Bladder-Preserving Trimodality Treatment for High-Grade T1 Bladder Cancer: Results From Phase II Protocol NRG Oncology/RTOG 0926.

PURPOSE: To investigate the use of radiation with radiosensitizing chemotherapy following repeated transurethral resection (trimodality therapy) as an alternative to radical cystectomy in T1 bladder cancer which has failed Bacillus Calmette-Guerin (BCG). PATIENTS AND METHODS: Patients with recurrent T1 bladders who had failed BCG and were recommended to undergo cystectomy were treated with trimodality therapy. The primary end point was 3-year freedom from cystectomy. Secondary end points were distant metastasis at 3 and 5 years, local recurrence, disease-specific and overall survival (OS), and safety. RESULTS: This single-arm phase II study enrolled 37 patients. Efficacy and safety were evaluated in 34 patients after three exclusions. The median follow-up was 5.1 years. The 3-year freedom from cystectomy rate was 88% (lower one-sided 97.5% confidence limit [CI], 72%), meeting the primary study goal. OS at 3 and 5 years was 69% (95% CI, 54 to 85) and 56% (95% CI, 39 to 74), respectively. The distant metastasis rates at 3 and 5 years were 12% (95% CI, 4 to 26) and 19% (95% CI, 7 to 34), respectively. Eight patients died due to urothelial cancer, 12 exhibited local recurrence at 3 years (cumulative incidence: 32%; 95% CI, 17 to 48), 18 experienced grade 3 adverse events, mostly hematological, and one developed grade 4 neutropenia. CONCLUSION: Trimodality therapy is an effective potential alternative to radical cystectomy for recurrent high-grade T1 urothelial cancer of the bladder. At 3 years, 88% of the patients remained free of cystectomy.

The impact of ammonia on particle formation in the Asian Tropopause Aerosol Layer.

During summer, ammonia emissions in Southeast Asia influence air pollution and cloud formation. Convective transport by the South Asian monsoon carries these pollutant air masses into the upper troposphere and lower stratosphere (UTLS), where they accumulate under anticyclonic flow conditions. This air mass accumulation is thought to contribute to particle formation and the development of the Asian Tropopause Aerosol Layer (ATAL). Despite the known influence of ammonia and particulate ammonium on air pollution, a comprehensive understanding of the ATAL is lacking. In this modelling study, the influence of ammonia on particle formation is assessed with emphasis on the ATAL. We use the EMAC chemistry-climate model, incorporating new particle formation parameterisations derived from experiments at the CERN CLOUD chamber. Our diurnal cycle analysis confirms that new particle formation mainly occurs during daylight, with a 10-fold enhancement in rate. This increase is prominent in the South Asian monsoon UTLS, where deep convection introduces high ammonia levels from the boundary layer, compared to a baseline scenario without ammonia. Our model simulations reveal that this ammonia-driven particle formation and growth contributes to an increase of up to 80% in cloud condensation nuclei (CCN) concentrations at cloud-forming heights in the South Asian monsoon region. We find that ammonia profoundly influences the aerosol mass and composition in the ATAL through particle growth, as indicated by an order of magnitude increase in nitrate levels linked to ammonia emissions. However, the effect of ammonia-driven new particle formation on aerosol mass in the ATAL is relatively small. Ammonia emissions enhance the regional aerosol optical depth (AOD) for shortwave solar radiation by up to 70%. We conclude that ammonia has a pronounced effect on the ATAL development, composition, the regional AOD, and CCN concentrations.

Engaging Family Members to Support Exclusive Breastfeeding, Responsive care, and Antiretroviral Therapy Adherence Among Families with Children who are HIV-Exposed and Uninfected.

Children who are HIV-exposed and uninfected (CHEU) are at increased risk for poor growth, health, and development compared to children who are HIV-unexposed and uninfected. To support families with CHEU, we assessed the acceptability of engaging family members to support women living with HIV (WLWH) with exclusive breastfeeding (EBF) and antiretroviral therapy (ART) adherence and to engage in responsive infant caregiving. We conducted trials of improved practices, a consultative research approach, that follows participants over time as they try recommended behaviors. We enrolled postpartum women in Lusaka, Zambia, who identified home supporters. At visit 1, WLWH were interviewed about current practices. At visit 2, WLWH and home supporters received tailored EBF, responsive care, and ART adherence counseling. At visit 3, WLWH and home supporters were interviewed about their experiences trying recommended practices for 2-3 weeks. Interview transcripts were analyzed thematically. Participants included 23 WLWH, 15 male partners, and 8 female family members. WLWH reported several barriers to EBF. The most common were fear of HIV transmission via breastfeeding-despite high ART adherence-and insufficient breastmilk. After counseling, WLWH reported less fear of HIV transmission and improved breastfeeding practices. Home supporters reported providing WLWH increased support for EBF and ART adherence and practicing responsive caregiving. Both male and female home supporters appreciated being included in counseling and more involved in caregiving, and WLWH valued the increased support. Families with CHEU need focused support. Tailored counseling and family support for WLWH show promise for improving EBF, responsive caregiving, and ART adherence.

Thyroid lesions in a population of domestic cats submitted to necropsy without clinical suspicion of thyroid disease.

Although hyperthyroidism is the most common endocrine disorder in elderly cats, systematic studies investigating the prevalence of thyroid lesions in feline animals are scarce. Our objective was to evaluate morphological changes in the thyroid glands of 61 cats submitted to necropsy without clinical suspicion of hyperthyroidism. Thirteen (13/61 [21.3%]) cats had thyroid enlargement and 54/61 (88.5%) had some histological thyroid changes. Proliferative lesions were histologically seen in 33/61 (54%) cats while non-proliferative lesions were observed in 48/61 (78.7%) cats. Thyroid hyperplasia (18/33 [54.5%]) and cystic adenoma (6/33 [18.2%]) were the most prevalent proliferative changes and lesions with little or no clinical significance (37/61 [60.6%]), degenerative (31/61 [50.8%]) and inflammatory changes (12/61 [19.7%]) were the most common non-proliferative changes. Among cats with proliferative lesions, 16/33 (48.4%) had a proliferation grade ≥A4, a grade previously associated with clinical hyperthyroidism. Although the cats from this study did not have any clinical diagnosis of thyroid disease, it is possible that one or more had some degree of clinically unnoticed thyroid dysfunction. The high prevalence of follicular lesions in this study highlights the importance of a more careful clinical and pathological investigation regarding thyroid diseases in mature and elderly cats.

Neuropsychology practice guidance for the neuropsychiatric aspects of Long COVID.

Objective: The coronavirus disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has had a profound global impact on individual health and well-being in adults and children. While most fully recover from COVID-19, a relatively large subgroup continues to experience persistent physical, cognitive, and emotional/behavioral symptoms beyond the initial infection period. The World Health Organization has termed this phenomenon "Post-COVID-19 Condition" (PCC), better known as "Long COVID." Due to the cognitive and psychosocial symptoms, neuropsychologists often assess and recommend treatment for individuals with Long COVID. However, guidance for neuropsychologists' involvement in clinical care, policy-making, and research has not yet been developed. The authors of this manuscript convened to address this critical gap and develop guidance for clinical neuropsychologists working with patients presenting with Long COVID. Method: Authors include pediatric and adult neuropsychologists with expertise in Long COVID and behavioral health. All authors have been engaged in clinical and research efforts examining the impact of COVID-19. Authors summarized the literature-to-date pertinent to the neuropsychiatric sequelae of Long COVID and developed guidance for neuropsychologists working with individuals with Long COVID. Conclusions: Research findings regarding neuropsychiatric symptoms associated with Long COVID are mixed and limited by methodological differences. As they practice and conduct research, neuropsychologists should remain mindful of the evolving and tenuous nature of the literature.

Impact of Long-term Storage in 4% Formaldehyde on Immunophenotypic Markers in Glutaraldehyde-treated Bovine Pericardium.

Bovine pericardium (BP) is widely used as a biomaterial for tissue engineering. Glutaraldehyde and formaldehyde are commonly employed in the reticulation processes to enhance the material's resistance and preservation. In this study, we assessed the impact of long-term storage in 4% formaldehyde on the quantitative expression of immunophenotypic markers in glutaraldehyde-treated BP. Histologic and immunohistochemical analyses were performed on 2 BP patches, manufactured in 2009 and 2020, respectively. Braile Biomédica provided the BP patches. Sections of BP were stained with H&E, Weigert, and picrosirius red, followed by immunolabeling for vimentin, laminin 5, collagen I, and collagen IV using a standardized protocol. Microscopic images were captured using light and polarized microscopy, and the area of the antibody signal was quantified using Image J Software. Histologic analysis showed no autolysis or significant changes in the patches. Immunohistochemical analysis revealed a diffuse distribution of collagen I and collagen IV throughout the connective tissue of the patches. The 2020 specimen exhibited higher expression levels of collagen I (21.36%) and collagen IV (24.67%) compared with the 2009 specimen (collagen I: 15.87%; collagen IV: 12.02%). Laminin did not show reactivity in either specimen. Notably, vimentin immunopositivity differed significantly between the patches, with a larger area of expression observed in the 2020 patch (54%) compared with the 2009 patch (13%). In summary, there were no substantial differences in immunophenotypic expression between the 2009 and 2020 BP patches, except for the higher vimentin expression in the 2020 BP patch.

PheMIME: an interactive web app and knowledge base for phenome-wide, multi-institutional multimorbidity analysis.

OBJECTIVES: To address the need for interactive visualization tools and databases in characterizing multimorbidity patterns across different populations, we developed the Phenome-wide Multi-Institutional Multimorbidity Explorer (PheMIME). This tool leverages three large-scale EHR systems to facilitate efficient analysis and visualization of disease multimorbidity, aiming to reveal both robust and novel disease associations that are consistent across different systems and to provide insight for enhancing personalized healthcare strategies. MATERIALS AND METHODS: PheMIME integrates summary statistics from phenome-wide analyses of disease multimorbidities, utilizing data from Vanderbilt University Medical Center, Mass General Brigham, and the UK Biobank. It offers interactive and multifaceted visualizations for exploring multimorbidity. Incorporating an enhanced version of associationSubgraphs, PheMIME also enables dynamic analysis and inference of disease clusters, promoting the discovery of complex multimorbidity patterns. A case study on schizophrenia demonstrates its capability for generating interactive visualizations of multimorbidity networks within and across multiple systems. Additionally, PheMIME supports diverse multimorbidity-based discoveries, detailed further in online case studies. RESULTS: The PheMIME is accessible at https://prod.tbilab.org/PheMIME/. A comprehensive tutorial and multiple case studies for demonstration are available at https://prod.tbilab.org/PheMIME_supplementary_materials/. The source code can be downloaded from https://github.com/tbilab/PheMIME. DISCUSSION: PheMIME represents a significant advancement in medical informatics, offering an efficient solution for accessing, analyzing, and interpreting the complex and noisy real-world patient data in electronic health records. CONCLUSION: PheMIME provides an extensive multimorbidity knowledge base that consolidates data from three EHR systems, and it is a novel interactive tool designed to analyze and visualize multimorbidities across multiple EHR datasets. It stands out as the first of its kind to offer extensive multimorbidity knowledge integration with substantial support for efficient online analysis and interactive visualization.

Retinoic acid induces human gastruloids with posterior embryo-like structures.

Gastruloids are a powerful in vitro model of early human development. However, although elongated and composed of all three germ layers, human gastruloids do not morphologically resemble post-implantation human embryos. Here we show that an early pulse of retinoic acid (RA), together with later Matrigel, robustly induces human gastruloids with posterior embryo-like morphological structures, including a neural tube flanked by segmented somites and diverse cell types, including neural crest, neural progenitors, renal progenitors and myocytes. Through in silico staging based on single-cell RNA sequencing, we find that human RA-gastruloids progress further than other human or mouse embryo models, aligning to E9.5 mouse and CS11 cynomolgus monkey embryos. We leverage chemical and genetic perturbations of RA-gastruloids to confirm that WNT and BMP signalling regulate somite formation and neural tube length in the human context, while transcription factors TBX6 and PAX3 underpin presomitic mesoderm and neural crest, respectively. Looking forward, RA-gastruloids are a robust, scalable model for decoding early human embryogenesis.

Calibration of variant effect predictors on genome-wide data masks heterogeneous performance across genes.

In silico variant effect predictions are available for nearly all missense variants but played a minimal role in clinical variant classification because they were deemed to provide only supporting evidence. Recently, the ClinGen Sequence Variant Interpretation (SVI) Working Group updated recommendations for variant effect prediction use. By analyzing control pathogenic and benign variants across all genes, they were able to compute evidence strength for predictor score intervals with some intervals generating moderate, strong, or even very strong evidence. However, this genome-wide approach could obscure heterogeneous predictor performance in different genes. We quantified the gene-by-gene performance of two top predictors, REVEL and BayesDel, by analyzing control variants in each predictor score interval in 3,668 disease-relevant genes. Approximately 10% of intervals had sufficient control variants for analysis, and ∼70% of these intervals exceeded the maximum number of incorrect predictions implied by the SVI recommendations. These trending discordant intervals arose owing to the divergence of the gene-specific distribution of predictions from the genome-wide distribution, suggesting that gene-specific calibration is needed in many cases. Approximately 22% of ClinVar missense variants of uncertain significance in genes we analyzed (REVEL = 100,629, BayesDel = 71,928) had predictions in trending discordant intervals. Thus, genome-wide calibrations could result in many variants receiving inappropriate evidence strength. To facilitate a review of the SVI's calibrations, we developed a web application enabling visualization of gene-specific predictions and trending concordant and discordant intervals.

Invasive candidiasis in dogs: A case report and review of the literature.

Invasive candidiasis is characterized by the systemic dissemination of Candida spp. and colonization of multiple organs. We are reporting a case of invasive candidiasis in a 3.5-year-old female mixed-breed dog with a history of limb injury. After clinical evaluation and complementary examinations a sepsis diagnose was established. The patient remained hospitalized under antibiotic therapy, dying three days later. Necropsy revealed white, nodular (pyogranulomas), and multifocal areas on the liver, button ulcers in the stomach and intestines, and a random lung consolidation. Impression smears were made from the liver and lung surface lesions during necropsy showing yeast and pseudohyphae structures. Fragments of these organs were sent for fungal culture and subsequent molecular etiologic characterization, identifying it as Candida albicans. Histological examination of different organs showed pyogranulomatous inflammation surrounding the necrosis areas, which were full of yeast and pseudohyphae, as evidenced by periodic acid Schiff and immunohistochemistry. Neutropenia, as a consequence of sepsis, associated with the use of antibiotics may have allowed yeast invasion and proliferation in the mucosa of the gastrointestinal tract, reaching the liver and lungs through hematogenous route. Invasive candidiasis is a rare canine disease, and no other cases of neutropenia associated with antibiotic therapy, as a predisposing factors, have been reported.

Leveraging the outcome of a frontal bone tumor facial reconstruction case by a multimodal approach.

The importance of multimodality in the diagnosis and treatment of medical conditions cannot be overemphasized. Herewith a case of facial malignancy encompassing all stages of management and requiring multimodal approaches for diagnosis, oncological treatment, anatomical reconstruction, and ultimately aesthetics and "identity" is presented.

Aedes aegypti oviposition in urban communities in the Northern Chihuahuan Desert.

BACKGROUND OBJECTIVES: Aedes aegypti (Linnaeus) is the vector of multiple arboviruses, the most important being dengue viruses (DENV) that causes more than 90 million cases per year. The expanded range of Ae. aegypti into temperate climates has contributed to the increasing risk of DENV to new human populations. As an effort to better understand the ecology of Ae. aegypti in a temperate climate, larval surveillance was conducted to identify oviposition locations of this species from 2016-2018 in two nonincorporated communities located in El Paso, Texas and Ciudad Juárez, Chihuahua, Mexico. METHODS: This survey was conducted inside and outside private residences examining any possible water holding containers to collect with a dipper, turkey baster, or Pasteur pipette. Larvae and pupae were transported to the laboratory and reared to adults for morphological identification. A total of 601 Ae. aegypti larvae were collected and reared to adults from 24 containers in the Sparks community. In contrast, a total of 68 Ae. aegypti were collected and reared to adults from seven containers in the Anapra community. RESULTS: In both locations, the predominant container type that yielded immature mosquitoes were plastic buckets. Although the results were based on a small sample size, the finding provided a preliminary understanding of the oviposition sites of Ae. aegypti in two urban communities in a temperate climate region. INTERPRETATION CONCLUSION: The identification of oviposition sites can be used to develop and implement vector control strategies.

Thermodynamic assessment of evaporation during molten steel testing onboard the International Space Station.

Evaporation control is a critical facility resource during solidification experiments that limits processing time and must be tracked to ensure facility health. A thermodynamic analysis was performed on a ternary FeCrNi sample processed onboard the International Space Station (ISS) using ESA Electromagnetic Levitation (EML) facility in a microgravity environment. A non-ideal solution-based mathematical model was applied for the overall sample mass loss prediction during this study. The overall sample mass loss prediction is consistent with the post-flight mass loss measurements. The species-specific findings from this study were validated using post-mission SEM-EDX surface evaluations by three different facilities. The bulk composition prediction was validated using SEM-EDX and wet chemical analysis. The non-ideal solution model was then applied to predict the composition of the dust generated during EML testing. The thicknesses of the deposited layer on the EML coil at various locations were also calculated using the geometry of the facility and results were validated with near-real-time dust layer predictions from toxicity tracking software developed by the German Space Center (DLR) Microgravity User Support Center (MUSC).

The Food Addiction Clinical Treatment (FACT) Manual: A Harm Reduction Treatment Approach.

While the construct of food addiction has been controversial, there is growing evidence that certain foods can activate biobehavioral and neurological mechanisms consistent with addiction to other substances. Despite increased evidence and acceptance of certain foods as addictive substances amongst the scientific community, there is a paucity of interventions available that are uniquely suited for the treatment of this condition. Further, many of the addiction and disordered eating treatment models currently utilized for food addiction are seemingly at odds, with the former often recommending complete abstinence from trigger foods and the latter promoting intake of all foods in moderation. The Food Addiction Clinical Treatment (FACT) manual was created as an alternative using an empirically supported harm-reduction model specifically targeted to treat the addiction and disordered eating features of food addiction. The purpose of the current article is to expose readers to the key tenets of the FACT manual, demonstrate the feasibility of this intervention with a sample of participants with severe food addiction, and discuss future directions for the treatment of food addiction. Positive outcomes from this intervention provide preliminary evidence for the efficacy of FACT for the treatment of food addiction with minimal negative adverse effects. Future research using randomized control trials and longer follow-up is needed to validate the FACT manual as an empirically supported treatment for food addiction.

Practice recommendations regarding parental presence in NICUs during pandemics caused by respiratory pathogens like COVID-19.

Aim: To co-create parental presence practice recommendations across Canadian NICUs during pandemics caused by respiratory pathogens such as COVID-19. Methods: Recommendations were developed through evidence, context, Delphi and Values and Preferences methods. For Delphi 1 and 2, participants rated 50 items and 20 items respectively on a scale from 1 (very low importance) to 5 (very high). To determine consensus, evidence and context of benefits and harms were presented and discussed within the Values and Preference framework for the top-ranked items. An agreement of 80% or more was deemed consensus. Results: After two Delphi rounds (n = 59 participants), 13 recommendations with the highest rated importance were identified. Consensus recommendations included 6 strong recommendations (parents as essential caregivers, providing skin-to-skin contact, direct or mothers' own expressed milk feeding, attending medical rounds, mental health and psychosocial services access, and inclusion of parent partners in pandemic response planning) and 7 conditional recommendations (providing hands-on care tasks, providing touch, two parents present at the same time, food and drink access, use of communication devices, and in-person access to medical rounds and mental health and psychosocial services). Conclusion: These recommendations can guide institutions in developing strategies for parental presence during pandemics caused by respiratory pathogens like COVID-19.

Type I Hsp40s/DnaJs aggregates exhibit features reminiscent of amyloidogenic structures.

A rise in temperature triggers a structural change in the human Type I 40 kDa heat shock protein (Hsp40/DnaJ), known as DNAJA1. This change leads to a less compact structure, characterized by an increased presence of solvent-exposed hydrophobic patches and ß-sheet-rich regions. This transformation is validated by circular dichroism, thioflavin T binding, and Bis-ANS assays. The formation of this ß-sheet-rich conformation, which is amplified in the absence of zinc, leads to protein aggregation. This aggregation is induced not only by high temperatures but also by low ionic strength and high protein concentration. The aggregated conformation exhibits characteristics of an amyloidogenic structure, including a distinctive X-ray diffraction pattern, seeding competence (which stimulates the formation of amyloid-like aggregates), cytotoxicity, resistance to SDS, and fibril formation. Interestingly, the yeast Type I Ydj1 also tends to adopt a similar ß-sheet-rich structure under comparable conditions, whereas Type II Hsp40s, whether human or from yeast, do not. Moreover, Ydj1 aggregates were found to be cytotoxic. Studies using DNAJA1- and Ydj1-deleted mutants suggest that the zinc-finger region plays a crucial role in amyloid formation. Our discovery of amyloid aggregation in a C-terminal deletion mutant of DNAJA1, which resembles a spliced homolog expressed in the testis, implies that Type I Hsp40 co-chaperones may generate amyloidogenic species in vivo.

Novel Textbook Outcomes following emergency laparotomy: Delphi exercise.

BACKGROUND: Textbook outcomes are composite outcome measures that reflect the ideal overall experience for patients. There are many of these in the elective surgery literature but no textbook outcomes have been proposed for patients following emergency laparotomy. The aim was to achieve international consensus amongst experts and patients for the best Textbook Outcomes for non-trauma and trauma emergency laparotomy. METHODS: A modified Delphi exercise was undertaken with three planned rounds to achieve consensus regarding the best Textbook Outcomes based on the category, number and importance (Likert scale of 1-5) of individual outcome measures. There were separate questions for non-trauma and trauma. A patient engagement exercise was undertaken after round 2 to inform the final round. RESULTS: A total of 337 participants from 53 countries participated in all three rounds of the exercise. The final Textbook Outcomes were divided into 'early' and 'longer-term'. For non-trauma patients the proposed early Textbook Outcome was 'Discharged from hospital without serious postoperative complications (Clavien-Dindo ≥ grade III; including intra-abdominal sepsis, organ failure, unplanned re-operation or death). For trauma patients it was 'Discharged from hospital without unexpected transfusion after haemostasis, and no serious postoperative complications (adapted Clavien-Dindo for trauma ≥ grade III; including intra-abdominal sepsis, organ failure, unplanned re-operation on or death)'. The longer-term Textbook Outcome for both non-trauma and trauma was 'Achieved the early Textbook Outcome, and restoration of baseline quality of life at 1 year'. CONCLUSION: Early and longer-term Textbook Outcomes have been agreed by an international consensus of experts for non-trauma and trauma emergency laparotomy. These now require clinical validation with patient data.

Cold-Induced Vasodilation, Rewarming, and Dexterity Impairment Following Second-Degree Frostbite.

Frostbite, a severe cold injury resulting from exposure to subfreezing temperatures, damages the skin and underlying tissues of the affected area and ranges in severity from first to fourth degree. This case report investigates the impact of second-degree frostbite suffered by a marine during winter training on cold-induced vasodilation (CIVD). Comparisons of CIVD before and after the injury revealed significant alterations in CIVD responses. CIVD, a physiological mechanism characterized by blood vessel dilation in response to cold exposure, plays a crucial role in operating in cold-weather environments and enhancing dexterity. The marine exhibited prolonged CIVD onset time, lower finger temperatures, increased pain sensations, and diminished dexterity after the frostbite injury during follow-up CIVD testing. The findings suggest that the frostbite-induced damage possibly compromised the microvascular function, contributing to the observed changes in CIVD. The marine reported persistent cold sensitivity and difficulty in maintaining hand warmth when assessed postinjury. This case underscores the potential long-term consequences of frostbite on CIVD and manual dexterity, emphasizing the importance of understanding these physiological changes for individuals engaged in cold-weather activities, particularly for military and occupational personnel.