in the United States with XP using modeling equations, and comparison of the observed and reported numbers of patients with XP with specific mutations. Results: A total of 156 pathogenic missense and nonsense mutations associated with XP were identified in the National Institutes of Health cohort and the Human Gene Mutation Database. The Genome Aggregation Database provided frequency data for 65 of these mutations, with a total allele frequency of 1.13%. The XPF (ERCC4) mutation, p.P379S, had an allele frequency of 0.4%, and the XPC mutation, p.P334H, had an allele frequency of 0.3%. With the Hardy-Weinberg equation, it was determined that there should be more than 8000 patients who are homozygous for these mutations in the United States. In contrast, only 3 patients with XP were reported as having the XPF mutation, and 1 patient was reported as having the XPC mutation. Conclusions and Relevance: The findings from this study suggest that clinicians should approach large genomic databases with caution when trying to correlate the clinical implications of genetic variants with the prevalence of disease risk. Unsuspected mutations in known genes with a predisposition for skin cancer may be responsible for some of the high frequency of skin cancers in the general population.

Longevity and Patau syndrome: what determines survival?

The authors report of an 8-year-old girl with non-mosaic Patau syndrome. The median life expectancy of Patau syndrome is 7-10 days, and 90% die in the first year of life. Survival is often attributed to mosaicism and the severity of associated malformations. We delineate the developing phenotype and review the literature discussing potential contributory factors to longevity.