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Defense costs in the United States have been on the rise for the past several decades. The price index used to measure defense costs has outpaced inflation in the overall [...]

ABSTRACT As bacterial symbionts transition from a motile free-living state to a sessile biofilm state, they must coordinate behavior changes suitable to each lifestyle. Cyclic diguanylate (c-di-GMP) is an intracellular signaling molecule that can regulate this transition, and it is synthesized by diguanylate cyclase (DGC) enzymes and degraded by phosphodiesterase (PDE) enzymes. Generally, c-di-GMP inhibits motility and promotes biofilm formation. While c-di-GMP and the enzymes that contribute to its metabolism have been well studied in pathogens, considerably less focus has been placed on c-di-GMP regulation in beneficial symbionts. Vibrio fischeri is the sole beneficial symbiont of the Hawaiian bobtail squid (Euprymna scolopes) light organ, and the bacterium requires both motility and biofilm formation to efficiently colonize. c-di-GMP regulates swimming motility and cellulose exopolysaccharide production in V. fischeri. The genome encodes 50 DGCs and PDEs, and while a few of these proteins have been characterized, the majority have not undergone comprehensive characterization. In this study, we use protein overexpression to systematically characterize the functional potential of all 50 V. fischeri proteins. All 28 predicted DGCs and 10 of the 14 predicted PDEs displayed at least one phenotype consistent with their predicted function, and a majority of each displayed multiple phenotypes. Finally, active site mutant analysis of proteins with the potential for both DGC and PDE activities revealed potential activities for these proteins. This work presents a systems-level functional analysis of a family of signaling proteins in a tractable animal symbiont and will inform future efforts to characterize the roles of individual proteins during lifestyle transitions.IMPORTANCECyclic diguanylate (c-di-GMP) is a critical second messenger that mediates bacterial behaviors, and Vibrio fischeri colonization of its Hawaiian bobtail squid host presents a tractable model in which to interrogate the role of c-di-GMP during animal colonization. This work provides systems-level characterization of the 50 proteins predicted to modulate c-di-GMP levels. By combining multiple assays, we generated a rich understanding of which proteins have the capacity to influence c-di-GMP levels and behaviors. Our functional approach yielded insights into how proteins with domains to both synthesize and degrade c-di-GMP may impact bacterial behaviors. Finally, we integrated published data to provide a broader picture of each of the 50 proteins analyzed. This study will inform future work to define specific pathways by which c-di-GMP regulates symbiotic behaviors and transitions.

Transgender and gender-diverse (TGD) persons represent a small but growing population in the United States. Accessing inclusive, equitable, and evidence-based healthcare remains a challenge for this patient population. Many TGD persons seek gender-affirming care, including gender-affirming hormonal therapy (GAHT) and gender-affirming surgery (GAS), to help ameliorate the physical and mental aspects of their gender incongruence. Both GAHT and GAS induce clinically important histopathologic and anatomic changes in breast tissue. Consequently, breast care in TGD persons has become an increasingly recognized topic of importance in gender-affirming care. However, there remains a scarce but growing base of literature specifically addressing the unique healthcare needs of breast care in TGD patients. This article will review how to establish trusting patient–provider relationships for TGD patients, gender inclusivity in breast clinics and imaging centers, the influence of GAHT and GAS on breast tissue, breast cancer screening recommendations and barriers, and breast cancer risk and treatment considerations in TGD persons.

Objective:. To assess the accuracy, quality, and readability of patient-focused breast cancer websites using expert evaluation and validated tools. Background:. Ensuring access to accurate, high-quality, and readable online health information supports informed decision-making and health equity but has not been recently evaluated. Methods:. A qualitative analysis on 50 websites was conducted; the first 10 eligible websites for the following search terms were included: “breast cancer,” “breast surgery,” “breast reconstructive surgery,” “breast chemotherapy,” and “breast radiation therapy.” Websites were required to be in English and not intended for healthcare professionals. Accuracy was evaluated by 5 breast cancer specialists. Quality was evaluated through the DISCERN questionnaire. Readability was measured using 9 standardized tests. Mean readability was compared with the American Medical Association and National Institutes of Health 6th grade recommendation. Results:. Nonprofit hospital websites had the highest accuracy (mean = 4.06, SD = 0.42); however, no statistical differences were observed in accuracy by website affiliation (P = 0.08). The overall mean quality score was 50.8 (“fair”/“good” quality) with no significant differences among website affiliations (P = 0.10). Mean readability was at the 10th grade reading level, the lowest being for commercial websites with a mean 9th grade reading level (SD = 2.38). All websites exceeded the American Medical Association- and National Institutes of Health-recommended reading level by 4.4 levels (P < 0.001). Websites with higher accuracy tended to have lower readability levels, whereas those with lower accuracy had higher readability levels. Conclusion:. As breast cancer treatment has become increasingly complex, improving online quality and readability while maintaining high accuracy is essential to promote health equity and empower patients to make informed decisions about their care.

Background:. Macromastia, defined as the abnormal enlargement of breasts, burdens individuals physically and psychologically, impacting their daily lives beyond aesthetics. Reduction mammoplasty offers relief by restoring proportional breast volume and appropriate contour. Surgical success relies on choosing a suitable individualized operative technique tailored to the patient’s presentation and postoperative goals. This study examines postoperative, patient-reported outcomes across different reduction techniques to gauge the impact of reduction technique on overall patient perspective of aesthetic and functional satisfaction. Methods:. A retrospective review identified reduction mammoplasty patients by a single surgeon between 2018 and 2022. Exclusion criteria included augmentation-related or cancer reconstructive procedures. Phone interviews were conducted using a survey adapted from BREAST-Q to assess postoperative outcomes in patients. Data analysis included Pearson chi-square test in STATA 16.1. Results:. Among 155 patients identified, 64 completed the survey. Average postsurgical interval was 24 months postoperative. After stratifying patients by operative technique, there was no significant difference in postoperative satisfaction among the cohorts with regard to nipple and breast appearance, sensation, symmetry, or shape. Conclusions:. This study highlights no significant disparity in perceived aesthetic or functional outcomes among different reduction mammoplasty techniques. Personalized considerations, such as patient factors, surgical expertise, and anatomical specifics, should guide technique selection, emphasizing individualized approaches over presumed superior methods for optimal results.

Postsurgical pyoderma gangrenosum (PSPG) is a rare, ulcerative skin condition that presents a diagnostic challenge due to its similar presentation to infectious etiologies in the postsurgical period—often leading to gratuitous and unnecessary surgery and antibiotic use. We report a 37-year-old female with breast cancer who received neoadjuvant chemotherapy and immunotherapy and underwent bilateral skin-sparing mastectomies who developed delayed bilateral mastectomy skin flap necrosis secondary to PSPG. This case had rare factors associated with the development of PSPG such as preoperative systemic therapy and a familial component. This case underscores the importance of early recognition of this rare disease and appropriate management of PSPG to prevent unnecessary interventions and ensure an optimal outcome. [ABSTRACT FROM AUTHOR]

PD-L1 immunohistochemistry (IHC) has become an established method for predicting cancer response to targeted anti-PD1 immunotherapies, including breast cancer (BC). The alternative PD-1 ligand, PD-L2, remains understudied but may be a complementary predictive marker. Prospective analysis of 32 breast cancers revealed divergent expression patterns of PD-L1 and PD-L2. PD-L1-positivity was higher in immune cells than in cancer cells (median = 5.0% vs. 0.0%; p = 0.001), whereas PD-L2-positivity was higher in cancer cells than immune cells (median = 30% vs. 5.0%; p = 0.001). Percent positivity of PD-L1 and PD-L2 were not correlated, neither in cancer cells nor immune cells. Based on a cut-point of ≥1% positivity, ER+ tumors (n = 23) were frequently PD-L2-positive (73.9%), whereas only 40.9% were PD-L1-positive. These data suggest differential control of cellular PD-L1 and PD-L2 expression in BC and a potential role for PD-L2 IHC as a complementary marker to PD-L1 to improve selection of aggressive ER+ BC that may benefit from anti-PD-1 therapy. [ABSTRACT FROM AUTHOR]

A woman in her 20s presented with nephrotic syndrome and hyperemesis in early pregnancy. Pertinent initial investigations revealed a severe acute kidney injury, a serum albumin of 19 g/L, a random protein creatinine ratio of 800 g/mol and microscopic haematuria. All immunological and infection serology testing including anti-glomerular basement membrane (anti-GBM; ELISA) were negative. Kidney biopsy demonstrated diffuse crescentic glomerulonephritis with cellular crescents involving >90% of glomeruli, with immunofluorescence demonstrating intense linear reactivity for IgG consistent with atypical anti-GBM glomerular nephritis. Early pregnancy termination and treatment with immunosuppression were chosen after shared decision-making between the patient and physician. The patient had a poor response to treatment and remained dialysis dependent 12 months later., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

As bacterial symbionts transition from a motile free-living state to a sessile biofilm state, they must coordinate behavior changes suitable to each lifestyle. Cyclic diguanylate (c-di-GMP) is an intracellular signaling molecule that can regulate this transition, and it is synthesized by diguanylate cyclase (DGC) enzymes and degraded by phosphodiesterase (PDE) enzymes. Generally, c-di-GMP inhibits motility and promotes biofilm formation. While c-di-GMP and the enzymes that contribute to its metabolism have been well studied in pathogens, considerably less focus has been placed on c-di-GMP regulation in beneficial symbionts. Vibrio fischeri is the sole beneficial symbiont of the Hawaiian bobtail squid ( Euprymna scolopes ) light organ, and the bacterium requires both motility and biofilm formation to efficiently colonize. c-di-GMP regulates swimming motility and cellulose exopolysaccharide production in V. fischeri . The genome encodes 50 DGCs and PDEs, and while a few of these proteins have been characterized, the majority have not undergone comprehensive characterization. In this study, we use protein overexpression to systematically characterize the functional potential of all 50 V . fischeri proteins. All 28 predicted DGCs and 10 of the 14 predicted PDEs displayed at least one phenotype consistent with their predicted function, and a majority of each displayed multiple phenotypes. Finally, active site mutant analysis of proteins with the potential for both DGC and PDE activities revealed potential activities for these proteins. This work presents a systems-level functional analysis of a family of signaling proteins in a tractable animal symbiont and will inform future efforts to characterize the roles of individual proteins during lifestyle transitions.IMPORTANCECyclic diguanylate (c-di-GMP) is a critical second messenger that mediates bacterial behaviors, and Vibrio fischeri colonization of its Hawaiian bobtail squid host presents a tractable model in which to interrogate the role of c-di-GMP during animal colonization. This work provides systems-level characterization of the 50 proteins predicted to modulate c-di-GMP levels. By combining multiple assays, we generated a rich understanding of which proteins have the capacity to influence c-di-GMP levels and behaviors. Our functional approach yielded insights into how proteins with domains to both synthesize and degrade c-di-GMP may impact bacterial behaviors. Finally, we integrated published data to provide a broader picture of each of the 50 proteins analyzed. This study will inform future work to define specific pathways by which c-di-GMP regulates symbiotic behaviors and transitions., Competing Interests: The authors declare no conflict of interest.

Background: Older adults (≥65 yr) account for the majority of emergency laparotomies in the UK and are well characterised with reported outcomes. In contrast, there is limited knowledge on those patients that require emergency laparotomy but do not undergo surgery (NoLaps)., Methods: A multicentre cohort study (n=64 UK surgical centres) recruited 750 consecutive NoLap patients (February 15th - November 15th 2021, inclusive of a 90-day follow up period). Each patient was admitted to hospital with a surgical condition treatable by an emergency laparotomy (defined by The National Emergency Laparotomy Audit (NELA) criteria), but a decision was made not to undergo surgery (NoLap)., Results: NoLap patients were predominately female (452 patients, 60%), of advanced age (median age 83.0 yr, interquartile range 77.0-88.8), frail (523 patients, 70%), and had severe comorbidity (750 patients, 100%); 99% underwent CT scanning. The commonest diagnoses were perforation (26%), small bowel obstruction (17%), and ischaemic bowel (13%). The 90-day mortality was 79% and influencing factors were >80 yr, underweight BMI, elevated serum lactate or creatinine concentration. The majority of patients died in hospital (77%), with those with ischaemic bowel dying early. For the 21% of NoLap patients that survived to 90 days, 77% returned home with increased care requirements., Conclusions: This study reports that the NoLap patient population present significant medical challenges because of their extreme levels of comorbidity, frailty, and physiology. Despite these complexities a fifth remained alive at 90 days. Further work is underway to explore this high-risk decision-making process., Clinical Trial Registration: ISRCTN14556210., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Background: Non-Hispanic Black women have lower breast cancer incidence but twice the mortality of non-Hispanic White women. Recent data suggest that the overall survival difference may not be observed in older women. This study aims to determine overall survival in women aged ≥70 years with operable breast cancer by race and ethnicity and factors contributing to overall survival., Methods: The National Cancer Database was queried to identify women aged ≥70 years with stage 0-III breast cancer from 2004 to 2018. Patients were separated by race and ethnicity: non-Hispanic White, non-Hispanic Black, Hispanic, and Other. To examine overall survival, a Cox proportional hazards model was created, and overall survival was calculated using the Kaplan-Meier method., Results: There were 304,345 eligible patients. The mean age was 76.8 years (standard deviation 5.5 years), and most were non-Hispanic White (85.2%), had Medicare (86.8%), had hormone receptor-positive breast cancer (78.7%), and underwent partial mastectomy (64.5%). Compared with non-Hispanic White women, non-Hispanic Black women had a higher prevalence of stage III disease (10.8% vs 7.5%, P < .001) and triple-negative breast cancer (16.7% vs 8.7% P < .001), and a longer time to treatment initiation (39.2 vs 32.3 days, P < .001). Median follow-up was 5.38 years (interquartile range: 3.83-7.46 years). Non-Hispanic Black women had the lowest median survival time compared with non-Hispanic White women (9.7 vs 10.4 years, P < .001). After adjusting for insurance type, receptor status, stage, comorbidity, time to treatment, and facility type, there was no increased risk of death for non-Hispanic Black patients (hazard ratio: 0.99, 95% confidence interval: 0.96-1.01, P = .29)., Conclusion: Although overall survival was lower in older non-Hispanic Black women, this difference resolved on multivariate modeling, suggesting that other factors likely influence overall survival for this cohort., Competing Interests: Conflict of Interest/Disclosure The authors have no conflicts of interest or disclosures to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Axillary assessment in breast cancer is key to determining an upfront surgery or neoadjuvant chemotherapy (NAC) approach. We investigated the false-negative rate (FNR) of axillary-node ultrasound-guided core-needle biopsy (US-CNBx) and the surgical management of pN ​+ ​patients., Methods: This single-institution study from 2010 to 2020 included patients with benign findings on US-CNBx and upfront surgery. Statistical analyses were performed via t-tests and chi-squared tests., Results: 95 axillae met inclusion, 23 were pN+, resulting in a US-CNBx FNR of 24.2 ​%. pN ​+ ​patients more frequently had cT2-T3 tumors vs pN0 patients (43.5 ​% vs 27.8 ​%, p ​= ​0.03). Of the 23 ​pN ​+ ​patients, 9 underwent breast-conserving surgery (BCS) and 14 underwent mastectomy. In those with BCS, 7 had 1-2 positive nodes, 2 had ≥3 nodes; 3 received an ALND. In those with mastectomies, 12 had 1-2 positive nodes, 2 had ≥3 positive nodes; 6 received an ALND., Conclusion: In this cohort, US-CNBx had a FNR of 24.2 ​%. pN ​+ ​patients had a greater frequency of cT2-cT3 tumors, therefore clinicians should be cognizant of potential occult nodal disease despite negative CNBx when deciding management., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable and long-lived degrader-mediated ternary complexes drive fast and profound target degradation; however, the mechanisms by which they affect target ubiquitination remain elusive. Here, we show cryo-EM structures of the VHL Cullin 2 RING E3 ligase with the degrader MZ1 directing target protein Brd4 BD2 toward UBE2R1-ubiquitin, and Lys 456 at optimal positioning for nucleophilic attack. In vitro ubiquitination and mass spectrometry illuminate a patch of favorably ubiquitinable lysines on one face of Brd4 BD2 , with cellular degradation and ubiquitinomics confirming the importance of Lys 456 and nearby Lys 368 /Lys 445 , identifying the "ubiquitination zone." Our results demonstrate the proficiency of MZ1 in positioning the substrate for catalysis, the favorability of Brd4 BD2 for ubiquitination by UBE2R1, and the flexibility of CRL2 for capturing suboptimal lysines. We propose a model for ubiquitinability of degrader-recruited targets, providing a mechanistic blueprint for further rational drug design.

Kidney transplant recipients are at increased risk of opportunistic infections and malignancy, including space-occupying intracranial lesions. Here, we present a case of a patient presenting with multiple intracranial lesions in the context of a distant history of transplantation. MRI findings were consistent with a large subcortical enhancing lesion. Leading differentials included posttransplant lymphoproliferative disorder and cerebral cryptococcoma. Brain biopsy was undertaken along with PCR testing on tissue detected Toxoplasma gondii and Epstein-Barr virus (EBV) DNA. Cerebral toxoplasmosis was diagnosed based on characteristic histology and negative EBV immunohistochemistry. This case demonstrates the difficulties and complexities in reaching a diagnosis in immunocompromised patients and the importance of brain biopsy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There are increasing calls for neurodivergent peoples' involvement in research into neurodevelopmental conditions. So far, however, this has tended to be achieved only through membership of external patient and public involvement (PPI) panels. The Regulating Emotions - Strengthening Adolescent Resilience (RE-STAR) programme is building a new participatory model of translational research that places young people with diagnoses of attention-deficit hyperactivity disorder (ADHD) and autism at the heart of the research team so that they can contribute to shaping and delivering its research plan., Aims: To outline the principles on which the RE-STAR participatory model is based and describe its practical implementation and benefits, especially concerning the central role of members of the Youth Researcher Panel (Y-RPers)., Method: The model presented is a culmination of a 24-month process during which Y-RPers moved from advisors to co-researchers integrated within RE-STAR. It is shaped by the principles of co-intentionality. The account here was agreed following multiple iterative cycles of collaborative discussion between academic researchers, Y-RPers and other stakeholders., Results: Based on our collective reflections we offer general guidance on how to effectively integrate young people with diagnoses of ADHD and/or autism into the core of the translational research process. We also describe the specific theoretical, methodological and analytical benefits of Y-RPer involvement in RE-STAR., Conclusions: Although in its infancy, RE-STAR has demonstrated the model's potential to enrich translational science in a way that can change our understanding of the relationship between autism, ADHD and mental health. When appropriately adapted we believe the model can be applied to other types of neurodivergence and/or mental health conditions.

Purpose: Nutrition is essential within cancer care, yet patient and carer access to nutrition care and information is variable. This study aimed to (1) investigate patient and carer access and perceptions, and health professional views and practices, relating to cancer nutrition information and care; and (2) co-design interactive resources to support optimal nutrition care., Methods: Patients and carers completed a survey regarding access to nutrition care and information. Seven multidisciplinary health service teams were invited to participate in a survey and focus group to assess barriers and enablers in nutrition practices. Focus groups were recorded, transcribed and thematically analyzed. Eligible patients, carers, and health professionals were invited to four virtual workshops utilizing experience-based co-design methods to identify nutrition priority areas and design resources. Workshop participant acceptability of the resources was measured., Results: Of 104 consumer survey respondents (n = 97 patients, n = 7 carers), 61% agreed that it "took too much time to find evidence-based nutrition and cancer information", and 46% had seen a dietitian. Thirty-four of 38 health professionals completed the survey and 30 participated in a focus group, and it was identified the greatest barriers to delivering nutrition care were lack of referral services, knowledge or skill gaps, and time. Twenty participants (n = 10 patients and carers, n = 10 health professionals) attended four workshops and co-designed a suite of 46 novel resources rated as highly acceptable., Conclusion: Improved communication, training, and availability of suitable resources could improve access to and support cancer nutrition information and care. New, co-designed cancer nutrition resources were created and deemed highly acceptable to patients, carers, and health professionals., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Measurement of graft dysfunction following kidney transplant through creatinine is well known to be impacted by many different factors. We report here a clinical scenario demonstrating the importance of dual measurement of glomerular filtration rate (GFR) based on creatinine and cystatin C while also examining within-subject variability of both tests., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Transgender and gender-diverse (TGD) persons represent a small but growing population in the United States. Accessing inclusive, equitable, and evidence-based healthcare remains a challenge for this patient population. Many TGD persons seek gender-affirming care, including gender-affirming hormonal therapy (GAHT) and gender-affirming surgery (GAS), to help ameliorate the physical and mental aspects of their gender incongruence. Both GAHT and GAS induce clinically important histopathologic and anatomic changes in breast tissue. Consequently, breast care in TGD persons has become an increasingly recognized topic of importance in gender-affirming care. However, there remains a scarce but growing base of literature specifically addressing the unique healthcare needs of breast care in TGD patients. This article will review how to establish trusting patient-provider relationships for TGD patients, gender inclusivity in breast clinics and imaging centers, the influence of GAHT and GAS on breast tissue, breast cancer screening recommendations and barriers, and breast cancer risk and treatment considerations in TGD persons.