The association of GNB5 with Alzheimer disease revealed by genomic analysis restricted to variants impacting gene function.

Disease-associated variants identified from genome-wide association studies (GWASs) frequently map to non-coding areas of the genome such as introns and intergenic regions. An exclusive reliance on gene-agnostic methods of genomic investigation could limit the identification of relevant genes associated with polygenic diseases such as Alzheimer disease (AD). To overcome such potential restriction, we developed a gene-constrained analytical method that considers only moderate- and high-risk variants that affect gene coding sequences. We report here the application of this approach to publicly available datasets containing 181,388 individuals without and with AD and the resulting identification of 660 genes potentially linked to the higher AD prevalence among Africans/African Americans. By integration with transcriptome analysis of 23 brain regions from 2,728 AD case-control samples, we concentrated on nine genes that potentially enhance the risk of AD: AACS, GNB5, GNS, HIPK3, MED13, SHC2, SLC22A5, VPS35, and ZNF398. GNB5, the fifth member of the heterotrimeric G protein beta family encoding Gß5, is primarily expressed in neurons and is essential for normal neuronal development in mouse brain. Homozygous or compound heterozygous loss of function of GNB5 in humans has previously been associated with a syndrome of developmental delay, cognitive impairment, and cardiac arrhythmia. In validation experiments, we confirmed that Gnb5 heterozygosity enhanced the formation of both amyloid plaques and neurofibrillary tangles in the brains of AD model mice. These results suggest that gene-constrained analysis can complement the power of GWASs in the identification of AD-associated genes and may be more broadly applicable to other polygenic diseases.

Idiopathic Spontaneous Pneumoperitoneum and Call for a Multi-Institutional Database.

Idiopathic spontaneous pneumoperitoneum (ISP) refers to intraperitoneal air of unknown origin when other more common etiologies such as traumatic, intrathoracic, and gynecologic etiologies have been excluded. We present a case of a 42-year-old woman with insignificant history presenting with ISP who underwent exploratory laparoscopy and thorough diagnostic workup that was ultimately unrevealing. This case report adds to the existing literature of ISP, and the authors recommend initiating a multi-institutional database to improve our understanding of ISP and contribute to developing consensus guidelines for presumed ISP.

Specific regulation of mechanical nociception by Gß5 involves GABA-B receptors.

Mechanical, thermal, and chemical pain sensation is conveyed by primary nociceptors, a subset of sensory afferent neurons. The intracellular regulation of the primary nociceptive signal is an area of active study. We report here the discovery of a Gß5-dependent regulatory pathway within mechanical nociceptors that restrains antinociceptive input from metabotropic GABA-B receptors. In mice with conditional knockout (cKO) of the gene that encodes Gß5 (Gnb5) targeted to peripheral sensory neurons, we demonstrate the impairment of mechanical, thermal, and chemical nociception. We further report the specific loss of mechanical nociception in Rgs7-Cre+/- Gnb5fl/fl mice but not in Rgs9-Cre+/- Gnb5fl/fl mice, suggesting that Gß5 might specifically regulate mechanical pain in regulator of G protein signaling 7-positive (Rgs7+) cells. Additionally, Gß5-dependent and Rgs7-associated mechanical nociception is dependent upon GABA-B receptor signaling since both were abolished by treatment with a GABA-B receptor antagonist and since cKO of Gß5 from sensory cells or from Rgs7+ cells potentiated the analgesic effects of GABA-B agonists. Following activation by the G protein-coupled receptor Mrgprd agonist ß-alanine, enhanced sensitivity to inhibition by baclofen was observed in primary cultures of Rgs7+ sensory neurons harvested from Rgs7-Cre+/- Gnb5fl/fl mice. Taken together, these results suggest that the targeted inhibition of Gß5 function in Rgs7+ sensory neurons might provide specific relief for mechanical allodynia, including that contributing to chronic neuropathic pain, without reliance on exogenous opioids.

Surgical Implications of LGBTQ+ Health Disparities: A Review.

Lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ+) patients face challenging health care disparities. However, due to restrictions in reporting and collection of sexual orientation and gender identity (SOGI) demographic data, comprehensive studies of surgical disparities in the LGBTQ+ population are limited. This review aims to summarize the existing literature describing surgical disparities in LGBTQ+ patients and to identify areas of surgical care in which further studies are warranted. This review addresses the literature in infectious diseases, substance use disorders, bariatrics, cardiovascular medicine, oncology, and laryngology as relevant to surgical practice. Understanding the current landscape of knowledge in LGBTQ+ surgical disparities and the areas where gaps in research exist will help the surgeon to create a framework of practice to provide more equitable care to LGBTQ+ patients.

Surgery Acting Internship Individual Learning Plans: Fostering Mentorship in the COVID-19 Era.

OBJECTIVE: Mentorship facilitates successful matching for surgical specialties. A formal mentorship plan may counteract restricted mentorship opportunities due to the COVID-19 pandemic. DESIGN: We surveyed medical students applying to surgery specialties who participated in our formalized mentorship program (MF) and those of a prior cohort who were informally mentored (MI). Epistemic Network Analysis was used to model qualitative responses. SETTING: University of Wisconsin School of Medicine and Public Health. PARTICIPANTS: Fourth-year medical students who matched into ACGME-accredited surgical specialties. RESULTS: MF students (n = 12) met with their mentors more frequently than MI students (n = 13; p = 0.03). Both groups received career guidance, letters of recommendation and application preparation. However, the MI cohort reported greater psychological and emotional support whereas the MF cohort reported more assistance with skills development. CONCLUSIONS: A formalized mentorship program fostered successful mentoring relationships despite limitations from the COVID-19 pandemic.

Interviewing For Residency as an LGBTQ+ Applicant: Compounded Problems With Virtual Interviewing.

Applying to and interviewing for residency positions can be challenging tasks for LGBTQ+ applicants. Resident and faculty surgeons have expressed challenges in disclosing their sexual orientation and/or gender identity throughout the recruitment process. Discrimination and lack of LGBTQ+ inclusion in the recruitment process may have been exacerbated by virtual interviews in response to the COVID-19 pandemic. The authors describe their experiences interviewing virtually for academic general surgery programs, and academic and university-affiliated/community residency programs as LGBTQ+ applicants. Several recommendations are offered to help reduce LGBTQ+ discrimination and to help make institutions more inclusive with the overall aim of making resident recruitment more inclusive for LGBTQ+ applicants.

Machine learning principles applied to CT radiomics to predict mucinous pancreatic cysts.

PURPOSE: Current diagnostic and treatment modalities for pancreatic cysts (PCs) are invasive and are associated with patient morbidity. The purpose of this study is to develop and evaluate machine learning algorithms to delineate mucinous from non-mucinous PCs using non-invasive CT-based radiomics. METHODS: A retrospective, single-institution analysis of patients with non-pseudocystic PCs, contrast-enhanced computed tomography scans within 1 year of resection, and available surgical pathology were included. A quantitative imaging software platform was used to extract radiomics. An extreme gradient boosting (XGBoost) machine learning algorithm was used to create mucinous classifiers using texture features only, or radiomic/radiologic and clinical combined models. Classifiers were compared using performance scoring metrics. Shapely additive explanation (SHAP) analyses were conducted to identify variables most important in model construction. RESULTS: Overall, 99 patients and 103 PCs were included in the analyses. Eighty (78%) patients had mucinous PCs on surgical pathology. Using multiple fivefold cross validations, the texture features only and combined XGBoost mucinous classifiers demonstrated an area under the curve of 0.72 ± 0.14 and 0.73 ± 0.14, respectively. By SHAP analysis, root mean square, mean attenuation, and kurtosis were the most predictive features in the texture features only model. Root mean square, cyst location, and mean attenuation were the most predictive features in the combined model. CONCLUSION: Machine learning principles can be applied to PC texture features to create a mucinous phenotype classifier. Model performance did not improve with the combined model. However, specific radiomic, radiologic, and clinical features most predictive in our models can be identified using SHAP analysis.

Pancreatic cyst characterization: maximum axial diameter does not measure up.

BACKGROUND: Unidimensional size is commonly used to risk stratify pancreatic cysts (PCs) despite inconsistent performance. The current study aimed to determine if unidimensional size, demonstrated by maximum axial diameter (MAD), is an appropriate surrogate measurement for volume and surface area. METHODS: Patients with cross-sectional imaging of PCs from 2012 to 2013 were identified. Cyst MAD, volume, and surface area were measured using quantitative imaging software. Non-pseudocystic PCs >1 cm were selected for inclusion to assess MAD correlation with volume and surface area. Cysts imaged twice >1 year apart were selected to evaluate volumetric growth rate. RESULTS: In total, 195 cysts were included. Overall, MAD was strongly correlated with volume (r = 0.83) and surface area (r = 0.93). However, cysts 1-2 cm and 2-3 cm were weakly correlated with volume and surface area: r = 0.78, 0.57 and 0.82, 0.61, respectively. Cyst volumes and surface areas varied widely within unidimensional size groups with 51% and 40% of volumes and surface areas overlapping unidimensional size groups, respectively. Estimated changes in volume poorly predicted measured changes in volume with 42% of cysts having >100% absolute percent difference. CONCLUSIONS: Pancreatic cyst volume and surface area may be useful adjunct measurements to risk stratify patients and surveil cyst changes and deserves further study.

Texture Analysis: An Emerging Clinical Tool for Pancreatic Lesions.

Radiologic characterization of pancreatic lesions is currently limited. Computed tomography is insensitive in detecting and characterizing small pancreatic lesions. Moreover, heterogeneity of many pancreatic lesions makes determination of malignancy challenging. As a result, invasive diagnostic testing is frequently used to characterize pancreatic lesions but often yields indeterminate results. Computed tomography texture analysis (CTTA) is an emerging noninvasive computational tool that quantifies gray-scale pixels/voxels and their spatial relationships within a region of interest. In nonpancreatic lesions, CTTA has shown promise in diagnosis, lesion characterization, and risk stratification, and more recently, pancreatic applications of CTTA have been explored. This review outlines the emerging role of CTTA in identifying, characterizing, and risk stratifying pancreatic lesions. Although recent studies show the clinical potential of CTTA of the pancreas, a clear understanding of which specific texture features correlate with high-grade dysplasia and predict survival has not yet been achieved. Further multidisciplinary investigations using strong radiologic-pathologic correlation are needed to establish a role for this noninvasive diagnostic tool.

Geriatrics Curriculum Needs Assessment for Dermatology Residency Programs.

BACKGROUND: Geriatric patients account for a growing proportion of dermatology clinic visits. Although their biopsychosocial needs differ from those of younger adults, there are no geriatrics training requirements for dermatology residency programs. OBJECTIVE: This study explored the state of geriatrics education in dermatology programs in 2016. METHODS: This constructivist study employed cross-sectional, mixed-methods analysis with triangulation of semistructured interviews, surveys, and commonly used curricular materials. We used purposive sampling of 5 US academic allopathic dermatology programs of different sizes, geographic locations, and institutional resources. Participants were interviewed about informal curricula, barriers, and suggestions for improving geriatrics education, and they also completed a survey about the geriatrics topics that should be taught. The constant comparative method with grounded theory was used for qualitative analysis. We identified formal geriatrics curricular content by electronically searching and counting relevant key texts. RESULTS: Fourteen of 17 participants (82%) agreed to be interviewed, and 10 of 14 (71%) responded to the survey. Themes of what should be taught included diagnosing and managing skin diseases common in older adults, holistic treatment, cosmetic dermatology, benign skin aging, and the basic science of aging. Topics currently covered that could be expanded included communication, systems-based challenges, ethical issues, safe prescribing, quality improvement, and elder abuse. Cosmetic dermatology was the most commonly taught formal geriatrics curricular topic. CONCLUSIONS: There were discrepancies among topics participants felt were important to teach about geriatric dermatology and curricular coverage of these areas. We identified challenges for expanding geriatrics curricula and potential solutions.

Transport of a kinesin-cargo pair along microtubules into dendritic spines undergoing synaptic plasticity.

Synaptic plasticity often involves changes in the structure and composition of dendritic spines. Vesicular cargos and organelles enter spines either by exocytosing in the dendrite shaft and diffusing into spines or through a kinesin to myosin hand-off at the base of spines. Here we present evidence for microtubule (MT)-based targeting of a specific motor/cargo pair directly into hippocampal dendritic spines. During transient MT polymerization into spines, the kinesin KIF1A and an associated cargo, synaptotagmin-IV (syt-IV), are trafficked in unison along MTs into spines. This trafficking into selected spines is activity-dependent and results in exocytosis of syt-IV-containing vesicles in the spine head. Surprisingly, knockdown of KIF1A causes frequent fusion of syt-IV-containing vesicles throughout the dendritic shaft and diffusion into spines. Taken together, these findings suggest a mechanism for targeting dendritic cargo directly into spines during synaptic plasticity and indicate that MT-bound kinesins prevent unregulated fusion by sequestering vesicular cargo to MTs.