fertilization, an essential step for the development of the malaria parasite in the mosquito, is a prime target for blocking pathogen transmission. Using phage peptide display screening, we ...identified MG1, a peptide that binds to male gametes and inhibits fertilization, presumably by competing with a female gamete ligand. Anti-MG1 antibodies bind to the female gamete surface and, by doing so, also inhibit fertilization. We determined that this antibody recognizes HSP90 on the surface of
female gametes. Our findings establish
HSP90 as a prime target for the development of a transmission-blocking vaccine.IMPORTANCEMalaria kills over half a million people every year and this number has not decreased in recent years. The development of new tools to combat this disease is urgently needed. In this article, we report the identification of a key molecule-HSP90-on the surface of the parasite's female gamete that is required for fertilization to occur and for the completion of the parasite cycle in the mosquito. HSP90 is a promising candidate for the development of a transmission-blocking vaccine.
Hypertrophic cardiomyopathy (HCM) is caused primarily by pathogenic variants in genes encoding sarcomere proteins. We report genetic testing results for HCM in 2,912 unrelated individuals with ...nonsyndromic presentations from a broad referral population over 10 years.
Genetic testing was performed by Sanger sequencing for 10 genes from 2004 to 2007, by HCM CardioChip for 11 genes from 2007 to 2011 and by next-generation sequencing for 18, 46, or 51 genes from 2011 onward.
The detection rate is ~32% among unselected probands, with inconclusive results in an additional 15%. Detection rates were not significantly different between adult and pediatric probands but were higher in females compared with males. An expanded gene panel encompassing more than 50 genes identified only a very small number of additional pathogenic variants beyond those identifiable in our original panels, which examined 11 genes. Familial genetic testing in at-risk family members eliminated the need for longitudinal cardiac evaluations in 691 individuals. Based on the projected costs derived from Medicare fee schedules for the recommended clinical evaluations of HCM family members by the American College of Cardiology Foundation/American Heart Association, our data indicate that genetic testing resulted in a minimum cost savings of about $0.7 million.
Clinical HCM genetic testing provides a definitive molecular diagnosis for many patients and provides cost savings to families. Expanded gene panels have not substantively increased the clinical sensitivity of HCM testing, suggesting major additional causes of HCM still remain to be identified.
Recent research has documented the harmful health consequences of structural-level stigma that targets sexual and gender minority (SGM) individuals. In the case of sexual and gender minority youth ...(SGMY), life trajectories are shaped not only by targeted, SGM-focused policies, but also by social policies more broadly which may have unique impacts on SGMY given their social position. However, little work has explored the pathways that connect both targeted and universal social policies and the health and well-being of SGMY. In this study, we conducted 68 qualitative interviews with SGMY in New York City (n = 30) and community stakeholders across the US (n = 38) and used the constant comparative method to identify the pathways through which social policies affect SGMY health and well-being. We propose three pathways that are shaped by specific inter-related social policies in ways that contribute to health inequities among SGMY: 1) access to social inclusion in educational settings; 2) housing-related regulations and subsequent (in)stability; and 3) access to material resources through labor market participation. We also highlight ways that SGMY, and organizations that support them, engage in agency and resistance to promote inclusion and wellbeing. Drawing on ecosocial theory, we demonstrate how policies work across multiple domains and levels to influence cycles of vulnerability and risk for SGMY. We close by discussing the implications of our findings for future research and policy.
•Structural-level stigma directly harms sexual and gender minority youth (SGMY).•Targeted and universal social policies affect SGMY cycles of vulnerability and risk.•Education, employment and housing policies differentially affect SGMY health.•We identified pathways between social policies and health outcomes for SGMY.
Rotavirus vaccination is discouraged during hospitalization given concerns regarding live attenuated virus transmission, although recommended upon discharge. Infants should have vaccination initiated ...by 104 days of age or they become age-ineligible. Our institution believed the known risk of severe disease in unvaccinated infants outweighed the theoretical risk of transmission. We routinely administer RotaTeq (RV5) to age-eligible hospitalized infants on enteral feeds. The objective of this study was to determine the safety of RV5 vaccination among vaccinated (VI) and unvaccinated infants (UVI) within the NICU.
A retrospective review identified VI between 2008 and 2010, and UVI geographically located near VI within 15 days of vaccination. We screened for gastrointestinal symptoms among UVI by using an electronic medical record query (trigger tool) to identify infants with orders for bowel rest, abdominal imaging, and antibiotics. Trigger-positive infants had full chart review.
Most VI (76%) were either asymptomatic (25% 24 of 96) or symptomatic but unchanged from baseline (51% 49 of 96) postvaccination. Although 24% of VI had clinical status changes postvaccination, none were directly attributed to RV5. Among 801 neighboring UVI, 10 (1.2%) had clinical status changes, none directly attributed to RV5, but mostly bacterial sepsis or preexisting gastrointestinal pathology. Two UVI underwent stool analysis; both negative for rotavirus.
RV5 was well tolerated in hospitalized infants, with most postvaccination symptoms attributed to preexisting symptoms. UVI seemed to have a low risk of symptomatic transmission. Inpatient administration ensures that age-eligible infants are vaccinated regardless of hospital duration. Prospective evaluation of safety and transmissibility is needed.
Keloids are disfiguring fibroproliferative lesions that can occur in susceptible individuals following any skin injury. They are extremely challenging to treat, with relatively low response rates to ...current therapies and high rates of recurrence after treatment. Although several distinct genetic loci have been associated with keloid formation in different populations, there has been no single causative gene yet identified and the molecular mechanisms guiding keloid development are incompletely understood. Further, although it is well known that keloids are more commonly observed in populations with dark skin pigmentation, the basis for increased keloid risk in skin of colour is not yet known. Because individuals with dark skin pigmentation are at higher risk for vitamin D deficiency, the role of vitamin D in keloid pathology has gained interest in the keloid research community. A limited number of studies have found lower serum vitamin D levels in patients with keloids, and reduced expression of the vitamin D receptor (VDR) in keloid lesions compared with uninjured skin. Vitamin D has documented anti‐inflammatory, anti‐proliferative and pro‐differentiation activities, suggesting it may have a therapeutic role in suppression of keloid fibrosis. Here we review the evidence supporting a role for vitamin D and VDR in keloid pathology.
Background: Polybrominated diphenyl ethers (PBDEs) are flame-retardant chemicals that accumulate in human tissues and are potential toxicants. Concentrations of PBDEs in human tissues have increased ...recently, and body burdens in the U.S. and Canadian populations are higher than in any other region. Objectives: Although metabolism in animal laboratory studies has been examined, no studies have explored the metabolism of these contaminants in human tissues. We undertook this study to determine whether PBDEs could be metabolized by human liver cells in vitro and to identify what types of metabolites are formed. Methods: We exposed hepatocytes from three different donors (two cryopreserved batches and one fresh batch) to solutions containing 10 μM of either of two environmentally relevant and prominent PBDE congeners-BDE-99 or BDE-209-for periods of 24-72 hr. We also conducted gene expression analysis to provide information on potential induction of xenobiotic metabolizing enzymes. Results: Exposing hepatocytes to BDE-99 resulted in the formation of 2,4,5-tribromophenol, two monohydroxylated pentabrominated diphenyl ether metabolites, and a yet unidentified tetrabrominated metabolite. No hydroxylated or debrominated metabolites were observed in the cells exposed to BDE-209. This suggests that BDE-209 was not metabolized, that nonextractable, covalently protein-bound metabolites were formed, or that the exposure time was not long enough for BDE-209 to diffuse into the cell to be metabolized. However, we observed up-regulation of genes encoding for cytochrome P450 monooxygenase (CYP) 1A2, CYP3A4, deiodinase type 1, and glutathione S-transferase M1 in hepatocyes exposed to both BDE-99 and BDE-209. Conclusions: Our in vitro results suggest that the human liver will likely metabolize some BDE congeners (e.g., BDE-99) in vivo. These metabolites have been shown to elicit greater toxicity than the parent BDE congeners in laboratory bioassays; thus, more research on body burdens and human health effects from these metabolites are warranted.
AbstractObjectiveTo determine whether an injection of platelet rich plasma improves outcomes after acute Achilles tendon rupture.DesignRandomised, placebo controlled, two arm, parallel group, ...participant and assessor masked, superiority trial.SettingSecondary care trauma units across 19 hospitals in the United Kingdom’s health service.ParticipantsRecruitment commenced in July 2015 and follow-up was completed in March 2018. 230 adults aged 18 years and over were included, with acute Achilles tendon rupture presenting within 12 days of injury and managed with non-surgical treatment. Exclusions were injury at the insertion or musculotendinous junction, major leg injury or deformity, diabetes mellitus, platelet or haematological disorder, systemic corticosteroids, anticoagulation treatment, and other contraindicating conditions.InterventionsParticipants were randomised 1:1 to platelet rich plasma (n=114) or placebo (dry needle; n=116) injection. All participants received standard rehabilitation care (ankle immobilisation followed by physiotherapy).Main outcomes and measuresPrimary outcome was muscle tendon function at 24 weeks, measured objectively with the limb symmetry index (injured/uninjured×100) in maximal work done during the heel rise endurance test (an instrumented measure of repeated single leg heel rises until fatigue). Secondary outcomes included patient reported function (Achilles tendon rupture score), quality of life (short form 12 version 2®), pain (visual analogue scale), goal attainment (patient specific functional scale), and adverse events. A central laboratory analysed the quality and content of platelet rich plasma. Analyses were by modified intention to treat.ResultsParticipants were 46 years old on average, and 57 (25%) of 230 were female. At 24 weeks, 202 (88%) participants completed the heel rise endurance test and 216 (94%) the patient reported outcomes. The platelet rich plasma was of good quality, with expected growth factor content. No difference was detected in muscle tendon function between participants receiving platelet rich plasma injections and those receiving placebo injections (limb symmetry index, mean 34.7% (standard deviation 17.7%) v 38.5% (22.8%); adjusted mean difference −3.9% (95% confidence interval −10.5% to 2.7%)) or in any secondary outcomes or adverse event rates. Complier average causal effect analyses gave similar findings.ConclusionsThere is no evidence to indicate that injections of platelet rich plasma can improve objective muscle tendon function, patient reported function, or quality of life after acute Achilles tendon rupture compared with placebo, or that they offer any patient benefit.Trial registrationISRCTN54992179.
Soybean (
L. Merr.) production is influenced by planting date, but its impact on yield in fields infested with
(Tassi) Goid. is unknown. A 3-year study was conducted in
-infested fields to assess the ...effects of planting date (PD) on disease severity and yield using eight genotypes, four of which are reported to be susceptible to charcoal rot (S), and four reported with moderate resistance (MR) to charcoal rot (CR). The genotypes were planted in early April, early May, and early June under irrigated and nonirrigated conditions. There was planting date by irrigation interaction for area under the disease progress curve (AUDPC) where May PD was significantly lower compared to April and June PDs in irrigated environments but not in nonirrigated environments. Correspondingly, yield in April PD was significantly lower than that of May and June. Interestingly, yield of S genotypes increased significantly with each subsequent PD, while yield of MR genotypes remained high across all three PDs. The interaction of genotypes by PD on yield revealed that the MR genotypes DT97-4290 and DS-880 had the greatest yields in May compared to April. While May PD had a decreased AUDPC and an increased yield across genotypes, the result of this research suggests that in fields infested with
, early May to early June planting coupled with appropriate cultivar selection provides maximum yield potential for western Tennessee and mid-southern soybean growers.
Stereotactic ablative radiotherapy (SABR) is a standard-of-care for medically-inoperable-early-stage non-small cell lung cancer (NSCLC). One third of patients progress and chemotherapy is rarely used ...in this population. We questioned if addition of the immune-checkpoint-inhibitor (ICI) atezolizumab to standard-of-care SABR can improve outcomes. We initiated a multi-institutional single-arm phase I study (NCT02599454) enrolling twenty patients with the primary endpoint of maximum tolerated dose (MTD); secondary endpoints of safety and efficacy; and exploratory mechanistic correlatives. Treatment is well tolerated and full dose atezolizumab (1200 mg) is the MTD. Efficacy signals include early responses (after 2 cycles of ICI, before initiation of SABR) in 17% of patients. Biomarkers of functional adaptive immunity, including T cell activation in the tumor and response to ex-vivo stimulation by circulating T cells, are highly predictive of benefit. These results require validation and are being tested in a phase III randomized trial.
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