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Comparative Effectiveness of Oral Ivermectin, 1% Permethrin Shampoo, and 4% Dimethicone Liquid Gel in Treatment of Pediculosis Capitis among School Children in Chachoengsao Province, Thailand.

Pediculosis capitis remains a persistent public health issue, especially in developing countries where resistance to standard neurotoxic pediculicides like permethrin is increasingly prevalent. This study aimed to compare the effectiveness of alternative treatment options against the standard care in a resource-limited setting. We conducted a single-blind randomized controlled trial involving three primary schools in Chachoengsao Province, Thailand (ClinicalTrials.gov: NCT06332872). Eighty-five female participants ages 6-13 years with active infestations were enrolled. Schools were randomly assigned to three treatment arms: 1) oral ivermectin (200 &#xb5;g/kg) on Days 0 and 7; 2) 1% permethrin shampoo on Days 0 and 7, or 3) 4% dimethicone liquid gel as a single dose on Day 0. The primary outcome was the cure rate, defined as the absence of live lice and viable nits upon clinical assessment on Day 9. Of the 66 participants included in the final per-protocol analysis, oral ivermectin achieved a cure rate of 95.5% (21/22), which was significantly higher than that of the 1% permethrin standard of care (37.0%; 10/27) and the 4% dimethicone physical suffocant (29.4%; 5/17) (P <0.001). Although dimethicone achieved high initial parasitic clearance on Day 0 (88.2%), a rapid reinfestation rate of 58.8% was observed by Day 9, indicating that a single-dose protocol may be clinically insufficient. Adverse events were mild and temporary across all groups. Oral ivermectin appears significantly more effective than both 1% permethrin and single-dose 4% dimethicone in this population. These findings suggest that permethrin resistance is clinically prevalent and relevant in this area.

Humans

Effects of acute inflammatory challenge on anhedonia and social reward processing: A randomized controlled trial of endotoxin.

Anhedonia is a core feature of depression that reflects reward system dysfunction. Acute inflammatory challenge has been shown to induce transient anhedonia and reward processing deficits, but its effects on distinct components of social reward processes remain poorly understood. This randomized, double-blind, placebo-controlled study evaluated anhedonia and social reward responsivity following acute inflammatory challenge. Low-dose endotoxin (0.8&#x202f;ng/kg body weight; n&#x202f;=&#x202f;18) or placebo (same volume of 0.9% saline; n&#x202f;=&#x202f;22) was administered to female adults (ages 25-44). Anhedonia (Snaith-Hamilton Pleasure Questionnaire) and blood samples for cytokine assessment were collected pre-infusion and 2 and 4&#x202f;h post-infusion. Social reward motivation (wanting to engage in a social task) was assessed at a baseline eligibility visit and 2&#x202f;h post-infusion. Sensitivity to positive social cues (attentional bias toward and recognition of happy faces) was assessed pre-infusion and 2&#x202f;h post-infusion. Results showed that endotoxin increased anhedonic symptoms (p&#x202f;=&#x202f;.005) and decreased social motivation by 2&#x202f;h post-infusion (p&#x202f;=&#x202f;.001); within the endotoxin condition, changes in both outcomes were associated with increases in TNF-&#x3b1; (p's&#x202f;<&#x202f;.04). A significant condition-by-time interaction for happy-face recognition (p&#x202f;=&#x202f;.011) was driven by increased accuracy in the placebo (p&#x202f;=&#x202f;.04) but not endotoxin (p&#x202f;=&#x202f;.43) condition. Endotoxin administration did not affect attentional bias toward happy faces. Findings suggest that acute inflammatory challenge induces anhedonia and reduces social motivation, with more limited effects on sensitivity to positive social cues, highlighting specific reward-related pathways through which immune activation may contribute to inflammation-associated depression. Future work could examine whether immune-related changes in social motivation contribute to motivational deficits in depression.

Humans

Catecholaminergic Contributions to Inhibitory Control Following Physical Fatigue: Behavioral and Neurophysiological Findings.

Acute physical fatigue can impair cognitive control, yet its underlying neurochemical mechanisms remain unclear. This study investigated whether catecholaminergic modulation influences behavioral and neural markers of inhibitory control following physical fatigue. Eighteen healthy, recreationally active adults (9 males, 9 females; 23.4&#xa0;&#xb1;&#xa0;2.2&#xa0;years) completed a randomized, triple-blind, placebo-controlled crossover study. On separate visits, participants received methylphenidate (MPH; 20&#xa0;mg; a dopamine and noradrenaline reuptake inhibitor), reboxetine (REB; 8&#xa0;mg; a noradrenaline reuptake inhibitor), or placebo. Physical fatigue was induced by repeated bilateral leg extensions to task failure. Cognitive performance was assessed before and after physical fatigue using a Go/No-Go task with electroencephalographic recording. Behavioral outcomes included reaction time and accuracy, while event-related potentials measured neural stages of response execution and inhibition (N2 and P3). Mixed-effects models were used for statistical analysis. For No-Go trials, a significant MPH&#xa0;&#xd7;&#xa0;Time interaction was observed for accuracy (p&#xa0;=&#xa0;0.008), with improved post-fatigue performance following MPH administration (p&#xa0;=&#xa0;0.048). At the neural level, MPH was associated with shorter fronto-central No-Go N2 latency (p&#xa0;=&#xa0;0.038) and altered fatigue-related changes in No-Go P3 latency (p&#xa0;=&#xa0;0.047). REB did not produce comparable behavioral or neural effects. These findings provide pharmacological evidence that catecholaminergic mechanisms contribute to inhibitory control following physical fatigue. The differential effects of MPH and REB suggest that selective noradrenergic enhancement alone is insufficient to maintain inhibitory control following physical fatigue. Instead, the findings implicate broader&#xa0;dopaminergic and noradrenergic mechanisms, potentially involving alterations in the temporal dynamics of inhibitory processing. TRIAL REGISTRATION: (G095422N and identifier NCT05880342).

Adult

Whole cell inactivated poly-bacterial preparation MV130 effect on nasal mucosal immunity and experimental human pneumococcal carriage: double-blind randomised controlled trial with controlled human infection model.

BACKGROUND: Bacterial mucosal immunotherapy has shown protection of children and adults from both viral and bacterial respiratory infections, offering the potential to reduce antimicrobial use, and hence also control antimicrobial resistance (AMR). Pneumococcal carriage of vaccine type Streptococcus pneumoniae remains high in Malawi despite infant conjugate vaccination and AMR is increasing. We compared nasal inflammation following sublingual bacterial immunotherapy including S. pneumoniae (MV130, Inmunotek, Spain) or placebo and determined the effect in an experimental human pneumococcal carriage model. METHODS: A double-blind, randomised, placebo-controlled trial in healthy adult volunteers was conducted at Queen Elizabeth Central Hospital in Blantyre, Malawi. Participants were randomly allocated to receive MV130 or placebo sublingually once daily for 42 days. Mucosal inflammation (neutrophil to T cell ratio, NTR) was measured in nasal micro-biopsies. Post-treatment, participants were challenged with 160,000 CFU/naris S. pneumoniae 6B (Spn6b). Experimental pneumococcal carriage rates post inoculation were compared between the two arms. All participants completing the study were included in the analysis. Prospective trial registration: PACTR202403820001276. FINDINGS: 107 participants were enrolled and randomised to MV130/placebo between May and December 2024. There were no serious adverse events, complete compliance was good (72%) and all adverse events were mild. 96 participants (53 male, 43 female) completed the study with 52 participants randomised to MV130 and 44 to placebo. There was no difference in mucosal inflammation (neutrophil to T cell ratio) at day 14 of the intervention MV130 NTR median = 0.737 (IQR 0.294, 2.059) and placebo NTR = 0.831 (IQR 0.450, 2.073), p = 0.64. Secondary analyses showed a rise in mucosal neutrophils after MV130 treatment and after experimental pneumococcal inoculation. There was no difference in nasal or serum anti-pneumococcal immunoglobulin or in experimental pneumococcal carriage proportion between MV130 (12/52, 23%) and placebo (10/44, 23%) groups (unadjusted risk ratio 1.02 (CI 0.49-2.12) p = 1.0). INTERPRETATION: MV130 induced non-specific mild neutrophil inflammation of the nasal mucosa but had no protective effect against experimental human pneumococcal carriage. FUNDING: Wellcome Trust.

Humans

ALG-020572, an Antisense Oligonucleotide for the Treatment of Chronic Hepatitis B Virus Infection Discontinued for Drug-Induced Liver Injury.

Current treatment options for chronic HBV infection are suboptimal in that they fail to suppress HBsAg levels. ALG-020572 is an antisense oligonucleotide designed to reduce viral protein synthesis through degradation of HBV mRNA. ALG-020572-401 was a double-blind, randomized, placebo-controlled trial consisting of two parts. Part 1 (single-ascending doses) evaluated the pharmacokinetics, safety and tolerability of single doses of ALG-020572 or placebo in healthy participants. In Part 2 (multiple dosing), participants with non-cirrhotic HBeAg-negative, virologically suppressed chronic HBV infection were administered up to 7 doses of ALG-020572 to evaluate safety, pharmacokinetics and antiviral activity. In Part 1, 32 participants were randomized to ALG 020572 or placebo. Single doses of ALG-020572 up to 480&#x2009;mg were well tolerated. The most common treatment-emergent adverse event reported was injection site reaction. ALG-020572 was rapidly absorbed and plasma exposures increased with dose. In Part 2, 8 participants with non-cirrhotic HBeAg-negative virologically suppressed chronic hepatitis B infection were enrolled and received up to 7 doses of ALG-020572. The study was prematurely discontinued after 4 participants experienced significant alanine aminotransferase elevations that were subsequently attributed to drug-induced liver injury. Single doses of ALG-020572 demonstrated a favourable pharmacokinetic and safety profile in healthy participants. Unexpectedly, ALG-020572 was poorly tolerated in participants with chronic HBV infection, resulting in the early termination of the study and further development of ALG-020572 due to idiosyncratic drug-induced liver injury, suggesting caution is required in the development of this class of drugs. Trial Registration: Registered at clinicaltrials.gov: NCT0500102.

Adult

Pre-clinical evaluation of the anticaries effect of an experimental Malva sylvestris extract mouthwash using a cariogenic model in situ.

OBJECTIVE: The aim of this study was to evaluate the antimicrobial and anticariogenic potential of Malva sylvestris extract on enamel and dentin in situ. METHODS: A double-blind crossover in situ study was conducted with 12 participants wearing palatal appliances containing two bovine enamel and two dentin specimens per 3 phases, a total of 72 enamel and dentin specimens. Biofilm formation and daily sucrose exposure were allowed. Treatments were applied twice daily in three phases: Malva sylvestris (2.5%, MS); fluoride (225 ppm, F); and placebo (P). After seven days, biofilm was collected from the bovine specimens for analysis of Lactobacillus spp. and mutans streptococci by Colony Forming Unit counts (CFU log&#x2081;&#x2080;/mL). Dental demineralization of the bovine specimens was assessed by transverse microradiography (TMR). RESULTS: MS did not reduce Lactobacillus spp. counts (CFU log&#x2081;&#x2080;/mL: enamel 6.63&#xb1;0.81; dentin 6.68&#xb1;0.92) compared to P (6.63&#xb1;0.70; 6.62&#xb1;0.51). F also did not differ (6.29&#xb1;0.75; 6.32&#xb1;0.41; ANOVA/Tukey, p>0.38). Mutans streptococci data were inconclusive. In enamel, both MS (2320.8&#xb1;768.2 %vol&#xb7;&#xb5;m; 101.6&#xb1;27.0 &#xb5;m) and F (1777.3&#xb1;733.3 %vol&#xb7;&#xb5;m; 95.8&#xb1;23.5 &#xb5;m) significantly reduced integrated mineral loss and lesion depth compared to P (3517.2&#xb1;1119.9 %vol&#xb7;&#xb5;m; 138.6&#xb1;19.5 &#xb5;m; ANOVA/Tukey, p&#x2264;0.0003). In dentin, MS significantly reduced integrated mineral loss (322.5 [250-580] %vol&#xb7;&#xb5;m) and lesion depth (30.1 [15-42.2] &#xb5;m) compared to P (880 [580-1705]; 58.3 [32.2-88.6] &#xb5;m; Kruskal-Wallis/Dunn, p&#x2264;0.001), while F (587.5 [305-720]; 25.2 [16.5-38.8] &#xb5;m) did not differ significantly (p>0.05). CONCLUSIONS: Malva sylvestris extract had no antimicrobial effect on Lactobacillus spp. counts, but significantly reduced enamel and dentin demineralization, showing anticaries effect comparable to fluoride. CLINICAL RELEVANCE: Malva sylvestris has demonstrated promising biological activity. This study investigates the antimicrobial efficacy of Malva sylvestris against cariogenic microorganisms in situ. Our findings provide relevant evidence that M. sylvestris exert significant anticaries effects using an in situ model.

Biofilms

Effect of ketofol versus Fentanyl-Midazolam sedation on neurological recovery in traumatic brain Injury: A randomised study.

Neurological recovery after traumatic brain injury (TBI) is multifactorial, and sedation is a cornerstone of neurocritical care because of its neuroprotective role. Although ketofol is widely used for anaesthesia, its effectiveness as a sedative regimen in the intensive care unit (ICU) has not been well studied. This preliminary exploratory double-blind, randomised study compared ketofol (KP) with fentanyl-midazolam (FM) sedation in adults with moderate-to-severe TBI. Sedation was administered for 72&#xa0;h and titrated to a Richmond Agitation-Sedation Scale (RASS) score&#xa0;&#x2264;&#xa0;&#xa0;-&#xa0;3. The primary outcome was the Extended Glasgow Outcome Scale (GOSE) at 30&#xa0;days. Secondary outcomes included GOSE at 90&#xa0;days, incidence of propofol infusion syndrome (PRIS), duration of mechanical ventilation, haemodynamic stability, and ICU and hospital length of stay. Of 120 enrolled patients, 111 were included in the final analysis (57 FM, 54 KP). Baseline characteristics, including injury severity and Marshall CT scores, were comparable. At 30&#xa0;days, good neurological recovery (GOSE 7-8) was more frequent in the KP group than the FM group (26% vs. 10.5%, p&#xa0;=&#xa0;0.03). At 90&#xa0;days, recovery remained higher with KP (44.4% vs. 33.3%), though the difference was not statistically significant (p&#xa0;=&#xa0;0.16). Multivariate analysis confirmed ketofol as an independent predictor of good recovery at 30&#xa0;days (adjusted OR 3.63, 95% CI 1.11-11.85, p&#xa0;=&#xa0;0.033). No PRIS occurred, and secondary outcomes were similar. Ketofol-based sedation was safe and may be associated with improved early neurological recovery compared with fentanyl-midazolam, with a favourable trend toward improved long-term neurological recovery.

Humans

GIP contributes to postprandial regulation of splanchnic blood supply in humans with type 2 diabetes: a randomised, single-blinded, placebo-controlled, crossover study.

AIMS/HYPOTHESIS: In healthy lean humans, endogenous glucose-dependent insulinotropic polypeptide (GIP) contributes significantly to the postprandial increase in arteria mesenterica superior blood flow. The vascular biology related to activation of the GIP receptor is markedly impaired in individuals with type 2 diabetes and is sometimes absent. In this population, we investigated the role of endogenous GIP on postprandial splanchnic blood flow by using the GIP receptor antagonist, GIP(3-30)NH2. The primary outcome of this study was the changes in blood flow in arteria mesenterica superior during oral glucose with or without GIP receptor antagonist infusion. METHODS: Ten participants with type 2 diabetes (age 20-80 years, BMI 20-35 kg/m2, and HbA1c >48 mmol/mol and <75 mmol/mol) were investigated in a randomised, placebo-controlled, crossover study. On four separate occasions, participants received the following treatment: oral glucose + i.v. GIP(3-30)NH2; oral glucose + i.v. saline (154 mmol/l NaCl); oral water + i.v. GIP(3-30)NH2; oral water + i.v. saline. Participants were randomly assigned to intervention groups using (random.org). Participants were unaware of allocation, while investigators were aware. No additional allocation concealment procedures were used. During all four interventions, splanchnic blood flow was measured using phase-contrast MRI in the arteria mesenterica superior, truncus coeliacus and vena portae during oral glucose (75 g) or water ingestion. The study was conducted at Rigshospitalet, Copenhagen. Liver volume and oxygenation, as well as gallbladder volume, were assessed. Blood samples were collected and analysed for insulin, C-peptide, GIP, glucagon and glucose. RESULTS: Oral glucose alone increased mean blood flow in arteria mesenterica superior by 57% (95% CI 26, 88) and this was 15% (95% CI -2, 32) lower during concomitant GIP receptor antagonist infusion, p=0.012. Infusion of GIP receptor antagonist during oral glucose treatment did also result in lower insulin secretion, C-peptide and C-peptide/glucose ratio compared with saline infusion, whereas glucagon levels and plasma glucose were unaffected. Oral water did not affect any outcomes. CONCLUSIONS/INTERPRETATION: Endogenous GIP contributes to postprandially increased splanchnic blood flow in people with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT06426823 FUNDING: This work was supported by the Novo Nordisk Foundation.

Humans

Effects of semaglutide and empagliflozin on markers of endothelial function in persons with type 2 diabetes: A post hoc analysis of a randomized clinical trial.

AIMS: The endothelium maintains vascular health by regulating blood flow and protecting against inflammatory damage. In type 2 diabetes (T2DM), however, hyperglycemia, hypertension, and hyperlipidemia place a significant burden on the endothelium, potentially leading to atherosclerosis and cardiovascular disease (CVD). While semaglutide and empagliflozin have been shown to reduce CVD risk in T2DM, it remains unclear whether these benefits are mediated by improved endothelial function. This post-hoc analysis explores the effects of these agents on markers of endothelial function, i.e. the reactive hyperaemic index (RHI) and the endothelial-derived cell adhesion molecules (CAMs) E-Selectin, ICAM-1, P-Selectin, and VCAM-1. METHODS: This was a post-hoc analysis of a 32-week randomized trial evaluating the separate and combined effects of semaglutide and empagliflozin on cardio-renal organ damage. One hundred and twenty participants with type 2 diabetes, age&#xa0;&#x2265;&#xa0;50 were randomized to four groups (semaglutide, empagliflozin, the combination or placebo). An increase in RHI and/or a decrease in CAMs were considered beneficial. RESULTS: RHI increased compared to baseline (0.11, 95%CI [0.008;0.21], p&#xa0;=&#xa0;0.03) but not compared to placebo in the semaglutide group (0.11, 95%CI [-0.04;0.24], p&#xa0;=&#xa0;0.16). There was no effect on RHI in the empagliflozin group. Compared to placebo, E-Selectin decreased significantly in the semaglutide and combination groups (-9, 95%CI [-14.1;-5.1] p&#xa0;<&#xa0;0.01 and&#xa0;-&#xa0;9, 95%CI [-14.3; -5.2] p&#xa0;<&#xa0;0.01, respectively). VCAM-1 increased in the same groups, compared to placebo (12.3, 95%CI[2.8;20.8] p&#xa0;=&#xa0;0.01 and 16.2, 95%CI [7.2;24.3], p&#xa0;<&#xa0;0.01, respectively).P-Selectin and ICAM-1 was not significantly affected in any of the groups, compared to placebo (p&#xa0;&#x2265;&#xa0;0.11 and p&#xa0;&#x2265;&#xa0;0.09, respectively). CONCLUSION: Semaglutide improved endothelial function compared to baseline, but not significantly versus placebo, which likely is due to limited power. CAM responses were heterogeneous, suggesting distinct roles in endothelial dysfunction and atherosclerosis. ClinicalTrialsRegister.eu: EudraCT 2019-000781-38.

Aged

Exercise with motor cortex high-definition transcranial direct current stimulation enhances cardiovascular efficiency and lower-limb function in multiple sclerosis: A crossover, double-blind, and proof-of-principle study.

Combining exercise with high-definition transcranial direct current stimulation (HD-tDCS) could offer a strategy to help people with Multiple Sclerosis improve outcomes. In this crossover study, participants with MS (Expanded Disability Status Scale &#x2265;3.0, n&#x202f;=&#x202f;12) and controls (n&#x202f;=&#x202f;10) completed baseline testing, followed by three randomized experimental conditions: 1) exercise+active HD-tDCS; 2) exercise+sham HD-tDCS; and 3) HD-tDCS alone. Exercise performance metrics [heart rate, work rate, heart rate-to-work rate (HR/WR) ratio, and perceived exertion] were compared across the exercise conditions. Secondary outcomes included the Symbol Digit Modalities Test (SDMT), Timed 25-Foot Walk (T25F), Nine-Hole Peg Test (9HPT), and acute symptom ratings (fatigue and pain), assessed pre-, immediately post-, and 1h-Post. Cardiovascular efficiency (HR/WR ratio) significantly improved during exercise+HD-tDCS compared to exercise alone, particularly in older MS participants (p&#x202f;=&#x202f;0.010). SDMT declined immediately post HD-tDCS alone, 1h-post-exercise alone, and at both time points during exercise+active HD-tDCS (p&#x202f;<&#x202f;0.05). Both groups increased walking speed only post-exercise+active HD-tDCS, while no condition affected upper-limb function (p&#x202f;<&#x202f;0.05). These results are in line with the tDCS literature in the general population, suggesting that tDCS improves exercise performance and selectively improves engaged motor function. The trade-off between physical and cognitive outcomes underscores the importance of personalized neuromodulation strategies in neurorehabilitation to maximize therapeutic benefits while minimizing adverse effects, and warrants further large-scale, long-term investigations of this approach in MS.

Humans

primary analysis of the RANDOMIZED eortc-2139/columbus-ad trial: Adjuvant encorafenib and binimetinib versus placebo in high-risk stage II BRAF-V600E/K melanoma.

PURPOSE: Stage IIB/IIC melanoma has a high risk of recurrence after resection. Combined BRAF/MEK inhibitor therapy showed benefit in resected high-risk stage III and advanced melanoma. The objective of this study was to investigate its role in stage IIB/IIC. METHODS: Adult patients with resected stage IIB/IIC cutaneous melanoma which had a BRAF V600E/K mutation were randomized 1:1 to receive encorafenib (enco) 450&#x202f;mg QD&#x202f;+&#x202f;binimetinib (bini) 45&#x202f;mg BID orally for one year or placebo. The study planned to randomize 815 patients and was designed to demonstrate superiority regarding recurrence-free survival (RFS). Following a premature termination of accrual, the study was amended with safety as the primary endpoint and RFS as secondary endpoint. RESULTS: Between June 9, 2022, and October 9, 2023, 339 patients were screened for a BRAF mutation and 110 randomized. Data cutoff was 19 Nov. 2024, after the last patient discontinued study participation. Among randomized patients, 87 (79%) had a BRAF V600E mutation, and 39 (35%) AJCC8 stage IIC. Median follow-up was 12 and 7 months for enco/bini and placebo arms, respectively. Among 54 patients who initiated enco&#x202f;+&#x202f;bini, grade &#x2265;&#x202f;3 treatment-related adverse events (AE) occurred in 13 (24%) patients, and 18 (33%) patients had an AE leading to permanent treatment discontinuation. RFS at 12 months was 86% (95% CI: 65-95%) in the enco&#x202f;+&#x202f;bini and 70% (95% CI: 46-85%) in the placebo arm, distant metastasis-free survival at 12 months was 92% (95% CI: 77-97%) for enco&#x202f;+&#x202f;bini and 82% (95% CI: 55-93%) for placebo. CONCLUSION: EORTC 2139 - Columbus-AD demonstrated a consistent and manageable safety profile and encouraging efficacy results for the combination of enco and bini in resected stage IIB/C BRAF V600E/K-mutated cutaneous melanomas.

Adult

MIC-based tuberculosis drug susceptibility testing using Sensititre MYCOTB: a diagnostic accuracy meta-analysis.

Accurate drug susceptibility testing (DST) is crucial for designing effective regimens for multidrug-resistant (MDR) and pre-extensively drug-resistant tuberculosis (pre-XDR TB). Sensititre MYCOTB enables simultaneous determination of minimum inhibitory concentrations (MICs) for multiple drugs, but its diagnostic performance varies across studies. This meta-analysis evaluated the diagnostic performance of Sensititre MYCOTB for key MDR and pre-XDR TB drugs. The protocol was registered in PROSPERO (CRD420251230599). PubMed, Cochrane, Google Scholar, Scopus, ONOS, Web of Science, ScienceDirect, and registries were systematically searched for studies published between 2010 and 2025. Studies comparing the Sensititre MYCOTB with reference DST for Mycobacterium tuberculosis complex (MTBC) were included. Bias assessment and pooled diagnostic accuracy estimates were generated. Fourteen studies, including 1,728 isolates, were analyzed. Rifampicin and isoniazid demonstrated high sensitivity (0.976 [95% CI: 0.94-0.99] and 0.977 [95% CI: 0.95-0.99]) and specificity (0.958 [95% CI: 0.84-0.98] and 0.957 [95% CI: 0.83-0.99], respectively) with low heterogeneity. Amikacin, kanamycin, and ofloxacin demonstrate good diagnostic accuracy, with high specificity (>0.98 [95% CI]). Moderate diagnostic accuracy was observed for ethambutol, streptomycin, ethionamide, and rifabutin. Cycloserine, moxifloxacin, and para-aminosalicylic acid showed inconsistent performance despite excellent specificity (>0.97 [95% CI]). Sensitivity analysis partially improved pooled sensitivity for moxifloxacin 0.801 (95% CI: 0.585-0.924) and para-aminosalicylic acid 0.76 (95% CI: 0.518-0.894), whereas cycloserine remained at 0.436 (95% CI: 0.190-0.725), although heterogeneity persisted. Sensititre MYCOTB DST demonstrates high diagnostic accuracy for MDR-TB and pre-XDR-TB drugs, while caution is required with cycloserine, moxifloxacin, and para-aminosalicylic acid. These findings support the integration of MIC-based testing into clinical decision-making.

Microbial Sensitivity Tests

A randomized trial of viral vector and adjuvanted protein HBV therapeutic vaccine in people with chronic hepatitis B on nucleos(t)ide analogs.

BACKGROUND: This study assessed the safety, efficacy, and immunogenicity of a therapeutic immunization strategy aimed at reaching a functional cure for chronic hepatitis B (CHB), relying on a heterologous prime-boost with viral vectors ChAd155-hIi-HBV and MVA-HBV, combined with sequential or concomitant administration of adjuvanted recombinant HBV proteins (HBc-HBs/AS01B). METHODS: This single-blind, randomized, controlled, first-in-human, phase 1/2 trial enrolled adults aged 18-65 years with HBeAg-negative CHB, virally suppressed on nucleos(t)ide analogs (NAs), with HBsAg >50&#xa0;IU/mL. Participants received NAs and the following regimens of 4 doses (8-week intervals): sequential administration of ChAd155-hIi-HBV, MVA-HBV, and 2 HBc-HBs/AS01B doses; co-administration of ChAd155-hIi-HBV+HBc-HBs/AS01B, followed by 3 co-administered MVA-HBV+HBc-HBs/AS01B doses; 4 HBc-HBs/AS01B doses; 2 placebo doses followed by ChAd155-hIi-HBV and MVA-HBV administered alone or with HBc-HBs/AS01B; or 4 placebo doses. Safety, efficacy (&#x2265;1-log decrease in quantitative (q)HBsAg or HBsAg loss 24 weeks post-dose 4 [day (D)337]), antibody, and T-cell responses were evaluated. RESULTS: In all, 134 participants were vaccinated. Grade 3 solicited adverse events (AEs) (median duration: 2-3 days) were more frequent after co-administration (systemic: 59.3%; administration-site: 33.3%) than sequential administration (systemic: 10.3%; administration-site: 12.8%) of high-dose viral vectors and proteins. No vaccine-related or fatal serious AEs were reported. After 4 doses, no participant had HBsAg loss or &#x2265;1-log decrease in qHBsAg (D337 vs. D1). Co-administration induced the strongest anti-HBs response (73.7% achieved anti-HBs &#x2265;10&#xa0;mIU/mL 2 weeks post-dose 4 vs. 40.0% after sequential administration). Both sequential and co-administration induced HBc-specific CD4+ and CD8+ T-cell responses, with a prime-boost effect of the viral vectors. CONCLUSIONS: Heterologous prime-boost with ChAd155-hIi-HBV and MVA-HBV, combined with sequential or co-administration of HBc-HBs/AS01B, had an acceptable safety profile, were moderately immunogenic, but no participants showed the expected efficacy outcome.

Humans

Safety of insulin eye drops in the treatment of open angle glaucoma: a randomized phase I clinical trial.

OBJECTIVE: The progression of glaucoma despite adequate intraocular pressure (IOP) control highlights the need for neuroprotective and neuroregenerative therapies. Preclinical studies suggest insulin promotes retinal ganglion cell survival and regeneration, but its safety in higher concentrations (100 and 500 units/mL), administered topically, has been poorly characterized in humans. We aim to assess the safety and tolerability of these two concentrations of insulin eye drops in patients with open-angle glaucoma (OAG). DESIGN: A phase I, randomized, double-blind, placebo-controlled, single-centre clinical trial. PARTICIPANTS: Patients with mild to moderate OAG were randomized 2:2:1 to receive once-daily topical insulin U-100, U-500, or placebo in 1 eye for 5 days, with follow-up visits at 1, 3, and 6 months. The primary safety outcomes include glycemia, serum potassium, ocular adverse events (AEs), and ocular tolerability scores. Secondary outcomes included IOP, best-corrected visual acuity (BCVA), retinal nerve fibre layer thickness, ganglion cell complex, visual field, and OCT angiography. RESULTS: Eighteen open-angle glaucoma patients were enrolled (mean age: 66.2 &#xb1; 10.1 years). No serious AEs related to insulin were observed. One asymptomatic, transient near-hypoglycemia event occurred in a fasting participant (3.9 mmol/L), with no recurrence after dietary adjustment. No significant changes were found in serum potassium, IOP, BCVA, visual fields, or OCT. Ocular symptoms in the insulin groups were limited to transient, mild burning sensation upon application. One participant experienced cystoid macular edema at 3 months, which was attributed to pre-existing ocular pathology. CONCLUSION: Topical insulin at 100 and 500 units/mL concentrations was well tolerated in patients for short-term use and did not result in significant systemic or ocular toxicity.

Aged

Phase 3 Trial of Oral Infigratinib in Children with Achondroplasia.

BACKGROUND: Achondroplasia is a genetic skeletal condition caused by FGFR3 pathogenic variants. Infigratinib, an oral FGFR1-3 tyrosine kinase inhibitor, down-regulates key pathways in the pathogenesis of achondroplasia. METHODS: In this phase 3, multicenter, double-blind, placebo-controlled trial, we randomly assigned children with achondroplasia (3 to 17 years of age) in a 2:1 ratio to receive infigratinib (at a dose of 0.25 mg per kilogram of body weight) or placebo once daily for 52 weeks. The primary end point was the change from baseline in the annualized height velocity in the infigratinib group as compared with the placebo group at week 52. Key secondary end points were the change from baseline in the height z score and in the upper-to-lower body segment ratio at week 52. The primary analysis evaluated the treatment effect at week 52 in the full analysis population, with missing data handled with a prespecified imputation approach. RESULTS: In all, 114 patients underwent randomization: 75 patients to receive infigratinib (with 1 withdrawal before treatment) and 39 patients to receive placebo. The difference between infigratinib and placebo in the least-squares mean change from baseline to week 52 was 1.74 cm per year (95% confidence interval [CI], 1.31 to 2.17; P<0.001) for the annualized height velocity, 0.32 (96% CI, 0.23 to 0.41; P<0.001) for the height z score, and -0.02 (96% CI, -0.06 to 0.01) for the upper-to-lower body segment ratio. Adverse events occurred in 71 of 74 patients (96%) in the infigratinib group and in 37 of 39 patients (95%) in the placebo group; serious adverse events occurred in 4 of 74 patients (5%) and 1 of 39 patients (3%), respectively. No serious adverse events or adverse events leading to treatment discontinuation were considered by the investigator to be related to infigratinib or placebo. CONCLUSIONS: In children with achondroplasia, treatment with once-daily oral infigratinib for 52 weeks resulted in a significantly greater increase from baseline in the annualized height velocity than placebo. (Funded by BridgeBio Pharma; PROPEL 3 ClinicalTrials.gov number, NCT06164951; EudraCT number, 2023-506130-67.).

Adolescent

No Efficacy of Dexamethasone Injections for Acute Sciatica: A Double-Blind Randomized Study Versus Saline.

BACKGROUND: The efficacy of caudal injections for patients with acute sciatica remains controversial. The DEXHIA study was designed to evaluate whether ultrasound-guided caudal injection of dexamethasone provides superior clinical outcomes compared with saline placebo. METHODS: This prospective, randomized, placebo-controlled, double-blind trial included adult patients with sciatica secondary to lumbar disc herniation of less than 3 months' duration. Participants were randomly assigned in a 1:1 ratio to receive either 16&#x2009;mg of dexamethasone (4&#x2009;mL) diluted with 16&#x2009;mL of saline (DEXA group) or 20&#x2009;mL of saline alone (PLACEBO group), administered by ultrasound-guided caudal epidural injection. The primary outcome was the change in the Oswestry Disability Index (ODI) at 3&#x2009;weeks. Secondary outcomes included leg pain and low back pain assessed by visual analogue scale (VAS), health-related quality of life (SF-36), need for repeat epidural injection, and need for lumbar surgery. Clinical assessments were performed at 3&#x2009;weeks, 3 months, and 6 months. RESULTS: A total of 106 patients were randomized, with 53 participants assigned to each treatment group. The primary endpoint was not met, as the improvement in ODI at 3&#x2009;weeks did not differ significantly between groups (mean change: -9.5&#x2009;&#xb1;&#x2009;4.4 in the DEXA group versus -13.8&#x2009;&#xb1;&#x2009;4.4 in the PLACEBO group; p&#x2009;=&#x2009;0.18). No significant differences were observed for any relevant secondary outcome at any follow-up time point. During the 6-month follow-up, 34 patients in the DEXA group and 30 patients in the PLACEBO group underwent a second, non-blinded injection of dexamethasone (ns). Lumbar surgery was performed in 10 patients in the DEXA group and nine patients in the PLACEBO group (ns). Injection-related adverse events were mild and transient but occurred more frequently in the DEXA group. CONCLUSIONS: Caudal injection of soluble dexamethasone conferred no clinical benefit over saline placebo in patients with acute sciatica. SIGNIFICANCE STATEMENT: Epidural injections are widely used worldwide for the treatment of resistant sciatica and have been extensively studied in multiple meta-analyses. However, their clinical value remains debated due to the limited methodological quality of most available studies. We conducted a methodologically rigorous randomized, placebo-controlled trial, which yielded negative results. These findings question the efficacy of caudal epidural injection of a non-particulate corticosteroid administered via a remote (sacrococcygeal) approach for disc-related sciatica. TRIAL REGISTRATION: The trial was registered under European Clinical Trials No. 2021-001571-17 and ClinicalTrials.gov identifier NCT05000658.

Adult

Blue light therapy delivered through light glasses improves sleep quality and daytime sleepiness in Parkinson's disease: A randomized trial.

BackgroundSleep disturbances, including excessive daytime sleepiness (EDS) and fragmented nocturnal sleep, are common in Parkinson's disease (PD) and significantly reduce quality of life. This pilot study evaluated the efficacy of a novel approach using blue light, delivered via dedicated glasses with integrated LED lights, to improve sleep and non-motor symptoms.MethodsRandomised, placebo-controlled, single-blind pilot study with a 2-week light intervention. Participants were assessed at baseline, two weeks, and five weeks. The study was designed to evaluate between- and within-group changes. Participants were randomly allocated to receive blue light therapy (n&#x2009;=&#x2009;15) or red light placebo (n&#x2009;=&#x2009;15), delivered via LED-integrated glasses for one hour, twice daily, given for a 2-week period. Primary outcome was improvement in sleep quality, assessed via the Pittsburgh Sleep Quality Index. Secondary outcomes included diary-based sleep outcomes, excessive daytime sleepiness, mood, anxiety, and motor symptoms.ResultsThere was a significant group&#x2009;&#xd7;&#x2009;time effect with blue light therapy leading to better Pittsburgh Sleep Quality Index scores (p&#x2009;=&#x2009;0.021). Between-group analyses showed that at two weeks a trend toward significance was observed (p&#x2009;=&#x2009;0.065), while sleep quality significantly improved at five weeks compared to placebo (p&#x2009;=&#x2009;0.029) with a large effect size (0.896). Excessive sleepiness improved in the blue light group (p&#x2009;<&#x2009;0.001), with a reduction in clinically relevant sleepiness from 50.0% to 6.7% (p&#x2009;=&#x2009;0.005).ConclusionsBlue light therapy delivered through dedicated glasses appeared to show an improvement in sleep quality and daytime sleepiness in individuals with PD. Blue light therapy offers a promising alternative to traditional light therapy utilising lower light intensities and eliminating the need for light boxes.

Aged

The effects of nitrate and nitrite supplementation on mitochondrial respiration in permeabilized muscle fibres in young healthy adults.

Nitric oxide (NO) is a direct regulator of mitochondrial respiration. Nitrate (NO3-) and nitrite (NO2-) are good sources of NO, but whether their effects on mitochondrial respiration differ between in vivo and in vitro administration remains unclear. In Study 1, 8 participants consumed NO3- -rich beetroot juice (BR) (&#x223c;12.8&#x202f;mmol NO3-) and NO3- -depleted placebo beetroot juice (PL) (&#x223c;0.08&#x202f;mmol NO3-) acutely and chronically for 2 weeks in a randomised, double-blind, crossover design. A substrate-uncoupler-inhibitor titration (SUIT) protocol was used to assess mitochondrial respiration using high-resolution respirometry (oxygen tension: &#x223c;200-450&#x202f;&#x3bc;M) in permeabilized muscle fibres. In Study 2, skeletal muscle samples were collected from 11 participants. In a randomised, crossover design, different doses (0, 1.5, and 3.0&#x202f;&#x3bc;M) of sodium nitrite (NaNO2) were administered to permeabilized muscle fibres. Mitochondrial respiration was measured using the same SUIT protocol under lower oxygen tension (&#x223c;50-200&#x202f;&#x3bc;M). Although muscle NO3- concentration significantly increased after both acute and chronic BR supplementation, mitochondrial respiration and exercise performance did not differ between PL and BR in either condition. Similarly, absolute oxygen flux across different respiratory states were not different between different doses of NaNO2. However, the leak control ratio, reflecting the degree of uncoupling of mitochondrial respiration, was significantly higher with 3.0&#x202f;&#x3bc;M NaNO2 administration (0.12&#x202f;&#xb1;&#x202f;0.05) compared to 0&#x202f;&#x3bc;M NaNO2 administration (0.09&#x202f;&#xb1;&#x202f;0.04, P&#x202f;=&#x202f;0.03). These findings, involving both in vivo and in vitro administration approaches, albeit in the presence of relatively high oxygen concentrations, suggest that neither NO3- nor NO2- improves mitochondrial respiration, at least in young healthy adults.

Humans