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Set against the backdrop of an antibiotic apocalypse in near future London. Rosa Scott, a brilliant and obsessive surgeon becomes Surgeon X, a vigilante doctor who uses experimental surgery and black market drugs to treat patients. But as Surgeon X, Rosa soon develops a godlike-complex, deciding who will live and who will die. Ultimately, she believes that to survive in this compromised world her own warped moral code is the one she must follow--even if it endangers those closest to her.

Doxycycline postexposure prophylaxis has been shown to prevent STIs in cisgender men and transgender women. In this trial involving cisgender women in Kenya, STI incidence was not lower with doxycycline than with standard care.

In an open-label, randomized study involving men who have sex with men, doxycycline use after high-risk sexual exposure reduced the incidence of sexually transmitted infections (chlamydia, gonorrhea, and syphilis).

The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18- to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.

Multiple medications in common use have been considered for the treatment of Covid-19. In this double-blind, randomized, placebo-controlled trial, ivermectin that was administered within 7 days after Covid-19 symptom onset was shown not to be of any clinical benefit.

Skin antisepsis with iodine povacrylex resulted in fewer surgical-site infections than antisepsis with chlorhexidine gluconate in patients with closed limb fractures but not in those with open fractures.

Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting. In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755. 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC0–6; 78·7 mg.h/L [95% CI 71·0–87·3] vs 26·0 mg.h/L [19·0–35·6]), maximum plasma concentrations (Cmax; 22·1 mg/L [19·9–24·6] vs 6·3 mg/L [4·9–8·3]), and concentrations in cerebrospinal fluid (0·60 mg/L [0·46–0·78] vs 0·21 mg/L [0·16–0·27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC0–6 (31·5 mg.h/L [24·1–41·1] vs 15·1 mg.h/L [12·8–17·7]), Cmax (7·4 mg/L [5·6–9·6] vs 3·9 mg/L [3·2–4·8]), and drug concentrations in the cerebrospinal fluid (2·43 mg/L [1·81–3·27] vs 1·52 mg/L [1·28–1·82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20–0·91; p=0·03). These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.

In a trial involving asymptomatic contacts of patients with PCR–confirmed Covid-19 in Spain, the authors compared the use of hydroxychloroquine with usual care. Postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons.

Abstract Context Dapagliflozin and other SGLT2 inhibitors are known to increase hematocrit, possibly due to its diuretic effects and hemoconcentration. Objective Since type 2 diabetes is a proinflammatory state and since hepcidin, a known suppressor of erythropoiesis, is increased in proinflammatory states, we investigated the possibility that dapagliflozin suppresses hepcidin concentrations and thus increases erythropoiesis. Design Prospective, randomized, and placebo-controlled study. Setting Single endocrinology center. Patients Fifty-two obese type 2 diabetes patients. Intervention Patients were randomized (1:1) to either dapagliflozin (10 mg daily) or placebo for 12 weeks. Blood samples were collected before and after treatments and serum, plasma, and mononuclear cells (MNC) were prepared. Main Outcome Measure Hepcidin and other hematopoietic factors. Results Following dapagliflozin treatment, there was a significant fall in HbA1c and a significant increase in hemoglobin concentration and hematocrit. Dapagliflozin treatment significantly reduced circulating hepcidin and ferritin concentrations while causing a significant increase in levels of the hepcidin inhibitor, erythroferrone, and a transient increase in erythropoietin. Additionally, dapagliflozin increased plasma transferrin levels and expression of transferrin receptors 1 and 2 in MNC, while there was no change in the expression of the iron cellular transporter, ferroportin. Dapagliflozin treatment also caused a decrease in hypoxia-induced factor-1α expression in MNC while it increased the expression of its inhibitor, prolyl hydroxylase-2. There were no significant changes in any of these indices in the placebo group. Conclusions We conclude that dapagliflozin increases erythropoiesis and hematocrit through mechanisms that involve the suppression of hepcidin and the modulation of other iron regulatory proteins.

Key Points Natural products continue to be an important source of leads for new medicines, despite reduced interest from large pharmaceutical companies. Screening collections of natural products can be assembled economically to provide excellent coverage of drug-like chemical space and in formats that are compatible with high-throughput bioassays. Metabolomics enables the rapid identification of novel compounds in complex mixtures of natural products and also provides a means to monitor the production of target molecules during fermentation or other production processes. Metagenomics and other genetic engineering techniques are enabling the production of target compounds in convenient systems, breaking away from the bottleneck otherwise created by microorganisms that are difficult to culture. Examples of recent and current applications of natural products are described for the discovery of antimicrobials and for inhibitors of protein–protein interactions, particularly as anticancer agents. The screening of natural products for lead molecules is an attractive strategy, as most natural products fall within biologically relevant chemical space. In this Review, Harvey, Edrada-Ebel and Quinn discuss how advanced screening, metabolomics and metagenomics approaches can be used in the identification, validation and production of naturally sourced compounds, and highlight examples of naturally derived antimicrobials and inhibitors of protein–protein interactions. Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein–protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.