National Institute for Health Research and Oxford Martin School.

SummaryBackground Paediatric multidrug-resistant (MDR) tuberculosis is a public health challenge of growing concern, accounting for an estimated 15% of all global cases of MDR tuberculosis. Clinical management is especially challenging, and recommendations are based on restricted evidence. We aimed to assess existing evidence for the treatment of MDR tuberculosis in children.

on behalf of the Blood Pressure Lowering Treatment Trialists' Collaboration à Objective: To assess the clinical relevance of regression to the mean for clinical trials and clinical practice. Methods: MEDLINE was searched until February 2018 for randomized trials of BP lowering with over 1000 patientyears follow-up per group. We estimated baseline mean BP, follow-up mean (usual) BP amongst patients grouped by 10 mmHg strata of baseline BP, and assessed effects of BP lowering on coronary heart disease (CHD) and stroke according to these BP levels. Results: Eighty-six trials (349 488 participants), with mean follow-up of 3.7 years, were included. Most mean BP change was because of regression to the mean rather than treatment. At high baseline BP levels, even after rigorous hypertension diagnosis, downwards regression to the mean caused much of the fall in BP. At low baseline BP levels, upwards regression to the mean increased BP levels, even in treatment groups. Overall, a BP reduction of 6/3 mmHg lowered CHD by 14% (95% CI 11-17%) and stroke by 18% (15-22%), and these treatment effects occurred at follow-up BP levels much closer to the mean than baseline BP levels. In particular, more evidence was available in the SBP 130-139 mmHg range than any other range. Benefits were apparent in numerous high-risk patient groups with baseline mean SBP less than 140 mmHg. Conclusion: Clinical practice should focus less on pretreatment BP levels, which rarely predict future untreated BP levels or rule out capacity to benefit from BP lowering in high cardiovascular risk patients. Instead, focus should be on prompt, empirical treatment to maintain lower BP for those with high BP and/or high risk.

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ImportanceThe human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior.ObjectiveTo determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD.Design, Setting, and ParticipantsThis double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021.InterventionsParticipants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo.Main Outcomes and MeasuresChanges in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level–dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal.ResultsOf the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass index of 24.9 (5.4). On viewing sexual videos, kisspeptin significantly modulated brain activity in key structures of the sexual-processing network on whole-brain analysis compared with placebo (mean absolute change [Cohen d] = 0.81 [95% CI, 0.41-1.21]; P =  .003). Furthermore, improvements in several secondary analyses were observed, including significant increases in penile tumescence in response to sexual stimuli (by up to 56% more than placebo; mean difference = 0.28 units [95% CI, 0.04-0.52 units]; P = .02) and behavioral measures of sexual desire—most notably, increased happiness about sex (mean difference = 0.63 points [95% CI, 0.10-1.15 points]; P = .02).Conclusions and RelevanceCollectively, this randomized clinical trial provides the first evidence to date showing that kisspeptin administration substantially modulates sexual brain processing in men with HSDD, with associated increases in penile tumescence and behavioral measures of sexual desire and arousal. These data suggest that kisspeptin has potential as the first pharmacological treatment for men with low sexual desire.Trial Registrationisrctn.org Identifier: ISRCTN17271094

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Background Hypoactive Sexual Desire Disorder (HSDD) is associated with dysfunctional brain activation in regions governing sexual responses, resulting in a deficiency or absence of sexual desire with marked distress. It is of major clinical importance given it affects 8% of men with detrimental effects on quality of life, interpersonal relationships and fertility, but so far has no licensed treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target owing to its emerging role in modulating reproductive behaviour in animal models and healthy men. However, there are no studies examining its effects in HSDD. To address this, we performed the first clinical study of kisspeptin in men with HSDD. Methods We examined the effects of kisspeptin administration (vs placebo) on brain activity during short and long erotic video tasks using functional MRI in 32 men with HSDD (mean ±SEM age 37.9 ±1.5 y, BMI 24.9 ±1.0 kg/m2). The short video task used 20-second segments of erotic video with non-erotic video as control. During the long video task, participants viewed a continuous eight-minute erotic video. To provide functional and behavioural relevance for the associated fMRI brain responses during the long erotic video, simultaneous penile tumescence and subjective level of arousal were recorded. Participants also completed psychometric and behavioural questionnaires. Standard analysis methods were used for fMRI data from the short videos task, and the long videos task used regressors derived from the subjective arousal and penile tumescence data. The statistical threshold used for both was Z=2.3, p < 0.05 (cluster-corrected). Results In response to visual erotic stimuli, kisspeptin administration significantly increased penile tumescence during the long video task compared to placebo, with kisspeptin increasing penile tumescence by 56% at six-minutes (p=0.002). In addition, kisspeptin increased participant-reported happiness about sex (p=0.02). During both video tasks, kisspeptin significantly modulated brain activity compared to placebo in key structures of the sexual-processing network, providing a mechanistic pathway for the increases in physiological and behavioural measures. In response to short erotic videos, kisspeptin enhanced left middle frontal gyrus and left anterior cingulate activity, and decreased activity in bilateral parahippocampus (all p<0.05). During the long video task, kisspeptin enhanced right fusiform gyrus and bilateral visual cortex activity, and decreased left frontal pole, right posterior cingulate and bilateral precuneus activity (all <0.05). Additionally, we observed positive correlations between the effects of kisspeptin on aforementioned brain activity and psychometric parameters of sexual desire and arousal (all p<0.01). Conclusion Collectively, we demonstrate for the first time that kisspeptin administration in men with HSDD increases penile tumescence and psychometric measures of sexual desire and arousal by modulating sexual brain processing. Taken together, our data suggest that kisspeptin-based therapeutics may offer a novel, effective and much-needed clinical strategy for men with HSDD. Presentation: Sunday, June 12, 2022 12:00 p.m. - 12:15 p.m.

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