Evaluate response of mismatch repair-deficient (dMMR) rectal cancer to neoadjuvant chemotherapy.
dMMR rectal tumors at Memorial Sloan Kettering Cancer Center (New York, NY) were retrospectively ...reviewed for characteristics, treatment, and outcomes. Fifty patients with dMMR rectal cancer were identified by IHC and/or microsatellite instability analysis, with initial treatment response compared with a matched MMR-proficient (pMMR) rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity.
Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), six (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors
= 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable with 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome with enrichment of germline
and
mutations when compared with 193 patients with Lynch syndrome-associated colon cancer (
, 57% vs 36%;
, 17% vs 9%;
< 0.003).
Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for Lynch syndrome in patients with dMMR rectal cancer.
Interactions between the microbiota and distal gut are important for the maintenance of a healthy intestinal barrier; dysbiosis of intestinal microbial communities has emerged as a likely contributor ...to diseases that arise at the level of the mucosa. Intraepithelial lymphocytes (IELs) are positioned within the epithelial barrier, and in the small intestine they function to maintain epithelial homeostasis. We hypothesized that colon IELs promote epithelial barrier function through the expression of cytokines in response to interactions with commensal bacteria. Profiling of bacterial 16S ribosomal RNA revealed that candidate bacteria in the order Bacteroidales are sufficient to promote IEL presence in the colon that in turn produce interleukin-6 (IL-6) in a MyD88 (myeloid differentiation primary response 88)-dependent manner. IEL-derived IL-6 is functionally important in the maintenance of the epithelial barrier as IL-6
mice were noted to have increased paracellular permeability, decreased claudin-1 expression, and a thinner mucus gel layer, all of which were reversed by transfer of IL-6
IELs, leading to protection of mice in response to Citrobacter rodentium infection. Therefore, we conclude that microbiota provide a homeostatic role for epithelial barrier function through regulation of IEL-derived IL-6.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives. To evaluate associations between oil and gas development (OGD) and mental health using cross-sectional data from a preconception cohort study, Pregnancy Study Online. Methods. We analyzed ...baseline data from a prospective cohort of US and Canadian women aged 21 to 45 years who were attempting conception without fertility treatment (2013–2023). We developed residential proximity measures for active OGD during preconception, including distance from nearest site. At baseline, participants completed validated scales for perceived stress (10-item Perceived Stress Scale, PSS) and depressive symptoms (Major Depression Inventory, MDI) and reported psychotropic medication use. We used log-binomial regression and restricted cubic splines to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs). Results. Among 5725 participants across 37 states and provinces, residence at 2 km versus 20 to 50 km of active OGD was associated with moderate to high perceived stress (PSS ≥ 20 vs < 20: PR = 1.08; 95% CI = 0.98, 1.18), moderate to severe depressive symptoms (MDI ≥ 20 vs < 20: PR = 1.27; 95% CI = 1.11, 1.45), and psychotropic medication use (PR = 1.11; 95% CI = 0.97, 1.28). Conclusions. Among North American pregnancy planners, closer proximity to OGD was associated with adverse preconception mental health symptomatology. ( Am J Public Health. Published online ahead of print July 11, 2024:e1–e12. https://doi.org/10.2105/AJPH.2024.307730 )
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CEKLJ, DOBA, FSPLJ, IZUM, KILJ, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Idiopathic generalized epilepsy (IGE) is a complex disease with high heritability, but little is known about its genetic architecture. Rare copy-number variants have been found to explain nearly 3% ...of individuals with IGE; however, it remains unclear whether variants with moderate effect size and frequencies below what are reliably detected with genome-wide association studies contribute significantly to disease risk. In this study, we compare the exome sequences of 118 individuals with IGE and 242 controls of European ancestry by using next-generation sequencing. The exome-sequenced epilepsy cases include study subjects with two forms of IGE, including juvenile myoclonic epilepsy (n = 93) and absence epilepsy (n = 25). However, our discovery strategy did not assume common genetic control between the subtypes of IGE considered. In the sequence data, as expected, no variants were significantly associated with the IGE phenotype or more specific IGE diagnoses. We then selected 3,897 candidate epilepsy-susceptibility variants from the sequence data and genotyped them in a larger set of 878 individuals with IGE and 1,830 controls. Again, no variant achieved statistical significance. However, 1,935 variants were observed exclusively in cases either as heterozygous or homozygous genotypes. It is likely that this set of variants includes real risk factors. The lack of significant association evidence of single variants with disease in this two-stage approach emphasizes the high genetic heterogeneity of epilepsy disorders, suggests that the impact of any individual single-nucleotide variant in this disease is small, and indicates that gene-based approaches might be more successful for future sequencing studies of epilepsy predisposition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Posttraumatic stress disorder occurs in as many as one in five combat veterans and is associated with a host of negative, long-term consequences to the individual, their families, and society at ...large. Trauma-focused treatments, such as Prolonged Exposure, result in clinically significant symptom relief for many. Adherence to these treatments (i.e., session attendance and homework compliance) is vital to ensuring recovery but can be challenging for patients. Engaging families in veterans' treatment could prove to be an effective strategy for promoting treatment adherence while also addressing long-standing calls for better family inclusion in treatment for posttraumatic stress disorder. This paper describes the methods of a pragmatic randomized controlled trial designed to evaluate if family inclusion in Prolonged Exposure can improve treatment adherence.
One hundred fifty-six veterans, with clinically significant symptoms of posttraumatic stress disorder, will be randomized to receive either standard Prolonged Exposure or Prolonged Exposure enhanced through family inclusion (Family-Supported Prolonged Exposure) across three different VA facilities. Our primary outcomes are session attendance and homework compliance. Secondary outcomes include posttraumatic stress disorder symptom severity, depression, quality of life, and relationship functioning. The study includes a concurrent process evaluation to identify potential implementation facilitators and barriers to family involvement in Prolonged Exposure within VA.
While the importance of family involvement in posttraumatic stress disorder treatment is non-controversial, there is no evidence base supporting best practices on how to integrate families into PE or any other individually focused trauma-focused treatments for posttraumatic stress disorder. This study is an important step in addressing this gap, contributing to the literature for both retention and family involvement in trauma-focused treatments.
ClinicalTrials.gov NCT03256227 . Registered on August 21, 2017.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
1 Department of Physiology, University of Kentucky, Lexington, Kentucky
2 School of Kinesiology, University of Illinois Chicago, Chicago
3 Howard Hughes Medical Institute, Northwestern University, ...Evanston, Illinois
4 Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois
5 The Genomics Institute of the Novartis Research Foundation, San Diego, California
Circadian rhythms are approximate 24-h behavioral and physiological cycles that function to prepare an organism for daily environmental changes. The basic clock mechanism is a network of transcriptional-translational feedback loops that drive rhythmic expression of genes over a 24-h period. The objectives of this study were to identify transcripts with a circadian pattern of expression in adult skeletal muscle and to determine the effect of the Clock mutation on gene expression. Expression profiling on muscle samples collected every 4 h for 48 h was performed. Using COSOPT, we identified a total of 215 transcripts as having a circadian pattern of expression. Real-time PCR results verified the circadian expression of the core clock genes, Bmal1 , Per2 , and Cry2 . Annotation revealed cycling genes were involved in a range of biological processes including transcription, lipid metabolism, protein degradation, ion transport, and vesicular trafficking. The tissue specificity of the skeletal muscle circadian transcriptome was highlighted by the presence of known muscle-specific genes such as Myod1 , Ucp3 , Atrogin1 ( Fbxo32 ), and Myh1 (myosin heavy chain IIX). Expression profiling was also performed on muscle from the Clock mutant mouse and sarcomeric genes such as actin and titin, and many mitochondrial genes were significantly downregulated in the muscle of Clock mutant mice. Defining the circadian transcriptome in adult skeletal muscle and identifying the significant alterations in gene expression that occur in muscle of the Clock mutant mouse provide the basis for understanding the role of circadian rhythms in the daily maintenance of skeletal muscle.
circadian rhythms; gene expression; MyoD; Clock mutant
Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital ...with COVID-19.
In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy RECOVERY), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.
Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 38% of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days IQR 5 to >28 vs 11 days 5 to >28) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).
In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication.
UK Research and Innovation (Medical Research Council) and National Institute of Health Research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Daily oral antiretroviral preexposure prophylaxis (PrEP) is a promising strategy for prevention of HIV-1 acquisition. Three clinical trials demonstrated PrEP efficacy; however, two PrEP trials among ...women did not find protection against HIV-1. One hypothesis proposed for these divergent results is that PrEP efficacy may be reduced in populations with higher HIV-1 incidence.
Using data from the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral tenofovir (TDF) and emtricitabine/tenofovir (FTC/TDF) PrEP among heterosexual HIV-1 serodiscordant couples from Kenya and Uganda, we assessed PrEP efficacy among subgroups at higher risk for HIV-1 acquisition, including subgroups of women with high HIV-1 incidence.
The overall placebo arm HIV-1 incidence was 2.0 per 100 person-years. Among higher risk subgroups, placebo arm HIV-1 incidence ranged from 3.9 to 6.6 per 100 person-years. In all subgroups, PrEP was protective against HIV-1 acquisition, with efficacy point estimates ranging from 64 to 84%. Among subgroups of women with placebo-arm HIV-1 incidence more than 5.0, efficacy estimates ranged from 64 to 84%. Monthly visit attendance for PrEP refills and tenofovir detection in plasma were high.
Among higher-risk subgroups in the Partners PrEP Study, including groups solely of higher-risk women, both TDF alone and combined FTC/TDF PrEP had consistently high efficacy for HIV-1 protection. PrEP, when used with high adherence, is a highly effective prevention strategy for higher risk heterosexuals. Prioritizing PrEP for persons at high risk of HIV-1 will maximize its prevention impact.
African large mammals are under extreme pressure from unsustainable hunting and habitat loss. Certain traits make large mammals particularly vulnerable. These include late age at first reproduction, ...long inter‐birth intervals, and low population density. Great apes are a prime example of such vulnerability, exhibiting all of these traits. Here we assess the rate of population change for the western chimpanzee, Pan troglodytes verus, over a 24‐year period. As a proxy for change in abundance, we used transect nest count data from 20 different sites archived in the IUCN SSC A.P.E.S. database, representing 25,000 of the estimated remaining 35,000 western chimpanzees. For each of the 20 sites, datasets for 2 different years were available. We estimated site‐specific and global population change using Generalized Linear Models. At 12 of these sites, we detected a significant negative trend. The estimated change in the subspecies abundance, as approximated by nest encounter rate, yielded a 6% annual decline and a total decline of 80.2% over the study period from 1990 to 2014. This also resulted in a reduced geographic range of 20% (657,600 vs. 524,100 km2). Poverty, civil conflict, disease pandemics, agriculture, extractive industries, infrastructure development, and lack of law enforcement, are some of the many reasons for the magnitude of threat. Our status update triggered the uplisting of the western chimpanzee to “Critically Endangered” on the IUCN Red List. In 2017, IUCN will start updating the 2003 Action Plan for western chimpanzees and will provide a consensus blueprint for what is needed to save this subspecies. We make a plea for greater commitment to conservation in West Africa across sectors. Needed especially is more robust engagement by national governments, integration of conservation priorities into the private sector and development planning across the region and sustained financial support from donors.
Pan troglodytes verus has declined by 80% over 24 years due poaching and habitat loss, its range was reduced by 20% from 657,600 to 524,100 km2, and about 35,000 chimpanzees now remain.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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