Right-sided Morgagni diaphragmatic hernia presenting as isolated left shoulder pain.

A woman in her 60s presented to the emergency department with excruciating, deep left shoulder pain and was found to have a right-sided Morgagni hernia, a rare type of congenital diaphragmatic hernia (CDH). She did not have chest pain, palpitations, shortness of breath, cough, abdominal pain, constipation, diarrhoea, nausea, vomiting or other symptoms classically associated with CDHs in adults. Laparoscopic robotic-assisted repair with mesh placement was performed, and the patient's recovery was uncomplicated, with no recurrence of shoulder pain. Our patient's presentation was unusual due to the absence of symptoms typically seen with CDHs in adults, and the presence of contralateral, left-sided shoulder pain with a right-sided Morgagni hernia.

Integrated organismal responses induced by projected levels of CO2 and temperature exposures in the early life stages of lake sturgeon.

Atmospheric CO2 and temperature are rising concurrently, and may have profound impacts on the transcriptional, physiological and behavioural responses of aquatic organisms. Further, spring snowmelt may cause transient increases of pCO2 in many freshwater systems. We examined the behavioural, physiological and transcriptomic responses of an ancient fish, the lake sturgeon (Acipenser fulvescens) to projected levels of warming and pCO2 during its most vulnerable period of life, the first year. Specifically, larval fish were raised in either low (16°C) or high (22°C) temperature, and/or low (1000 µatm) or high (2500 µatm) pCO2 in a crossed experimental design over approximately 8 months. Following overwintering, lake sturgeon were exposed to a transient increase in pCO2 of 10,000 µatm, simulating a spring melt based on data in freshwater systems. Transcriptional analyses revealed potential connections to otolith formation and reduced growth in fish exposed to high pCO2 and temperature in combination. Network analyses of differential gene expression revealed different biological processes among the different treatments on the edges of transcriptional networks. Na+/K+-ATPase activity increased in fish not exposed to elevated pCO2 during development, and mRNA abundance of the ß subunit was most strongly predictive of enzyme activity. Behavioural assays revealed a decrease in total activity following an acute CO2 exposure. These results demonstrate compensatory and compounding mechanisms of pCO2 and warming dependent on developmental conditions in lake sturgeon. Conserved elements of the cellular stress response across all organisms provide key information for how other freshwater organisms may respond to future climate change.

Transcriptome-wide association analysis identifies candidate susceptibility genes for prostate-specific antigen levels in men without prostate cancer.

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10 × 10-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61 × 10-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25 × 10-6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in a TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a GWAS. Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability of >0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

The role of the antennal glands and gills in acid-base regulation and ammonia excretion of a marine osmoconforming brachyuran.

The excretory mechanisms of stenohaline marine osmoconforming crabs are often compared to those of the more extensively characterized euryhaline osmoregulating crabs. These comparisons may have limitations, given that unlike euryhaline brachyurans the gills of stenohaline marine osmoconformers possess ion-leaky paracellular pathways and lack the capacity to undergo ultrastructural changes that can promote ion-transport processes in dilute media. Furthermore, the antennal glands of stenohaline marine osmoconformers are poorly characterized making it difficult to determine what role urinary processes play in excretion. In the presented study, ammonia excretory processes as well as related acid-base equivalent transport rates and mechanisms were investigated in the Dungeness crab, Metacarcinus magister - an economically valuable stenohaline marine osmoconforming crab. Isolated and perfused gills were found to predominantly eliminate ammonia through a microtubule network-dependent active NH4+ transport mechanism that is likely performed by cells lining the arterial pockets of the gill lamella where critical Na+/K+-ATPase detection was observed. The V-type H+-ATPase - a vital component to transbranchial ammonia excretion mechanisms of euryhaline crabs - was not found to contribute significantly to ammonia excretion; however, this may be due to the transporter's unexpected apical localization. Although unconnected to ammonia excretion rates, a membrane-bound isoform of carbonic anhydrase was localized to the apical and basolateral membranes of lamella suited for respiration. Urine was found to contain significantly less ammonia as well as carbonate species than the hemolymph, indicating that unlike those of some euryhaline crabs the antennal glands of the Dungeness crab reabsorb these molecules rather than eliminate them for excretion.

A Preliminary Controlled Trial of Endoscopic Ultrasound-guided Fiducial Markers to Guide Pancreas Surgery.

OBJECTIVE: Endoscopic ultrasound (EUS) is routinely used for fiducial marker placement (FMP) to guide stereotactic radiation of pancreatic tumors, but EUS-FMP explicitly to guide surgery has not been studied in a prospective, controlled manner. Multipurpose EUS systems have been developed that facilitate simultaneous EUS-FMP at the time of biopsy. We aimed to evaluate the feasibility of EUS-FMP to guide pancreatic resection. METHODS: In this prospective trial, we enrolled patients with resectable pancreas masses undergoing tissue sampling and placed preloaded fiducials immediately after biopsy. Intraprocedure confirmation of carcinoma, neuroendocrine, and nonlymphomatous neoplasia by rapid on-site evaluation and lesion size <4 cm was required. The main outcomes were the feasibility and ease of preoperative placement and intraoperative detection of the markers using predefined Likert scales. RESULTS: In 20 patients, EUS-FMP was successful before planned surgery and placement was technically straightforward (Likert Scale: 9.1 ± 1.3; range: 1, most challenging to 10, most facile). Intraoperative detection was feasible and improved when compared with a pre-established comparator of 5 representing an equivalent lesion without a marker (Likert Scale: 7.8 ± 2.2; range: 1, most difficult to 10, most facile; P = 0.011). The mean tumor size on EUS was 1.7 ± 0.9 (range: 0.5 to 3.6) cm. CONCLUSION: EUS-FMP is feasible and safe for resectable pancreatic tumors before surgery and may assist in perioperative detection. Preloaded fiducials may be considered for placement at the time of initial referral for EUS-fine needle biopsy.

Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.

Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

The carbonyl-lock mechanism underlying non-aromatic fluorescence in biological matter.

Challenging the basis of our chemical intuition, recent experimental evidence reveals the presence of a new type of intrinsic fluorescence in biomolecules that exists even in the absence of aromatic or electronically conjugated chemical compounds. The origin of this phenomenon has remained elusive so far. In the present study, we identify a mechanism underlying this new type of fluorescence in different biological aggregates. By employing non-adiabatic ab initio molecular dynamics simulations combined with a data-driven approach, we characterize the typical ultrafast non-radiative relaxation pathways active in non-fluorescent peptides. We show that the key vibrational mode for the non-radiative decay towards the ground state is the carbonyl elongation. Non-aromatic fluorescence appears to emerge from blocking this mode with strong local interactions such as hydrogen bonds. While we cannot rule out the existence of alternative non-aromatic fluorescence mechanisms in other systems, we demonstrate that this carbonyl-lock mechanism for trapping the excited state leads to the fluorescence yield increase observed experimentally, and set the stage for design principles to realize novel non-invasive biocompatible probes with applications in bioimaging, sensing, and biophotonics.

Zirconium Coordination Chemistry and Its Role in Optimizing Hydroxymate Chelation: Insights from Molecular Dynamics.

In the past decade, there has been a growth in using Zirconium-89 (89Zr) as a radionuclide in nuclear medicine for cancer diagnostic imaging and drug discovery processes. Although one of the most popular chelators for 89Zr, desferrioxamine (DFO) is typically presented as a hexadentate ligand, our work suggests a different scenario. The coordination structure of the Zr4+-DFO complex has primarily been informed by DFT-based calculations, which typically ignore temperature and therefore entropic and dynamic solvent effects. In this work, free energy calculations using molecular dynamics simulations, where the conformational fluctuations of both the ligand and the solvent are explicitly included, are used to compare the binding of Zr4+ cations with two different chelators, DFO and 4HMS, the latter of which is an octadentate ligand that has been recently proposed as a better chelator due to the presence of four hydroxymate groups. We find that thermally induced disorder leads to an open hexadentate chelate structure of the Zr4+-DFO complex, leaving the Zr4+ metal exposed to the solvent. A stable coordination of Zr4+ with 4HMS, however, is formed by involving both hydroxamate groups and water molecules in a more closely packed structure.

Improving fine needle aspiration to predict the tumor biological aggressiveness in pancreatic neuroendocrine tumors using Ki-67 proliferation index, phosphorylated histone H3 (PHH3), and BCL-2.

INTRODUCTION: Surgery is the only known cure for sporadic pancreatic neuroendocrine tumors (PNETs). Therefore, the prediction of the PNETs biological aggressiveness evaluated on endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has a significant impact on clinical management. The proliferation rate of Ki-67 in PNETs can help to predict the biological aggressiveness of the tumor. In addition, there is a relatively new proliferation marker called phosphorylated histone H3 (PHH3) that can identify and quantify dividing cells in tissue samples, which is a marker highly specific to mitotic figures. Other markers such as BCL-2 also contribute to tumorigenesis and may be involved in the differentiation of neuroendocrine cells. MATERIALS AND METHODS: A retrospective observational study was performed on patients undergoing surveillance for PNETs from January 2010 to May 2021. Data collection included the patients' age, sex, tumor location, tumor size in the surgical specimen, and tumor grade in FNA. The 2019 World Health Organization (WHO) classification guideline was followed to diagnose PNETs, including grade and stage. Immunohistochemical stainings for Ki-67, PHH3 and BCL-2 in PNETs were performed. RESULTS: After excluding cell blocks containing fewer than 100 tumor cells, 44 patients with EUS-FNA and surgical resection specimens were included in this study. There were 19 cases of G1 PNETs, 20 cases of G2 PNETs, and 5 cases of G3 PNETs. The grade assigned based on the Ki-67 index was higher and more sensitive than that based on the mitotic count using H&E slides in some cases of G2 and G3 PNETs. However, there was no significant difference between the mitotic count using PHH3-positive tumor cells and the Ki-67 index to grade PNETs. All grade 1 tumors (19 cases) on surgical resection specimens were correctly graded on FNA (100 % concordance rate). Within the 20 G2 PNETs, 15 cases of grade 2 on surgical resection specimens were graded correctly on FNA based on the Ki-67 index only. Five cases of grade 2 PNETs on surgical resection specimens were graded as grade 1 on FNA when using only the Ki-67 index. Three of five grade 3 tumors on surgical resection specimens were graded as grade 2 on FNA based on the Ki-67 index only. Using only FNA Ki-67 to predict PNET tumor grade, the concordance (accuracy) rate was 81.8 % in total. However, all these eight cases (5 cases of G2 PNETs and 3 cases of G3 PNETs) were graded correctly by using the Ki-67 index plus mitotic rate (using PHH3 IHC stains). Four of 18 (22.2 %) patients with PNETs were positive for BCL-2 stain. In these 4 cases positive for BCL-2 stains, 3 cases were G2 PNETs and one case was G3 PNETs. CONCLUSION: Grade and the proliferative rate in EUS-FNA can be used to predict the tumor grade in surgical resection specimens. However, when using only FNA Ki-67 to predict PNET tumor grade, about 18 % of cases were downgraded by one level. To solve the problem, immunohistochemical staining for BCL-2 and especially PHH3 would be helpful. Our results demonstrated that the mitotic count using PHH3 IHC stains not only improved the accuracy and precision of PNET grading in the surgical resection specimens, but also could reliably be used in routine scoring of mitotic figures of FNA specimens.

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry.

BACKGROUND: Genetic factors play an important role in prostate cancer (PCa) susceptibility. OBJECTIVE: To discover common genetic variants contributing to the risk of PCa in men of African ancestry. DESIGN, SETTING, AND PARTICIPANTS: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. RESULTS AND LIMITATIONS: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4). CONCLUSIONS: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. PATIENT SUMMARY: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Characterization of two novel ammonia transporters, HIAT1α and HIAT1ß, in the American Horseshoe Crab, Limulus polyphemus.

The American horseshoe crab, Limulus polyphemus, excretes nitrogenous waste in the form of toxic ammonia across their book gills. The mechanism of this branchial excretion is yet unknown. In the current study, two isoforms of a novel ammonia transporter, LpHIAT1α and LpHIAT1ß, have been identified in L. polyphemus. Both isoforms have 12 predicted transmembrane regions and share 82.7% of amino acid identity to each other, and 77-86% amino acid homology to HIAT1 found in fish and crustaceans. In L. polyphemus, both isoforms were expressed in the gills, coxal glands, and brain. Slightly higher mRNA expression levels of LpHIAT1α were observed in the peripheral mitochondria-poor region of the gill (PMPA), central mitochondria-rich region of the gill (CMRA), and brain compared to the LpHIAT1ß isoform. A functional expression analysis of LpHIAT1α and LpHIAT1ß in Xenopus laevis oocytes resulted in a significantly lower uptake of the radiolabeled ammonia analogue 3H-methylamine when compared to controls, indicating an ammonia excretory function of the proteins. Exposure to elevated environmental ammonia (HEA, 1 mmol l-1 NH4Cl) caused an increase in mRNA expression of LpHIAT1ß in the ion-conductive ventral gill half. High mRNA expression of both isoforms in the brain, and the observation that LpHIAT1α and LpHIAT1ß likely mediate cellular ammonia excretion, suggests that these highly conserved ammonia transporters have an important housekeeping function in cellular ammonia elimination.

Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: A meta-analysis within diverse populations.

Background: We recently developed a multi-ancestry polygenic risk score (PRS) that effectively stratifies prostate cancer risk across populations. In this study, we validated the performance of the PRS in the multi-ancestry Million Veteran Program and additional independent studies. Methods: Within each ancestry population, the association of PRS with prostate cancer risk was evaluated separately in each case-control study and then combined in a fixed-effects inverse-variance-weighted meta-analysis. We further assessed the effect modification by age and estimated the age-specific absolute risk of prostate cancer for each ancestry population. Results: The PRS was evaluated in 31,925 cases and 490,507 controls, including men from European (22,049 cases, 414,249 controls), African (8794 cases, 55,657 controls), and Hispanic (1082 cases, 20,601 controls) populations. Comparing men in the top decile (90-100% of the PRS) to the average 40-60% PRS category, the prostate cancer odds ratio (OR) was 3.8-fold in European ancestry men (95% CI = 3.62-3.96), 2.8-fold in African ancestry men (95% CI = 2.59-3.03), and 3.2-fold in Hispanic men (95% CI = 2.64-3.92). The PRS did not discriminate risk of aggressive versus nonaggressive prostate cancer. However, the OR diminished with advancing age (European ancestry men in the top decile: ≤55 years, OR = 7.11; 55-60 years, OR = 4.26; >70 years, OR = 2.79). Men in the top PRS decile reached 5% absolute prostate cancer risk ~10 years younger than men in the 40-60% PRS category. Conclusions: Our findings validate the multi-ancestry PRS as an effective prostate cancer risk stratification tool across populations. A clinical study of PRS is warranted to determine whether the PRS could be used for risk-stratified screening and early detection. Funding: This work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers U19 CA214253 to C.A.H., U01 CA257328 to C.A.H., U19 CA148537 to C.A.H., R01 CA165862 to C.A.H., K99 CA246063 to B.F.D, and T32CA229110 to F.C), the Prostate Cancer Foundation (grants 21YOUN11 to B.F.D. and 20CHAS03 to C.A.H.), the Achievement Rewards for College Scientists Foundation Los Angeles Founder Chapter to B.F.D, and the Million Veteran Program-MVP017. This research has been conducted using the UK Biobank Resource under application number 42195. This research is based on data from the Million Veteran Program, Office of Research and Development, and the Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the United States Government.

The concordance between wide-area transepithelial sampling with computer-assisted 3-dimensional analysis (WATS-3D) and standard endoscope biopsy in the detection of Barrett's esophagus and esophageal dysplasia.

INTRODUCTION: Barrett's esophagus (BE) is a premalignant condition that leads to susceptibility to developing adenocarcinoma. The most common endoscopic surveillance technique is forceps biopsy, which involves sampling the specimen every 1 to 2 cm along the length of the lesion. This technique has a low sensitivity and often leaves the majority of the esophageal mucosa untested. Recently, the use of wide-area transepithelial sampling with computer-assisted 3-dimensional analysis (WATS-3D) has received much attention. However, there is little known about this novel technique, and this research aims to add to our knowledge of WATS-3D by comparing it to traditional forceps biopsy. MATERIALS AND METHODS: A retrospective observational study was performed. All existing GI biopsy cases diagnosed with WATS-3D were identified from the institutional pathology databases of NYU Langone Hospital - Long Island from 2019 to 2021. Data collection included patients' age, sex, and dysplasia results. Existing pathology reports and CDx diagnostics were reviewed. All the existing slides of the biopsy cases were pulled out and reviewed. Dysplasia was classified as no dysplasia, indefinite for dysplasia, lowgrade dysplasia, and high-grade dysplasia. RESULTS: A total of 109 cases were included in this study. There are 59 cases diagnosed as BE with forceps biopsy, 72 cases by WATS-3D, and 77 cases by WATS-3D combined with forceps biopsy. The sensitivity of detecting BE was significantly increased by WATS-3D and further by WATS-3D combined with forceps biopsy. In 59 cases diagnosed as BE with forceps biopsy, 50 cases were classified as no dysplasia, 3 cases were indefinite for dysplasia, 5 cases were low-grade dysplasia, and 1 case was high-grade dysplasia. In 72 cases diagnosed as BE by WATS-3D, 64 cases were classified as no dysplasia, 7 cases were indefinite for dysplasia, 1 case was high-grade dysplasia, and no cases with low-grade dysplasia. In 77 cases diagnosed as BE by WATS-3D combined with forceps biopsy, 63 cases were classified as no dysplasia, 8 cases were indefinite for dysplasia, 5 cases with low-grade dysplasia, and 1 case was highgrade dysplasia. The maximal longitudinal extent of the esophageal mucosal changes strongly correlated with the severity of BE. CONCLUSION: Compared to traditional forceps biopsy, WATS-3D was more sensitive in finding intestinal metaplasia. However, WATS-3D could not clearly discriminate low-grade dysplasia from indefinite for dysplasia and tended to classify low-grade dysplasia as indefinite for dysplasia. The addition of WATS-3D to forceps biopsy resulted in an increase in diagnostic yield and thus an increase in the quality of patient care.

Pediatric pleuropulmonary synovial sarcoma: A case report in a recurrent spontaneous pneumothorax.

Pleuropulmonary Synovial Sarcoma is a rare lung cancer with a prevalence of <1% among all lung cancers. Little is known about the clinical presentation, disease process, and appropriate treatment. Here we present a 9-year-old male who was taken to the operating room for pleurodesis and blebectomy due to a recurrent spontaneous pneumothorax. Final pathology showed a bleb with an associated mass positive for Pleuropulmonary synovial sarcoma.

Computational Evolution Protocol for Peptide Design.

Computational peptide design is useful for therapeutics, diagnostics, and vaccine development. To select the most promising peptide candidates, the key is describing accurately the peptide-target interactions at the molecular level. We here review a computational peptide design protocol whose key feature is the use of all-atom explicit solvent molecular dynamics for describing the different peptide-target complexes explored during the optimization. We describe the milestones behind the development of this protocol, which is now implemented in an open-source code called PARCE. We provide a basic tutorial to run the code for an antibody fragment design example. Finally, we describe three additional applications of the method to design peptides for different targets, illustrating the broad scope of the proposed approach.

Prevalence of Inherited Mutations in Breast Cancer Predisposition Genes among Women in Uganda and Cameroon.

BACKGROUND: Sub-Saharan Africa (SSA) has a high proportion of premenopausal hormone receptor negative breast cancer. Previous studies reported a strikingly high prevalence of germline mutations in BRCA1 and BRCA2 among Nigerian patients with breast cancer. It is unknown if this exists in other SSA countries. METHODS: Breast cancer cases, unselected for age at diagnosis and family history, were recruited from tertiary hospitals in Kampala, Uganda and Yaoundé, Cameroon. Controls were women without breast cancer recruited from the same hospitals and age-matched to cases. A multigene sequencing panel was used to test for germline mutations. RESULTS: There were 196 cases and 185 controls with a mean age of 46.2 and 46.6 years for cases and controls, respectively. Among cases, 15.8% carried a pathogenic or likely pathogenic mutation in a breast cancer susceptibility gene: 5.6% in BRCA1, 5.6% in BRCA2, 1.5% in ATM, 1% in PALB2, 0.5% in BARD1, 0.5% in CDH1, and 0.5% in TP53. Among controls, 1.6% carried a mutation in one of these genes. Cases were 11-fold more likely to carry a mutation compared with controls (OR = 11.34; 95% confidence interval, 3.44-59.06; P < 0.001). The mean age of cases with BRCA1 mutations was 38.3 years compared with 46.7 years among other cases without such mutations (P = 0.03). CONCLUSIONS: Our findings replicate the earlier report of a high proportion of mutations in BRCA1/2 among patients with symptomatic breast cancer in SSA. IMPACT: Given the high burden of inherited breast cancer in SSA countries, genetic risk assessment could be integrated into national cancer control plans.

Third distant recurrence of benign thymoma in a patient with myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease where antibodies attack the presynaptic terminals at the neuromuscular junction causing progressive weakness. Associated with thymomas, resection can improve symptoms. A 29-year-old woman with MG who underwent two previous thymectomies, at ages 11 and 15 presented 14 years later with recurrent MG symptoms and an anterior mediastinal mass. Robotic-assisted thoracoscopic excision of the mediastinal mass was performed without complications. She recovered well and had improvement of her MG symptoms. Thymectomy can significantly improve symptoms in MG even for patients who do not have a thymoma. Reports of distant benign thymoma recurrence are rare. MG patients require continued monitoring and vigilance, even after thymectomy. Benign thymomas can recur even after significant time intervals, and utilisation of the robotic platform for recurrent thymoma excision is safe, even following two sternotomies. Patient symptoms improve with redo thymectomy.

Alzheimer's Disease-Associated ß-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection.

Amyloid-ß peptide (Aß) fibrilization and deposition as ß-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aß is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aß antimicrobial activities. Thus, infection can seed and dramatically accelerate ß-amyloid deposition. Here, we show Aß oligomers bind herpesvirus surface glycoproteins, accelerating ß-amyloid deposition and leading to protective viral entrapment activity in 5XFAD mouse and 3D human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce ß-amyloidosis in brain. These data support the notion that Aß might play a protective role in CNS innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aß amyloidosis.