Multisensory Logic of Infant-Directed Aggression by Males.

Newborn mice emit signals that promote parenting from mothers and fathers but trigger aggressive responses from virgin males. Although pup-directed attacks by males require vomeronasal function, the specific infant cues that elicit this behavior are unknown. We developed a behavioral paradigm based on reconstituted pup cues and showed that discrete infant morphological features combined with salivary chemosignals elicit robust male aggression. Seven vomeronasal receptors were identified based on infant-mediated activity, and the involvement of two receptors, Vmn2r65 and Vmn2r88, in infant-directed aggression was demonstrated by genetic deletion. Using the activation of these receptors as readouts for biochemical fractionation, we isolated two pheromonal compounds, the submandibular gland protein C and hemoglobins. Unexpectedly, none of the identified vomeronasal receptors and associated cues were specific to pups. Thus, infant-mediated aggression by virgin males relies on the recognition of pup's physical traits in addition to parental and infant chemical cues.

Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome.

BACKGROUND: Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and squamous-cell carcinoma. The cause is unknown, and mortality is high. METHODS: We evaluated four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM. Genomic sequencing independently identified three heterozygous variants in a specific region of the gene that encodes signal transducer and activator of transcription 4 (STAT4). Primary skin fibroblast and cell-line assays were used to define the functional nature of the genetic defect. We also assayed gene expression using single-cell RNA sequencing of peripheral-blood mononuclear cells to identify inflammatory pathways that may be affected in DPM and that may respond to therapy. RESULTS: Genome sequencing revealed three novel heterozygous missense gain-of-function variants in STAT4. In vitro, primary skin fibroblasts showed enhanced interleukin-6 secretion, with impaired wound healing, contraction of the collagen matrix, and matrix secretion. Inhibition of Janus kinase (JAK)-STAT signaling with ruxolitinib led to improvement in the hyperinflammatory fibroblast phenotype in vitro and resolution of inflammatory markers and clinical symptoms in treated patients, without adverse effects. Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that were appropriately modified through JAK inhibition. CONCLUSIONS: Gain-of-function variants in STAT4 caused DPM in the families that we studied. The JAK inhibitor ruxolitinib attenuated the dermatologic and inflammatory phenotype in vitro and in the affected family members. (Funded by the American Academy of Allergy, Asthma, and Immunology Foundation and others.).

Chin Dysmorphology in the Primary Rhinoplasty Population: Prevalence, Objective Analysis, and Implications.

BACKGROUND: Chin flaws are far more common than recognized. Denial of genioplasty by parents or adult patients can present a surgical planning enigma, especially in patients with microgenia and chin deviation. This study aims to investigate the frequency of chin imperfections on patients seeking rhinoplasty, review the conundrum they generate, and offer management suggestions based on over 40 years of the senior author's experience. METHODS: This review included 108 consecutive patients presenting for primary rhinoplasty. Demographics, soft tissue cephalometrics, and surgical details were obtained. Exclusion criteria included prior orthognathic or isolated chin surgery, mandiblular trauma, or congenital craniofacial deformities. RESULTS: Of the 108 patients, 92 (85.2%) were female. Mean age was 30.8 years (SD±13, range 14-72). Ninety-seven (89.8%) patients exhibited some degree of objective chin dysmorphology. Fifteen (13.9%) had Class I deformities (macrogenia), 63 (58.3%) Class II (microgenia), and 14 (12.9%) Class III (combined macro and microgenia in the horizontal or vertical vectors). Forty-one (38%) patients had Class IV deformities (asymmetry). While all patients were offered the opportunity to correct chin flaws, only 11 (10.1%) underwent such procedures. Five (4.6%) patients had simultaneous osseous genioplasty (mean advancement 7.8mm, range 5-9mm); 7 (6.5%) received fat grafting to the chin (mean volume 4.4cc, range 1-9cc). CONCLUSIONS: A considerable proportion of primary rhinoplasty patients possess quantifiable chin dysmorphology on circumspect examination, high-resolution photographs and cephalometric analysis. Only a small number agree to surgical interventions that pursue full facial harmony. Potential reasons for these findings, patient aversion, and mitigation strategies will be discussed. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Anatomy Camp: A Medical Student-Run Outreach Program.

Anatomy Camp is a medical student-run program for underserved youth from communities near the university. Middle and high school students are invited to visit the medical school for an afternoon of interacting with medical students, informal learning of anatomy and wellness, and becoming inspired to consider medical and STEM professions.

The Diversity of Vasectomy Reversal Providers and Their Web-based Advertising Habits in the United States.

OBJECTIVE: To better understand the internet advertising material published on clinician websites for the 30,000 men who undergo evaluation for vasectomy reversal (VR), which is a technically demanding procedure requiring microsurgical expertise. METHODS: Internet search trends for "vasectomy" and "vasectomy reversal" from 2004 to 2022 were assessed using Google Trends. Search engines were then queried on a state-by-state basis for physicians performing VR and the available information aggregated and analyzed using standard statistical approaches. RESULTS: VR search volume consistently represented roughly one-tenth of the search volume for vasectomy. One hundred and ninety reversal clinics were identified in 44 of 50 states with the highest number identified in the southeast region and an overall median price of $6500. Ninety percent of physicians were male and completed residencies in urology. Other specialties included obstetrics and gynecology, general surgery, family medicine and orthopedic surgery. Forty-two percent of urologists had completed infertility fellowships. Sixty percent of physicians utilized a microscope, and 4.7% of physicians explicitly stated they did not perform vasoepididymostomy even when indicated. Fifty two percent of clinics reported VR success rates as high as 100%, and 34% of clinics reported pregnancy outcomes. Twenty-five percent of clinics reported out-of-pocket VR pricing and 26% discussed possible complications. CONCLUSION: VR is a technically demanding cash-pay procedure being performed by physicians with a wide array of backgrounds and outcomes. Urologists should strive to lead by example and report their training, personal experiences, and expected outcomes to enable optimal medical decision making for each patient.

Assessment of Comorbidities Associated With Allergic Contact Dermatitis in the United States: A Retrospective Claims-Based Study.

BACKGROUND: Allergic contact dermatitis (ACD) is a common dermatologic disease. Patch testing remains the criterion standard for diagnosis. In clinical practice, avoidance may be limited by patient occupation or noncompliance, the pervasive nature of the culprit agent, or barriers to expert care because of socioeconomic, cultural, or geographic factors. Thus, ACD is frequently chronic and/or recurrent; however, the comorbidities associated with ACD are not well characterized. OBJECTIVE: The aim of the study is to identify associations between ACD and psychiatric, sleep health, cardiovascular, and infectious conditions. METHODS: In this study, we used a large US claims database to identify comorbidities associated with ACD diagnosed after patch testing, including psychiatric, sleep health, cardiovascular, and infectious conditions. We also stratified these associations by chronicity of disease. RESULTS: We identified associations between ACD and psychiatric, sleep-related, cardiovascular, and infectious comorbidities. We also found that more chronic ACD was associated with more infectious comorbidities. All of these associations remained significant on further subanalysis when patients with AD and venous stasis were excluded. CONCLUSIONS: Allergic contact dermatitis is associated with multiple comorbidities. Further study is required to corroborate these findings, determine causality, and to explore the impact of possible interventions in the workup and management of this common and often debilitating disease.

Characterization of comorbidity heterogeneity among 13,667 patients with hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disorder characterized by recurrent abscesses in the groin and flexural areas. HS is associated with a wide range of comorbidities that complicate the disease course. Although these comorbidities have been well described, it remains unclear how these comorbidities coassociate and whether comorbidity profiles affect disease trajectory. In addition, it is unknown how comorbidity associations are modulated by race and sex. In this comprehensive analysis of 77 million patients in a large US population-based cohort, we examined coassociation patterns among HS comorbidities and identified clinically relevant phenotypic subtypes within HS. We demonstrated that these subtypes not only differed among races, but also influenced clinical outcomes as measured by HS-related emergency department visits and cellulitis. Taken together, our findings provide key insights that elucidate the unique disease trajectories experienced by patients with HS and equip clinicians with a framework for risk stratification and improved targeted care in HS.

Gaps in Treatment and Surveillance: Head and Neck Cancer Care in a Safety-Net Hospital.

OBJECTIVE: Treatment delays and suboptimal adherence to posttreatment surveillance may adversely affect head and neck cancer (HNC) outcomes. Such challenges can be exacerbated in safety-net settings that struggle with limited resources and serve a disproportionate number of patients vulnerable to gaps in care. This study aims to characterize treatment delays and adherence with posttreatment surveillance in HNC care at an urban tertiary care public hospital in San Francisco. STUDY DESIGN: Retrospective chart review. SETTING: Urban tertiary care public hospital in San Francisco. SUBJECTS AND METHODS: We identified all cases of HNC diagnosed from 2008 to 2010 through the electronic medical record. We abstracted data, including patient characteristics, disease characteristics, pathology and radiology findings, treatment details, posttreatment follow-up, and clinical outcomes. RESULTS: We included 64 patients. Median time from diagnosis to treatment initiation (DTI) was 57 days for all patients, 54 days for patients undergoing surgery only, 49 days for patients undergoing surgery followed by adjuvant radiation ± chemotherapy, 65 days for patients undergoing definitive radiation ± chemotherapy, and 29 days for patients undergoing neoadjuvant chemotherapy followed by radiation or chemoradiation. Overall, 69% of patients completed recommended treatment. Forty-two of 61 (69%) patients demonstrated adherence to posttreatment visits in year 1; this fell to 14 out of 30 patients (47%) by year 5. CONCLUSION: DTI was persistently prolonged in this study compared with prior studies in other public hospital settings. Adherence to posttreatment surveillance was suboptimal and continued to decline as the surveillance period progressed.

Publisher Correction: Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy.

The original version of this Article contained errors in Fig. 7. In panels e and f, the graph titles incorrectly read 'LNCaP-AdtNs' and 'LAPC4-AdtNs', respectively. These errors have now been corrected in both the PDF and HTML versions of the Article.

Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy.

Despite recent advances, the efficacy of androgen/androgen receptor (AR)-targeted therapy remains  limited for many patients with metastatic prostate cancer. This is in part because prostate cancers adaptively switch to the androgen/AR-independent pathway for survival and growth, thereby conferring therapy resistance. Tumor hypoxia is considered as a major cause of treatment resistance. However, the exact mechanism is largely unclear. Here we report that chronic-androgen deprivation therapy (ADT) in the condition of hypoxia induces adaptive androgen/AR-independence, and therefore confers resistance to androgen/AR-targeted therapy, e.g., enzalutamide. Mechanistically, this is mediated by glucose-6-phosphate isomerase (GPI), which is transcriptionally repressed by AR in hypoxia, but restored and increased by AR inhibition. In turn, GPI maintains glucose metabolism and energy homeostasis in hypoxia by redirecting the glucose flux from androgen/AR-dependent pentose phosphate pathway (PPP) to hypoxia-induced glycolysis pathway, thereby reducing the growth inhibitory effect of enzalutamide. Inhibiting GPI overcomes the therapy resistance in hypoxia in vitro and increases enzalutamide efficacy in vivo.