Application of Community Detection Methods to Identify Emergency General Surgery-Specific Regional Networks.

Importance: There is growing interest in developing coordinated regional systems for nontraumatic surgical emergencies; however, our understanding of existing emergency general surgery (EGS) care communities is limited. Objective: To apply network analysis methods to delineate EGS care regions and compare the performance of this method with the Dartmouth Health Referral Regions (HRRs). Design, Setting, and Participants: This cross-sectional study was conducted using the 2019 California and New York state emergency department and inpatient databases. Eligible participants included all adult patients with a nonelective admission for common EGS conditions. Interhospital transfers (IHTs) were identified by transfer indicators or temporally adjacent hospitalizations at 2 different facilities. Data analysis was conducted from January to May 2024. Exposure: Admission for primary EGS diagnosis. Main Outcomes and Measures: Regional EGS networks (RENs) were delineated by modularity optimization (MO), a community detection method, and compared with the plurality-based Dartmouth HRRs. Geographic boundaries were compared through visualization of patient flows and associated health care regions. Spatial accuracy of the 2 methods was compared using 6 common network analysis measures: localization index (LI), market share index (MSI), net patient flow, connectivity, compactness, and modularity. Results: A total of 1 244 868 participants (median [IQR] age, 55 [37-70 years]; 776 725 male [62.40%]) were admitted with a primary EGS diagnosis. In New York, there were 405 493 EGS encounters with 3212 IHTs (0.79%), and 9 RENs were detected using MO compared with 10 Dartmouth HRRs. In California, there were 839 375 encounters with 10 037 IHTs (1.20%), and 14 RENs were detected compared with 24 HRRs. The greatest discrepancy between REN and HRR boundaries was in rural regions where one REN often encompassed multiple HRRs. The MO method was significantly better than HRRs in identifying care networks that accurately captured patients living within the geographic region as indicated by the LI and MSI for New York (mean [SD] LI, 0.86 [1.00] for REN vs 0.74 [1.00] for HRR; mean [SD] MSI, 0.16 [0.13] for REN vs 0.32 [0.21] for HRR) and California (mean [SD] LI, 0.83 [1.00] for REN vs 0.74 [1.00] for HRR; mean [SD] MSI, 0.19 [0.14] for REN vs 0.39 [0.43] for HRR). Nearly 27% of New York hospitals (37 of 139 hospitals [26.62%]) and 15% of California hospitals (48 of 336 hospitals [14.29%]) were reclassified into a different community with the MO method. Conclusions and Relevance: Development of optimal health delivery systems for EGS patients will require knowledge of care patterns specific to this population. The findings of this cross-sectional study suggest that network science methods, such as MO, offer opportunities to identify empirical EGS care regions that outperform HRRs and can be applied in the development of coordinated regional systems of care.

The benefit of sentinel lymph node biopsy in elderly patients with melanoma: A retrospective analysis of SEER Medicare data (2010-2018).

BACKGROUND: Sentinel lymph node status is critical for melanoma staging and treatment. However, the factors influencing SLNB and its oncologic benefits in elderly patients are unclear. METHODS: We conducted a retrospective analysis of patients aged ≥65 with clinically node-negative melanoma and Breslow depth ≥1 â€‹mm, using Surveillance, Epidemiology, and End Results Medicare database (2010-2018). Multivariable logistic regression assessed SLNB likelihood by demographic and clinical factors, and Cox-proportional hazard models evaluated overall and melanoma-specific mortality (MSM) for SLNB recipients versus non-recipients. RESULTS: Of 13,160 melanoma patients, 62.29 â€‹% underwent SLNB. SLNB was linked to reduced all-cause mortality (HR: 0.65 [95%CI 0.61-0.70]) and MSM (HR: 0.76 [95%CI 0.67-0.85]). Older age, non-White race, male sex, and unmarried status was associated with decreased SLNB likelihood, while cardiopulmonary, neurologic, and secondary cancer comorbidities were associated with increased SLNB likelihood. CONCLUSIONS: Though less frequently performed, SLNB is associated with lower mortality in elderly melanoma patients. Advanced age alone should not contraindicate SLNB.

Increased Risk of Acute Aortic Events following COVID-19 and Influenza Respiratory Viral Infections.

BACKGROUND: Acute respiratory viral infections have been associated with an increased incidence of adverse cardiovascular events. However, it is unclear whether severe respiratory viral infections are associated with an increased risk of acute aortic syndromes (AAS). This study was designed to assess whether Coronavirus disease 2019 (COVID-19) and Influenza illnesses are associated with an increased incidence of subsequent AAS in the US population. METHODS: We used the MarketScan database (2011-2021) to identify patients 18-99 years of age without prior diagnosis of aortic pathology who were diagnosed with COVID-19 or Influenza. Identified patients were matched 1:1 by age and sex to control patients without COVID-19 or Influenza. The primary outcome was incidence of AAS (dissection, intramural hematoma, penetrating aortic ulcer, or aneurysm rupture) within 180-days of a viral infection. The association between infection and risk of developing an AAS was analyzed using multivariate Cox proportional hazards models. RESULTS: We identified 1,775,698 patients, including 779,229 (44%) with mild COVID-19, 42,141 (2%) with severe COVID-19, and 66,479 (4%) with Influenza that were matched to 887,849 (50%) control patients without COVID-19 or Influenza illnesses. A total of 164 patients experienced AAS within 6-months after diagnosis, which was highest among those after severe COVID-19. The predicted incidence of AAS was significantly higher among patients after severe COVID-19 (14.1 events/100,000 person-years), mild COVID-19 (13.3 events/100,000), and influenza (13.3 events/100,000) when compared to control patients (2.6 events/100,000). In risk-adjusted Cox regression models, severe COVID-19 (HR:5.4, 95% CI:2.8-10.4; P < 0.01), mild COVID-19 (HR:5.1, 95% CI:3.3-7.7; P < 0.01) and influenza (HR:5.1, 95% CI:2.6-9.7; P < 0.01) diagnoses were associated with a significantly increased risk of AAS within 180-days when compared to matched controls. CONCLUSIONS: There is an increased risk of developing acute aortic event in the months following illness with Influenza or COVID-19. These data highlight the need to closely monitor at-risk patients following a viral respiratory infection.

Hispanic Ethnicity and Fertility Outcomes.

OBJECTIVE: To assess the association between ethnicity and fertility outcomes for men in a statewide cohort. METHODS: We linked data from the Utah Population Database and Subfertility Health Assisted Reproduction and Environment database, to comprise a cohort of sub-fertile men who underwent semen analysis between 1998 and 2017 in Utah. A multivariable Cox proportional hazard model was constructed to understand the impact of ethnicity on fertility outcomes in our cohort. RESULTS: A total of 11,363 men were included. 1039 (9.1%) were Hispanic. 39.7% of men in the lowest socioeconomic status group were Hispanic (P <.001). When controlling for demographic and clinical factors, the number of live births was reduced for Hispanic men (hazard ratios [HR] = 0.62 [0.57-0.67], P <.001). Though fertility treatment had a positive effect (HR 1.242 [1.085-1.421], P <.001), in competing risks models, Hispanic men were less likely to use fertility treatment (HR = 0.633 [0.526-0.762], P <.001). CONCLUSION: Hispanic ethnicity is significantly associated with a lower likelihood of successful fertility outcomes in Utah. Hispanic men had nearly a 40% reduced likelihood of live births when controlling for sociodemographic factors. Our results indicate that, depending on age, Hispanic men have up to approximately 14 fewer live births per 100 men per year, pointing to a significant disparity in fertility outcomes in the state of Utah. Given 15.1% of Utah's population identifies as Hispanic and 18.7% of the United States population identifies as Hispanic on the 2020 Census, a better understanding of the association of ethnicity and fertility outcomes is imperative.

Recurrence of severe diverticulitis is associated with age and birth decade.

BACKGROUND: The risk of recurrence is an important consideration when deciding to treat patients medically or with elective colectomy after recovery from diverticulitis. It is unclear whether age is associated with recurrence. This study aimed to examine the relationship between age and the risk of recurrent diverticulitis while considering important epidemiologic factors, such as birth decade. METHODS: The Utah Population Database was used to identify individuals with incident severe diverticulitis, defined as requiring an emergency department visit or hospitalization, between 1998 and 2018. This study measured the relationship between age and recurrent severe diverticulitis after adjusting for birth decade and other important variables, such as sex, urban/rural status, complicated diverticulitis, and body mass index using a Cox proportional hazards model. RESULTS: The cohort included 8606 individuals with a median age of 61 years at index diverticulitis diagnosis. After adjustment, among individuals born in the same birth decade, increasing age at diverticulitis onset was associated with an increased risk of recurrent diverticulitis (hazard ratio [HR] for 10 years, 1.8; 95% CI, 1.5-2.1). Among individuals with the same age of onset, those born in a more recent birth decade were also at greater risk of recurrent diverticulitis (HR, 1.9; 95% CI, 1.6-2.3). CONCLUSION: Among individuals with an index episode of severe diverticulitis, recurrence was associated with increasing age and more recent birth decade. Clinicians may wish to employ age-specific strategies when counseling patients regarding treatment options after a diverticulitis diagnosis.

Animal migration in the Anthropocene: threats and mitigation options.

Animal migration has fascinated scientists and the public alike for centuries, yet migratory animals are facing diverse threats that could lead to their demise. The Anthropocene is characterised by the reality that humans are the dominant force on Earth, having manifold negative effects on biodiversity and ecosystem function. Considerable research focus has been given to assessing anthropogenic impacts on the numerical abundance of species/populations, whereas relatively less attention has been devoted to animal migration. However, there are clear linkages, for example, where human-driven impacts on migration behaviour can lead to population/species declines or even extinction. Here, we explore anthropogenic threats to migratory animals (in all domains - aquatic, terrestrial, and aerial) using International Union for the Conservation of Nature (IUCN) Threat Taxonomy classifications. We reveal the diverse threats (e.g. human development, disease, invasive species, climate change, exploitation, pollution) that impact migratory wildlife in varied ways spanning taxa, life stages and type of impact (e.g. from direct mortality to changes in behaviour, health, and physiology). Notably, these threats often interact in complex and unpredictable ways to the detriment of wildlife, further complicating management. Fortunately, we are beginning to identify strategies for conserving and managing migratory animals in the Anthropocene. We provide a set of strategies that, if embraced, have the potential to ensure that migratory animals, and the important ecological functions sustained by migration, persist.

Describing patterns of familial cancer risk in subfertile men using population pedigree data.

STUDY QUESTION: Can we simultaneously assess risk for multiple cancers to identify familial multicancer patterns in families of azoospermic and severely oligozoospermic men? SUMMARY ANSWER: Distinct familial cancer patterns were observed in the azoospermia and severe oligozoospermia cohorts, suggesting heterogeneity in familial cancer risk by both type of subfertility and within subfertility type. WHAT IS KNOWN ALREADY: Subfertile men and their relatives show increased risk for certain cancers including testicular, thyroid, and pediatric. STUDY DESIGN, SIZE, DURATION: A retrospective cohort of subfertile men (N = 786) was identified and matched to fertile population controls (N = 5674). Family members out to third-degree relatives were identified for both subfertile men and fertile population controls (N = 337 754). The study period was 1966-2017. Individuals were censored at death or loss to follow-up, loss to follow-up occurred if they left Utah during the study period. PARTICIPANTS/MATERIALS, SETTING, METHODS: Azoospermic (0 × 106/mL) and severely oligozoospermic (<1.5 × 106/mL) men were identified in the Subfertility Health and Assisted Reproduction and the Environment cohort (SHARE). Subfertile men were age- and sex-matched 5:1 to fertile population controls and family members out to third-degree relatives were identified using the Utah Population Database (UPDB). Cancer diagnoses were identified through the Utah Cancer Registry. Families containing ≥10 members with ≥1 year of follow-up 1966-2017 were included (azoospermic: N = 426 families, 21 361 individuals; oligozoospermic: N = 360 families, 18 818 individuals). Unsupervised clustering based on standardized incidence ratios for 34 cancer phenotypes in the families was used to identify familial multicancer patterns; azoospermia and severe oligospermia families were assessed separately. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to control families, significant increases in cancer risks were observed in the azoospermia cohort for five cancer types: bone and joint cancers hazard ratio (HR) = 2.56 (95% CI = 1.48-4.42), soft tissue cancers HR = 1.56 (95% CI = 1.01-2.39), uterine cancers HR = 1.27 (95% CI = 1.03-1.56), Hodgkin lymphomas HR = 1.60 (95% CI = 1.07-2.39), and thyroid cancer HR = 1.54 (95% CI = 1.21-1.97). Among severe oligozoospermia families, increased risk was seen for three cancer types: colon cancer HR = 1.16 (95% CI = 1.01-1.32), bone and joint cancers HR = 2.43 (95% CI = 1.30-4.54), and testis cancer HR = 2.34 (95% CI = 1.60-3.42) along with a significant decrease in esophageal cancer risk HR = 0.39 (95% CI = 0.16-0.97). Thirteen clusters of familial multicancer patterns were identified in families of azoospermic men, 66% of families in the azoospermia cohort showed population-level cancer risks, however, the remaining 12 clusters showed elevated risk for 2-7 cancer types. Several of the clusters with elevated cancer risks also showed increased odds of cancer diagnoses at young ages with six clusters showing increased odds of adolescent and young adult (AYA) diagnosis [odds ratio (OR) = 1.96-2.88] and two clusters showing increased odds of pediatric cancer diagnosis (OR = 3.64-12.63). Within the severe oligozoospermia cohort, 12 distinct familial multicancer clusters were identified. All 12 clusters showed elevated risk for 1-3 cancer types. An increase in odds of cancer diagnoses at young ages was also seen in five of the severe oligozoospermia familial multicancer clusters, three clusters showed increased odds of AYA diagnosis (OR = 2.19-2.78) with an additional two clusters showing increased odds of a pediatric diagnosis (OR = 3.84-9.32). LIMITATIONS, REASONS FOR CAUTION: Although this study has many strengths, including population data for family structure, cancer diagnoses and subfertility, there are limitations. First, semen measures are not available for the sample of fertile men. Second, there is no information on medical comorbidities or lifestyle risk factors such as smoking status, BMI, or environmental exposures. Third, all of the subfertile men included in this study were seen at a fertility clinic for evaluation. These men were therefore a subset of the overall population experiencing fertility problems and likely represent those with the socioeconomic means for evaluation by a physician. WIDER IMPLICATIONS OF THE FINDINGS: This analysis leveraged unique population-level data resources, SHARE and the UPDB, to describe novel multicancer clusters among the families of azoospermic and severely oligozoospermic men. Distinct overall multicancer risk and familial multicancer patterns were observed in the azoospermia and severe oligozoospermia cohorts, suggesting heterogeneity in cancer risk by type of subfertility and within subfertility type. Describing families with similar cancer risk patterns provides a new avenue to increase homogeneity for focused gene discovery and environmental risk factor studies. Such discoveries will lead to more accurate risk predictions and improved counseling for patients and their families. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health (Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): R01 HD106112). The authors have no conflicts of interest relevant to this work. TRIAL REGISTRATION NUMBER: N/A.

Proposed revision of the American Association for Surgery of Trauma Renal Organ Injury Scale: Secondary analysis of the Multi-institutional Genitourinary Trauma Study.

BACKGROUND: This study updates the American Association for the Surgery of Trauma (AAST) Organ Injury Scale (OIS) for renal trauma using evidence-based criteria for bleeding control intervention. METHODS: This was a secondary analysis of a multicenter retrospective study including patients with high-grade renal trauma from seven level 1 trauma centers from 2013 to 2018. All eligible patients were assigned new renal trauma grades based on revised criteria. The primary outcome used to measure injury severity was intervention for renal bleeding. Secondary outcomes included intervention for urinary extravasation, units of packed red blood cells transfused within 24 hours, and mortality. To test the revised grading system, we performed mixed-effect logistic regression adjusted for multiple baseline demographic and trauma covariates. We determined the area under the curve (AUC) to assess accuracy of predicting bleeding interventions from the revised grading system and compared this to 2018 AAST OIS. RESULTS: Based on the 2018 OIS grading system, we included 549 patients with AAST grades III to V injuries and computed tomography scans (III, 52% [n = 284]; IV, 45% [n = 249]; and V, 3% [n = 16]). Among these patients, 89% experienced blunt injury (n = 491), and 12% (n = 64) underwent intervention for bleeding. After applying the revised grading criteria, 60% (n = 329) of patients were downgraded, and 4% (n = 23) were upgraded; 2.8% (n = 7) downgraded from grade V to IV, and 69.5% (n = 173) downgraded from grade IV to III. The revised renal trauma grading system demonstrated improved predictive ability for bleeding interventions (2018 AUC, 0.805; revised AUC, 0.883; p = 0.001) and number of units of packed red blood cells transfused. When we removed urinary injury from the revised system, there was no difference in its predictive ability for renal hemorrhage intervention. CONCLUSION: A revised renal trauma grading system better delineates the need for hemostatic interventions than the current AAST OIS renal trauma grading system. LEVEL OF EVIDENCE: Diagnostic Test/Criteria; Level III.

Transgenerational effects of paternal exposures: the role of germline de novo mutations.

Germline de novo mutations (DNMs) refer to spontaneous mutations arising during gametogenesis, resulting in genetic changes within germ cells that are subsequently transmitted to the next generation. While the impact of maternal exposures on germline DNMs has been extensively studied, more recent studies have begun to highlight the increasing importance of the effects of paternal factors. In this review, we have summarized the existing literature on how various exposures experienced by fathers affect the germline DNM burden in their spermatozoa, as well as their consequences for semen analysis parameters, pregnancy outcomes, and offspring health. A growing body of literature supports the conclusion that advanced paternal age (APA) correlates with a higher germline DNM rate in offspring. Furthermore, lifestyle choices, environmental toxins, assisted reproductive techniques (ART), and chemotherapy are associated with the accumulation of paternal DNMs in spermatozoa, with deleterious consequences for pregnancy outcomes and offspring health. Ultimately, our review highlights the clear importance of the germline DNM mode of inheritance, and the current understanding of how this is affected by various paternal factors. In addition, we explore conflicting reports or gaps of knowledge that should be addressed in future research.

Untreated hypogonadism and testosterone replacement therapy in hypogonadal men are associated with a decreased risk of subsequent prostate cancer: a population-based study.

We sought to understand the relationship between hypogonadism and testosterone replacement therapy (TRT) in hypogonadal men on the risk of developing localized and metastatic prostate cancer. We used the Merative MarketScan database of commercial claims encounters to identify men diagnosed with hypogonadism. These men were matched to eugonadal men who served as controls. Multivariate negative binomial regression analysis of prostate cancer diagnoses, hypogonadism, and TRT in hypogonadal men adjusting for various known confounding factors was used to understand the impact of hypogonadism and TRT on prostate cancer risk. We identified 3,222,904 men who met inclusion criteria, of which 50% were diagnosed with hypogonadism (1,611,452) and each were matched to a control (1,611,452). The incidence of prostate cancer was 2.16%, 1.55%, and 1.99% in eugonadal controls, hypogonadal men on TRT, and hypogonadal men without TRT, respectively (p < 0.001). Untreated hypogonadism was independently associated with a decreased risk of localized prostate cancer (IRR 0.46, 95% CI 0.43-0.50, p < 0.001) compared to eugonadal controls. Hypogonadal men on TRT also had a significantly decreased risk of localized prostate cancer (IRR 0.49, 95% CI 0.45-0.53, p < 0.001). Furthermore, hypogonadal men on TRT (IRR 0.21, 95% CI 0.19-0.24, p < 0.001) or without TRT (IRR 0.20, 95% CI 0.18-0.22, p < 0.001) both had significantly decreased risk of metastatic prostate cancer, respectively. Our population-based analysis suggests that untreated hypogonadism in men is associated with a 50% decreased incidence of localized prostate cancer and an 80% decreased incidence of metastatic prostate cancer. TRT in hypogonadal men was also associated with a decreased risk of subsequent prostate cancer. Further research is needed to better understand the relationship between hypogonadism and TRT in hypogonadal men on the risk of subsequent prostate cancer.

Single-Photon Emission Computed Tomography/Computed Tomography Utilization for Extremity Melanomas at a High-Volume Center.

INTRODUCTION: Planar lymphoscintigraphy (PL) is commonly used in mapping before sentinel lymph node biopsy (SLNB) for invasive cutaneous melanoma. Recently, single-photon emission computed tomography (SPECT)/ computed tomography (CT) has been utilized, in addition to PL, for detailed anatomic information and detection of sentinel lymph nodes (SLNs) outside of the primary nodal basin in truncal and head and neck melanoma. Following a protocol change due to COVID-19, our institution began routinely obtaining both PL and SPECT-CT imaging for all melanoma SLN mapping. We hypothesized that SPECT-CT is associated with higher instances of SLNBs from "nontraditional" nodal basins (NTNB) for extremity melanomas. METHODS: Patients with extremity melanoma (2017-2022) who underwent SLNB were grouped into SPECT-CT with PL versus PL alone. Outcomes were total SLNs removed, + or-SLN status, total NTNB sampled, and postoperative complication rate. Poisson regression and logistic regression models were used to assess association of SPECT-CT with patient outcomes. RESULTS: Of 380 patients with extremity melanoma, 42.11% had SPECT-CT. There were no differences between the groups with regards to age at diagnosis or sex. From 2020 to 2022, all patients underwent SPECT-CT. SPECT-CT was associated with increased odds of SLNB from an NTNB, (odds ratio = 2.39 [95% confidence interval: 1.25-4.67]). There was no difference in odds of number of SLNs sampled, SLN positivity rate, or postoperative complication rate with SPECT-CT. CONCLUSIONS: Routine SPECT-CT was associated with higher incidence of SLNB in NTNB but did not increase number of SLNs removed or SLN positivity rate. The added value of routine SPECT-CT in cutaneous melanoma of the extremities remains to be defined.

Cost and utilization analysis of concurrent versus staged testicular prosthesis implantation for radical orchiectomy.

PURPOSE: American Urological Association guidelines recommend testicular prosthesis discussion prior to orchiectomy. Utilization may be low. We compared outcomes and care utilization between concurrent implant (CI) and staged implant (SI) insertion after radical orchiectomy. MATERIALS & METHODS: The MarketScan Commercial claims database (2008-2017) was queried for men ages >18 years who underwent radical orchiectomy for testicular mass, stratified as orchiectomy with no implant, CI, or SI. 90-day outcomes included rate of reoperation, readmission, emergency department (ED) presentation, and outpatient visits. Regression models provided rate ratio comparison. RESULTS: 8803 patients (8564 no implant, 190 CI, 49 SI; 2.7% implant rate) were identified with no difference in age, Charlson Comorbidity Index, insurance plan, additional cancer treatment, or metastasis. Median perioperative cost at orchiectomy (+/- implant) for no implant, CI, and SI were $5682 (3648-8554), $7823 (5403-10973), and $5380 (4130-10521), respectively (p<0.001). Median perioperative cost for SI at implantation was $8180 (4920-14591) for a total cost (orchiectomy + implant) of $13650 (5380 + 8180). CI patients were more likely to have follow-up (p = 0.006) with more visits (p = 0.030) compared to the SI group post-implantation but had similar follow-up (p = 0.065) and less visits (p = 0.025) compared to the SI patients' post-orchiectomy period. Overall explant rates were 4.7% for CI and 14.3% for SI (p = 0.04) with a median time to explant of 166 (IQR: 135-210) and 40 days (IQR: 9.5-141.5; p = 0.06). Median cost of removal was $2060 (IQR: 967-2880). CONCLUSIONS: CI placement has less total perioperative cost, lower explant rate, and similar postoperative utilization to SI.

The association between parental age differences and perinatal outcomes.

STUDY QUESTION: Are there significant associations existing between parental age differences and adverse perinatal outcomes? SUMMARY ANSWER: Large differences in parental age are associated with adverse perinatal outcomes, particularly with older mothers paired with younger fathers. WHAT IS KNOWN ALREADY: The association between advanced maternal age and perinatal outcomes is well-documented with women over 35 years showing an increased risk of several adverse outcomes. Other studies have identified potential associations between advanced paternal age and adverse perinatal outcomes. STUDY DESIGN, SIZE, DURATION: A historical (retrospective) cohort analysis was performed utilizing a multivariable logistic regression model to evaluate the association between varying differences in parental age and adverse perinatal outcomes while controlling for demographic and health-related covariates. Data were compiled from the National Vital Statistics System for 20 613 704 births between 2012 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Parental age differences, categorized into eleven 4-year intervals, were stratified by seven maternal age categories and evaluated for their associations with adverse perinatal outcomes. Main outcome measures included low birth weight, very low birth weight, preterm birth, very preterm birth, small size for gestational age, low 5-min appearance, pulse, grimace, activity, and respiration score, congenital defects, and chromosomal anomalies. MAIN RESULTS AND THE ROLE OF CHANCE: Increased parental age differences, in either direction, were associated with significant risks for all adverse outcomes, aside from congenital defects, even when controlling for maternal age. Restricting maternal age to the reference range of 25-29 years, infants born to fathers aged 9-12 years younger (n = 3773) had 27% (odds ratio (OR) 1.27, 95% CI, 1.17-1.37) higher odds of having any adverse perinatal outcome. Infants born to fathers aged >16 years older (n = 98 555) had 14% (OR 1.14, 95% CI, 1.12-1.16) higher odds of having any adverse perinatal outcome. LIMITATIONS, REASONS FOR CAUTION: Data extracted from US birth certificates may be compromised by errors in reporting or documentation. Information regarding the mother's socioeconomic status was estimated using proxy variables and may be susceptible to uncontrolled factors. Use of a pre-compiled dataset may potentially exclude additional maternal comorbidities that could impact perinatal outcomes. WIDER IMPLICATIONS OF FINDINGS: Older mothers paired with younger fathers demonstrated the highest risk, even when maternal age was below the threshold of 35 years. For the clinical setting, parental age differences should be considered alongside maternal and paternal age when assessing risks of adverse perinatal outcomes for potential parents. This is particularly relevant for older women with younger male partners as this may exacerbate the impact of advanced maternal age. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the NIH Research Fellowship T35 Training Grant. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Coronavirus Disease 2019 (COVID-19) and Venous Thromboembolism During Pregnancy and Postpartum.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased risk for macro- and micro-thrombi. Consensus guidelines recommend use of thromboprophylaxis in nonobstetric patients with SARS-CoV-2 infection admitted to the hospital. National-level studies evaluating venous thromboembolism (VTE) among pregnant and postpartum individuals with and without SARS-CoV-2 infection have not been completed. We performed a retrospective cohort study of individuals aged 18 years or older delivering at more than 20 weeks of gestation with data in the MarketScan Commercial Insurance Database from 2016 through 2020. Of 811,008 deliveries, SARS-CoV-2 infection during pregnancy or through 6 weeks postpartum was associated with increased risk for VTE compared with no infection (1.0% vs 0.5%, adjusted hazard ratio 2.62, 95% CI 1.60-4.29). Findings support further consideration of thromboprophylaxis in the obstetric population with SARS-CoV-2 infection.

Incidence and Risk Factors for Postoperative Venous Thromboembolism After Gender Affirming Vaginoplasty: A Retrospective Analysis of a Large Insurance Claims Database.

OBJECTIVES: To investigate the incidence and associated risk factors of venous thromboembolism (VTE) after gender affirming vaginoplasty. METHODS: We searched International Business Machines Corporation (IBM) Marketscan, a commercial claims database, for Current Procedural Terminology and International Classification of Diseases (ICD) procedure codes to identify patients who underwent gender affirming vaginoplasty from 2011-2020. We quantified deep venous thrombosis and pulmonary embolism using ICD-9 and ICD-10 codes found within 90 days after surgery. Univariate and multivariate analyses were performed to establish association between VTE events and age, residency location, and comorbidities. RESULTS: We identified 1588 patients who underwent gender affirming vaginoplasty. Overall, 1.1% of patients experienced a VTE within 90 days following surgery. Patients who experienced postoperative VTE were older, more likely to have had a prior VTE, less likely to be from an urban area, and more likely to have a higher Charlson Comorbidity Index score. Among patients with postoperative VTE, 47.1% had previous VTE. Among patients without a postoperative VTE, 1.3% had previous VTE. CONCLUSION: In patients undergoing gender affirming vaginoplasty, the incidence of postoperative VTE was 1.1%. Older age, rurality, increased comorbidities, and prior VTE were associated with increased risk of postoperative VTE. Current guidelines do not recommend cessation of gender affirming hormone therapy (GAHT) prior to vaginoplasty. Further research is needed to evaluate if certain high-risk patients would benefit from perioperative adjustment of GAHT or perioperative VTE prophylaxis.

Exogenous Testosterone Replacement Therapy Is Associated with Increased Risk for Vascular Graft Infections Among Hypogonadal Men.

BACKGROUND: Vascular graft infections (VGIs) are a major source of morbidity following vascular bypass surgery. Hypogonadal men may be at increased risk for impaired wound healing and infections, but it is unclear if testosterone replacement therapy (TRT) mitigates this risk. We designed this study to evaluate the relationship between hypogonadism and the use of testosterone replacement therapy (TRT) with subsequent risk for developing a VGI. METHODS: We performed a retrospective analysis of claims in the MarketScan database identifying men greater than 18 years of age who underwent placement of a prosthetic graft in the peripheral arterial circulation from January 2009 to December 2020. Patients were stratified based on diagnosis of hypogonadism and use of TRT within 180 days before surgery. The primary outcome was VGI and the need for surgical excision. The association between hypogonadism and TRT use on risk of VGI was analyzed using Kaplan-Meier plots and multivariate Cox proportional hazards models. RESULTS: We identified 18,312 men who underwent a prosthetic bypass graft procedure in the upper and lower extremity during the study period, of which 802 (5%) had diagnosis of hypogonadism. Among men with hypogonadism, 251 (31%) were receiving TRT. Patients on TRT were younger, more likely to be diabetic, and more likely develop a VGI during follow-up (14% vs. 8%; P < 0.001) that was in the lower extremity. At 5 years, freedom from VGI was significantly lower for hypogonadal men on TRT than patients not on TRT or without hypogonadism (Log rank P < 0.001). In Cox regression models adjusted for age, diabetes, obesity, smoking, corticosteroid use, and procedure type, hypogonadal men on TRT were at a significantly increased risk of graft infection (hazard ratio (HR):1.94, 95% confidence interval (CI):1.4-2.7; P < 0.001) compared to controls. CONCLUSIONS: This study demonstrates TRT among hypogonadal men is associated with an increased risk of prosthetic VGIs. Temporary cessation of TRT should be considered for men undergoing prosthetic graft implants, particularly those in the lower extremity.

Diverticulitis Familiality: A Statewide Case-Control Study.

BACKGROUND: The etiology of diverticulitis is multifactorial and poorly understood. We estimated the familiality of diverticulitis using the Utah Population Database, a statewide database linking medical records with genealogy data. STUDY DESIGN: We identified patients with diverticulitis diagnosed between 1998 and 2018 and age- and sex-matched controls in the Utah Population Database. Risk of diverticulitis in family members of patients and controls was calculated using multivariable Poisson models. We performed exploratory analyses to determine the association of familial diverticulitis with severity of disease and age of onset. RESULTS: The study population included 9,563 diverticulitis patients (with 229,647 relatives) and 10,588 controls (with 265,693 relatives). Relatives of patients were more likely to develop diverticulitis (incidence rate ratio [IRR] 1.5, 95% CI 1.4 to 1.6) compared with relatives of controls. There was an elevated risk of diverticulitis among first-degree (IRR 2.6, 95% CI 2.3 to 3.0), second-degree (IRR 1.5, 95% CI 1.3 to 1.6), and third-degree relatives of patients (IRR 1.3, 95% CI 1.2 to 1.4). Complicated diverticulitis was more common among relatives of patients compared with relatives of controls (IRR 1.6, 95% CI 1.4 to 1.8). Age at diverticulitis diagnosis was similar between groups (relatives of patients 0.2 years older than relatives of controls, 95% CI -0.5 to 0.9). CONCLUSIONS: Our results indicate that the first-, second-, and third-degree relatives of diverticulitis patients are at elevated risk of developing diverticulitis. This information may aid surgeons in counseling patients and family members about diverticulitis risk and can inform the development of future risk-stratification tools. Further work is needed to clarify the causal role and relative contribution of various genetic, lifestyle, and environmental factors in the development of diverticulitis.

Familial Associations of Prevalence and Cause-Specific Mortality for Thoracic Aortic Disease and Bicuspid Aortic Valve in a Large-Population Database.

BACKGROUND: Thoracic aortic disease and bicuspid aortic valve (BAV) likely have a heritable component, but large population-based studies are lacking. This study characterizes familial associations of thoracic aortic disease and BAV, as well as cardiovascular and aortic-specific mortality, among relatives of these individuals in a large-population database. METHODS: In this observational case-control study of the Utah Population Database, we identified probands with a diagnosis of BAV, thoracic aortic aneurysm, or thoracic aortic dissection. Age- and sex-matched controls (10:1 ratio) were identified for each proband. First-degree relatives, second-degree relatives, and first cousins of probands and controls were identified through linked genealogical information. Cox proportional hazard models were used to quantify the familial associations for each diagnosis. We used a competing-risk model to determine the risk of cardiovascular-specific and aortic-specific mortality for relatives of probands. RESULTS: The study population included 3 812 588 unique individuals. Familial hazard risk of a concordant diagnosis was elevated in the following populations compared with controls: first-degree relatives of patients with BAV (hazard ratio [HR], 6.88 [95% CI, 5.62-8.43]); first-degree relatives of patients with thoracic aortic aneurysm (HR, 5.09 [95% CI, 3.80-6.82]); and first-degree relatives of patients with thoracic aortic dissection (HR, 4.15 [95% CI, 3.25-5.31]). In addition, the risk of aortic dissection was higher in first-degree relatives of patients with BAV (HR, 3.63 [95% CI, 2.68-4.91]) and in first-degree relatives of patients with thoracic aneurysm (HR, 3.89 [95% CI, 2.93-5.18]) compared with controls. Dissection risk was highest in first-degree relatives of patients who carried a diagnosis of both BAV and aneurysm (HR, 6.13 [95% CI, 2.82-13.33]). First-degree relatives of patients with BAV, thoracic aneurysm, or aortic dissection had a higher risk of aortic-specific mortality (HR, 2.83 [95% CI, 2.44-3.29]) compared with controls. CONCLUSIONS: Our results indicate that BAV and thoracic aortic disease carry a significant familial association for concordant disease and aortic dissection. The pattern of familiality is consistent with a genetic cause of disease. Furthermore, we observed higher risk of aortic-specific mortality in relatives of individuals with these diagnoses. This study provides supportive evidence for screening in relatives of patients with BAV, thoracic aneurysm, or dissection.

Genitourinary Radiation Injury Following Prostate Cancer Treatment: Assessment of Cost and Health Care System Burden.

OBJECTIVE: To evaluate the healthcare resource impact of radiation injury following prostate cancer treatment. METHODS: Using IBM MarketScan, we performed a retrospective study of men with prostate cancer who were treated with radiotherapy and subsequently developed low-grade (LGRI) and high-grade radiation injury (HGRI). Radiation injury diagnoses included bladder neck stenosis, hematuria/cystitis, fistula, ureteral stricture, and incontinence. LGRI and HGRI included injury diagnosis without intervention and with intervention, respectively. Health care visits and costs were measured over 5 time periods including 2 years before radiation, 1 year before radiation, radiation to injury diagnosis, injury diagnosis to first intervention (LGRI), and following first intervention (HGRI). Negative binomial regression modeling was used to assess the effect of radiation injury on average cost adjusting for demographics and comorbidities. RESULTS: Between 2008 and 2017, we identified 121,027 men who received radiotherapy following prostate cancer diagnosis of which 10,057 (8.3%) experienced a HGRI. The frequency of urologic visits and average costs were similar in those without injury and LGRI. However, men with HGRI experienced higher visit frequency and monthly costs. Amongst high-grade injuries, urinary fistula had the highest frequency of visit utilization at 378 visits before first intervention and 245 visits after first intervention. Following radiation injury diagnosis, the average monthly cost was twice as high in those with HGRI ($85.78) compared to LGRI ($38.66). CONCLUSIONS: HGRI was associated with increased urologic health care use and average monthly cost when compared to those who experienced LGRI or no injury. Urinary fistula was associated with the largest resource burden.

Environmental exposure to industrial air pollution is associated with decreased male fertility.

OBJECTIVE: To understand how chronic exposure to industrial air pollution is associated with male fertility through semen parameters. DESIGN: Retrospective cohort study. PATIENTS: Men in the Subfertility, Health, and Assisted Reproduction cohort who underwent a semen analysis in the two largest healthcare systems in Utah from 2005-2017 with ≥1 measured semen parameter (N = 21,563). INTERVENTION(S): Residential histories for each man were constructed using locations from administrative records linked through the Utah Population Database. Industrial facilities with air emissions of nine endocrine-disrupting compound chemical classes were identified from the Environmental Protection Agency Risk-Screening Environmental Indicators microdata. Chemical levels were linked with residential histories for the 5 years before each semen analysis. MAIN OUTCOME MEASURES: Semen analyses were classified as azoospermic or oligozoospermic (< 15 M/mL) using World Health Organization cutoffs for concentration. Bulk semen parameters such as concentration, total count, ejaculate volume, total motility, total motile count, and total progressive motile count were also measured. Multivariable regression models with robust standard errors were used to associate exposure quartiles for each of the nine chemical classes with each semen parameter, adjusting for age, race, and ethnicity, as well as neighborhood socioeconomic disadvantage. RESULTS: After adjustment for demographic covariates, several chemical classes were associated with azoospermia and decreased total motility and volume. For exposure in the 4th relative to 1st quartile, significant associations were observed for acrylonitrile (ßtotal motility = -0.87 pp), aromatic hydrocarbons (odds ratio [OR]azoospermia = 1.53; ßvolume = -0.14 mL), dioxins (ORazoospermia = 1.31; ßvolume = -0.09 mL; ßtotal motility = -2.65 pp), heavy metals (ßtotal motility = -2.78pp), organic solvents (ORazoospermia = 1.75; ßvolume = -0.10 mL), organochlorines (ORazoospermia = 2.09; ßvolume = -0.12 mL), phthalates (ORazoospermia = 1.44; ßvolume = -0.09 mL; ßtotal motility = -1.21 pp), and silver particles (ORazoospermia = 1.64; ßvolume = -0.11 mL). All semen parameters significantly decreased with increasing socioeconomic disadvantage. Men who lived in the most disadvantaged areas had concentration, volume, and total motility of 6.70 M/mL, 0.13 mL, and 1.79 pp lower, respectively. Count, motile count, and total progressive motile count all decreased by 30-34 M. CONCLUSION(S): Several significant associations between chronic low-level environmental exposure to endocrine-disrupting compound air pollution from industrial sources and semen parameters were observed. The strongest associations were seen for increased odds of azoospermia and declines in total motility and volume. More research is needed to further explore additional social and exposure factors as well as expand on the risk posed to male reproductive health by the studied chemicals.