Comparative Effectiveness of Baloxavir Marboxil and Oseltamivir Treatment in Reducing Household Transmission of Influenza: A Post Hoc Analysis of the BLOCKSTONE Trial.

BACKGROUND: The transmission of influenza virus in households, especially by children, is a major route of infection. Prior studies suggest that timely antiviral treatment of ill cases may reduce infection in household contacts. The aim of the study was to compare the effects of oseltamivir (OTV) and baloxavir marboxil (BXM) treatment of index cases on the secondary attack rate (SAR) of influenza within household. METHODS: A post hoc analysis was done in BLOCKSTONE trial-a placebo-controlled, double-blinded post-exposure prophylaxis of BXM. Data were derived from the laboratory-confirmed index cases' household contacts who received placebo in the trial and also from household members who did not participate in the trial but completed illness questionnaires. To assess the SAR of household members, multivariate analyses adjusted for factors including age, vaccination status, and household size were performed and compared between contacts of index cases treated with BXM or OTV. RESULTS: In total, 185 index cases (116 treated with BXM and 69 treated with OTV) and 410 household contacts (201 from trial, 209 by questionnaire) were included. The Poisson regression modeling showed that the SAR in household contacts of index cases treated with BXM and OTV was 10.8% and 18.5%, respectively; the adjusted relative reduction in SAR was 41.8% (95% confidence interval: 1.0%-65.7%, p = 0.0456) greater with BXM than OTV. Similar reductions were found in contacts from the trial and those included by questionnaire. CONCLUSION: BXM treatment of index cases appeared to result in a greater reduction in secondary household transmission than OTV treatment.

Virtual reality perceptual training can improve the temporal discrimination ability of swinging during softball batting.

Perception and action uncoupling in fastball sports anticipatory training is often criticized. Nevertheless, perception-only training offers distinct advantages, such as flexibility concerning time, place, and injury limitations. Therefore, the effectiveness of this training approach warrants evaluation. This study developed a virtual reality (VR) training system based on the idea that the two visual pathways in the brain are associated with visual information attributes, rather than perception or action. A key feature of this study's perception-only training was its presentation of not only the opponent's kinematics but also the ball's flight information (the attributes that guide hitting) to train the visual system necessary for real situations. Seventeen female softball batters were assigned to two groups: a training group (N = 9) and a control group (N = 8). Only the training group underwent the VR anticipatory skill training to discriminate the different ball speeds. Both groups completed a perception test and an action test on the VR during the pre- and post-training periods. The perception test assessed response accuracy (RA) in discriminating ball speed, and the action test assessed the temporal difference in swing onset (delta onset). Comparison of these two outcome variables between groups revealed that perception-only training improved both perceptual and action responses. This study demonstrated the effectiveness of perception-only training and emphasized the need for its thoughtful utilization and design.

Heteroresistance to cefiderocol in carbapenem-resistant Acinetobacter baumannii in the CREDIBLE-CR study was not linked to clinical outcomes: a post hoc analysis.

IMPORTANCE: The population analysis profiling (PAP) test is considered the "gold standard" method to detect heteroresistance. It exposes bacteria to increasing concentrations of antibiotics at high cell densities to detect any minority resistant subpopulations that might be missed by the low inoculums used for reference susceptibility tests. However, its clinical relevance has not been well established. In the CREDIBLE-CR study, a numerically increased all-cause mortality was observed in the cefiderocol arm relative to the best available therapy arm for patients with Acinetobacter spp. infections. Heteroresistance has independently been proposed by another research group as a potential explanation of the mortality difference. An analysis of the baseline carbapenem-resistant Acinetobacter calcoaceticus-baumannii complex isolates from patients treated with cefiderocol in the CREDIBLE-CR study showed the highest clinical cure rate and the lowest mortality for patients with PAP-heteroresistant isolates compared with PAP-susceptible or PAP-resistant isolates. These findings contradict the abovementioned hypothesis that heteroresistance contributed to the increased mortality.

Efficacy and safety of zuranolone in Japanese adults with major depressive disorder: A double-blind, randomized, placebo-controlled, phase 2 clinical trial.

AIM: To evaluate the efficacy and safety of an oral, once-daily, 14-day treatment course of zuranolone in Japanese patients with major depressive disorder (MDD). METHODS: This multicenter, randomized, double-blind, placebo-controlled study randomized eligible patients (1:1:1) to receive oral zuranolone 20 mg, zuranolone 30 mg, or placebo once daily for 14 days (treatment-period), followed by two 6-week follow-up periods. The primary endpoint was change from baseline in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score on Day 15. RESULTS: Overall, 250 patients (enrolled: 07/07/2020-05/26/2021) were randomized to receive placebo (n = 83), zuranolone 20 mg (n = 85), or zuranolone 30 mg (n = 82). The demographic and baseline characteristics were balanced between groups. The adjusted mean (standard error) change from baseline in the HAMD-17 total score on Day 15 was -6.22 (0.62), -8.14 (0.62), and - 8.31 (0.63) in the placebo, zuranolone 20-mg, and zuranolone 30-mg groups, respectively. Significant differences in the adjusted mean (95% confidence interval [CI]) for zuranolone 20 mg versus placebo (-1.92; [-3.65, -0.19]; P = 0.0296) and zuranolone 30 mg versus placebo (-2.09; [-3.83, -0.35]; P = 0.0190) groups were observed on Day 15, and also as early as Day 3. A nonsignificant yet distinct drug-placebo separation was observed during follow-up. Somnolence (placebo [3.7%], zuranolone 20 mg [10.6%], and zuranolone 30 mg [20.7%]) and dizziness (3.7%, 9.4%, and 9.8%, respectively) were more common with zuranolone. CONCLUSION: Oral zuranolone was safe and demonstrated significant improvements in depressive symptoms, as assessed by HAMD-17 total score change from baseline over 14 days in Japanese patients with MDD.

Improving Traditional Registrational Trial End Points: Development and Application of a Desirability of Outcome Ranking End Point for Complicated Urinary Tract Infection Clinical Trials.

BACKGROUND: Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience. METHODS: Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience, we developed a DOOR end point for infectious disease syndromes and demonstrated how this could be applied to 3 registrational drug trials (ZEUS, APEKS-cUTI, and DORI-05) for complicated urinary tract infections (cUTIs). ZEUS compared fosfomycin to piperacillin/tazobactam, APEKS-cUTI compared cefiderocol to imipenem, and DORI-05 compared doripenem to levofloxacin. Using DOOR, we estimated the probability of a more desirable outcome with each investigational antibacterial drug. RESULTS: In each RCT, the DOOR distribution was similar and the probability that a patient in the investigational arm would have a more desirable outcome than a patient in the control arm had a 95% confidence interval containing 50%, indicating no significant difference between treatment arms. DOOR facilitated improved understanding of potential trade-offs between clinical efficacy and safety. Partial credit and subgroup analyses also highlight unique attributes of DOOR. CONCLUSIONS: DOOR can effectively be used in registrational cUTI trials. The DOOR end point presented here can be adapted for other infectious disease syndromes and prospectively incorporated into future clinical trials.

Simplified Virtual Reality System Can Be Used to Evaluate the Temporal Discrimination Ability in Softball Batting as in the Real Environment.

Recently, virtual reality (VR) technology has developed rapidly and has increasingly come to be used in the sports field. VR technology ranges from large, highly immersive devices to simple devices such as smartphones, and the respective usefulness and shortcomings of different device types have been debated. Simple devices have advantages such as portability, but also provide only a weak sense of realism. It is important to understand the purpose and extent to which VR technologies can be used. Our purpose in this study was to briefly measure one of the cognitive-motor abilities used in softball batting: temporal discrimination ability in swing onset when a batter faces two types of balls thrown at different speeds. We investigated whether a simplified head-mounted display (HMD) system can evaluate such cognitive-motor ability to the same extent as in a real environment. Ten elite female softball batters swung at fastballs and slowballs randomly thrown by the same pitcher in both real and 3D VR environments, with the same range of trajectories. We then compared the temporal discrimination ability of swing onset analyzed by video analysis between environments. We found that the discrimination ability in VR is almost the same as in reality. In addition, questionnaire items on the VR system related to user experience and cybersickness showed overall promising responses. However, we also found that the system had some issues that need to be considered, such as leading to early swing onset and large variability in it. We discussed the usefulness and limitations of the VR system by combining the results for swing onset with the questionnaire responses. By understanding the characteristics of VR technology and using it as an efficient evaluation and training of players, the sports field can make significant progress.

Outcomes with Cefiderocol Treatment in Patients with Bacteraemia Enrolled into Prospective Phase 2 and Phase 3 Randomised Clinical Studies.

INTRODUCTION: A post hoc, descriptive analysis of three prospective, randomised, controlled clinical studies investigating cefiderocol in gram-negative bacterial infections was conducted to assess its efficacy in patients with baseline bacteraemia. METHODS: Data from APEKS-cUTI (NCT02321800), APEKS-NP (NCT03032380) and CREDIBLE-CR (NCT02714595) studies were assessed individually. Patients received cefiderocol 2g, q8h, for 7-14 days or comparators (imipenem/cilastatin [APEKS-cUTI], meropenem [APEKS-NP] or best available therapy [BAT; CREDIBLE-CR]). Bacteraemia and clinical outcomes were assessed at early assessment (EA), end of treatment (EOT) and test of cure (TOC) for patients in the intention-to-treat populations with baseline blood samples positive for aerobic gram-negative species. Eradication, persistence or recurrence of baseline blood pathogen was confirmed from follow-up blood cultures; in the absence of follow-up blood cultures, clinical response, administration of additional antibiotics and vital status were used to assess bacteraemia outcome. RESULTS: Of 885 patients randomised, 84 had bacteraemia and 89 (cefiderocol: 55, comparators: 34) gram-negative pathogens were isolated, namely Enterobacterales (n = 62) and non-fermenters (n = 27). At EA, on-therapy bacteraemia eradication rates in APEKS-cUTI, APEKS-NP and CREDIBLE-CR were 100% (19/19), 50.0% (4/8) and 72.0% (18/25) with cefiderocol. Corresponding rates for comparators were 77.8% (7/9), 100% (10/10) and 69.2% (9/13), respectively. Persistence in blood at EA was seen in six patients overall (cefiderocol: 3, comparators: 3); indeterminate responses were common (cefiderocol: 8, comparators: 3), usually due to lack of blood cultures. Clinical cure/improvement rates at EA in APEKS-cUTI, APEKS-NP and CREDIBLE-CR were 100% (19/19), 62.5% (5/8) and 64.0% (16/25) with cefiderocol. Corresponding rates for comparators were 77.8% (7/9), 90.0% (9/10) and 30.8% (4/13), respectively. Bacteraemia eradication rates with cefiderocol in APEKS-cUTI, APEKS-NP and CREDIBLE-CR were 89.5%, 37.5% and 60.0% at EOT and 78.9%, 12.5% and 44.0% at TOC. CONCLUSION: This descriptive analysis suggests that cefiderocol may be a useful treatment option for gram-negative bacteraemia, including pathogens resistant to other antibiotics.

Cefiderocol for the Treatment of Infections Due to Metallo-B-lactamase-Producing Pathogens in the CREDIBLE-CR and APEKS-NP Phase 3 Randomized Studies.

In the CREDIBLE-CR and APEKS-NP studies, cefiderocol treatment was effective against gram-negative bacteria producing metallo-B-lactamases; rates of clinical cure (70.8% [17/24]), microbiological eradication (58.3% [14/24]), and day 28 all-cause mortality (12.5% [3/24]) compared favorably with comparators of best-available therapy and high-dose meropenem (40.0% [4/10], 30.0% [3/10], and 50.0% [5/10], respectively).

Relationship between baseline clinical characteristics and efficacy of lusutrombopag in thrombocytopenic patients with chronic liver disease: post hoc analysis of two placebo-controlled phase 3 trials.

OBJECTIVE: Lusutrombopag is a thrombopoietin receptor agonist approved to treat thrombocytopenia in patients with chronic liver disease (CLD). This post hoc analysis of the Japanese L-PLUS 1 and global L-PLUS 2 trials aimed to clarify factors related to platelet count increase after lusutrombopag treatment. METHODS: In L-PLUS 1, Pearson's correlation coefficients were used to evaluate correlations between platelet count and spleen index, thrombopoietin concentration, white blood cell (WBC) counts, and red blood cell counts (intent-to-treat [ITT] population). Associations between platelet count increase after lusutrombopag treatment and each parameter were assessed by regression analysis and mixed-effect model for repeated measures (MMRM). Associations between time-dependent changes in platelet count increase and each parameter were also examined in the L-PLUS 2 lusutrombopag ITT population by MMRM. RESULTS: In L-PLUS 1, the baseline platelet count was correlated with pretreatment spleen index (r = -0.23, 95% confidence interval [CI] -0.41 to -0.03) and WBC count (r = 0.26, 95% CI 0.06 to 0.43). No selected parameters were associated with the maximum platelet count increase from baseline. Patients with WBC counts below the normal range showed smaller platelet count increases after lusutrombopag treatment than patients with WBC counts within the normal range (p = .0028). In L-PLUS 2 (p = .0533), findings were similar and confirmed by larger pooled data of L-PLUS 1/L-PLUS 2 (p = .0021). CONCLUSIONS: This post hoc analysis revealed a possible association between baseline WBC count and platelet count increase after lusutrombopag treatment. WBC count could be a relevant factor for lusutrombopag efficacy.

Reconstructing the household transmission of influenza in the suburbs of Tokyo based on clinical cases.

BACKGROUND: Influenza is a public health issue that needs to be addressed strategically. The assessment of detailed infectious profiles is an important part of this effort. Household transmission data play a key role in estimating such profiles. We used diagnostic and questionnaire-based data on influenza patients at a Japanese clinic to estimate the detailed infectious period (as well as incubation period, symptomatic and infectious periods, and extended infectious period after recovery) and the secondary attack ratio (SAR) of influenza for households of various sizes based on a modified Cauchemez-type model. RESULTS: The data were from enrolled patients with confirmed influenza who were treated at the Hirotsu Clinic (Kawasaki, Japan) with a neuraminidase inhibitor (NAI) during six northern hemisphere influenza seasons between 2010 and 2016. A total of 2342 outpatients, representing 1807 households, were included. For influenza type A, the average incubation period was 1.43 days (95% probability interval, 0.03-5.32 days). The estimated average symptomatic and infective period was 1.76 days (0.33-4.62 days); the extended infective period after recovery was 0.25 days. The estimated SAR rose from 20 to 32% as household size increased from 3 to 5. For influenza type B, the average incubation period, average symptomatic and infective period, and extended infective period were estimated as 1.66 days (0.21-4.61), 2.62 days (0.54-5.75) and 1.00 days, respectively. The SAR increased from 12 to 21% as household size increased from 3 to 5. CONCLUSION: All estimated periods of influenza type B were longer than the corresponding periods for type A. However, the SAR for type B was less than that for type A. These results may reflect Japanese demographics and treatment policy. Understanding the infectious profiles of influenza is necessary for assessing public health measures.

Peripheral endothelial function can be improved by daily consumption of water containing over 7 ppm of dissolved hydrogen: A randomized controlled trial.

BACKGROUND: Measurement of the reactive hyperemia index (RHI) using peripheral arterial tonometry (PAT) has shown benefits in the evaluation of vascular endothelial function and prediction of cardiovascular disease prognosis. Thus, it is important to examine the factors that promote the RHI. In this study, we aimed to investigate the effect of molecular hydrogen (H2) on reactive hyperemia-PAT of the small arteries of fingers in healthy people. METHODS: To determine the efficacy of H2 for improving peripheral vascular endothelial function, water containing high H2 concentrations was administered to participants, and the Ln_RHI was measured in the finger vasculature. Sixty-eight volunteers were randomly divided into two groups: a placebo group (n = 34) that drank molecular nitrogen (N2)-containing water and a high H2 group (n = 34) that drank high H2 water (containing 7 ppm of H2: 3.5 mg H2 in 500-mL water). The Ln_RHI was measured before ingesting the placebo or high H2 water, 1 h and 24 h after the first ingestion, and 14 days after daily ingestion of high H2 water or the placebo. The mixed effects model for repeated measures was used in data analysis. RESULTS: The high H2 group had a significantly greater improvement in Ln_RHI than the placebo group. Ln_RHI improved by 22.2% (p<0.05) at 24 h after the first ingestion of high H2 water and by 25.4% (p<0.05) after the daily consumption of high H2 water for 2 weeks. CONCLUSIONS: Daily consumption of high H2 water improved the endothelial function of the arteries or arterioles assessed by the PAT test. The results suggest that the continuous consumption of high H2 water contributes to improved cardiovascular health.