Zfp106 binds to G-quadruplex RNAs and inhibits RAN translation and formation of RNA foci caused by G4C2 repeats.

Expansion of intronic GGGGCC repeats in the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Transcription of the expanded repeats results in the formation of RNA-containing nuclear foci and altered RNA metabolism. In addition, repeat-associated non-AUG (RAN) translation of the expanded GGGGCC-repeat sequence results in the production of highly toxic dipeptide-repeat (DPR) proteins. GGGGCC repeat-containing transcripts form G-quadruplexes, which are associated with formation of RNA foci and RAN translation. Zfp106, an RNA-binding protein essential for motor neuron survival in mice, suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Here, we show that Zfp106 inhibits formation of RNA foci and significantly reduces RAN translation caused by GGGGCC repeats in cultured mammalian cells, and we demonstrate that Zfp106 coexpression reduces the levels of DPRs in C9orf72 patient-derived cells. Further, we show that Zfp106 binds to RNA G-quadruplexes and causes a conformational change in the G-quadruplex structure formed by GGGGCC repeats. Together, these data demonstrate that Zfp106 suppresses the formation of RNA foci and DPRs caused by GGGGCC repeats and suggest that the G-quadruplex RNA-binding function of Zfp106 contributes to its suppression of GGGGCC repeat-mediated cytotoxicity.

Evaluation of the diagnostic sensitivity and specificity of two pen-side tests for detecting African swine fever virus in experimentally infected pigs.

African swine fever virus (ASFV) has spread through many countries and regions worldwide, causing significant losses. Timely detection of ASFV-infected pigs is crucial for disease control. In this study, we assessed the performance of two pen-side tests: a portable real-time PCR (qPCR) test for detecting viral genomic DNA and a lateral flow immunoassay (LFIA) for detecting viral antigens. To determine the time from infection to the earliest detection, 10 ASFV-seronegative pigs were inoculated intramuscularly with 104.0 hemadsorption dose 50 of a highly virulent ASFV strain. Whole blood and oral swab samples were alternately collected from each group of five pigs daily until all succumbed to the infection. Samples were promptly subjected to the two pen-side tests upon collection, and a subset was transported to a veterinary diagnostic laboratory for analysis using a reference qPCR assay. Viral genomic DNA was consistently detected by the reference qPCR assay in all blood samples from 2 days postinfection (dpi), preceding the onset of clinical signs, and in oral swabs from 4 dpi onwards. The portable qPCR test demonstrated comparable performance to the reference qPCR assay for both whole blood and oral swab samples. The LFIA exhibited 100% specificity when testing with whole blood samples but showed reduced sensitivity, particularly for blood samples collected early or late after infection. The antigen test did not perform well with oral swabs.

Temporal Trends in the Rate of Revision Total Knee Arthroplasty for Prosthetic Joint Infection.

Background: Perioperative practices have been introduced over the last decade to decrease the risk of periprosthetic joint infection (PJI). We sought to determine whether rates of revision total knee arthroplasty (TKA) for PJI decreased during the period 2006-2016. Methods: This observational cohort study used data from the New York Statewide Planning and Research Cooperative System to identify patients undergoing TKA in 2006-2016. Data through 2017 were used to determine if patients underwent revision TKA for PJI (including debridement, antibiotics and implant retention) within 1 year of the primary surgery. A generalized estimating equation model, clustered by hospital, was used to examine the impact of time on likelihood of revision TKA for PJI. Results: In 2006-2016, 233,165 primary TKAs performed were included. Mean age was 66.1 (standard deviation 10.3) years, and 65% were women. Overall, 0.5% of the patients underwent revision TKA for PJI within 1 year of surgery. The generalized estimating equation model showed that for primary TKA performed in 2006-2013, year of surgery did not impact the likelihood of revision TKA for PJI (odds ratio 1.00, 95% confidence interval 0.97-1.03, P = .9221), but that for primary TKA performed in 2014-2016, the likelihood decreased by year (odds ratio 0.76, 95% confidence interval 0.66-0.88, P = .0002). Conclusions: The likelihood of revision TKA for PJI was stable from 2006 to 2013 but declined during the period 2014-2016 across patient and hospital categories. This decline could be due to infection mitigation strategies or other unmeasured factors.

Foreign Body-Related Liver Abscess: A Case Study on Fishbone.

Foreign body-related complications are rare but possibly fatal events in clinical practice. Liver abscess as a result of gastrointestinal perforation caused by foreign bodies is even more rare. We report a case of a 63-year-old man who was admitted with fever and left epigastric pain. Further investigation revealed a liver abscess without resolution despite antibiotic therapy for several weeks. In the second admission, an enhanced computerized tomography scan revealed multiple abscesses in the left lobe of the liver, with a linear radio-dense foreign body within the collection. Open surgery was performed to extract the foreign body. The patient made a satisfactory postoperative recovery without complications and was discharged on the sixth postoperative day.

Scaling up a brief alcohol intervention to prevent HIV infection in Vietnam: a cluster randomized, implementation trial.

BACKGROUND: Evidence-based interventions (EBIs) often address normative behaviors. If a behavior is also common among clinicians, they may be skeptical about the necessity or effectiveness of an EBI. Alternatively, clinicians' attitudes and behaviors may be misaligned, or they may lack the knowledge and self-efficacy to deliver the EBI. Several EBIs address unhealthy alcohol use, a common and often culturally acceptable behavior. But unhealthy alcohol use may be particularly harmful to people with HIV (PWH). Here, we present an implementation trial using an experiential implementation strategy to address clinicians' knowledge, attitudes, and behaviors. Clinicians receive the experiential intervention before they begin delivering an evidence-based brief alcohol intervention (BAI) to PWH with unhealthy alcohol use. METHODS: Design: In this hybrid type 3 implementation-effectiveness cluster randomized controlled trial, ART clinics (n = 30) will be randomized 1:1 to facilitation, a flexible strategy to address implementation barriers, or facilitation plus the experiential brief alcohol intervention (EBAI). In the EBAI arm, clinicians, irrespective of their alcohol use, will be offered the BAI as experiential learning. EBAI will address clinicians' alcohol-related attitudes and behaviors and increase their knowledge and confidence to deliver the BAI. PARTICIPANTS: ART clinic staff will be enrolled and assessed at pre-BAI training, post-BAI training, 3, 12, and 24 months. All PWH at the ART clinics who screen positive for unhealthy alcohol use will be offered the BAI. A subset of PWH (n = 810) will be enrolled and assessed at baseline, 3, and 12 months. OUTCOMES: We will compare implementation outcomes (acceptability, fidelity, penetration, costs, and sustainability) and effectiveness outcomes (viral suppression and alcohol use) between the two arms. We will assess the impact of site-level characteristics on scaling-up the BAI. We will also evaluate how experiencing the BAI affected clinical staff's alcohol use and clinic-level alcohol expectations in the EBAI arm. DISCUSSION: This trial contributes to implementation science by testing a novel strategy to implement a behavior change intervention in a setting in which clinicians themselves may engage in the behavior. Experiential learning may be useful to address normative and difficult to change lifestyle behaviors that contribute to chronic diseases. TRIAL REGISTRATION: NCT06358885 (04/10/2024), https://clinicaltrials.gov/study/NCT06358885 .

New α-glucosidase inhibitory xanthones from the fruits of Garcinia schomburgkiana.

Two previously unreported xanthones, xanthoschomes A and B (1 and 2), along with six known xanthones, α-mangostin (3), ß-mangostin (4), γ-mangostin (5), garcinone C (6), 2-(γ,γ-dimethylallyl)-1,7-dihydroxy-3-methoxyxanthone (7), and dulxanthone D (8), have been isolated from the fruits of Vietnamese Garcinia schomburgkiana. The structures of all isolated compounds were fully characterised using spectroscopic data and comparison with the previous literature. All isolated compounds were evaluated for their in vitro α-glucosidase inhibitory activity. Compounds 1-8 demonstrated effective α-glucosidase inhibition, with the IC50 ranging from 2.91 to 26.0 µM, outperforming the standard acarbose (IC50 179 µM). Among these isolated compounds, compound 8 exhibited the highest inhibitory activity against α-glucosidase, with an IC50 value of 2.91 µM.

Distribution and Population Genetic Structure of the Hau Giang Medaka, Oryzias haugiangensis, Along the East Coast of the Indochinese Peninsula.

The east coast of the Indochinese Peninsula is a well-known transition zone from subtropical to tropical systems, yet only a small number of studies have been conducted on the biogeography and phylogeography of aquatic organisms in this region. The Hau Giang medaka, Oryzias haugiangensis, was originally described from the Mekong Delta in southern Vietnam, and later reported also from southeastern Thailand, west of the Mekong Delta region. However, the species' full geographic range and population genetic structures remain unknown. Field surveys showed a widespread distribution of this species along the east coast of the Indochinese Peninsula, as far as northern Vietnam. A mitochondrial gene phylogeny and population genetic structure analysis using genome-wide single nucleotide polymorphisms revealed that the populations of O. haugiangensis are highly structuralized along the east coast of Vietnam, with the southernmost Mekong Delta population clearly separated from three populations north of central Vietnam. Further field collections are necessary to determine the boundary between the southern and northern populations, and the presence or absence of a hybrid zone.

Silver nanoparticles alter the dimerization of Aß42 studied by REMD simulations.

The aggregation of amyloid beta (Aß) peptides is associated with the development of Alzheimer's disease (AD). However, there has been a growing belief that the oligomerization of Aß species in different environments has a neurotoxic effect on the patient's brain, causing damage. It is necessary to comprehend the compositions of Aß oligomers in order to develop medications that may effectively inhibit these neurotoxic forms that affect the nervous system of AD patients. Thus, dissociation or inhibition of Aß aggregation may be able to prevent AD. To date, the search for traditional agents and biomolecules has largely been unsuccessful. In this context, nanoparticles have emerged as potential candidates to directly inhibit the formation of Aß oligomers. The oligomerization of the dimeric Aß peptides with or without the influence of a silver nanoparticle was thus investigated using temperature replica-exchange molecular dynamics (REMD) simulations. The physical insights into the dimeric Aß oligomerization were clarified by analyzing intermolecular contact maps, the free energy landscape of the dimeric oligomer, secondary structure terms, etc. The difference in obtained metrics between Aß with or without a silver nanoparticle provides a picture of the influence of silver nanoparticles on the oligomerization process. The underlying mechanisms that are involved in altering Aß oligomerization will be discussed. The obtained results may play an important role in searching for Aß inhibitor pathways.

Alchemical approach performance in calculating the ligand-binding free energy.

Alchemical binding free energy calculations are one of the most accurate methods for estimating ligand-binding affinity. Assessing the accuracy of the approach over protein targets is one of the most interesting issues. The free energy difference of binding between a protein and a ligand was calculated via the alchemical approach. The alchemical approach exhibits satisfactory accuracy over four targets, including AmpC beta-lactamase (AmpC); glutamate receptor, ionotropic kainate 1 (GluK1); heat shock protein 90 (Hsp90); and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). In particular, the correlation coefficients between calculated binding free energies and the respective experiments over four targets range from 0.56 to 0.86. The affinity computed via free energy perturbation (FEP) simulations is overestimated over the experimental value. Particularly, the electrostatic interaction free energy rules the binding process of ligands to AmpC and GluK1. However, the van der Waals (vdW) interaction free energy plays an important role in the ligand-binding processes of HSP90 and SARS-CoV-2 Mpro. The obtained results associate with the hydrophilic or hydrophobic properties of the ligands. This observation may enhance computer-aided drug design.

A ratiometric substrate for rapid evaluation of transfer hydrogenation efficiency in solution.

A cyclometalated iridium(III) complex bearing a self-immolative quinolinium moiety was developed as a ratiometric substrate for transfer hydrogenation studies. This photoluminescent probe allowed the rapid screening of a variety of Ir catalysts using a microplate reader, offering a convenient method to assess activity using a minimum amount of catalyst sample.

De novo-designed transmembrane proteins bind and regulate a cytokine receptor.

Transmembrane (TM) domains as simple as a single span can perform complex biological functions using entirely lipid-embedded chemical features. Computational design has the potential to generate custom tool molecules directly targeting membrane proteins at their functional TM regions. Thus far, designed TM domain-targeting agents have been limited to mimicking the binding modes and motifs of natural TM interaction partners. Here, we demonstrate the design of de novo TM proteins targeting the erythropoietin receptor (EpoR) TM domain in a custom binding topology competitive with receptor homodimerization. The TM proteins expressed in mammalian cells complex with EpoR and inhibit erythropoietin-induced cell proliferation. In vitro, the synthetic TM domain complex outcompetes EpoR homodimerization. Structural characterization reveals that the complex involves the intended amino acids and agrees with our designed molecular model of antiparallel TM helices at 1:1 stoichiometry. Thus, membrane protein TM regions can now be targeted in custom-designed topologies.

Enhancing the electronic and optical properties of the metal/semiconductor NbS2/BSe nanoheterostructure towards advanced electronics.

Metal-semiconductor (M-S) contacts play a vital role in advanced applications, serving as crucial components in ultracompact devices and exerting a significant impact on overall device performance. Here, in this work, we design a M-S nanoheterostructure between a metallic NbS2 monolayer and a semiconducting BSe monolayer using first-principles prediction. The stability of such an M-S nanoheterostructure is verified and its electronic and optical properties are also considered. Our results indicate that the NbS2/BSe nanoheterostructure is structurally, mechanically and thermally stable. The formation of the NbS2/BSe heterostructure leads to the generation of a Schottky contact with the Schottky barrier ranging from 0.36 to 0.51 eV, depending on the stacking configurations. In addition, the optical absorption coefficient of the NbS2/BSe heterostructure can reach up to 5 × 105 cm-1 at a photon energy of about 5 eV, which is still greater than that in the constituent NbS2 and BSe monolayers. This finding suggests that the formation of the M-S NbS2/BSe heterostructure gives rise to an enhancement in the optical absorption of both NbS2 and BSe monolayers. Notably, the tunneling probability and the contact tunneling-specific resistivity at the interface of the NbS2/BSe heterostructure are low, indicating its applicability in emerging nanoelectronic devices, such as Schottky diodes and field-effect transistors. Our findings offer valuable insights for the practical utilization of electronic devices based on the NbS2/BSe heterostructure.

Natural compounds inhibit Monkeypox virus methyltransferase VP39 in silico studies.

VP39, an essential 2'-O-RNA methyltransferase enzyme discovered in Monkeypox virus (MPXV), plays a vital role in viral RNA replication and transcription. Inhibition of the enzyme may prevent viral replication. In this context, using a combination of molecular docking and molecular dynamics (MDs) simulations, the inhibitory ability of NCI Diversity Set VII natural compounds to VP39 protein was investigated. It should be noted that the computed binding free energy of ligand via molecular docking and linear interaction energy (LIE) approaches are in good agreement with the corresponding experiments with coefficients of R=0.72 and 0.75, respectively. NSC 319990, NSC 196515 and NSC 376254 compounds were demonstrated that can inhibit MPVX methyltransferase VP39 protein with the similar affinity compared to available inhibitor sinefungin. Moreover, nine residues involving Gln39, Gly68, Gly72, Asp95, Arg97, Val116, Asp138, Arg140 and Asn156 may be argued that they play an important role in binding process of inhibitors to VP39.Communicated by Ramaswamy H. Sarma.

Gut Microbiome of Patients With Breast Cancer in Vietnam.

PURPOSE: Gut microbiota play an important role in human health, including cancer. Cancer and its treatment, in turn, may alter the gut microbiome. To understand this complex relationship, we profiled the gut microbiome of 356 Vietnamese patients with breast cancer. MATERIALS AND METHODS: Stool samples were collected before chemotherapy, with 162 pre- and 194 postsurgery. The gut microbiome was measured by shotgun metagenomic sequencing. Associations of gut microbial diversity, taxa abundance, and gut microbiome health index (GMHI) with sociodemographic, clinical factors, and tumor characteristics were evaluated. RESULTS: Postsurgery samples were associated with significantly lower α- and ß-diversities (P < .001) and showed significant differences in the abundance of 15% of 2,864 investigated taxa (false discovery rate [FDR] <0.1) compared with presurgery samples. An unhealthy gut microbiome was prevalent among patients with breast cancer, with a mean GMHI of -0.79 and -2.81 in pre- and postsurgery stool samples, respectively. In an analysis of 162 presurgery stool samples, diagnosis delay was significantly associated with lower α-diversity, variation in ß-diversity, an increased abundance of species Enorma massiliensis, and a decreased abundance of Faecalicoccus pleomorphus. High intake of fiber was significantly associated with lower α-diversity and a higher abundance of species belonging to Bifidobacterium, Prevotella, and Bacteroides gena (FDR < 0.1). We did not find that cancer stage and subtype, menopausal status, comorbidity, antibiotic use during 3 months before stool collection, or physical activity was significantly associated with α- and ß-diversities or GMHI although a few significant differences were observed in taxa abundance. CONCLUSION: Our study revealed that diagnosis delay, high fiber intake, and breast cancer surgery, which is always followed by antibiotic prophylaxis in Vietnam, led to a less diverse and unhealthy gut microbiome among patients with breast cancer.

Endoscopic port access resection of left atrial myxoma: Clinical outcomes and a single surgeon's learning curve experience.

Objectives: To evaluate the safety and efficacy of the port access approach for left atrial (LA) myxoma resection and to analyze the learning curve for this procedure. Methods: Thirty-six consecutive patients with LA myxoma who underwent port access surgery between April 2018 and March 2023 were enrolled in this retrospective study. The procedure included (1) unilateral or bilateral femoral artery cannulation; (2) the use of three 5-mm trocars and a 20- to 30-mm port; (3) a transseptal, biatrial, or LA approach depending on the location of the tumor base; and (4) complete or subendocardial tumor resection. CUSUM analysis was used to evaluate the aortic cross-clamp (ACC) time and cardiopulmonary bypass (CPB) time learning curves. Variables among the learning curve phases were compared. Results: The average ACC and CPB times were 49 (range, 45-79) minutes and 127 (range, 120-164) minutes, respectively. There was 1 case of conversion to sternotomy due to aortic root bleeding and 1 case of unilateral pulmonary edema. CUSUMACCtime analysis included 3 phases: phase I, the initial learning period (cases 1-11); phase II, the technical competence period (cases 12-23); and phase III, the challenging period (cases 24-36). Conclusions: The port access approach is safe and feasible for LA myxoma resection. According to the learning curve analysis, 11 cases are required to achieve technical competence, and 23 cases are required to address highly challenging cases.

Gut microbiome in association with chemotherapy-induced toxicities among patients with breast cancer.

BACKGROUND: Little research has focused on the relationship between gut microbiome and chemotherapy-induced toxicity. METHODS: This prospective study involves 301 patients with breast cancer who had prechemotherapy stool samples collected. Gut microbiome was sequenced by shotgun metagenomics; associations with chemotherapy-induced toxicities during first-line treatment by gut microbial diversity, composition, and metabolic pathways with severe (i.e., grade ≥3) hematological and gastrointestinal toxicities were evaluated via multivariable logistic regression. RESULTS: High prechemotherapy α-diversity was associated with a significantly reduced risk of both severe hematological toxicity (odds ratio [OR] = 0.94; 95% CI, 0.89-0.99; p = .048) and neutropenia (OR = 0.94; 95% CI, 0.89-0.99; p = .016). A high abundance of phylum Synergistota, class Synergistia, and order Synergistales were significantly associated with a reduced risk of severe neutropenia; conversely, enrichment of phylum Firmicutes C, class Negativicutes, phylum Firmicutes I, and class Bacilli A, order Paenibacillales were significantly associated with an increased risk of severe neutropenia (p range: 0.012-2.32 × 10-3; false discovery rate <0.1). Significant positive associations were also observed between severe nausea/vomiting and high Chao1 indexes, ß-diversity (p < .05), 20 species belonging to the family Lachnospiraceae, Oscillospiraceae, and Ruminococcaceae (p value range: 6.14 × 10-3 to 1.33 × 10-5; false discovery rate <0.1), and three metabolic pathways involved in reductive tricarboxylic acid cycle I and cycle II, and an incomplete reductive tricarboxylic acid cycle (p < .01). Conversely, a high abundance of species Odoribacter laneus and the pathway related to the L-proline biosynthesis II were inversely associated with severe nausea/vomiting. CONCLUSIONS: Our study suggests that gut microbiota may be a potential preventive target to reduce chemotherapy-induced toxicity.

Closing Dichloramine Decomposition Nitrogen and Oxygen Mass Balances: Relative Importance of End-Products from the Reactive Nitrogen Species Pathway.

In drinking water chloramination, monochloramine autodecomposition occurs in the presence of excess free ammonia through dichloramine, the decay of which was implicated in N-nitrosodimethylamine (NDMA) formation by (i) dichloramine hydrolysis to nitroxyl which reacts with itself to nitrous oxide (N2O), (ii) nitroxyl reaction with dissolved oxygen (DO) to peroxynitrite or mono/dichloramine to nitrogen gas (N2), and (iii) peroxynitrite reaction with total dimethylamine (TOTDMA) to NDMA or decomposition to nitrite/nitrate. Here, the yields of nitrogen and oxygen-containing end-products were quantified at pH 9 from NHCl2 decomposition at 200, 400, or 800 µeq Cl2·L-1 with and without 10 µM-N TOTDMA under ambient DO (∼500 µM-O) and, to limit peroxynitrite formation, low DO (≤40 µM-O). Without TOTDMA, the sum of free ammonia, monochloramine, dichloramine, N2, N2O, nitrite, and nitrate indicated nitrogen recoveries ±95% confidence intervals were not significantly different under ambient (90 ± 6%) and low (93 ± 7%) DO. With TOTDMA, nitrogen recoveries were less under ambient (82 ± 5%) than low (97 ± 7%) DO. Oxygen recoveries under ambient DO were 88-97%, and the so-called unidentified product of dichloramine decomposition formed at about three-fold greater concentration under ambient compared to low DO, like NDMA, consistent with a DO limitation. Unidentified product formation stemmed from peroxynitrite decomposition products reacting with mono/dichloramine. For a 2:2:1 nitrogen/oxygen/chlorine atom ratio and its estimated molar absorptivity, unidentified product inclusion with uncertainty may close oxygen recoveries and increase nitrogen recoveries to 98% (ambient DO) and 100% (low DO).

Correction: Schuderer et al. Risk Factors for Flap Loss: Analysis of Donor and Recipient Vessel Morphology in Patients Undergoing Microvascular Head and Neck Reconstructions. J. Clin. Med. 2023, 12, 5206.

In the original publication by Schuderer et al., there was a mistake in Table 1 as published [...].

Long-term Outcomes of Chemoradiation for Muscle-invasive Bladder Cancer in Noncystectomy Candidates. Final Results of NRG Oncology RTOG 0524-A Phase 1/2 Trial of Paclitaxel + Trastuzumab with Daily Radiation or Paclitaxel Alone with Daily Irradiation.

BACKGROUND: Chemo-radiation is a well-established alternative to radical cystectomy in patients with muscle-invasive bladder cancer. Many patients due to age or medical comorbidity are unfit for either radical cystectomy, or standard cisplatin- or 5-fluorouracil-based chemoradiation, and do not receive appropriate treatment with curative intent. We treated patients with a less aggressive protocol employing seven weekly doses of paclitaxel and daily irradiation. In those whose tumors showed overexpression of her2/neu, seven weekly doses of trastuzumab were also administered. OBJECTIVE: To report the long-term survival outcomes and toxicity results of the of NRG Oncology RTOG 0524 study. DESIGN, SETTING, AND PARTICIPANTS: Seventy patients were enrolled and 65 (median age: 76 yr) were deemed eligible. Patients were assigned to daily radiation and weekly paclitaxel + trastuzumab (group 1, 20 patients) or to daily radiation plus weekly paclitaxel (group 2, 45 patients) based on tumor her2/neu overexpression. Radiation was delivered in 1.8 Gy fractions to a total dose of 64.8 Gy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was unresolved treatment-related toxicity. The secondary endpoints were complete response rate, protocol completion rate, and disease-free and overall survival. RESULTS AND LIMITATIONS: Protocol therapy was completed by 60% (group 1) and 76% (group 2); complete response rates at 12 wk were 62% in each group. Acute treatment-related adverse events (AEs) of grade ≥3 were observed in 80% in group 1 and 58% in group 2. There was one treatment-related grade 5 AE in group 1. Unresolved acute treatment-related toxicity was 35% in group 1 and 31% in group 2. The median follow-up was 2.3 yr in all patients and 7.2 yr in surviving patients. Overall survival at 5 yr was 25.0% in group 1 and 37.8% in group 2 (33.8% overall). At 5 yr, disease-free survival was 15.0% in group 1 and 31.1% in group 2. CONCLUSIONS: In a cohort of patients with muscle-invasive bladder cancer who are not candidates for cystectomy or cisplatin chemotherapy, chemoradiation therapy offers a treatment with a significant response rate and 34% 5-yr overall survival. While there were many AEs in this medically fragile group, there were few grade 4 events and one grade 5 event attributable to therapy. PATIENT SUMMARY: Patients with invasive bladder cancer who cannot tolerate surgery were treated with radiation and systemic therapy without surgically removing their bladders. Most patients tolerated the treatment, were able to keep their bladders, and showed a significant treatment response rate.

Who Gets Sick From COVID-19? Sociodemographic Correlates of Severe Adult Health Outcomes During Alpha- and Delta-Variant Predominant Periods: September 2020-November 2021.

BACKGROUND: Because COVID-19 case data do not capture most SARS-CoV-2 infections, the actual risk of severe disease and death per infection is unknown. Integrating sociodemographic data into analysis can show consequential health disparities. METHODS: Data were merged from September 2020 to November 2021 from 6 national surveillance systems in matched geographic areas and analyzed to estimate numbers of COVID-19-associated cases, emergency department visits, and deaths per 100 000 infections. Relative risks of outcomes per infection were compared by sociodemographic factors in a data set including 1490 counties from 50 states and the District of Columbia, covering 71% of the US population. RESULTS: Per infection with SARS-CoV-2, COVID-19-related morbidity and mortality were higher among non-Hispanic American Indian and Alaska Native persons, non-Hispanic Black persons, and Hispanic or Latino persons vs non-Hispanic White persons; males vs females; older people vs younger; residents in more socially vulnerable counties vs less; those in large central metro areas vs rural; and people in the South vs the Northeast. DISCUSSION: Meaningful disparities in COVID-19 morbidity and mortality per infection were associated with sociodemography and geography. Addressing these disparities could have helped prevent the loss of tens of thousands of lives.