Tracing energy inputs into the seafloor using carbonate sediments.

Carbonate rocks provide unique and valuable sedimentary archives for secular changes in Earth's physical, chemical, and biological processes. However, reading the stratigraphic record produces overlapping, nonunique interpretations that stem from the difficulty in directly comparing competing biological, physical, or chemical mechanisms within a common quantitative framework. We built a mathematical model that decomposes these processes and casts the marine carbonate record in terms of energy fluxes across the sediment-water interface. Results showed that physical, chemical, and biological energy terms across the seafloor are subequal and that the energetic dominance of different processes varies both as a function of environment (e.g., onshore vs. offshore) as well as with time-varying changes in seawater chemistry and with evolutionary changes in animal abundance and behavior. We applied our model to observations from the end-Permian mass extinction-a massive upheaval in ocean chemistry and biology-revealing an energetic equivalence between two hypothesized drivers of changing carbonate environments: a reduction in physical bioturbation increased carbonate saturation states in the oceans. Early Triassic occurrences of 'anachronistic' carbonates-facies largely absent from marine environments after the Early Paleozoic-were likely driven more by reduction in animal biomass than by repeated perturbations to seawater chemistry. This analysis highlighted the importance of animals and their evolutionary history in physically shaping patterns in the sedimentary record via their impact on the energetics of marine environments.

Histone H3K18 & H3K23 acetylation directs establishment of MLL-mediated H3K4 methylation.

In an unmodified state, positively charged histone N-terminal tails engage nucleosomal DNA in a manner which restricts access to not only the underlying DNA but also key tail residues subject to binding and/or modification. Charge-neutralizing modifications, such as histone acetylation, serve to disrupt this DNA-tail interaction, facilitating access to such residues. We previously showed that a polyacetylation-mediated chromatin "switch" governs the read-write capability of H3K4me3 by the MLL1 methyltransferase complex. Here, we discern the relative contributions of site-specific acetylation states along the H3 tail and extend our interrogation to other chromatin modifiers. We show that the contributions of H3 tail acetylation to H3K4 methylation by MLL1 are highly variable, with H3K18 and H3K23 acetylation exhibiting robust stimulatory effects and that this extends to the related H3K4 methyltransferase complex, MLL4. We show that H3K4me1 and H3K4me3 are found preferentially co-enriched with H3 N-terminal tail proteoforms bearing dual H3K18 and H3K23 acetylation (H3{K18acK23ac}). We further show that this effect is specific to H3K4 methylation, while methyltransferases targeting other H3 tail residues (H3K9, H3K27, & H3K36), a methyltransferase targeting the nucleosome core (H3K79), and a kinase targeting a residue directly adjacent to H3K4 (H3T3) are insensitive to tail acetylation. Together, these findings indicate a unique and robust stimulation of H3K4 methylation by H3K18 and H3K23 acetylation and provide key insight into why H3K4 methylation is often associated with histone acetylation in the context of active gene expression.

Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.

Iron-based biomarkers for personalizing pharmacological ascorbate therapy in glioblastoma: insights from a phase 2 clinical trial.

BACKGROUND: Pharmacological ascorbate (intravenous delivery reaching plasma concentrations ≈ 20 mM; P-AscH-) has emerged as a promising therapeutic strategy for glioblastoma. Recently, a single-arm phase 2 clinical trial demonstrated a significant increase in overall survival when P-AscH- was combined with temozolomide and radiotherapy. As P-AscH- relies on iron-dependent mechanisms, this study aimed to assess the predictive potential of both molecular and imaging-based iron-related markers to enhance the personalization of P-AscH- therapy in glioblastoma participants. METHODS: Participants (n = 55) with newly diagnosed glioblastoma were enrolled in a phase 2 clinical trial conducted at the University of Iowa (NCT02344355). Tumor samples obtained during surgical resection were processed and stained for transferrin receptor and ferritin heavy chain expression. A blinded pathologist performed pathological assessment. Quantitative susceptibility mapping (QSM) measures were obtained from pre-radiotherapy MRI scans following maximal safe surgical resection. Circulating blood iron panels were evaluated prior to therapy through the University of Iowa Diagnostic Laboratory. RESULTS: Through univariate analysis, a significant inverse association was observed between tumor transferrin receptor expression and overall and progression-free survival. QSM measures exhibited a significant, positive association with progression-free survival. Subjects were actively followed until disease progression and then were followed through chart review or clinical visits for overall survival. CONCLUSIONS: This study analyzes iron-related biomarkers in the context of P-AscH- therapy for glioblastoma. Integrating molecular, systemic, and imaging-based markers offers a multifaceted approach to tailoring treatment strategies, thereby contributing to improved patient outcomes and advancing the field of glioblastoma therapy.

HIGHLIGHTS: Pharmacological ascorbate shows significant promise to enhance glioblastoma clinical outcomes. Transferrin receptor and ferritin heavy chain expression represent potential molecular markers to predict pharmacological ascorbate treatment response. Quantitative Susceptibility Mapping is an MRI technique that can serve as a non-invasive marker of iron metabolism to evaluate progression-free survival. Systemic iron metabolic markers are readily available diagnostic tests that can potentially be used to prognosticate overall survival.

StreptomeDB 3.0: an updated compendium of streptomycetes natural products.

Antimicrobial resistance is an emerging global health threat necessitating the rapid development of novel antimicrobials. Remarkably, the vast majority of currently available antibiotics are natural products (NPs) isolated from streptomycetes, soil-dwelling bacteria of the genus Streptomyces. However, there is still a huge reservoir of streptomycetes NPs which remains pharmaceutically untapped and a compendium thereof could serve as a source of inspiration for the rational design of novel antibiotics. Initially released in 2012, StreptomeDB (http://www.pharmbioinf.uni-freiburg.de/streptomedb) is the first and only public online database that enables the interactive phylogenetic exploration of streptomycetes and their isolated or mutasynthesized NPs. In this third release, there are substantial improvements over its forerunners, especially in terms of data content. For instance, about 2500 unique NPs were newly annotated through manual curation of about 1300 PubMed-indexed articles, published in the last five years since the second release. To increase interoperability, StreptomeDB entries were hyperlinked to several spectral, (bio)chemical and chemical vendor databases, and also to a genome-based NP prediction server. Moreover, predicted pharmacokinetic and toxicity profiles were added. Lastly, some recent real-world use cases of StreptomeDB are highlighted, to illustrate its applicability in life sciences.

Variable digestibility of captive northern greater galagos (Otolemur garnettii) fed experimental "frugivorous" and "invertebrate" diets.

Few studies have addressed the nutritional ecology of galagos. Observations of galagos in the wild reveal that they rely on fruits and invertebrates to varying degrees depending on their availability. We conducted a 6-week comparative dietary analysis of a colony of captive-housed northern greater galagos (Otolemur garnettii), which included five females and six males with known life histories. We compared two experimental diets. The first was fruit dominated and the second was invertebrate dominated. For each diet, we examined dietary intake and apparent dry matter digestibility over the course of 6 weeks. We found significant differences between the apparent digestibility of the diets, with the "invertebrate" diet being more digestible than the "frugivorous" diet. The lower apparent digestibility of the "frugivorous" diet was driven by the higher fiber contents of the fruits provided to the colony. However, variation in apparent digestibility of both diets was found among individual galagos. The experimental design used in this study may provide useful dietary data for the management of captive colonies of galagos and other strepsirrhine primates. This study may also be helpful for understanding the nutritional challenges faced by free-ranging galagos through time and across geographic space.

Venetoclax exposure-efficacy and exposure-safety relationships in patients with treatment-naïve acute myeloid leukemia who are ineligible for intensive chemotherapy.

This study evaluated venetoclax population pharmacokinetics (popPK) in patients with treatment-naïve acute myeloid leukemia and assessed the relationship between venetoclax exposure and clinical response for venetoclax in combination with either a hypomethylating agent (HMA) or low-dose cytarabine (LDAC). A total of 771 patients who received venetoclax from 5 Phase 1-3 studies were included in the popPK model. Exposure-response analyses included data from 575 patients for venetoclax/placebo plus HMA and 279 patients for venetoclax/placebo plus LDAC. The popPK model successfully characterized venetoclax plasma concentrations over time and confirmed venetoclax exposure did not vary significantly with age, weight, sex, mild to moderate hepatic impairment, or mild to severe renal impairment. Asian patients had 67% higher mean relative bioavailability than non-Asian patients, however the range of exposures in Asian patients was similar to non-Asian patients. For all efficacy endpoints with both treatment combinations, efficacy was higher in the venetoclax treatment groups compared with the respective control arm of placebo plus azacitidine or LDAC. Within patients who received venetoclax, no significant exposure-efficacy relationships were identified for either treatment combination, indicating that the beneficial effects of venetoclax were already maximized in the dose ranges studied. There was no apparent effect of venetoclax exposure on treatment-emergent Grade ≥3 thrombocytopenia or infections for either combination. Rates of treatment-emergent Grade ≥3 neutropenia were higher in the venetoclax treatment arms compared with the respective control arms; however, within patients who received venetoclax, there was only a shallow relationship or no apparent relationship with venetoclax exposure for venetoclax plus HMA or LDAC, respectively. Along with the efficacy and safety data previously published, the exposure-response analyses support the venetoclax dose regimens of 400 mg once daily (QD) plus HMA and 600 mg QD plus LDAC in treatment-naïve AML patients who are ineligible for intensive chemotherapy.

Decisive points for pregnancy losses in beef cattle.

Beef cattle producers rely on each of their cows to produce a marketable calf each year to maintain a sustainable operation. Within the first month of gestation, pregnancy failures have been recorded to be upwards of 40-50%. From fertilisation to birth, there are numerous factors contributing to pregnancy failure. From the beginning of gestation oocyte competence is often a large factor impacting fertility as the dam contributes all mRNA for initial embryo development. Other factors contributing to early embryonic infertility include hormonal concentration and heat stress. After the embryo enters the uterus, it becomes critical for the uterus to be receptive to the developing conceptus. The embryo then begins to elongate and secrete interferon-tau to initiate maternal recognition of pregnancy; a requirement to establish and maintain bovine pregnancies. After a pregnancy completes these steps, placentation actively begins around day 22 of pregnancy and lasts until organogenesis. The fetal phase follows the embryonic phase where disease and/or toxins are often the cause of pregnancy failure at this period. However, fetal mortality has been reported to occur in less than 10% of pregnancies. Understanding of the many factors influencing infertility needs to be further investigated to increase pregnancy success in beef cattle.

Arsenic trioxide dose capping to decrease toxicity in the treatment of acute promyelocytic leukemia.

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

Growth of Neanderthal infants from Krapina (120-130 ka), Croatia.

Modern humans have a slow and extended period of childhood growth, but to what extent this ontogenetic pathway was present in Neanderthals is debated. Dental development, linked to the duration of somatic growth across modern primates, is the main source for information about growth and development in a variety of fossil primates, including humans. Studies of Neanderthal permanent teeth report a pace of development either similar to recent humans or relatively accelerated. Neanderthal milk teeth, which form and emerge before permanent teeth, provide an opportunity to determine which pattern was present at birth. Here we present a comparative study of the prenatal and early postnatal growth of five milk teeth from three Neanderthals (120 000-130 000 years ago) using virtual histology. Results reveal regions of their milk teeth formed quickly before birth and over a relatively short period of time after birth. Tooth emergence commenced towards the earliest end of the eruption schedules displayed by extant human children. Advanced dental development is consistent with expectations for Neanderthal infant feeding.

Gaussian versus Non-Gaussian Filtering of Phase-Insensitive Nonclassicality.

Measures of quantum properties are essential to understanding the fundamental differences between quantum and classical systems as well as quantifying resources for quantum technologies. Here, two broad classes of bosonic phase-space functions, which are filtered versions of the Glauber-Sudarshan P function, are compared with regard to their ability to uncover nonclassical effects of light through their negativities. Gaussian filtering of the P function yields the family of s-parametrized quasiprobabilities, while more powerful regularized nonclassicality quasiprobabilities are obtained by non-Gaussian filtering. A method is proposed to directly sample such phase-space functions for the restricted case of phase-independent quantum states from balanced homodyne measurements. This overcomes difficulties of previous approaches that manually append uniformly distributed optical phases to the measured quadrature data. We experimentally demonstrate this technique for heralded single- and two-photon states using balanced homodyne detection with varying efficiency. The s-parametrized quasiprobabilities, which can be directly sampled, are non-negative for detection efficiencies below 0.5. By contrast, we show that significant negativities of non-Gaussian filtered quasiprobabilities uncover nonclassical effects for arbitrarily low efficiencies.

Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial.

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325-0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395-1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151-0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days' therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients.

BACKGROUND: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

In Silico Finite Element Analysis of the Foot Ankle Complex Biomechanics: A Literature Review.

Computational approaches, especially finite element analysis (FEA), have been rapidly growing in both academia and industry during the last few decades. FEA serves as a powerful and efficient approach for simulating real-life experiments, including industrial product development, machine design, and biomedical research, particularly in biomechanics and biomaterials. Accordingly, FEA has been a "go-to" high biofidelic software tool to simulate and quantify the biomechanics of the foot-ankle complex, as well as to predict the risk of foot and ankle injuries, which are one of the most common musculoskeletal injuries among physically active individuals. This paper provides a review of the in silico FEA of the foot-ankle complex. First, a brief history of computational modeling methods and finite element (FE) simulations for foot-ankle models is introduced. Second, a general approach to build an FE foot and ankle model is presented, including a detailed procedure to accurately construct, calibrate, verify, and validate an FE model in its appropriate simulation environment. Third, current applications, as well as future improvements of the foot and ankle FE models, especially in the biomedical field, are discussed. Finally, a conclusion is made on the efficiency and development of FEA as a computational approach in investigating the biomechanics of the foot-ankle complex. Overall, this review integrates insightful information for biomedical engineers, medical professionals, and researchers to conduct more accurate research on the foot-ankle FE models in the future.

A Prospective Study of Peritransplant Sorafenib for Patients with FLT3-ITD Acute Myeloid Leukemia Undergoing Allogeneic Transplantation.

FLT3-ITD-mutated acute myeloid leukemia (AML) remains a therapeutic challenge. FLT3 inhibition in the setting of minimal residual disease and a new immune system via allogeneic transplantation offers a promise of improved survival for these patients. We performed a prospective study of patients with FLT3-ITD AML undergoing allogeneic transplant that was conducted to evaluate the safety, tolerability, and outcome of sorafenib administered peritransplant. Sorafenib dosing was individualized, starting at 200 mg twice a day (BID), and titrated based on tolerability or toxicities until a tolerable dose was identified. Forty-four patients, with a median age of 52 years, undergoing allogeneic transplant were started on sorafenib in the peritransplant period (21 pretransplant). The median duration of post-transplant follow-up was 27.6 months (range, 5.2 to 60.4). Overall survival was 76% at both 24 and 36 months. Event-free survival at 24 and 36 months was 74% and 64%, respectively. Ten patients died in the post-transplant period, with 6 deaths due to relapsed leukemia and 4 from transplant-associated toxicity. Tolerable doses ranged from 200 mg every other day to 400 mg BID with similar exposure. Correlative studies evaluating FLT3 inhibition via a plasma inhibitory activity assay showed consistent inhibition of FLT3 at all tolerability-determined dosing levels. Sorafenib is well tolerated in the peritransplant setting irrespective of the conditioning intensity or the donor source. Our findings indicate that sorafenib dosing can be individualized in the post-transplantation setting according to patient tolerability. This approach results in effective in vivo FLT3 inhibition and yields encouraging survival results.

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.

Pregnancy outcomes in women with primary biliary cholangitis and primary sclerosing cholangitis: a retrospective cohort study.

OBJECTIVE: To determine maternal, obstetric and neonatal outcomes in a cohort of women with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). DESIGN: Retrospective cohort study. SETTING: Ten specialist centres managing pregnant women with liver disease. POPULATION: Women with a diagnosis of PBC and PSC and a pregnancy of ≥20 completed weeks of gestation. METHODS: Retrospective case notes review. MAIN OUTCOME MEASURES: Adverse outcomes were defined as: maternal - development of ascites, variceal bleeding, encephalopathy and jaundice; obstetric events - gestational hypertension, pre-eclampsia and postpartum haemorrhage; and neonatal - stillbirth, preterm delivery and admission to neonatal unit. The relationship of alanine transferase (ALT) and bile acid levels with gestation at delivery was studied. RESULTS: The first recorded pregnancies of 34 women with PSC and 27 women with PBC were analysed. There were 60 live births and one intrapartum stillbirth that did not occur in the context of maternal cholestasis. The overall median gestation of delivery was 38 weeks but the rate of preterm birth was 28% (17/61 deliveries), 76% (13/17) of which were spontaneous. Gestation at birth negatively correlated with maternal serum ALT concentration at booking (P = 0.017) and serum bile acid concentration during pregnancy (P = 0.016). There were no other significant correlations and maternal and neonatal outcomes were good. CONCLUSIONS: Pregnancy in PBC and PSC is well tolerated, but women should be counselled regarding the increased risk of preterm birth. Measurement of maternal ALT and bile acids may help identify women at risk of preterm delivery. TWEETABLE ABSTRACT: Pregnancy in women with PBC and PSC is well tolerated; however, rates of preterm birth are high and are related to maternal bile acid levels.

Alkaloids with Anti-Onchocercal Activity from Voacanga africana Stapf (Apocynaceae): Identification and Molecular Modeling.

A new iboga-vobasine-type isomeric bisindole alkaloid named voacamine A (1), along with eight known compounds-voacangine (2), voacristine (3), coronaridine (4), tabernanthine (5), iboxygaine (6), voacamine (7), voacorine (8) and conoduramine (9)-were isolated from the stem bark of Voacangaafricana. The structures of the compounds were determined by comprehensive spectroscopic analyses. Compounds 1, 2, 3, 4, 6, 7 and 8 were found to inhibit the motility of both the microfilariae (Mf) and adult male worms of Onchocerca ochengi, in a dose-dependent manner, but were only moderately active on the adult female worms upon biochemical assessment at 30 µM drug concentrations. The IC50 values of the isolates are 2.49-5.49 µM for microfilariae and 3.45-17.87 µM for adult males. Homology modeling was used to generate a 3D model of the O. ochengi thioredoxin reductase target and docking simulation, followed by molecular dynamics and binding free energy calculations attempted to offer an explanation of the anti-onchocercal structure-activity relationship (SAR) of the isolated compounds. These alkaloids are new potential leads for the development of antifilarial drugs. The results of this study validate the traditional use of V. africana in the treatment of human onchocerciasis.

Development of Grade II Acute Graft-versus-Host Disease Is Associated with Improved Survival after Myeloablative HLA-Matched Bone Marrow Transplantation using Single-Agent Post-Transplant Cyclophosphamide.

Post-transplant cyclophosphamide (PTCy) can be used as the sole immunosuppression after myeloablative conditioning (MAC) for HLA-matched bone marrow transplantation (BMT). However, the effects of graft-versus-host disease (GVHD) with this platform are undefined. We retrospectively analyzed 298 consecutive adult patients with hematologic malignancies who engrafted after MAC HLA-matched sibling donor (MSD; n = 187) or HLA-matched unrelated donor (MUD; n = 111) T-cell-replete BMT with PTCy 50 mg/kg on days +3 and +4. After MSD and MUD BMT, 35% and 57% of patients, respectively, developed grade II acute GVHD (aGVHD) by 100 days, 11% and 14% grade III to IV aGVHD by 100 days, and 9% and 16% chronic GVHD (cGVHD) by 1 year. In landmark analyses at 100 days after HLA-matched BMT, 4-year overall survival (OS) and progression-free survival (PFS) were 57% (95% confidence interval [CI], .49 to .67) and 40% (95% CI, .31 to .51) in patients without grades II to IV aGVHD, and 68% (95% CI, .59 to .78) and 54% (95% CI, .44 to .65) in patients with grade II aGVHD. In adjusted time-dependent multivariable analyses, grade II aGVHD was associated with improved OS (hazard ratio, .58; 95% CI, .37 to .89; P = .01) and PFS (hazard ratio, .50; 95% CI, .34 to .74; P < .001) after HLA-matched BMT with PTCy. The ability of PTCy to limit grades III to IV aGVHD and cGVHD while maintaining grade II aGVHD may contribute to its effectiveness, and further attempts to reduce aGVHD may be detrimental.

Prevalence and predictors of airflow obstruction in an HIV tertiary care clinic in Montreal, Canada: a cross-sectional study.

OBJECTIVES: The reported prevalence of chronic obstructive pulmonary disease (COPD) in people living with HIV (PLWHIV) varies widely. Our objective was to estimate the prevalence of airflow obstruction and COPD in unselected PLWHIV and identify characteristics that increase the risk of nonreversible airflow obstruction in order to guide case finding strategies for COPD. METHODS: All adults attending the Chronic Viral Illness Service were invited to participate in the study, regardless of smoking status or history of known COPD/asthma. Individuals underwent spirometric testing both before and after use of a salbutamol bronchodilator. Airflow obstruction was defined as forced expiratory volume in 1 s (FEV1 )/forced vital capacity (FVC) < 0.7 post-bronchodilation, whereas COPD was defined as FEV1 /FVC < 0.7 post-bronchodilation and Medical Research Council (MRC) score > 2. Multivariate logistic regression was used to evaluate risk factors associated with airflow obstruction, reported as adjusted odds ratios (aORs). RESULTS: Five hundred and three participants successfully completed spirometry testing. The median (Q1; Q3) age was 52 (44; 58) years. The median (Q1; Q3) CD4 count was 598 (438; 784) cells/µL and the median (Q1; Q3) nadir CD4 count was 224 (121; 351) cells/µL. There were 119 (24%) current smokers and 145 (29%) former smokers. Among those screened, 54 (11%) had airflow obstruction whereas three (1%) of the participants had COPD. Factors that were associated with airflow obstruction included a history of smoking [aOR 2.2; 95% confidence interval (CI) 1.1; 4.7], older age (aOR 1.6; 95% CI 1.2; 2.2), and lower CD4 count (aOR 0.8; 95% CI 0.7; 1.0). CONCLUSIONS: Airflow obstruction was relatively uncommon. Our findings suggest that PLWHIV who are ≥50 years old, smokers and those with nadir CD4 counts ≤ 200 cells/µL could be targeted to undergo spirometry to diagnose chronic airflow obstruction.