Multi-ethnic heterozygote frequencies of cancer susceptibility genes to inform counseling of reproductive risk.

Purpose: Pathogenic germline variants (PGVs) in a subset of cancer predisposition genes (CPGs) are associated with adult-onset autosomal dominant (AD) cancer susceptibility and life-limiting autosomal recessive (AR) disease. Counseling in adult cancer genetics clinics regarding reproductive risk for PGV heterozygotes is limited.

Methods: Estimated heterozygote frequencies across ancestries were calculated for AD CPGs with AR risk (ATM, BRCA1, BRCA2, BRIP1, FH, NBN, MLH1, MSH2, MSH6, PMS2, RAD51C, SDHA, SDHB, and SDHD) from gnomADv.

Dopaminergic Axon Tracts Within a Hyaluronic Acid Hydrogel Encasement to Restore the Nigrostriatal Pathway.

Parkinson's disease is characterized by motor deficits emerging from insufficient dopamine in the striatum after degeneration of dopaminergic neurons and their long-projecting axons comprising the nigrostriatal pathway. To address this, a tissue-engineered nigrostriatal pathway (TE-NSP) featuring a tubular hydrogel with a collagen/laminin core that encases aggregated dopaminergic neurons and their axonal tracts is developed. This engineered microtissue can be implanted to replace neurons and axons with fidelity to the lost pathway and thus may provide dopamine according to feedback from host circuitry.

Granulocyte colony stimulating factor promotes scarless tissue regeneration.

Mammals typically heal with fibrotic scars, and treatments to regenerate human skin and hair without a scar remain elusive. We discovered that mice lacking C-X-C motif chemokine receptor 2 (CXCR2 knockout [KO]) displayed robust and complete tissue regeneration across three different injury models: skin, hair follicle, and cartilage. Remarkably, wild-type mice receiving plasma from CXCR2 KO mice through parabiosis or injections healed wounds scarlessly.

Recruitment of CXCR4+ type 1 innate lymphoid cells distinguishes sarcoidosis from other skin granulomatous diseases.

Sarcoidosis is a multiorgan granulomatous disease that lacks diagnostic biomarkers and targeted treatments. Using blood and skin from patients with sarcoid and non-sarcoid skin granulomas, we discovered that skin granulomas from different diseases exhibit unique immune cell recruitment and molecular signatures. Sarcoid skin granulomas were specifically enriched for type 1 innate lymphoid cells (ILC1s) and B cells and exhibited molecular programs associated with formation of mature tertiary lymphoid structures (TLSs), including increased CXCL12/CXCR4 signaling.

CXCL9, CXCL10, and CCL19 synergistically recruit T lymphocytes to skin in lichen planus.

Lichen planus (LP) is a chronic, debilitating, inflammatory disease of the skin and mucous membranes that affects 1%-2% of Americans. Its molecular pathogenesis remains poorly understood, and there are no FDA-approved treatments. We performed single-cell RNA sequencing on paired blood and skin samples (lesional and nonlesional tissue) from 7 patients with LP.

Effect of gamification with a support partner to increase physical activity in older adults at risk for Alzheimer's disease: The STEP 4Life randomized clinical trial.

Introduction: Physical activity is associated with reduced risk of cognitive and functional decline but scalable, sustainable interventions for populations at risk for Alzheimer's disease (AD) and AD and related dementias (ADRD) are lacking.

Methods: A 12-week randomized-controlled trial was conducted with a 3-week follow-up using a national AD prevention registry (GeneMatch). The control group (n = 50) set step goals and received daily feedback.

Clinical management of TP53 mosaic variants found on germline genetic testing.

Background: Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management.

Patients And Methods: Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing.

Distinct genomic and immunologic tumor evolution in germline -driven breast cancers.

Pathogenic germline alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of with no recurrent oncogenic variants except (HER2) amplification.

Mechanoepigenetic regulation of extracellular matrix homeostasis via Yap and Taz.

Cells integrate mechanical cues to direct fate specification to maintain tissue function and homeostasis. While disruption of these cues is known to lead to aberrant cell behavior and chronic diseases, such as tendinopathies, the underlying mechanisms by which mechanical signals maintain cell function are not well understood. Here, we show using a model of tendon de-tensioning that loss of tensile cues in vivo acutely changes nuclear morphology, positioning, and expression of catabolic gene programs, resulting in subsequent weakening of the tendon.

Plasma protein and venous thromboembolism: prospective cohort and mendelian randomisation analyses.

We conducted cohort and Mendelian randomisation (MR) analyses to examine the associations of circulating proteins with risk of venous thromboembolism (VTE) to provide evidence basis for disease prevention and drug development. Cohort analysis was performed in 11 803 participants without baseline VTE. Cox regression was used to estimate the associations between 257 proteins and VTE risk.

Clinical practice selectively follows acute appendicitis guidelines.

Introduction: Acute appendicitis is a common surgical emergency, and the standard approach to diagnosis and management has been codified in several practice guidelines. Adherence to these guidelines provides insight into independent surgical practice patterns and institutional resource constraints as impediments to best practice. We explored data from the recent ESTES SnapAppy observational cohort study to determine guideline compliance in contemporary practice to identify opportunities to close evidence-to-practice gaps.

Techniques for mesoappendix transection and appendix resection: insights from the ESTES SnapAppy study.

Introduction: Surgically managed appendicitis exhibits great heterogeneity in techniques for mesoappendix transection and appendix amputation from its base. It is unclear whether a particular surgical technique provides outcome benefit or reduces complications.

Material And Methods: We undertook a pre-specified subgroup analysis of all patients who underwent laparoscopic appendectomy at index admission during SnapAppy (ClinicalTrials.

Surgical management of acute appendicitis during the European COVID-19 second wave: safe and effective.

Introduction: The COVID-19 (SARS-CoV-2) pandemic drove acute care surgeons to pivot from long established practice patterns. Early safety concerns regarding increased postoperative complication risk in those with active COVID infection promoted antibiotic-driven non-operative therapy for select conditions ahead of an evidence-base. Our study assesses whether active or recent SARS-CoV-2 positivity increases hospital length of stay (LOS) or postoperative complications following appendectomy.

Graded operative autonomy in emergency appendectomy mirrors case-complexity: surgical training insights from the SnapAppy prospective observational study.

Introduction: Surgical skill, a summation of acquired wisdom, deliberate practice and experience, has been linked to improved patient outcomes. Graded mentored exposure to pathologies and operative techniques is a cornerstone of surgical training. Appendectomy is one of the first procedures surgical trainees perform independently.

Successful Discharge of Short Stay Veterans from VA Community Living Centers.

The Veterans Health Administration (VHA) long-term care rebalancing initiative encouraged VA Community Living Centers (CLCs) to shift from long-stay custodial-focused care to short-stay skilled and rehabilitative care. Using all VA CLC admissions during 2007-2010 categorized as needing short-stay rehabilitation or skilled nursing care, we assessed the patient and facility rates of successful discharge to the community (SDC) of these short-stay Veterans. We found large variation in inter- as well as intra- facility SDC rates across the rehabilitation and skilled nursing short-stay cohorts.

Current state and future directions of genomic medicine in aortic dissection: A path to prevention and personalized care.

Aortic dissection confers high mortality and morbidity rates despite advances in treatment, impacts quality of life, and contributes immense burden to the healthcare system globally. Efforts to prevent aortic dissection through screening and management of modifiable risk factors and early detection of aneurysms should incorporate genomic information, as it is integral to stratifying risk. However, effective integration of genomic-guided risk assessment into clinical practice will require addressing implementation barriers that currently permeate our healthcare systems.

Clinical and Psychological Factors Associated With Return to Work Among United States Diplomats Who Sustained a Work-Related Injury While on Assignment in Havana, Cuba.

Objective: To determine factors associated with return to work in US diplomats injured during a work assignment in Cuba.

Methods: In this case series work ability was determined at each visit. Questionnaires used included the Symptom Score Questionnaire, Beck Anxiety Inventory, Beck Depression Inventory, Quality-of-Life Inventory, and Patient Health Questionnaire.

Restoring lost nigrostriatal fibers in Parkinson's disease based on clinically-inspired design criteria.

Parkinson's disease is a neurodegenerative disease affecting around 10 million people worldwide. The death of dopaminergic neurons in the substantia nigra and the axonal fibers that constitute the nigrostriatal pathway leads to a loss of dopamine in the striatum that causes the motor symptoms of this disease. Traditional treatments have focused on reducing symptoms, while therapies with human fetal or stem cell-derived neurons have centered on implanting these cells in the striatum to restore its innervation.

Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses.

[Figure: see text].