Impact of sociodemographic status and sex on chronic rhinosinusitis and olfaction in people with cystic fibrosis.

BACKGROUND: Sociodemographic status (SDS) including race/ethnicity and socioeconomic status as approximated by education, income, and insurance status impact pulmonary disease in people with cystic fibrosis (PwCF). The relationship between SDS and chronic rhinosinusitis (CRS) remains understudied. METHODS: In a prospective, multi-institutional study, adult PwCF completed the 22-Question SinoNasal Outcome Test (SNOT-22), Smell Identification Test (SIT), Questionnaire of Olfactory Disorder Negative Statements (QOD-NS), and Cystic Fibrosis Questionnaire-Revised (CFQ-R). Lund-Kennedy scores, sinus computed tomography, and clinical data were collected. Data were analyzed across race/ethnicity, sex, and socioeconomic factors using multivariate regression. RESULTS: Seventy-three PwCF participated with a mean age of 34.7 ± 10.9 years and 49 (67.1%) were female. Linear regression identified that elexacaftor/tezacaftor/ivacaftor (ETI) use (ß = â€’4.09, 95% confidence interval [CI] [‒6.08, ‒2.11], p < 0.001), female sex (ß = â€’2.14, 95% CI [‒4.11, ‒0.17], p = 0.034), and increasing age (ß = â€’0.14, 95% CI [‒0.22, ‒0.05], p = 0.003) were associated with lower/better endoscopy scores. Private health insurance (ß = 17.76, 95% CI [5.20, 30.32], p = 0.006) and >16 educational years (ß = 13.50, 95% CI [2.21, 24.80], p = 0.020) were associated with higher baseline percent predicted forced expiratory volume in one second (ppFEV1). Medicaid/Medicare insurance was associated with worse endoscopy scores, CFQ-R respiratory scores, and ppFEV1 (all p < 0.017), and Hispanic/Latino ethnicity was associated with worse SNOT-22 scores (p = 0.047), prior to adjustment for other cofactors. No other SDS factors were associated with SNOT-22, QOD-NS, or SIT scores. CONCLUSIONS: Differences in objective measures of CRS severity exist among PwCF related to sex, age, and ETI use. Variant status and race did not influence patient-reported CRS severity measures or olfaction in this study. Understanding how these factors impact response to treatment may improve care disparities among PwCF. CLINICAL TRIALS: NCT04469439.

Using social risks to predict unplanned hospital readmission and emergency care among hospitalized Veterans.

OBJECTIVES: (1) To estimate the association of social risk factors with unplanned readmission and emergency care after a hospital stay. (2) To create a social risk scoring index. DATA SOURCES AND SETTING: We analyzed administrative data from the Department of Veterans Affairs (VA) Corporate Data Warehouse. Settings were VA medical centers that participated in a national social work staffing program. STUDY DESIGN: We grouped socially relevant diagnoses, screenings, assessments, and procedure codes into nine social risk domains. We used logistic regression to examine the extent to which domains predicted unplanned hospital readmission and emergency department (ED) use in 30 days after hospital discharge. Covariates were age, sex, and medical readmission risk score. We used model estimates to create a percentile score signaling Veterans' health-related social risk. DATA EXTRACTION: We included 156,690 Veterans' admissions to a VA hospital with discharged to home from 1 October, 2016 to 30 September, 2022. PRINCIPAL FINDINGS: The 30-day rate of unplanned readmission was 0.074 and of ED use was 0.240. After adjustment, the social risks with greatest probability of readmission were food insecurity (adjusted probability = 0.091 [95% confidence interval: 0.082, 0.101]), legal need (0.090 [0.079, 0.102]), and neighborhood deprivation (0.081 [0.081, 0.108]); versus no social risk (0.052). The greatest adjusted probabilities of ED use were among those who had experienced food insecurity (adjusted probability 0.28 [0.26, 0.30]), legal problems (0.28 [0.26, 0.30]), and violence (0.27 [0.25, 0.29]), versus no social risk (0.21). Veterans with social risk scores in the 95th percentile had greater rates of unplanned care than those with 95th percentile Care Assessment Needs score, a clinical prediction tool used in the VA. CONCLUSIONS: Veterans with social risks may need specialized interventions and targeted resources after a hospital stay. We propose a scoring method to rate social risk for use in clinical practice and future research.

Identifying factors and causal chains associated with optimal implementation of Lynch syndrome tumor screening: An application of coincidence analysis.

PURPOSE: This study compared Lynch syndrome universal tumor screening (UTS) across multiple health systems (some of which had two or more distinct UTS programs) to understand multi-level factors that may impact the successful implementation of complex programs. METHODS: Data from 66 stakeholder interviews were used to conduct multi-value coincidence analysis (mv-CNA) and identify key factors that consistently make a difference in whether UTS programs were implemented and optimized at the system level. RESULTS: The selected CNA model revealed combinations of conditions that distinguish 4 optimized UTS programs, 10 non-optimized programs, and 4 systems with no program. Fully optimized UTS programs had both a maintenance champion and a positive inner setting. Two independent paths were unique to non-optimized programs: 1) positive attitudes and a mixed inner setting, or 2) limited planning & engaging among stakeholders. Negative views about UTS evidence or lack of knowledge about UTS led to a lack of planning and engaging, which subsequently prevented program implementation. CONCLUSION: The model improved our understanding of program implementation in health care systems and informed the creation of a toolkit to guide UTS implementation, optimization, and changes. Our findings and toolkit may serve as a use case to increase the successful implementation of other complex precision health programs.

American Rhinologic Society Expert Practice Statement: Indications and Recommendations for Septoplasty in Children.

The goal of this American Rhinologic Society Expert Practice Statement (EPS) is to provide recommendations and guidance through evidence-based consensus statements regarding pediatric septoplasty. This EPS was developed following the previously published methodology and approval process. The topics of interest included appropriate indications, safety and efficacy, timing, relevant quality of life instruments, and surgical techniques. Following a modified Delphi approach, six statements were developed, five of which reached consensus and one that did not. These statements and accompanying evidence are summarized along with an assessment of future needs.

Multi-institutional validation of an AI-based sinus CT analytic platform with olfactory assessments.

KEY POINTS: AI-based CT sinus analysis may have advantages over visual based systems, for example, Lund-Mackay score. Here, we show multi-institutional validation of an AI algorithm using novel OMC classification. Significant, robust correlations are seen between algorithm outputs and clinical outcomes.

A human autoimmune organoid model reveals IL-7 function in coeliac disease.

In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Coeliac disease (CeD) is an autoimmune disease in which dietary gluten-derived peptides bind to the major histocompatibility complex (MHC) class II human leukocyte antigen molecules (HLA)-DQ2 or HLA-DQ8 to initiate immune-mediated duodenal mucosal injury1-4. Here, we generated air-liquid interface (ALI) duodenal organoids from intact fragments of endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The immune diversity of ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells and myeloid cells, with extensive T-cell and B-cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing organoids derived from CeD patients, and this was antagonized by blocking MHC-II or NKG2C/D. Gluten epitopes stimulated a CeD organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production. Functional studies in CeD organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8+ T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction. Furthermore, endogenous IL-7 was markedly upregulated in patient biopsies from active CeD compared with remission disease from gluten-free diets, predominantly in lamina propria mesenchyme. By preserving the epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, enables mechanistic investigation and establishes a proof of principle for the organoid modelling of autoimmunity.

Prestroke Physical Activity Matters for Functional Limitations: A Longitudinal Case-Control Study of 12,860 Participants.

OBJECTIVE: In the chronic phase after a stroke, limitations in activities of daily living (ADLs) and instrumental activities of daily living (IADLs) initially plateau before steadily increasing. The benefits of prestroke physical activity on these limitations remain unclear. To clarify this relationship, the effect of physical activity on the long-term evolution of functional limitations in a cohort of people with stroke compared to a cohort of matched adults without stroke was examined. METHODS: Longitudinal data from 2143 people with stroke and 10,717 adults without stroke aged 50 years and older were drawn from a prospective cohort study based on the Survey of Health, Ageing and Retirement in Europe (2004-2022; 8 data collection waves). Physical activity was assessed in the prestroke wave. Functional limitations were assessed in the poststroke waves. Each person with stroke was matched with 5 adults without stroke who had similar propensity scores computed on the basis of key covariates, including baseline age, sex, body mass index, limitations in ADLs and IADLs, chronic conditions, and country of residence, before any of the participants from either cohort had experienced a stroke. RESULTS: Results showed an interaction between stroke status and physical activity on ADL limitations (b = -0.076; 95% CI = -0.142 to -0.011), with the effect of physical activity being stronger in people with stroke (b = -0.345; 95% CI = -0.438 to -0.252) than in adults without stroke (b = -0.269; 95% CI = -0.269 to -0.241). CONCLUSION: The beneficial effect of prestroke physical activity on ADL limitations after stroke is stronger than its effect in matched adults without stroke followed for a similar number of years. IMPACT: Physical activity, an intervention within the physical therapist's scope of practice, is effective in reducing the risk of functional dependence after stroke. Moreover, prestroke levels of physical activity can inform the prognosis of functional dependence in people with stroke.

Rapid, Multiplexed, and Enzyme-Free Nucleic Acid Detection Using Programmable Aptamer-Based RNA Switches.

Rapid, simple, and low-cost diagnostic technologies are crucial tools for combatting infectious disease. We describe a class of aptamer-based RNA switches or aptaswitches that recognize target nucleic acid molecules and initiate folding of a reporter aptamer. Aptaswitches can detect virtually any sequence and provide an intense fluorescent readout without intervening enzymes, generating signals in as little as 5 minutes and enabling detection by eye with minimal equipment. Aptaswitches can be used to regulate folding of seven fluorogenic aptamers, providing a general means of controlling aptamers and an array of multiplexable reporter colors. Coupling isothermal amplification reactions with aptaswitches, we reach sensitivities down to 1 RNA copy/µL in one-pot reactions. Application of multiplexed all-in-one reactions against RNA from clinical saliva samples yields an overall accuracy of 96.67% for detection of SARS-CoV-2 in 30 minutes. Aptaswitches are thus versatile tools for nucleic acid detection that are readily integrated into rapid diagnostic assays.

The Burden of Nonsteroidal Anti-Inflammatory Drug-Exacerbated Respiratory Disease: Interplay Between Quality of Life and Economic Implications.

Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) presents a significant challenge in clinical management owing to recalcitrant disease with accompanying profound impacts on patient quality of life. Although asthma represents a significant component of this disease, quality of life disruptions are driven primarily by recalcitrant sinonasal problems, olfactory dysfunction, and the associated psychosocial and dietary implications. This review delves into specific quality of life metrics used to assess NSAID-ERD and the associated health care burden and financial implications of this disease, offering insights into the comparative challenges in chronic rhinosinusitis with nasal polyps when available. The article reviews the associated costs and cost-effectiveness of NSAID-ERD-directed therapies, including endoscopic sinus surgery, aspirin desensitization, and biologic therapy. Although some of these emerging treatment approaches show promise, they also present numerous unanswered questions, reflecting the dynamic nature of this field. As the landscape of NSAID-ERD management continues to evolve, this review provides insights into the challenges faced by clinicians and underscores the need for further research to optimize patient care and quality of life outcomes.

Evaluation of Porcine-Derived Collagen Membranes for Soft Tissue Augmentation in the Oral Cavity: An In Vivo Study.

The use of porcine-derived collagen membranes (PDCM) to improve intraoral soft tissue rehabilitation remains under investigation. Different degrees of crosslinking have yielded differences in resorption time and inflammation surrounding collagen membranes. The aim of this study was to evaluate the in vivo performance of bilayered PDCMs with varying degrees of crosslinking for the regeneration of oral soft tissue defects. Bilateral split-thickness oral mucosa defects were created in mandibles of beagles (n=17) and assigned to one of the following: bilayer PDCM (high crosslinking porcine dermis in sheet form-H-xlink) and (low crosslinking porcine dermis in sheet form-L-xlink), bilayer PDCM (non-crosslinked predicate collagen membrane in spongy form-Ctrl), or negative control (Sham) and compared with positive control (unoperated). Animals were euthanized after 4-, 8-, or 12-weeks of healing to evaluate soft tissue regeneration and remodeling through histomorphometric analyses. H-xlink membranes presented delayed healing with a poorly developed epithelial layer (analogous to the sham group) across time points. Relative to Ctrl at 8 and 12 weeks, defects treated with H-xlink presented no difference in semiquantitative scores (P > 0.05), while L-xlink exhibited greater healing (P = 0.042, P = 0.043, at 8 and 12 weeks, respectively). Relative to positive control, L-xlink exhibited similar healing at 8 weeks and greater healing at 12 weeks (P = 0.037) with a well-developed epithelial layer. Overall, groups treated with L-xlink presented with greater healing relative to the positive control after 12 weeks of healing and may serve as an alternative to autologous grafts for intraoral soft tissue regeneration.

Cytochrome oxidase requirements in Bordetella reveal insights into evolution towards life in the mammalian respiratory tract.

Little is known about oxygen utilization during infection by bacterial respiratory pathogens. The classical Bordetella species, including B. pertussis, the causal agent of human whooping cough, and B. bronchiseptica, which infects nearly all mammals, are obligate aerobes that use only oxygen as the terminal electron acceptor for electron transport-coupled oxidative phosphorylation. B. bronchiseptica, which occupies many niches, has eight distinct cytochrome oxidase-encoding loci, while B. pertussis, which evolved from a B. bronchiseptica-like ancestor but now survives exclusively in and between human respiratory tracts, has only three functional cytochrome oxidase-encoding loci: cydAB1, ctaCDFGE1, and cyoABCD1. To test the hypothesis that the three cytochrome oxidases encoded within the B. pertussis genome represent the minimum number and class of cytochrome oxidase required for respiratory infection, we compared B. bronchiseptica strains lacking one or more of the eight possible cytochrome oxidases in vitro and in vivo. No individual cytochrome oxidase was required for growth in ambient air, and all three of the cytochrome oxidases conserved in B. pertussis were sufficient for growth in ambient air and low oxygen. Using a high-dose, large-volume persistence model and a low-dose, small-volume establishment of infection model, we found that B. bronchiseptica producing only the three B. pertussis-conserved cytochrome oxidases was indistinguishable from the wild-type strain for infection. We also determined that CyoABCD1 is sufficient to cause the same level of bacterial burden in mice as the wild-type strain and is thus the primary cytochrome oxidase required for murine infection, and that CydAB1 and CtaCDFGE1 fulfill auxiliary roles or are important for aspects of infection we have not assessed, such as transmission. Our results shed light on the environment at the surface of the ciliated epithelium, respiration requirements for bacteria that colonize the respiratory tract, and the evolution of virulence in bacterial pathogens.

Cerebral hypoperfusion exacerbates traumatic brain injury in male but not female mice.

Mild-moderate traumatic brain injuries (TBIs) are prevalent, and while many individuals recover, there is evidence that a significant number experience long-term health impacts, including increased vulnerability to neurodegenerative diseases. These effects are influenced by other risk factors, such as cardiovascular disease. Our study tested the hypothesis that a pre-injury reduction in cerebral blood flow (CBF), mimicking cardiovascular disease, worsens TBI recovery. We induced bilateral carotid artery stenosis (BCAS) and a mild-moderate closed-head TBI in male and female mice, either alone or in combination, and analyzed CBF, spatial learning, memory, axonal damage, and gene expression. Findings showed that BCAS and TBI independently caused a ~10% decrease in CBF. Mice subjected to both BCAS and TBI experienced more significant CBF reductions, notably affecting spatial learning and memory, particularly in males. Additionally, male mice showed increased axonal damage with both BCAS and TBI compared to either condition alone. Females exhibited spatial memory deficits due to BCAS, but these were not worsened by subsequent TBI. Gene expression analysis in male mice highlighted that TBI and BCAS individually altered neuronal and glial profiles. However, the combination of BCAS and TBI resulted in markedly different transcriptional patterns. Our results suggest that mild cerebrovascular impairments, serving as a stand-in for preexisting cardiovascular conditions, can significantly worsen TBI outcomes in males. This highlights the potential for mild comorbidities to modify TBI outcomes and increase the risk of secondary diseases.

Effect of traditional roughage-based or limit-fed, high-energy diets on growth performance and digestion in newly received growing cattle and subsequent implications on feedlot growth performance and carcass characteristics.

The objective was to determine the effects of ad libitum-fed roughage-based diets or limit-fed high-energy diets on growth performance, behavior, health, and digestion in newly received growing cattle and subsequent implications on feedlot growth performance and carcass characteristics. In experiment 1, 409 crossbred heifers (initial body weight [BW] = 279 ±â€…24 kg) in 32 pens were used in a randomized block design. Heifers were fed one of two dietary treatments: a total mixed ration with 0.99 Mcal net energy for gain (NEg)/kg dry matter (DM) fed ad libitum (0.99AL) or 1.32 Mcal NEg/kg DM limit-fed at 85% of intake of heifers fed 0.99AL (1.32LF85%). Both diets contained 40% DM as a branded wet corn gluten feed. In experiment 2, 370 crossbred heifers (initial BW = 225 ±â€…20 kg) were used in a randomized block design and were fed a diet formulated to contain 0.99 Mcal of NEg/kg DM for ad libitum intake or a diet formulated to contain 1.32 Mcal of NEg/kg DM and fed at 2.2% of BW daily (DM basis; 1.32LF2.2). For experiments 1 and 2, treatment integrity was maintained through the finishing phase where cattle were fed a common diet. Cattle were sorted by BW into heavy and light groups prior to finishing, with light cattle fed longer than heavy cattle to reach similar harvest BW. In experiment 3, eight ruminally cannulated heifers (average BW = 305 ±â€…23 kg) were used in a 2-period cross-over design and fed treatments from experiment 1 to assess digestibility and ruminal fermentation characteristics. Gain:feed was 47% and 35% greater (P < 0.01) in experiments 1 and 2, respectively, for limit-fed heifers compared with 0.99AL heifers. Rumination time was greater (P < 0.01) for 0.99AL compared with limit-fed treatments in experiments 1 and 2. Activity was greater (P < 0.01) for 1.32LF2.2 than for 0.99AL in experiment 2. In experiment 1, more (P = 0.03) carcasses from light-sort heifers than carcasses from heavy-sort heifers had livers with large, active abscesses. In experiment 2, finishing phase morbidity was greater (P < 0.01) for 1.32LF2.2 than for 0.99AL. Light-sort groups had fewer (P < 0.01) edible livers than heavy-sort groups, suggesting that greater number of days on feed may increase the risk of liver abscess prevalence and condemnation. In experiment 3, apparent total-tract DM and organic matter digestibilities were greater (P < 0.01) for 1.32LF85% than for 0.99AL. Overall, dietary treatments during the growing phase had little carryover effect on feedlot growth performance, carcass characteristics, or liver abscesses prevalence at harvest.

Spending, utilization, and coverage for chronic rhinosinusitis with nasal polyposis therapies among Medicare Advantage beneficiaries.

KEY POINTS: CRSwNP-specific mean total annual spending ranged from $5,837 (EDS-FLU) to $28,058 (dupilumab). Most CRSwNP patients receiving biologics had comorbid asthma and did not undergo sinus surgery. While biologics were covered by most Medicare Part D plans, only 37% of plans covered EDS-FLU.

Video analysis of anterior cruciate ligament tears of professional basketball players in the National Basketball Association.

BACKGROUND: Anterior cruciate ligament (ACL) tears are devastating for elite athletes, including those in the National Basketball Association (NBA). The purpose of this study was to describe common in-game mechanisms of injury, playing situations, and anatomic positioning of players who sustained an ACL injury in the NBA. METHODS: ACL tears which occurred in NBA games during the previous 16 seasons (2007-2022) and had accessible video clips were identified through publicly available reports. RESULTS: Thirty-one ACL tears were identified with quality videos available. Nearly all players were on offense (93.5%, 29/31). Most ACL tears (29/31, 93.5%) did not involve direct contact to the injured extremity. The most common physical activity at the time of injury was landing from any type of jump (45.2%, 14/31). Anatomically, the knee was frequently in early flexion (58.8%, 10/17) and abducted (77.4%, 24/31); the foot was commonly abducted (87.1%, 27/31); and the hip was usually abducted (64.5%, 20/31) and flexed (80.6%, 25/31). Almost all players had another individual near them at the time of injury, with 90.3% (28/31) and 96.8% (30/31) having someone within 2ft and 5ft. CONCLUSIONS: Most ACL tears occurred inside the lane, regardless of mechanism of injury (26/31, 83.9%). ACL tears in the NBA were primarily not due to direct contact of the injured extremity but did have common anatomic patterns. The findings of this study can be used in the future to help reduce the risk of injury through the adaptation of current training activities.

Headache and Facial Pain/Pressure in the Chronic Rhinosinusitis Population: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the severity and prevalence of headache and facial pain/pressurere in the chronic rhinosinusitis (CRS) population. DATA SOURCES: CINAHL, PubMed, Scopus. REVIEW METHODS: The literature was searched from inception through June 2023 for English language articles documenting "headache" or "facial pain/pressure" and "chronic rhinosinusitis." Data collected included Lund-MacKay computed tomography score, Lund-Kennedy endoscopy score, sinonasal outcome test, and visual analog scale. Meta-analyses were performed on continuous measures (mean), proportions (%), and regression. RESULTS: A total of 69 studies were included with 8643 CRS patients and 703 control patients. The CRS group had a mean age of 44.1 (range: 16-82; 95% confidence interval [CI]: 40.3-48) and 86.1% [95% CI: 76.4-93.5] with nasal polyposis. The control group had a mean age of 39.2 (range: 17-88; 95% CI: 28.7-49.8). All CRS subgroups had significantly more severe headache and facial pain/pressure when compared to the control (P < .0001). Patients without polyps had significantly more severe facial pain/pressure and headache when compared to patients with polyps (P < .0001). Facial pain/pressure is a moderate problem or worse in 29.8% of polypoid patients versus 56.4% of nonpolypoid patients; Δ26.6% [95% CI: 0.7-50; P = .045]. CONCLUSIONS: Across all outcome metrics, CRS patients experience significantly more severe headache and facial pain/pressure when compared to a control population. Nonpolypoid patients experience significantly more severe facial pain/pressure and headache when compared to polypoid patients. The majority of nonpolypoid patients experience facial pain/pressure that is moderate in severity or worse.

Medically Tailored Meals for Patients With Cirrhosis and Hepatic Encephalopathy: The BRAINFOOD Proof-of-concept Trial.

Background and aims: Guidelines recommend that patients with hepatic encephalopathy (HE) receive a high-protein diet (roughly 1 g/kg actual body weight). Concommitant sodium restriction, low health literacy, and food insecurity limit patients' ability to meet this goal. We aimed to determine the feasibility of home-delivered high-protein medically tailored meals (MTMs) for patients with a recent episode of overt HE. Methods: We enrolled patients with prior overt HE on active HE therapy in a 6-month trial of MTM. All received 21 home-delivered meals/week with protein snacks (mid-day and bedtime) for 12 weeks. Patients completed follow-up at week 24. The primary outcome was feasibility. Additional outcomes included change in protein and micronutrient intake (measured using 24 h dietary recalls performed by dieticians), cognitive function (Animal Naming Test [ANT]; EncephalApp Stroop), physical function (Liver Frailty Index [LFI]), and quality of life (Short Form-8 Health Survey [SF-8]). Healthcare utilization was also assessed. Results: Ten patients competed the study with >90% of MTM consumed. Protein intake rose from 74.6 ± 25.1 g at baseline to 93.8 ± 24.3 g on MTM (P = 0.04). Branched-chain amino acids also increased-valine 3.73 ± 1.26 g to 5.17 ± 1.28 g, isoleucine 3.32 ± 1.18 to 4.69 ± 1.55, leucine 5.83 ± 2.00 to 7.49 ± 2.07, all P < 0.001. The LFI score improved from 4.42 ± 0.32 to 3.96 ± 0.82 by the end of the MTM phase (P = 0.03). SF-8 quality-of-life scores improved from 55.5 ± 15.5 at baseline to 64.7 ± 18.3 after the MTM phase, to 64.4 ± 19.1 at the end of the study (P = 0.1). EncephalApp Stroop time improved from 227 ± 94 to 194 ± 58s by the end of the MTM phase (P = 0.08). ANT scores were similarly non-significantly improved. Conclusion: Home-delivered MTMs are feasible, increase protein consumption, and may improve patient wellbeing. A randomized trial is needed.

Efficacy of late-onset antiviral treatment in immune-compromised hosts with persistent SARS-CoV-2 infection.

The immunocompromised are at high risk of prolonged SARS-CoV-2 infection and progression to severe COVID-19. However, efficacy of late-onset direct-acting antiviral (DAA) therapy with therapeutics in clinical use and experimental drugs to mitigate persistent viral replication is unclear. In this study, we employed an immunocompromised mouse model, which supports prolonged replication of SARS-CoV-2 to explore late-onset treatment options. Tandem immuno-depletion of CD4 + and CD8 + T cells in C57BL/6 mice followed by infection with SARS-CoV-2 variant of concern (VOC) beta B.1.351 resulted in prolonged infection with virus replication for five weeks after inoculation. Early-onset treatment with nirmatrelvir/ritonavir (paxlovid) or molnupiravir was only moderately efficacious, whereas the experimental therapeutic 4'-fluorourdine (4'-FlU, EIDD-2749) significantly reduced virus load in upper and lower respiratory compartments four days post infection (dpi). All antivirals significantly lowered virus burden in a 7-day treatment regimen initiated 14 dpi, but paxlovid-treated animals experienced rebound virus replication in the upper respiratory tract seven days after treatment end. Viral RNA was detectable 28 dpi in paxlovid-treated animals, albeit not in the molnupiravir or 4'-FlU groups, when treatment was initiated 14 dpi and continued for 14 days. Low-level virus replication continued 35 dpi in animals receiving vehicle but had ceased in all treatment groups. These data indicate that late-onset DAA therapy significantly shortens the duration of persistent virus replication in an immunocompromised host, which may have implications for clinical use of antiviral therapeutics to alleviate the risk of progression to severe disease in highly vulnerable patients. Importance: Four years after the onset of the global COVID-19 pandemic, the immunocompromised are at greatest risk of developing life-threatening severe disease. However, specific treatment plans for this most vulnerable patient group have not yet been developed. Employing a CD4 + and CD8 + T cell-depleted immunocompromised mouse model of SARS-CoV-2 infection, we explored therapeutic options of persistent infections with standard-of-care paxlovid, molnupiravir, and the experimental therapeutic 4'-FlU. Late-onset treatment initiated 14 days after infection was efficacious, but only 4'-FlU was rapidly sterilizing. No treatment-experienced viral variants with reduced susceptibility to the drugs emerged, albeit virus replication rebounded in animals of the paxlovid group after treatment end. This study supports the use of direct-acting antivirals for late-onset management of persistent SARS-CoV-2 infection in immunocompromised hosts. However, treatment courses likely require to be extended for maximal therapeutic benefit, calling for appropriately powered clinical trials to meet the specific needs of this patient group.

Continued Success of Venetoclax in t(11;14) Multiple Myeloma Despite Negative Trials.

The June Hot Topics focuses on the challenges venetoclax regimens have faced in multiple myeloma trials.

Transport properties of indium-alloyed and indium telluride nanostructured bismuth telluride.

Nanostructured thermoelectric materials ideally reduce lattice thermal conductivity without harming the electrical properties. Thus, to truly improve the thermoelectric performance, the quality factor, which is proportional to the weighted mobility divided by the lattice thermal conductivity of the material, must be improved. Precipitates of In2Te3 form in the state-of-the-art Bi2Te3 with crystallographic alignment to the Bi2Te3 structure. Like epitaxy in films, this can be called endotaxy in solids. This natural epitaxy in a 3-dimensional solid is ideally situated to scatter phonons but produces minimal electronic scattering and, therefore, maintains high mobility. Here, we study the effects of In-alloying in Bi2Te3 at high In concentrations (about 4 at%), enough to produce the endotaxial microstructure. It is found that such concentrations of indium in Bi2Te3 significantly alter the electronic structure, reducing the effective mass and weighted mobility so significantly as to effectively destroy the thermoelectric properties even though the lattice thermal conductivity is successfully reduced.