Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial.

BACKGROUND: The GOG240 trial established bevacizumab with chemotherapy as standard first-line therapy for metastatic or recurrent cervical cancer. In the BEATcc trial (ENGOT-Cx10-GEICO 68-C-JGOG1084-GOG-3030), we aimed to evaluate the addition of an immune checkpoint inhibitor to this standard backbone. METHODS: In this investigator-initiated, randomised, open-label, phase 3 trial, patients from 92 sites in Europe, Japan, and the USA with metastatic (stage IVB), persistent, or recurrent cervical cancer that was measurable, previously untreated, and not amenable to curative surgery or radiation were randomly assigned 1:1 to receive standard therapy (cisplatin 50 mg/m2 or carboplatin area under the curve of 5, paclitaxel 175 mg/m2, and bevacizumab 15 mg/kg, all on day 1 of every 3-week cycle) with or without atezolizumab 1200 mg. Treatment was continued until disease progression, unacceptable toxicity, patient withdrawal, or death. Stratification factors were previous concomitant chemoradiation (yes vs no), histology (squamous cell carcinoma vs adenocarcinoma including adenosquamous carcinoma), and platinum backbone (cisplatin vs carboplatin). Dual primary endpoints were investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumours version 1.1 and overall survival analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03556839, and is ongoing. FINDINGS: Between Oct 8, 2018, and Aug 20, 2021, 410 of 519 patients assessed for eligibility were enrolled. Median progression-free survival was 13·7 months (95% CI 12·3-16·6) with atezolizumab and 10·4 months (9·7-11·7) with standard therapy (hazard ratio [HR]=0·62 [95% CI 0·49-0·78]; p<0·0001); at the interim overall survival analysis, median overall survival was 32·1 months (95% CI 25·3-36·8) versus 22·8 months (20·3-28·0), respectively (HR 0·68 [95% CI 0·52-0·88]; p=0·0046). Grade 3 or worse adverse events occurred in 79% of patients in the experimental group and in 75% of patients in the standard group. Grade 1-2 diarrhoea, arthralgia, pyrexia, and rash were increased with atezolizumab. INTERPRETATION: Adding atezolizumab to a standard bevacizumab plus platinum regimen for metastatic, persistent, or recurrent cervical cancer significantly improves progression-free and overall survival and should be considered as a new first-line therapy option. FUNDING: F Hoffmann-La Roche.

Preventive Effects of Dental Pulp Stem Cell-conditioned Media on Anti-RANKL Antibody-Related Osteonecrosis of the Jaw.

Medication-related osteonecrosis of the jaw is a serious disease occurring in patients with cancer and osteoporosis, who are undergoing treatment with antiresorptive agents (ARAs) such as bisphosphonate (BP) or denosumab, an antibody targeting receptor activator of NF-κB ligand. Recently, stem cell-based therapy has been shown to be effective in preventing the development of bisphosphonate-related osteonecrosis of the jaw. However, studies on denosumab-related osteonecrosis of the jaw (DRONJ) remain limited. Here, the efficacy of treatment with dental pulp stem cell conditioned media (DPSC-CM) in preventing DRONJ in a murine model was evaluated. Local administration of DPSC-CM into the extraction socket of a mouse with DRONJ decreased the number of empty osteocyte lacunae and the prevalence of ONJ. In tissues surrounding the extraction sockets in the DPSC-CM-treated group, the expression of inflammatory cytokines was attenuated and that of osteogenesis-related molecules was enhanced compared to that in the control group. Further, the expression of Wnt signaling molecules, which had been suppressed, was improved. These findings collectively suggest that DPSC-CM prevents ONJ development in a murine DRONJ model.

Uncovering associations between gender nonconformity, psychosocial factors, and mental health in adolescents: a birth cohort study.

BACKGROUND: Little information is available on the association between gender nonconformity during adolescence and subsequent mental health. While the distress related to gender nonconformity may be socially produced rather than attributed to individual-level factors, further research is needed to better understand the role of psychosocial factors in this context. METHOD: We analyzed data from the Tokyo Teen Cohort, obtained through random sampling of adolescents born between 2002 and 2004. We used inverse probability weighting to examine the association of gender nonconformity at ages 12 and 14 as a time-varying variable with subsequent mental health at age 16, while accounting for time-fixed and time-varying confounders. Furthermore, we used a weighting approach to investigate the mediating role of modifiable psychosocial factors in this association, addressing exposure-mediator and mediator-mediator interactions. RESULTS: A total of 3171 participants were analyzed. Persistent gender nonconforming behavior at ages 12 and 14 was associated with subsequent depression (ß = 2.02, 95% confidence interval [CI] 0.85 to 3.19) and psychotic experiences (ß = 0.33, 95% CI 0.14 to 0.52) at age 16. The results remained robust in sensitivity analyses. Approximately 30% of the association between gender nonconformity and depression was consistently mediated by a set of psychosocial factors, namely loneliness, bullying victimization, and relationships with mother, father, and friends. CONCLUSIONS: Persistent gender nonconformity during adolescence is associated with subsequent mental health. Psychosocial factors play a vital mediating role in this association, highlighting the essential need for social intervention and change to reduce stigmatization and ameliorate mental health challenges.

Constitutively active GPR43 is crucial for proper leukocyte differentiation.

The G protein-coupled receptors, GPR43 (free fatty acid receptor 2, FFA2) and GPR41 (free fatty acid receptor 3, FFA3), are activated by short-chain fatty acids produced under various conditions, including microbial fermentation of carbohydrates. Previous studies have implicated this receptor energy homeostasis and immune responses as well as in cell growth arrest and apoptosis. Here, we observed the expression of both receptors in human blood cells and a remarkable enhancement in leukemia cell lines (HL-60, U937, and THP-1 cells) during differentiation. A reporter assay revealed that GPR43 is coupled with Gαi and Gα12/13 and is constitutively active without any stimuli. Specific blockers of GPR43, GLPG0974 and CATPB function as inverse agonists because treatment with these compounds significantly reduces constitutive activity. In HL-60 cells, enhanced expression of GPR43 led to growth arrest through Gα12/13 . In addition, the blockage of GPR43 activity in these cells significantly impaired their adherent properties due to the reduction of adhesion molecules. We further revealed that enhanced GPR43 activity induces F-actin formation. However, the activity of GPR43 did not contribute to butyrate-induced apoptosis in differentiated HL-60 cells because of the ineffectiveness of the inverse agonist on cell death. Collectively, these results suggest that GPR43, which possesses constitutive activity, is crucial for growth arrest, followed by the proper differentiation of leukocytes.

Comparison of mirabegron and vibegron for clinical efficacy and safety in female patients with overactive bladder: a multicenter prospective randomized crossover trial.

PURPOSE: To compare the efficacy and safety of mirabegron and vibegron in female OAB patients. METHODS: We conducted a multicenter, prospective, randomized crossover study of female patients with OAB. The patients were assigned to Group MV (mirabegron for 8 weeks, followed by vibegron for 8 weeks) or group VM (vibegron for 8 weeks, followed by mirabegron for 8 weeks). The primary endpoint was the change in OABSS from baseline, and the secondary endpoint was the change in FVC parameters. After completion of the study, each patient was asked which drug was preferable. RESULTS: A total of 83 patients were enrolled (40 and 43 in groups MV and VM, respectively). At 8th and 16th week, 33 and 29 in Group MV and 34 and 27 in Group VM continued to receive the treatment. The change in PVR was not significantly different between treatment with mirabegron and vibegron. The changes in OABSS, nighttime frequency, mean, and maximum voided volume were similar between mirabegron and vibegron. The mean change in the daytime frequency was greater in the vibegron than in the mirabegron. Of the 56 patients, 15 (27%) and 30 (53%) preferred mirabegron and vibegron, respectively. The remaining 11 patients (20%) showed no preference. The change in the urgency incontinence score during vibegron was better in patients who preferred vibegron to mirabegron. CONCLUSION: The efficacies of mirabegron and vibegron in female patients was similar. The patients' preference for vibegron could depend on the efficacy of vibegron for urgency incontinence.

Longitudinal associations between subjective cognitive impairment, pain and depressive symptoms in home-dwelling older adults: Modelling within-person effects.

OBJECTIVES: Cognitive impairment, pain and depressive symptoms are common and interrelated factors in older adults. However, the directionality and specificity of their association remains unclarified. This study explored whether these factors prospectively increase reciprocal risk and examined the longitudinal association between these factors and quality of life (QoL). METHODS: This study used longitudinal data from The Older Persons and Informal Caregivers Survey Minimal Data Set (TOPICS-MDS; the Netherlands). Older adults self-reported cognitive impairment, pain, depressive symptoms and QoL at baseline and after 6 and 12 months of follow-up. The Random Intercept Cross-Lagged Panel Model was used to assess the prospective association between the three factors, while a multilevel linear regression analysis in a two-level random intercept model was used to examine the longitudinal associations between the three factors and QoL at the within-person level. RESULTS: The data of 11,582 home-dwelling older adults with or without subjective cognitive impairment were analysed. At the within-person level, pain at 6 months was associated with subsequent depressive symptoms (ß = 0.04, p = 0.024). The reverse association from depression to pain, and longitudinal associations between pain and subjective cognitive impairment and between depressive symptoms and subjective cognitive impairment were non-significant. Pain, depressive symptoms and subjective cognitive impairment showed a significant association with poor QoL 6 months later. CONCLUSIONS: A directional relationship was observed from pain to depressive symptoms. Pain reduction holds a potential benefit in the prevention of depressive symptoms, ultimately optimising the QoL of older adults.

Sex differences in the association between epicardial adipose tissue volume and left atrial volume index.

BACKGROUND: Sex disparities in the association between epicardial adipose tissue volume (EATV) and cardiovascular disease have been reported. The sex-dependent effects of EATV on left atrial (LA) size have not been elucidated. METHODS: Consecutive 247 subjects (median 65 [interquartile range 57, 75] years; 67% of men) who underwent multi-detector computed tomography without significant coronary artery disease or moderate to severe valvular disease were divided into two groups: patients with sinus rhythm (SR) or atrial fibrillation (AF). Sex differences in the association between the EATV index (EATVI) (mL/m2) and LA volume index (LAVI) in 63 SR (28 men and 35 women) and 184 AF (137 men and 47 women) patients were evaluated using univariate and multivariate regression analyses. RESULTS: In overall that includes both men and women, the relationship between EATVI and LAVI was not significantly correlated for patients with SR and AF. The relationship between EATVI and LAVI differed between men and women in both SR and AF groups. In SR patients, there was a positive relationship between EATVI and LAVI in men, but not in women. In contrast, in patients with AF, a negative relationship was found between EATVI and LAVI in women, whereas no association was found in men. CONCLUSIONS: We evaluated sex differences in the association between EATVI and LAVI in patients with either SR or AF, and found a positive relationship in men with SR and a negative relationship in women with AF. This is the first report to evaluate sex differences in the relationship between EATVI and LAVI, suggesting that EAT may play a role, at least in part, in sex differences in the etiology of AF.

High cost of chemotherapy for gynecologic malignancies.

BACKGROUND: The prognosis of gynecological malignancies has improved with the recent advent of molecularly targeted drugs and immune checkpoint inhibitors. However, these drugs are expensive and contribute to the increasing costs of medical care. METHODS: The Japanese Clinical Oncology Group (JCOG) Health Economics Committee conducted a questionnaire survey of JCOG-affiliated facilities from July 2021 to June 2022 to assess the prevalence of high-cost regimens. RESULTS: A total of 57 affiliated facilities were surveyed regarding standard regimens for advanced ovarian and cervical cancers for gynecological malignancies. Responses were obtained from 39 facilities (68.4%) regarding ovarian cancer and 37 (64.9%) concerning cervical cancer, with respective case counts of 854 and 163. For ovarian cancer, 505 of 854 patients (59.1%) were treated with regimens that included PARP inhibitors, costing >500 000 Japanese yen monthly, while 111 patients (13.0%) received treatments that included bevacizumab, with costs exceeding 200 000 Japanese yen monthly. These costs are ~20 and ~10 times higher than those of the conventional regimens, respectively. For cervical cancer, 79 patients (48.4%) were treated with bevacizumab regimens costing >200 000 Japanese yen per month, ~10 times the cost of conventional treatments. CONCLUSIONS: In this survey, >70% of patients with ovarian cancer were treated with regimens that included poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors or bevacizumab; ~50% of patients with cervical cancer were treated with regimens containing bevacizumab. These treatments were ~10 and ~20 times more expensive than conventional regimens, respectively. These findings can inform future health economics studies, particularly in assessing cost-effectiveness and related matters.

Re-administration of platinum-based chemotherapy for recurrent endometrial cancer: an ancillary analysis of the SGSG-012/GOTIC-004/Intergroup study.

BACKGROUND: We previously demonstrated the applicability of the concept of "platinum sensitivity" in recurrent endometrial cancer. Although immune checkpoint inhibitors have been widely incorporated into endometrial cancer treatment, the debate continues regarding treatment options in patients with recurrent endometrial cancer who have previously received platinum-based chemotherapy. In this study, we assessed the duration of response to secondary platinum-based treatment using pooled data from the SGSG-012/GOTIC-004/Intergroup study. METHODS: Among the 279 participants in the SGSG-012/GOTIC-004/Intergroup study wherein platinum-based chemotherapy was re-administered for managing recurrent endometrial cancer between January 2005 and December 2009, 130 (47%) responded to chemotherapy. We compared the relationship between platinum-free interval and duration of secondary platinum-based treatment using pooled data. RESULTS: In 40 patients (31%), the duration of response to secondary platinum-based treatment exceeded the platinum-free interval. The duration of response to secondary platinum-based treatment exceeded 12 months in 51 patients (39%) [platinum-free interval: < 12 months, 14/48 (29%); 12-23 months, 18/43 (42%); 24-35 months, 8/19 (42%); ≥ 36 months, 11/20 (55%)]. In particular, in eight patients (6%), the duration of response to secondary platinum-based treatment exceeded 36 months [platinum-free interval: < 12 months, 3/48 (6%); 12-23 months, 0/19 (0%); 24-35 months, 2/19 (11%); ≥ 36 months, 3/20 (15%)]. CONCLUSIONS: Re-administration of platinum-based chemotherapy for recurrent endometrial cancer may result in a long-term response exceeding the platinum-free interval in some patients. Even in the current situation, where immune checkpoint inhibitors have been introduced, re-administration of platinum-based chemotherapy is worth considering.

Anterior talofibular ligament footprint dimension measured using three-dimensional magnetic resonance imaging.

OBJECTIVE: Knowledge of footprint anatomy is essential for ankle anterior talofibular ligament repair and reconstruction. We aimed to determine the intra- and inter-rater measurement reliability of the anterior talofibular ligament footprint dimension using three-dimensional MRI. METHODS: MRI images of 20 ankles with intact ligaments, including 11 with a single bundle and nine with double-bundle ligaments, were analyzed. Imaging was performed using a 3.0-Tesla MRI. Isotropic three-dimensional proton density-weighted images with a voxel size of 0.6 mm were obtained. The fibular and talar footprints were manually segmented using image processing software to create three-dimensional ligament footprints. The lengths, widths, and areas of each sample were measured. A certified orthopedic surgeon and a senior orthopedic fellow performed the measurements twice at 6-week intervals. The intra- and inter-rater differences in the measurements were calculated. RESULTS: The length, width, and area of the single-bundle fibular footprint were 8.7 mm, 5.4 mm, and 37.4 mm2, respectively. Those of the talar footprint were 8.4 mm, 4.3 mm, and 30.1 mm2, respectively. The inferior bundle of the double-bundle ligament was significantly smaller than the single and superior bundles (p < 0.001). No differences were observed between intra-rater measurements by either rater, with maximum differences of 0.7 mm, 0.5, and 1.7 mm2, in length, width, and area, respectively. The maximum inter-rater measurement differences were 1.9 mm, 0.5, and 2.4 mm2, respectively. CONCLUSION: Measurements of the anterior talofibular ligament dimensions using three-dimensional MRI were sufficiently reliable. This measurement method provides in vivo quantitative data on ligament footprint anatomy.

Continuous local antibiotic perfusion for deep infection of the foot and ankle.

BACKGROUND: This study aimed to report the outcome of deep infections of the foot and ankle, which are among the most challenging orthopedic conditions to treat, after continuous local antibiotic perfusion. METHODS: Eleven patients with deep foot and ankle infections were treated with continuous local antibiotic perfusion between January 2019 and March 2024. After surgical debridement, we performed continuous perfusion of high concentrations of gentamicin (60 mg/50 ml) directly into the infected bone and soft tissue for two weeks using bone marrow needles and double-lumen tubes. Patient characteristics, infection relapse, and adverse events were investigated. RESULTS: The mean age of the patients was 53 years (range 12-79 years), with six males and five females. The infections were controlled without additional surgeries in ten patients with a mean follow-up of 40 months (12-62 months). Two patients developed a fungal infection, of which one required an additional debridement surgery, and the other was treated with oral antifungal medication. No adverse events occurred due to high-concentration gentamicin. CONCLUSIONS: Short-term infection control was achieved using continuous local antibiotic perfusion; thus, it can be a treatment option for deep infections of the foot and ankle.

Intra- and interrater measurement reliability of lateral ankle ligament attachment locations using three-dimensional magnetic resonance imaging.

BACKGROUND: We aimed to evaluate the intra- and interrater measurement reliability of the lateral ankle ligament attachment locations using three-dimensional magnetic resonance imaging. METHODS: We analysed 54 participants with a mean age of 43 years who underwent three-dimensional ankle magnetic resonance imaging and had normal lateral ligaments. Bony landmarks of the distal fibula, talus, and calcaneus were identified in the reconstructed images. The centers of the anterior talofibular ligament and calcaneofibular ligament attachments were also identified. The distances between the landmarks and attachments were measured. Two raters performed the measurements twice, and intra- and interrater intraclass correlation coefficients were calculated. RESULTS: The intrarater intraclass correlation coefficient values were between 0.71 and 0.96 for the anterior talofibular ligament attachment measurements and between 0.77 and 0.95 for the calcaneofibular ligament attachments. The interrater intraclass correlation coefficient was higher than 0.7, except for the distance between the anterior talofibular ligament superior bundle and fibular obscure tubercle. The fibular attachment of a single-bundle anterior talofibular ligament was located 13.3 mm from the inferior tip and 43% along the anterior edge of the distal fibula. The superior and inferior bundles of the double-bundle ligament were located at 43% and 23%, respectively. The calcaneofibular ligament fibular attachment was 5.5 mm from the inferior tip, at 16% along the anterior edge of the distal fibula. CONCLUSION: The measurements of anterior talofibular ligament and calcaneofibular ligament attachment locations identified on three-dimensional magnetic resonance imaging were sufficiently reliable. This measurement method provides in vivo anatomical data on the lateral ankle ligament anatomy.

Variability in sonographic anterior drawer test measurements of the ankle: Experienced versus beginner examiners.

BACKGROUND: This study aimed to clarify the variability in the measurements of stress sonography of the ankle and determine the effects of examiner experience on the measurements. METHODS: Twenty examiners (10 experienced and 10 beginners) were included in the study. Each examiner performed stress ultrasonography on a patient with a chronic anterior talofibular ligament injury and a patient with an intact ligament using the reverse anterior drawer method. Changes in ligament length before versus after stress were determined. The same 20 examiners performed ultrasonography on two other patients with an injured or intact ATFL using the anterior drawer method. The length change values and variance were compared between the groups using t-tests and F-tests. RESULTS: Using the reverse anterior drawer method, the change in the anterior talofibular ligament length was 3.3 mm (range, 2.2-4.8 mm) in the experienced group and 2.7 mm (0.0-4.1 mm) in the beginner group for the ligament injured patient. The length changes for the patient with intact anterior talofibular ligament were 0.5 mm (0.1-0.9 mm) and 0.4 mm (-0.1-1.5 mm) in the experienced and beginner groups, respectively. There were no significant intergroup differences in measurement amount (P = 0.37) or variance (P = 0.72). Similarly, using the anterior drawer method, no significant differences between the groups were found in measurement amount or variance. CONCLUSION: The quantitative evaluation of stress sonography of the ankle was variable regardless of examiner experience or stress method, particularly in patients with an anterior talofibular ligament injury. The amount of variability appeared to be unacceptably large for clinical application. Our study results highlight the need for technical standardization.

Characteristics of Nonunion After Arthroscopic Ankle Arthrodesis: A Multicenter Retrospective Cohort Study.

Nonunion is a major complication of arthroscopic ankle arthrodesis. However, the characteristics and risk factors of nonunion are not well understood. This retrospective multicenter observational study aimed to clarify the characteristics of nonunion after arthroscopic ankle arthrodesis. We included 154 patients who underwent arthroscopic ankle arthrodesis at any 1 of 5 institutions. Patients were divided into 2 groups: union and nonunion, and the groups were compared. Age, sex, body mass index, diabetes, smoking, corticosteroid use, diagnosis, treatment information, treatment protocol, radiographic evaluation, and patient-reported outcomes were recorded and analyzed. On radiographs, bony union was observed in 142 ankles (91.0%) but not in 12 ankles (9.0%). Postoperative radiographic tibial bony gap (mm) was significantly larger in the nonunion group (medial = 1.98, center = 1.65, anterior = 2.21, middle = 1.72, posterior = 3.01) than in the union group (medial = 1.35, center = 1.13, anterior = 1.28, middle = 1.03, posterior = 2.03). Furthermore, the visual analog score (VAS) of pain and pain-related self-administered foot evaluation questionnaire (SAFE-Q) subscale score significantly worsened in the nonunion group (VAS = 3.83, SAFE-Q subscale score = 69.8) compared to that in the union group (VAS = 1.35, SAFE-Q subscale score = 76.6). A larger radiographic tibiotalar bony gap was observed in the nonunion group. Other measurement outcomes were not associated with nonunion. Additionally, patient-reported outcomes markedly worsened in the nonunion group.

The effects of a teacher-led online mental health literacy program for high school students: a pilot cluster randomized controlled trial.

BACKGROUND: Adolescents are vulnerable to mental health problems, and this vulnerability may be enhanced in situations such as the present COVID-19 pandemic. Online mental health literacy (MHL) education may help adolescents maintain/improve their mental health, especially in situations where face-to-face education is difficult. AIMS: To evaluate the effects of a teacher-led "online Short MHL Program (o-SMHLP)" delivered online to grade 10 students in their classrooms. METHODS: Students (age 15-16) were randomly assigned to an o-SMHLP group (n = 115 (3 classes)) or a control group (n = 155 (4 classes)) at the class level. The program consisted of a 20-minute session which included an animated video. The students completed a self-report questionnaire pre- and post-intervention assessing outcomes including: "Knowledge about mental health/illnesses", "Recognition of necessity to seek help", "Intention to seek help", and "Unwillingness to socialize with people having mental illness". Mixed effects modeling was employed for analyses. RESULTS: All outcomes were significantly improved in the intervention group compared to the control group post-intervention, except for "intention to seek help". CONCLUSIONS: The present study shows the effectiveness of an online MHL intervention while identifying the need for the development of effective online programs targeting adolescents' "intention to seek help".

Incisura tangent method to determine the transsyndesmotic axis for syndesmotic fixation.

BACKGROUND: Clamping along the transsyndesmotic (TS) axis decreases the risk of malreduction when reducing syndesmotic diastasis. We aimed to measure the difference between the TS axis and the axis determined by the newly proposed fluoroscopic incisura tangent (IT) method. The measurements were compared to those between the TS axis and those based on the center-center (CC) and talar dome lateral (TL) methods. METHODS: We analyzed computed tomographic images of 43 normal ankles. The IT view was simulated using a digitally reconstructed radiograph, in which the anterior and posterior fibular incisura tubercles overlapped on the internally rotated anteroposterior view. The interaxis angle between the TS and the axes determined by the IT method was measured on the axial computed tomographic image corresponding to the radiographic image. The same procedure was repeated using the CC and TL methods. The measured values were compared between the three methods using a one-factor analysis of variance. Furthermore, the measurements of the anteverted and retroverted incisurae were compared for each fluoroscopic method. RESULTS: The mean interaxis angles between the TS were - 0.5 degrees, 6.3 degrees, and - 1.8 degrees for the IT, CC, and TL methods, respectively, with a significantly larger value for the CC method than for the IT and TL methods (P < .001). No significant difference was found in the interaxis angle in the anteverted (-0.1 degrees) and retroverted (-1.0 degrees) incisurae when using the IT method (P = .15). The angles in the retroverted incisurae were larger than those of the anteverted incisurae for the CC and TL methods. CONCLUSION: The fluoroscopic IT method accurately estimated the TS axis. The interaxis angles were consistent, regardless of the incisura anatomy. The fluoroscopic method can be used to clamp and fix the syndesmosis along the TS axis. LEVEL OF EVIDENCE: Ⅳ.

Adolescent psychotic experiences before and during the COVID-19 pandemic: a prospective cohort study.

BACKGROUND: Understanding the etiology of psychosis is essential to the development of preventive interventions. The COVID-19 pandemic provides a rare natural experiment that can expand our understanding of the role of social factors in the trajectories and etiology of psychosis across adolescence, particularly in Tokyo where the prevalence of actual COVID-19 infection remained low. We hypothesized that the likelihood of self-reporting psychotic experiences (PEs) would increase following the onset of the COVID-19 pandemic. METHODS: The Tokyo Teen Cohort (TTC) is a prospective cohort study of adolescents in the general population of the Tokyo metropolitan area, followed from age 10 to 16 years. We used multi-level linear regression models to test the associations between the phase of the COVID-19 pandemic and self-reported PEs. RESULTS: Among 1935 adolescents included in the analysis, a rapid increase in PEs occurred at the onset of the COVID-19 pandemic, following approximately 6 years of steady decline across prior waves. This association was more pronounced for boys compared to girls. This increase became more pronounced as the pandemic moved into later phases, defined based on contemporaneous sociopolitical changes in Tokyo (i.e. changes to school closure, social distancing guidelines, and the state of emergency status). CONCLUSIONS: The steady decline in PEs across adolescence was halted and reversed concurrent with the COVID-19 pandemic onset, despite very low rates of COVID-19 infection. This implicates COVID-19 related socioenvironmental factors as contributory etiological factors in the development of PEs in this adolescent cohort.

Mediators between canagliflozin and renoprotection vary depending on patient characteristics: Insights from the CREDENCE trial.

AIM: To identify the mediators between canagliflozin and renoprotection in patients with type 2 diabetes at a high risk of end-stage kidney disease (ESKD). METHODS: In this post hoc analysis of the CREDENCE trial, the effect of canagliflozin on potential mediators (42 biomarkers) at 52 weeks and the association between changes in mediators and renal outcomes were evaluated using mixed-effects and Cox models, respectively. The renal outcome was a composite of ESKD, serum creatinine doubling or renal death. The percentage of the mediating effect of each significant mediator was calculated based on changes in the hazard ratios of canagliflozin after additional adjustment of the mediator. RESULTS: Changes in haematocrit, haemoglobin, red blood cell (RBC) count and urinary albumin-to-creatinine ratio (UACR) at 52 weeks significantly mediated 47%, 41%, 40% and 29% risk reduction with canagliflozin, respectively. Further, 85% mediation was attributed to the combined effect of haematocrit and UACR. A large variation in mediating effects by haematocrit change existed among the subgroups, ranging from 17% in those patients with a UACR of more than 3000 mg/g to 63% in patients with a UACR of 3000 mg/g or less. In the subgroups with a UACR of more than 3000 mg/g, UACR change was the highest mediating factor (37%), driven by the strong association between UACR decline and renal risk reduction. CONCLUSIONS: The renoprotective effects of canagliflozin in patients at a high risk of ESKD can be significantly explained by changes in RBC variables and UACR. The complementary mediating effects of RBC variables and UACR may support the renoprotective effect of canagliflozin in different patient groups.

Canagliflozin reduces proteinuria by targeting hyperinsulinaemia in diabetes patients with heart failure: A post hoc analysis of the CANDLE trial.

AIM: To investigate factors associated with proteinuria regression in patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin. MATERIALS AND METHODS: This study was a post hoc analysis of the CANDLE trial (UMIN000017669), which compared the effect of 24 weeks of treatment with canagliflozin or glimepiride for changes in N-terminal pro-brain natriuretic peptide in patients with T2DM and chronic heart failure (CHF). Factors associated with regression of proteinuria at 24 weeks were evaluated with multivariate logistic models. RESULTS: The rate of regression of proteinuria was higher (28/102, 27.5% vs. 12/112, 10.7%), and that of progression was lower (9/102, 8.8% vs. 26/112, 23.2%), in the canagliflozin versus the glimepiride group (P = .0001). There were no differences in the change in the estimated glomerular filtration rate category between groups. Insulin level, homeostatic model assessment of ß-cell function, homeostatic model assessment for insulin resistance and estimated plasma volume were decreased at 24 weeks in the regression subclass but not in the progression subclass, suggesting that regression of proteinuria is associated with the declines in these values in the canagliflozin group. Higher insulin level at baseline was solely associated with proteinuria regression in the multivariate logistic regression model (baseline insulin, as per a 1-mlU/L increase, odds ratio 1.24 [1.05-1.47], P = .011). CONCLUSIONS: In patients with T2DM and CHF, regression of proteinuria with canagliflozin treatment was associated with the pretreatment insulin level. These results may provide clinicians with novel mechanistic insights into the beneficial effects of canagliflozin on renal outcomes and may warrant discussion for selecting preferred patient profiles, including pretreatment insulin levels.

The implication of calf circumference and grip strength in osteoporosis and bone mineral density among hemodialysis patients.

BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD), nutritional status, and uremia management have been emphasized for bone management in hemodialysis patients. Nevertheless, valuable data on the importance of muscle mass in bone management are limited, including whether conventional management alone can prevent osteoporosis. Thus, the importance of muscle mass and strength, independent of the conventional management in osteoporosis prevention among hemodialysis patients, was evaluated. METHODS: Patients with a history of hemodialysis 6 months or longer were selected. We assessed the risk for osteoporosis associated with calf circumference or grip strength using multivariable adjustment for indices of CKD-MBD, nutrition, and dialysis adequacy. Moreover, the associations between bone mineral density (BMD), calf circumference, grip strength, and bone metabolic markers were also evaluated. RESULTS: A total of 136 patients were included. The odds ratios (95% confidence interval) for osteoporosis at the femoral neck were 1.25 (1.04-1.54, P < 0.05) and 1.08 (1.00-1.18, P < 0.05) per 1 cm shorter calf circumference or 1 kg weaker grip strength, respectively. Shorter calf circumference was significantly associated with a lower BMD at the femoral neck and lumbar spine (P < 0.001). Weaker grip strength was also associated with lower BMD at the femoral neck (P < 0.01). Calf circumference or grip strength was negatively correlated with bone metabolic marker values. CONCLUSION: Shorter calf circumference or weaker grip strength was associated with osteoporosis risk and lower BMD among hemodialysis patients, independent of the conventional therapies.