Emerging priorities and concerns in the wake of the COVID-19 pandemic: qualitative and quantitative findings from a United States national survey.

Purpose: The present study examines how the coronavirus disease 2019 (COVID-19) experience affected values and priorities. Methods: This cross-sectional study collected data between January and April 2023, from 1,197 individuals who are chronically ill or part of a general population sample. Using open-ended prompts and closed-ended questions, we investigated individuals' perceptions about COVID-19-induced changes in what quality of life means to them, what and who are important, life focus, and changes in norms and stressors. Data analyses included content and psychometric analysis, leading to latent profile analysis (LPA) to characterize distinct groups, and analysis of variance and chi-squared to compare profile groups' demographic characteristics. Results: About 75% of the study sample noted changes in values and/or priorities, particularly in the greater prominence of family and friends. LPA yielded a four-profile model that fit the data well. Profile 1 (Index group; 64% of the sample) had relatively average scores on all indicators. Profile 2 (COVID-Specific Health & Resignation to Isolation Attributable to COVID-19; 5%) represented COVID-19-specific preventive health behaviors along with noting the requisite isolation and disengagement entailed in the social distancing necessary for COVID-19 prevention. Profile 3 (High Stress, Low Trust; 25%) represented high multi-domain stress, with the most elevated scores both on focusing on being true to themselves and perceiving people to be increasingly uncivil. Profile 4 (Active in the World, Low Trust; 6%) was focused on returning to work and finding greater meaning in their activities. These groups differed on race, marital status, difficulty paying bills, employment status, number of times they reported having had COVID-19, number of COVID-19 boosters received, whether they had Long COVID, age, BMI, and number of comorbidities. Conclusion: Three years after the beginning of the worldwide COVID-19 pandemic, its subjective impact is notable on most study participants' conceptualization of quality of life, priorities, perspectives on social norms, and perceived stressors. The four profile groups reflected distinct ways of dealing with the long-term effects of COVID-19.

Differences in HIV-1 reservoir size, landscape characteristics and decay dynamics in acute and chronic treated HIV-1 Clade C infection.

Background: Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by early initiation has been shown to enable post-treatment viral control in some cases but the underlying mechanisms are not fully understood. We hypothesized that ART initiated during the hyperacute phase of infection before peak will affect the size, decay dynamics and landscape characteristics of HIV-1 subtype C viral reservoirs. Methods: We studied 35 women at high risk of infection from Durban, South Africa identified with hyperacute HIV infection by twice weekly testing for plasma HIV-1 RNA. Study participants included 11 who started ART at a median of 456 (297-1203) days post onset of viremia (DPOV), and 24 who started ART at a median of 1 (1-3) DPOV. We used peripheral blood mononuclear cells (PBMC) to measure total HIV-1 DNA by ddPCR and to sequence reservoir viral genomes by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation. Results: Whereas ART in hyperacute infection blunted peak viremia compared to untreated individuals (p<0.0001), there was no difference in total HIV-1 DNA measured contemporaneously (p=0.104). There was a steady decline of total HIV DNA in early treated persons over 1 year of ART (p=0.0004), with no significant change observed in the late treated group. Total HIV-1 DNA after one year of treatment was lower in the early treated compared to the late treated group (p=0.02). Generation of 697 single viral genome sequences revealed a difference in the longitudinal proviral genetic landscape over one year between untreated, late treated, and early treated infection: the relative contribution of intact genomes to the total pool of HIV-1 DNA after 1 year was higher in untreated infection (31%) compared to late treated (14%) and early treated infection (0%). Treatment initiated in both late and early infection resulted in a more rapid decay of intact (13% and 51% per month) versus defective (2% and 35% per month) viral genomes. However, intact genomes were still observed one year post chronic treatment initiation in contrast to early treatment where intact genomes were no longer detectable. Moreover, early ART reduced phylogenetic diversity of intact genomes and limited the seeding and persistence of cytotoxic T lymphocyte immune escape variants in the reservoir. Conclusions: Overall, our results show that whereas ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding, it was nevertheless associated with more rapid decay of intact viral genomes, decreased genetic complexity and immune escape in reservoirs, which could accelerate reservoir clearance when combined with other interventional strategies.

Identifying novel data-driven subgroups in congenital heart disease using multi-modal measures of brain structure.

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.

Mesocorticolimbic system reactivity to alcohol use-related visual cues as a function of alcohol sensitivity phenotype: A pilot fMRI study.

Low sensitivity (LS) to alcohol is a risk factor for alcohol use disorder (AUD). Compared to peers with high sensitivity (HS), LS individuals drink more, report more problems, and exhibit potentiated alcohol cue reactivity (ACR). Heightened ACR suggests LS confers AUD risk via incentive sensitization, which is thought to take place in the mesocorticolimbic system. This study examined neural ACR in LS and HS individuals. Young adults (N = 32, M age=20.3) were recruited based on the Alcohol Sensitivity Questionnaire (HS: n = 16; LS: n = 16; 9 females/group). Participants completed an event-related fMRI ACR task. Group LS had higher ACR in left ventrolateral prefrontal cortex than group HS. In group LS, ACR in left caudomedial orbitofrontal cortex or left putamen was low at low alcohol use levels and high at heavier or more problematic alcohol use levels, whereas the opposite was true in group HS. Alcohol use level also was associated with the level of ACR in left substantia nigra among males in group LS. Taken together, results suggest elevated mesocorticolimbic ACR among LS individuals, especially those using alcohol at hazardous levels. Future studies with larger samples are warranted to determine the neurobiological loci underlying LS-based amplified ACR and AUD risk.

Expiratory Threshold Loading and Attentional Performance.

INTRODUCTION: While there are numerous factors that may affect pilot attentional performance, we hypothesize that an increased expiratory work of breathing experienced by fighter pilots may impose a "distraction stimulus" by creating an increased expiratory effort sensation. Therefore, the purpose of this study was to determine the extent to which increasing expiratory pressure time product or expiratory effort sensation impacts attentional performance.METHODS: Data was collected on 10 healthy participants (age: 29 ± 6 yr). Participants completed six repetitions of a modified Masked Conjunctive Continuous Performance Task protocol while breathing against four different expiratory threshold loads. Repeated measures analysis of variances and generalized additive mixed effects models were used to investigate the effects of expiratory threshold load conditions on expiratory pressure time product, expiratory effort sensation, and the influence of altered end tidal gases on Masked Conjunctive Continuous Performance Task scores.RESULTS: The overall median hit reaction times were significantly longer as the expiratory threshold loads increased. Specific shape-conjunctive and non-conjunctive median hit reaction times were longer with increased expiratory effort sensation. Additionally, increased expiratory effort sensation did not significantly change commission error rates, but did significantly increase omission error rates.DISCUSSION: The findings of our work suggest that both progressively greater expiratory threshold loads during spontaneous breathing and expiratory effort sensation may impair subjects' attentional performance due to longer reaction times and increased stimuli recognition error rates.Kelley EF, Cross TJ, Johnson BD. Expiratory threshold loading and attentional performance. Aerosp Med Hum Perform. 2024; 95(7):367-374.

Soccer Game Turned Bloody: A Case of Exercise-Induced Ischemic Colitis.

Ischemic colitis (IC) should be considered as a cause for gastrointestinal symptoms in patients with recent vigorous physical activity. Vasoconstriction driven by increased sympathetic tone during exercise is believed to mediate exercise-induced IC. In this report, a 21-year-old man with no medical history developed self-resolving, sudden-onset hematochezia and abdominal pain after playing in a collegiate soccer match for 90 minutes. Colonoscopy with biopsy showed changes consistent with IC. He improved without further treatment. In most cases, exercise-induced IC resolves completely with supportive care and correction of hypovolemia. Careful monitoring is appropriate before pursuing further evaluation.

Current Approaches and Novel New Agents in the Treatment of Chronic Lymphocytic Leukemia.

The treatment of CLL has evolved from traditional chemoimmunotherapy (CIT) to an increasing number of targeted and biologic approaches. Randomized trials have demonstrated superiority of covalent bruton tyrosine kinase inhibitors (cBTKis) over CIT, and second-generation compounds such as acalabrutinib and zanubrutinib appear to have a more favorable efficacy/safety profile than ibrutinib. The noncovalent BTKi, pirtobrutinib, has shown impressive activity after failure of the cBTKis and is quite tolerable. The Bcl-2 inhibitor venetoclax plus a CD20, generally obinutuzumab, provides a high level of efficacy as initial treatment or after failure on a cBTKi, with many patients achieving a state of undetectable minimal residual disease. Promising novel approaches include BTK degraders, bispecific antibodies, and chimeric antigen receptor T-cell (CAR-T)-cell therapy. What is clear is that CIT is archaic, and current and future targeted approaches will continue to improve the outcome for patients with chronic lymphocytic leukemia.

Comparative transcriptome analysis of canola carrying a single vs stacked resistance genes against clubroot.

Pyramiding resistance genes may expand the efficacy and scope of a canola variety against clubroot (Plasmodiophora brassicae), a serious threat to canola production in western Canada. However, the mechanism(s) of multigenic resistance, especially the potential interaction among clubroot resistance (CR) genes, are not well understood. In this study, transcriptome was compared over three canola (Brassica napus L.) inbred/hybrid lines carrying a single CR gene in chromosome A03 (CRaM, Line 16) or A08 (Crr1rutb, Line 20), and both genes (CRaM+Crr1rutb, Line 15) inoculated with a field population (L-G2) of P. brassicae pathotype X, a new variant found in western Canada recently. The line16 was susceptible, while lines 15 and 20 were partially resistant. Functional annotation identified differential expression of genes (DEGs) involved in biosynthetic processes responsive to stress and regulation of cellular process; The Venn diagram showed that the partially resistant lines 15 and 20 shared 1,896 differentially expressed genes relative to the susceptible line 16, and many of these DEGs are involved in defense responses, activation of innate immunity, hormone biosynthesis and programmed cell death. The transcription of genes involved in Pathogen-Associated Molecular Pattern (PAMP)-Triggered and Effector-Triggered Immunity (PTI and ETI) was particularly up-regulated, and the transcription level was higher in line 15 (CRaM + Crr1rutb) than in line 20 (Crr1rutb only) for most of the DEGs. These results indicated that the partial resistance to the pathotype X was likely conferred by the CR gene Crr1rutb for both lines 15 and 20 that functioned via the activation of both PTI and ETI signaling pathways. Additionally, these two CR genes might have synergistic effects against the pathotype X, based on the higher transcription levels of defense-related DEGs expressed by inoculated line 15, highlighting the benefit of gene stacking for improved canola resistance as opposed to a single CR gene alone.

Single-fraction radiation retreatment for bone metastases: role of a rapid access clinic.

OBJECTIVES: This study investigates retreatment rates in single-fraction radiation therapy (SFRT) for painful bone metastasis in patients with limited life expectancy. We compared retreatment-free survival (RFS) in patients from a rapid access bone metastases clinic (RABC) and non-RABC patients, identifying factors associated with retreatment. METHODS: In this observational study, we analysed RABC patients who received SFRT between April 2018 and November 2019, using non-RABC SFRT patients as a comparison group. Patients with prior or perioperative radiation therapy (RT) were excluded. The primary endpoint was same-site and any-site retreatment with RT or surgery. Patient characteristics were compared using χ2 and Student's t-tests, with RFS estimates based on a multistate model considering death as a competing risk using Aalen-Johansen estimates. RESULTS: We identified 151 patients (79 RABC, 72 non-RABC) with 225 treatments (102 RABC, 123 non-RABC) meeting eligibility criteria. Of the 22 (10.8%) same-site retreatments, 5 (22.7%) received surgery, 14 (63.6%) received RT and 3 (13.6%) received both RT and surgery. We found no significant differences in any-site RFS (p=0.97) or same-site RFS (p=0.11). CONCLUSIONS: RFS is high and similar comparable in the RABC and non-RABC cohorts. Retreatment rates are low, even in patients with low Eastern Cooperative Oncology Group scores.

A novel sustainable immunoassay for sensitive detection of atrazine based on the anti-idiotypic nanobody and recombinant full-length antibody.

Immunoassays have been widely used to determine small-molecule compounds in food and the environment, meeting the challenge of obtaining false positive or negative results because of the variance in the batches of antibodies and antigens. To resolve this problem, atrazine (ATR) was used as a target, and anti-idiotypic nanobodies for ATR (AI-Nbs) and a recombinant full-length antibody against ATR (ATR-rAb) were prepared for the development of a sustainable enzyme-linked immunosorbent assay (ELISA). AI-Nb-7, AI-Nb-58, and AI-Nb-66 were selected from an immune phage display library. ATR-rAb was produced in mammalian HEK293 (F) cells. Among the four detection methods explored, the assay using AI-Nb-66 as a coating antigen and ATR-rAb as a detection reagent yielded a half maximal inhibitory concentration (IC50) of 1.66 ng mL-1 for ATR and a linear range of 0.35-8.73 ng mL-1. The cross-reactivity of the assay to ametryn was 64.24%, whereas that to terbutylazine was 38.20%. Surface plasmon resonance (SPR) analysis illustrated that these cross-reactive triazine compounds can bind to ATR-rAb to varying degrees at high concentrations; however, the binding/dissociation kinetic curves and the response values at the same concentration are different, which results in differences in cross-reactivity. Homology modeling and molecular docking revealed that the triazine ring is vital in recognizing triazine compounds. The proposed immunoassay exhibited acceptable recoveries of 84.40-105.36% for detecting fruit, vegetables, and black tea. In conclusion, this study highlights a new strategy for developing sustainable immunoassays for detecting trace pesticide contaminants.

Peroxidase-mediated mucin cross-linking drives pathologic mucus gel formation in IL-13-stimulated airway epithelial cells.

Mucus plugs occlude airways to obstruct airflow in asthma. Studies in patients and in mouse models show that mucus plugs occur in the context of type 2 inflammation, and studies in human airway epithelial cells (HAECs) show that interleukin 13 (IL-13) activated cells generate pathologic mucus independently of immune cells. To determine how HAECs autonomously generate pathologic mucus, we used a magnetic microwire rheometer to characterize the viscoelastic properties of mucus secreted under varying conditions. We found that normal HAEC mucus exhibits viscoelastic liquid behavior and that mucus secreted by IL-13 activated HAECs exhibits solid-like behavior caused by mucin cross-linking. In addition, IL-13 activated HAECs show increased peroxidase activity in apical secretions, and an overlaid thiolated polymer (thiomer) solution shows an increase in solid behavior that is prevented by peroxidase inhibition. Furthermore, gene expression for thyroid peroxidase (TPO), but not lactoperoxidase (LPO), is increased in IL-13 activated HAECs and both TPO and LPO catalyze the formation of oxidant acids that cross-link thiomer solutions. Finally, gene expression for TPO in airway epithelial brushings is increased in asthma patients with high airway mucus plug scores. Together, our results show that IL-13 activated HAECs autonomously generate pathologic mucus via peroxidase-mediated cross-linking of mucin polymers.

Correspondence between the alcohol-P3 event-related potential and alcohol reward phenotypes among young adults.

BACKGROUND: Behavioral economic theory suggests that the value of alcohol depends upon elements of the choice context, such that increasing constraints on alternatives (e.g., price) or increasing the benefits of alcohol (e.g., social context) may result in greater likelihood of heavy drinking. The P3 event-related potential elicited by alcohol-related cues, a proposed marker of incentive salience, may be an electrophysiological parallel for behavioral economic alcohol demand. However, these indices have not been connected in prior research, and studies typically do not disaggregate social influences in the context of alcohol cue reactivity. METHOD: The current study recruited heavy drinking young adults (N = 81) who completed measures of alcohol use and alcohol demand, in addition to a 2 (social/nonsocial) × 2 (alcohol/nonalcohol) visual oddball task to elicit the P3. RESULTS: In multilevel models controlling for demographic characteristics, P3 reactivity was greater to alcohol (p < 0.001) and social (p < 0.001) cues than to nonalcohol and nonsocial cues, but without a significant interaction. Higher alcohol consumption (p = 0.02) and lower elasticity of demand (p = 0.01) were associated with greater P3 response to alcohol than nonalcohol cues. CONCLUSIONS: The results highlight a brain-behavior connection that may be an important marker for alcohol reward across units of analysis and may be sensitive to changes in the economic choice contexts that influence the likelihood of alcohol use.

A new strategy to generate nanobodies for the coumaphos based on the synthesized nanobody libraries.

To break through the bottleneck in preparation of nanobody (Nb) for chemical contaminants induced by the difficulties in the synthesis of immunogen, complexity and unexpectable efficiency of immunization, a novel strategy to generate Nbs based on the designed synthetic Nb libraries with final size up to 109 cfu/mL was adopted and succeeded in selection of anti-coumaphos Nb A4. Furthermore, an affinity-matured mutant Nb 3G was obtained from the secondary library. Finally, an ic-ELISA was established with the limit of detection for coumaphos low to 1.90 ng/mL, 6.4-fold improved than the parent Nb A4, and the detection range from 3.06 to 15.77 ng/mL. Meanwhile, the recovery rate of vegetable samples was from 89.9% to 98.5%. Finally, the accuracy was testified by the standard UPLC-MS/MS method with R2 up to 0.99. Overall, fully synthetic Nb libraries constructed in this work provided an alternative possibility to generate the specific Nbs for chemical contaminants.

Response of sea surface temperature to atmospheric rivers.

Atmospheric rivers (ARs), responsible for extreme weather conditions, are mid-latitude systems that can cause significant damage to coastal areas. While forecasting ARs beyond two weeks remains a challenge, past research suggests potential benefits may come from properly accounting for the changes in sea surface temperature (SST) through air-sea interactions. In this paper, we investigate the impact of ARs on SST over the North Pacific by analyzing 25 years of ocean reanalysis data using an SST budget equation. We show that in the region of strong ocean modification, ocean dynamics can offset over 100% of the anomalous SST warming that would otherwise arise from atmospheric forcing. Among all ocean processes, ageostrophic advection and vertical mixing (diffusion and entrainment) are the most important factors in modifying the SST tendency response. The SST tendency response to ARs varies spatially. For example, in coastal California, the driver of enhanced SST warming is the reduction in ageostrophic advection due to anomalous southerly winds. Moreover, there is a large region where the SST shows a warming response to ARs due to the overall reduction in the total clouds and subsequent increase in total incoming shortwave radiation.

Escalated-dose radiotherapy for unresected locally advanced pancreatic cancer: Patterns of care and survival in the United States.

INTRODUCTION: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated-dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. METHODS: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas-directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional-dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. RESULTS: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas-directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80-0.91; p < 0.001) with longer OS versus CDR. DISCUSSION AND CONCLUSIONS: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real-world results additionally provide an estimate of effect size of EDR for future prospective trials.

Quinolinyl-based multitarget-directed ligands with soluble epoxide hydrolase and fatty acid amide hydrolase inhibitory activities: Synthetic studies and pharmacological evaluations.

Simultaneous inhibition of soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) with a single small molecule represents a novel therapeutic approach in treating inflammatory pain, since both targets are involved in pain and inflammation processes. In this study using multi-target directed ligands methodology we designed and synthesized 7 quinolinyl-based dual sEH/FAAH inhibitors, using an optimized microwave-assisted Suzuki-Miyaura coupling reaction and tested their potency in human FAAH and human, rat, and mouse sEH inhibition assays. The structure-activity relationship study showed that quinolinyl moiety is well tolerated in the active sites of both enzymes, yielding several very potent dual sEH/FAAH inhibitors with the IC50 values in the low nanomolar range. The most potent dual inhibitor 4d was further evaluated in stability assay in human and rat plasma where it performed better than the standard Warfarin while in vivo study revealed that 1 mg/kg 4d can inhibit acute inflammatory pain in male rats to a similar degree as the traditional nonsteroidal anti-inflammatory drug ketoprofen (30 mg/kg) after intraperitoneal injection. ADMET prediction studies for this dual inhibitor show favorable pharmacokinetic properties which will guide the future in vivo evaluations.

Evaluating parental personal utility of pediatric genetic and genomic testing in a diverse, multilingual population.

There is increasing evidence of the clinical utility of genetic and genomic testing (GT); however, factors influencing personal utility of GT, especially in diverse, multilingual populations, remain unclear. We explored these factors in a diverse cohort of parents/guardians (participants) whose children received clinical GT through the NYCKidSeq program. A total of 847 participants completed surveys at baseline, post-results disclosure, and 6 months (6m) post-results. The largest population groups were Hispanic/Latino(a) (48%), White/European American (24%), and Black/African American (16%). Personal utility was assessed using the Personal Utility scale (PrU), adapted for pediatric populations and included on the surveys. Three PrU subscales were identified using factor analysis: practical, educational, and parental psychological utility. Overall personal utility summary score and the three subscales significantly decreased after receiving results and over time. Hispanic/Latino(a) participants identified greater overall personal utility than European American and African American participants at all timepoints (p<0.001) as did participants whose children received positive/likely positive results compared with those with negative and uncertain results (post-results: p<0.001 and <0.001; 6m post-results: p=0.002 and <0.001, respectively). Post-results, higher utility subscale scores were associated with lower education levels (practical, parental psychological: p≤0.02) and higher levels of trust in the healthcare system (practical, parental psychological: p≤0.04). These findings help to understand the perspectives of diverse parents/guardians, which is critical to tailoring pre- and post-test counseling across a variety of populations and clinical settings.

Phase I trial of single-photon emission computed tomography-guided liver-directed radiotherapy for patients with low functional liver volume.

BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single-photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection. METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose-limiting toxicities were assessed 6-8 weeks and 6 months after completing radiotherapy. RESULTS: All 12 patients had colorectal liver metastases and received prior hepatotoxic chemotherapy; 8 patients underwent prior liver resection. Median computed tomography anatomical nontumor liver volume was 1584 cc (range = 764-2699 cc). Median SPECT functional liver volume was 1117 cc (range = 570-1928 cc). Median nontarget computed tomography and SPECT liver volumes below the volumetric dose constraint were 997 cc (range = 544-1576 cc) and 684 cc (range = 429-1244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No dose-limiting toxicities were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%. CONCLUSION: Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process, which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function. TRIAL REGISTRATION: NCT02626312.

Cardiac genetic test yields and genotype-phenotype correlations from large cohort investigated by medical examiner's office.

BACKGROUND: Few reports describe the yield of postmortem genetic testing from medical examiners' offices or correlate genetic test results with autopsy-confirmed phenotypes from a large cohort. OBJECTIVES: To report results from cardiomyopathy- and cardiac arrhythmia-associated genetic testing in conjunction with autopsy findings of cases investigated at the United States' largest medical examiner office. METHODS: Postmortem cases tested from 2015 to 2022 with a cardiomyopathy- and cardiac arrhythmia-associated gene panel were reviewed. American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines were used to classify variant pathogenicity. Correlations of pathogenic/likely pathogenic variants (P/LPVs) with cardiac pathology were evaluated. RESULTS: The cohort included 1107 decedents of diverse ages and ethnicities. P/LPVs were detected in 87 (7.9%) cases, with 73 and 14 variants in cardiomyopathy and cardiac arrhythmia genes, respectively. Variants of uncertain significance were detected in 437 (39.5%) cases. The diagnostic yield (percentage of P/LPV) in decedents with cardiomyopathy (26.1%) was significantly higher than those without (P<.0001). The diagnostic yield was significantly lower in infants (0.7%) than older age groups (ranging from 1 to 74 years old, 5.7%-25.9%), which had no statistical difference between their yields. The diagnostic yields by cardiac autopsy findings were 54.0% for hypertrophic cardiomyopathy, 47.1% for arrhythmogenic cardiomyopathy, 20.0% for myocardial fibrosis, 19.0% for dilated cardiomyopathy, and 11.3% for myocarditis. Most P/LPVs were in MYBPC3, TTN, PKP2, SCN5A, MYH7, and FLNC. Ten P/LPVs were novel. CONCLUSIONS: Our results support the importance of performing postmortem genetic testing on decedents of all ages with cardiomyopathy, cardiac lesions insufficient to diagnosis a specific cardiomyopathy (e.g., myocardial fibrosis), and myocarditis. Combined postmortem cardiac examination and genetic analysis are advantageous in accurately determining the underlying cause of death and informing effective clinical care of family members.

Malathion exposure may increase infertility risk among US Adults: Results from the 2015-2016 NHANES.

BACKGROUND AND PURPOSE: Organophosphate pesticides such as malathion are the most widely used pesticides. Despite endocrine-disrupting effects, there is a paucity of information regarding chronic exposure to non-persistent organopesticides such as malathion. The purpose of this study is to describe the exposure burden among U.S. residents as well as possible impacts on fertility. METHODS: Population-based data collected by the National Health and Nutrition Examination Survey (NHANES) between 2015 and 2016 were used to perform a retrospective analysis on urinary concentrations of malathion diacid. Samples were assessed from 1703 adult participants, statistically weighted to represent over 231 million individuals. General linear models were used to examine associations between exposure and reproductive health measures among pre-menopausal women. RESULTS: Detectable concentrations of malathion diacid were identified in 16.1 % (n = 254) of samples. Concentrations were higher among women who reported seeing a physician due to difficulties becoming pregnant (P < 0.001; r2 = 0.12) as well as among women who reported trying for at least a year to become pregnant (P < 0.001; r2 = 0.06). CONCLUSIONS: Exposure to malathion is associated with a history of reproductive health challenges among women.