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The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear. We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 μg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization. A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19-related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups. Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo. (Funded by FastGrants and others; TOGETHER ClinicalTrials.gov number, NCT04727424.).

Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease.

We recently showed that eumenorrheic, ovulatory women with obesity experience suppressed antral follicle dynamics, as evidenced by fewer recruitment events, selectable follicles and dominant follicles. Ovulatory follicles were selected for preferential growth at smaller diameters and lower luteal progesterone production was also observed. Weight loss is posited to improve reproductive function in women with obesity. However, the mechanisms underlying these improvements are unclear. The objective of this study was to contrast ovarian follicular growth and endocrine dynamics in eumenorrheic women with obesity, before and after a weight-loss intervention. | Twelve reproductive age females with obesity (total percent body fat ≥35%) and regular menstrual cycles (21-35 days) were evaluated by serial ovarian transvaginal ultrasonography and venipuncture every-other-day for one complete inter-ovulatory interval (IOI) (pre-intervention) and after a 6-month hypocaloric dietary intervention (post-intervention). The number and diameters of all follicles ≥2mm at each visit were documented offline using the Grid Method. Growth profiles of individual follicles which grew to >7mm were recorded using the Identity Method to document antral follicle recruitment events, selection, and ovulation. Clinical, morphologic, and endocrine features were compared pre- and post-intervention using paired t-tests and mixed models. | Participants lost an average of 9.5±3.8% total body weight (IQR: 7.7-12.6%). Antral follicle counts (AFC) across the IOI were lower post-intervention versus pre-intervention (PINTERVENTION=0. 002), driven by fewer 2-5mm follicles (PINTERVENTION=0. 001). Participants tended to exhibit more recruitment events (Pre: 1. 0±0.7 vs. Post: 2. 0±0.9, P=0. 09) and more selectable (6-9mm) follicles before and after weight loss (4±3 vs. 6±4 respectively, P=0. 07). A greater number of selectable follicles achieved a diameter of >10mm across the IOI post-intervention (PINTERVENTION=0. 001). Ovulatory follicles were also selected at larger diameters after the intervention (Pre: 7.3±2.9mm vs. Post: 10.9±2.6, P=0. 01). Dominant and ovulatory follicle growth kinetics were similar before and after the intervention (All, P>0. 05). Luteal progesterone concentrations were higher in women after the intervention (Pre: 5.3±3.7 vs. Post: 6.3±4.7ng/mL, P<0. 0001). | Eumenorrheic women with obesity demonstrate changes in follicle dynamics with weight loss following a hypocaloric dietary intervention. Development of more dominant follicles, a larger diameter at selection, and increased luteal progesterone production suggests increased responsiveness to gonadotropins with weight loss. Further studies are needed to elucidate the metabolic mechanisms driving any transient or sustained changes in ovarian physiology with hypocaloric dietary interventions aimed at weight loss. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Growth and development are usually adversely affected in children and adolescents with Cushing's syndrome 1 – 7 . The syndrome may be caused by excessive secretion of corticotropin by the pituitary gland or an ectopic corticotropin-secreting tumor, or by autonomous secretion of cortisol by an adrenal tumor, bilateral micronodular adrenal hyperplasia, or other autonomous adrenal processes 8 , 9 . The diagnosis of Cushing's syndrome continues to challenge the diagnostic skills of physicians. In this report we present information on the clinical presentation, diagnostic evaluation, and treatment of 59 consecutive children and adolescents with hypercortisolism. Methods Subjects Since 1982, 59 children and adolescents (37 . . .

Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease.

Despite their diversity, disaster-affected mountain regions around the world share many common experiences. Top-down bureaucratic and technocratic mind-sets continue to dominate understandings of and responses to natural and human-made disasters in these marginalized communities. Consequently, global economic and political powers exploit disaster as an opportunity to dominate the spaces of disaster-affected communities. Critical local pedagogy provides many opportunities to transform the current knowledge-production practices that inform disaster responses. The contributors to this chapter show that the conceptual apparatuses, analytical methods, and representation styles in critical pedagogical practices vary as they are guided by the place-specific commitments of those working together

SQ109 is a tuberculosis drug candidate that has high potency against Mycobacterium tuberculosis and is thought to function at least in part by blocking cell wall biosynthesis by inhibiting the MmpL3 transporter. It also has activity against bacteria and protozoan parasites that lack MmpL3, where it can act as an uncoupler, targeting lipid membranes and Ca2+ homeostasis. Here, we synthesized 19 analogs of SQ109 and tested them against bacteria: M. smegmatis, M. tuberculosis, M. abscessus, Bacillus subtilis and Escherichia coli, as well as against the protozoan parasites, Trypanosoma brucei, T. cruzi, Leishmania donovani, L. mexicana and Plasmodium falciparum. Activity against the mycobacteria was generally less than with SQ109 and was reduced by increasing the size of the alkyl adduct, but two analogs were ~4-8 fold more active than was SQ109 against M. abscessus, including a highly drug resistant strain harboring a A309P mutation in MmpL3. There was also better activity than found with SQ109 with other bacteria and protozoa. Of particular interest, we found that the adamantyl C-2 ethyl, butyl, phenyl and benzyl analogs had 4-10x increased activity against P. falciparum asexual blood stages, together with low toxicity to a human HepG2 cell line, making them of interest as new anti-malarial drug leads. We also used surface plasmon resonance to investigate the binding of inhibitors to MmpL3, and differential scanning calorimetry to investigate binding to lipid membranes. There was no correlation between MmpL3 binding and M. tuberculosis or M. smegmatis cell activity, suggesting that MmpL3 is not a major target, in mycobacteria. However, some of the more active species decreased lipid phase transition temperatures, indicating increased accumulation in membranes, expected to lead to enhanced uncoupler activity.

Background and Methods Cushing's syndrome is rare in children and adolescents. We analyzed the clinical presentation, diagnostic evaluation, and treatment of 59 patients with Cushing's syndrome between the ages of 4 and 20 years who were admitted to the National Institutes of Health during the period from 1982 to 1992. The cause of hypercortisolism was identified by low- and high-dose dexamethasone suppression tests, the ovine corticotropin-releasing hormone (CRH) stimulation test, imaging studies, and bilateral sampling of the inferior petrosal sinuses combined with administration of CRH. Results Fifty patients had Cushing's disease, six had primary adrenal disease, and three had ectopic corticotropin secretion. The initial signs were excessive weight gain in 90 percent of the patients and growth retardation in 83 percent. Most patients (81 percent) had normal bone age at the time of diagnosis. Forty-seven percent had hypertension, whereas only 19 percent had mental or behavioral problems. The high-dose dexamethasone suppression test and the CRH stimulation test identified 68 and 80 percent, respectively, of the patients with Cushing's disease. Magnetic resonance imaging of the pituitary indicated the presence of tumor in 52 percent of the patients with pituitary adenomas. The maximal central-to-peripheral ratio of plasma corticotropin during sampling of the interior petrosal sinuses was ≥ 2.5 in all the patients with Cushing's disease and <2.5 in those with ectopic corticotropin secretion. Remission of hypercortisolism was achieved in 48 of the 49 patients who underwent transsphenoidal surgery for Cushing's disease, in all 6 of the patients who underwent adrenalectomy for primary adrenal disease, and in the 2 patients in whom the ectopic source of corticotropin could be identified. Conclusions Weight gain and growth retardation are common clinical characteristics of Cushing's syndrome in children and adolescents. Diagnostic evaluation of such patients with CRH stimulation alone and combined with inferior petrosal sinus sampling and imaging studies is accurate, and therapy is usually successful.