Memory T-cell enriched haploidentical transplantation with NK cell addback results in promising long-term outcomes: a phase II trial.

BACKGROUND: Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen. METHODS: In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy. RESULTS: The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72-98) and 88% (95% CI: 67-96); ≥ CR2 were 81% (95% CI: 61-92) and 68% (95% CI: 47-82) and refractory disease were 32% (95% CI: 11-54) and 20% (95% CI: 6-40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64-87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/µL and 140/µL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035). CONCLUSION: The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611).

A phase I/II study of adoptive SARS-CoV-2-specific T cells in immunocompromised hosts with or at risk of severe COVID-19 infection.

BACKGROUND: Post-transplant or hematological cancer patients have a higher risk of mortality after infection with ancestral and early variants of severe acute respiratory syndrome (SARS)-CoV-2. Adoptive cell therapy (ACT) with virus-specific T cells (VSTs) could augment endogenous T cell immunity to avoid disease deterioration before viral clearance. METHODS: We established a third-party SARS-CoV-2-specific T cell (COVID-T) bank in 2020 (NCT04351659) using convalescent and/or vaccinated donors. In a phase I/II study (NCT04457726), 13 adult and pediatric patients, acutely positive for SARS-CoV-2 and predicted to have a high chance of mortality, were recruited from September 2021 to February 2022. Twelve patients received a single dose of COVID-T cells, matched on at least 1 HLA. RESULTS: A dose of either 75,000 or 150,000 IFN-γ+CD3+ cells/m2 SARS-COV-2-specific T cells did not cause cytokine release syndrome, acute respiratory distress syndrome, or graft-versus-host disease. In the 8 patients who had detectable donor SARS-COV-2-specific T cells after ACT, none progressed to severe disease or died with COVID-19. In contrast, among the other four patients without evidence of donor micro-chimerism, two died of COVID-19. CONCLUSIONS: Long-acting third-party VSTs from convalescent or vaccinated donors could be expediently produced and might be clinically useful in future pandemics, particularly before global vaccination is implemented.

Virtual group Cognitive Stimulation Therapy (vCST) for dementia: mixed methods feasibility randomised controlled trial.

BACKGROUND AND OBJECTIVES: Cognitive Stimulation Therapy (CST) is an evidence-based group intervention for people with dementia , with benefits for cognition and quality of life when delivered face-to-face. Many people are unable to attend face-to-face groups for reasons including health and transport issues. This study aimed to assess the feasibility and acceptability of online or 'virtual' CST (vCST). RESEARCH DESIGN AND METHODS: Single-blind, randomised controlled feasibility design with qualitative interviews. 46 people with mild to moderate dementia were randomly allocated to attend either 14 sessions of twice-weekly vCST (n = 24) or treatment as usual (TAU, defined as usual care; n = 22) over seven weeks. Cognition, quality of life and depression were assessed pre and post-treatment. Qualitative interviews (n=16) with participants and carers were analysed using thematic analysis. RESULTS: High levels of attendance, adherence, fidelity to the manual and completion of outcomes were recorded. Recruitment appeared feasible although randomisation may not have been acceptable to some. There were no statistical differences noted between vCST and TAU in any of the outcomes evaluated, although both quantitative and qualitative data indicated acceptability, with qualitative reports of improved outcomes including cognition. DISCUSSION AND IMPLICATIONS: vCST appeared feasible to deliver but did not result in any changes in outcomes, as expected from an underpowered feasibility trial. CST is the main psychosocial intervention delivered for dementia in UK memory services and globally; with many services moving towards virtual CST delivery. Therefore, a fully powered RCT of the effectiveness of vCST is feasible and justified.

Implementation of First-trimester Screening and Prevention of Preeclampsia: a Stepped Wedge Cluster-randomized Trial in Asia.

BACKGROUND: This trial aimed to assess the efficacy, acceptability and safety of a first-trimester screen-and-prevent strategy for preterm preeclampsia (PE) in Asia. METHODS: Between 1st August 2019 and 28th February 2022, this multicenter stepped wedge cluster randomized trial included maternity/diagnostic units from ten regions in Asia. The trial started with a period where all recruiting centers provided routine antenatal care without study-related intervention. At regular six-week intervals, one cluster was randomized to transit from non-intervention phase to intervention phase. In the intervention phase, women underwent first-trimester screening for preterm PE using a Bayes theorem-based triple-test. High-risk women, with adjusted risk for preterm PE ≥ 1 in 100, received low-dose aspirin from <16 weeks until 36 weeks. RESULTS: Overall, 88.04% (42,897/48,725) of women agreed to undergo first-trimester screening for preterm PE. Among those identified as high-risk in the intervention phase, 82.39% (2,919/3,543) received aspirin prophylaxis. There was no significant difference in the incidence of preterm PE between the intervention and non-intervention phases (adjusted odds ratio [aOR] 1.59; 95% confidence interval [CI] 0.91 to 2.77). However, among high-risk women in the intervention phase, aspirin prophylaxis was significantly associated with a 41% reduction in the incidence of preterm PE (aOR 0.59; 95%CI 0.37 to 0.92). Additionally, it correlated with 54%, 55% and 64% reduction in the incidence of PE with delivery at <34 weeks (aOR 0.46; 95%CI 0.23 to 0.93), spontaneous preterm birth <34 weeks (aOR 0.45; 95%CI 0.22 to 0.92) and perinatal death (aOR 0.34; 95%CI 0.12 to 0.91), respectively. There was no significant between-group difference in the incidence of aspirin-related severe adverse events. CONCLUSIONS: The implementation of the screen-and-prevent strategy for preterm PE is not associated with a significant reduction in the incidence of preterm PE. However, low-dose aspirin effectively reduces the incidence of preterm PE by 41% among high-risk women. The screen-and-prevent strategy for preterm PE is highly accepted by a diverse group of women from various ethnic backgrounds beyond the original population where the strategy was developed. These findings underpin the importance of the widespread implementation of the screen-and-prevent strategy for preterm PE on a global scale.

Effectiveness of Cognitive Stimulation Therapy (CST) for mild to moderate dementia: A systematic literature review and meta-analysis of randomised control trials using the original CST protocol.

AIMS: We aimed to conduct a systematic literature review and meta-analysis to evaluate the efficacy of the original 14 session Cognitive Stimulation Therapy (CST) protocol in improving cognitive function and related outcomes in people with mild to moderate dementia. METHODS: Four databases were searched, up to May 2023, for randomized controlled trials of CST using the original protocol. Pre- and post-test means and measures of dispersion for intervention and control groups were extracted for each reported outcome and used to calculate effect sizes. Effect sizes were grouped by outcome and pooled in inverse variance weighted random effects models. RESULTS: Twelve studies were identified as meeting inclusion criteria. Of these, ten were given either a 'high' or 'medium' quality rating. The pooled results indicated that CST had a significant beneficial impact on global cognition, language, working memory, depression, neuropsychiatric symptoms, communication, self-reported quality of life and severity of dementia. CONCLUSIONS: CST as delivered in adherence to the original 14-session protocol is an efficacious treatment for mild to moderate dementia with improvements in cognition, affective symptoms and quality of life demonstrated from global trials.

Validation of the first-trimester machine learning model for predicting pre-eclampsia in an Asian population.

OBJECTIVES: To evaluate the performance of an artificial intelligence (AI) and machine learning (ML) model for first-trimester screening for pre-eclampsia in a large Asian population. METHODS: This was a secondary analysis of a multicenter prospective cohort study in 10 935 participants with singleton pregnancies attending for routine pregnancy care at 11-13+6 weeks of gestation in seven regions in Asia between December 2016 and June 2018. We applied the AI+ML model for the first-trimester prediction of preterm pre-eclampsia (<37 weeks), term pre-eclampsia (≥37 weeks), and any pre-eclampsia, which was derived and tested in a cohort of pregnant participants in the UK (Model 1). This model comprises maternal factors with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor (PlGF). The model was further retrained with adjustments for analyzers used for biochemical testing (Model 2). Discrimination was assessed by area under the receiver operating characteristic curve (AUC). The Delong test was used to compare the AUC of Model 1, Model 2, and the Fetal Medicine Foundation (FMF) competing risk model. RESULTS: The predictive performance of Model 1 was significantly lower than that of the FMF competing risk model in the prediction of preterm pre-eclampsia (0.82, 95% confidence interval [CI] 0.77-0.87 vs. 0.86, 95% CI 0.811-0.91, P = 0.019), term pre-eclampsia (0.75, 95% CI 0.71-0.80 vs. 0.79, 95% CI 0.75-0.83, P = 0.006), and any pre-eclampsia (0.78, 95% CI 0.74-0.81 vs. 0.82, 95% CI 0.79-0.84, P < 0.001). Following the retraining of the data with adjustments for the PlGF analyzers, the performance of Model 2 for predicting preterm pre-eclampsia, term pre-eclampsia, and any pre-eclampsia was improved with the AUC values increased to 0.84 (95% CI 0.80-0.89), 0.77 (95% CI 0.73-0.81), and 0.80 (95% CI 0.76-0.83), respectively. There were no differences in AUCs between Model 2 and the FMF competing risk model in the prediction of preterm pre-eclampsia (P = 0.135) and term pre-eclampsia (P = 0.084). However, Model 2 was inferior to the FMF competing risk model in predicting any pre-eclampsia (P = 0.024). CONCLUSION: This study has demonstrated that following adjustment for the biochemical marker analyzers, the predictive performance of the AI+ML prediction model for pre-eclampsia in the first trimester was comparable to that of the FMF competing risk model in an Asian population.

A working memory intervention for children with prenatal alcohol exposure: Pilot study.

Cogmed© is a computerized working memory training program designed to improve attention and working memory. We examined the short- and long-term impacts of a 25-session Cogmed© intervention on working memory and other cognitive and learning domains in children with prenatal alcohol exposure (PAE) and typically developing children. Participants included 38 children (4 - 13 years old) from Alberta, Canada in two groups: PAE (n = 20) and typically developing (n = 18). Significant improvements in areas of working memory and attentional control for both the PAE and the typically developing group were reported immediately after intervention completion (short-term impact). The gains on some measures were retained at five-week follow up (long-term impact). Preliminary findings indicate that computerized interventions may positively impact WM and attention control and that these changes may be maintained after a delay period.

Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother-child pairs.

Previous studies report an association between maternal diabetes mellitus (MDM) and attention-deficit/hyperactivity disorder (ADHD), often overlooking unmeasured confounders such as shared genetics and environmental factors. We therefore conducted a multinational cohort study with linked mother-child pairs data in Hong Kong, New Zealand, Taiwan, Finland, Iceland, Norway and Sweden to evaluate associations between different MDM (any MDM, gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (PGDM)) and ADHD using Cox proportional hazards regression. We included over 3.6 million mother-child pairs between 2001 and 2014 with follow-up until 2020. Children who were born to mothers with any type of diabetes during pregnancy had a higher risk of ADHD than unexposed children (pooled hazard ratio (HR) = 1.16, 95% confidence interval (CI) = 1.08-1.24). Higher risks of ADHD were also observed for both GDM (pooled HR = 1.10, 95% CI = 1.04-1.17) and PGDM (pooled HR = 1.39, 95% CI = 1.25-1.55). However, siblings with discordant exposure to GDM in pregnancy had similar risks of ADHD (pooled HR = 1.05, 95% CI = 0.94-1.17), suggesting potential confounding by unmeasured, shared familial factors. Our findings indicate that there is a small-to-moderate association between MDM and ADHD, whereas the association between GDM and ADHD is unlikely to be causal. This finding contrast with previous studies, which reported substantially higher risk estimates, and underscores the need to reevaluate the precise roles of hyperglycemia and genetic factors in the relationship between MDM and ADHD.

Consistency of Feces Affects Defecatory Function.

Background/Aims: It is a common belief that constipated patients have hard feces that contributes to the difficulties defecating. To the best of our knowledge, no studies had been published on controlled evacuation of simulated feces with different consistencies. Methods: Twelve normal subjects were recruited for studies with the simulated feces device "Fecobionics" of different consistency (silicone shore 0A-40A corresponding to Bristol stool form scale types 2-4). The subjects filled out questionnaires and had the balloon expulsion test and anorectal manometry done for reference. The Fecobionics probes were inserted in rectum in random order with +20 minutes between insertions. The bag was filled to urge-to-defecate and evacuations took place in privacy. Non-parametric statistics with median and quartiles are provided. Results: One subject was excluded due to technical issues, and another had abnormal anorectal manometry-balloon expulsion test. The 4 females/6 males subjects were aged 23 (range 20-48) years. Most differences were observed between the 0A and 10A probe (duration, maximum bag pressure, duration x maximum bag pressure, and relaxation of the front pressure and the bend angle during evacuation), eg, the duration was 9 (8-12) seconds at 0A and 18 (12-21) seconds at 10A (P < 0.05), and maximum bag pressure was 107 (96-116) cmH2O at 0A and 140 (117-162) cmH2O at 10A (P < 0.05). The bend angle before evacuation differed between the probes whereas only the 10A differed from 40A during defecation. The 10A was harder to evacuate than the 0A probe. Except for the bend angles, no further significant change was observed from 10A to 40A. Conclusion: Fecal consistency affects defecatory parameters.

The central role of natural killer cells in mediating acute myocarditis after mRNA COVID-19 vaccination.

BACKGROUND: Vaccine-related acute myocarditis is recognized as a rare and specific vaccine complication following mRNA-based COVID-19 vaccinations. The precise mechanisms remain unclear. We hypothesized that natural killer (NK) cells play a central role in its pathogenesis. METHODS: Samples from 60 adolescents with vaccine-related myocarditis were analyzed, including pro-inflammatory cytokines, cardiac troponin T, genotyping, and immunophenotyping of the corresponding activation subsets of NK cells, monocytes, and T cells. Results were compared with samples from 10 vaccinated individuals without myocarditis and 10 healthy controls. FINDINGS: Phenotypically, high levels of serum cytokines pivotal for NK cells, including interleukin-1ß (IL-1ß), interferon α2 (IFN-α2), IL-12, and IFN-γ, were observed in post-vaccination patients with myocarditis, who also had high percentage of CD57+ NK cells in blood, which in turn correlated positively with elevated levels of cardiac troponin T. Abundance of the CD57+ NK subset was particularly prominent in males and in those after the second dose of vaccination. Genotypically, killer cell immunoglobulin-like receptor (KIR) KIR2DL5B(-)/KIR2DS3(+)/KIR2DS5(-)/KIR2DS4del(+) was a risk haplotype, in addition to single-nucleotide polymorphisms related to the NK cell-specific expression quantitative trait loci DNAM-1 and FuT11, which also correlated with cardiac troponin T levels in post-vaccination patients with myocarditis. CONCLUSION: Collectively, these data suggest that NK cell activation by mRNA COVID-19 vaccine contributed to the pathogenesis of acute myocarditis in genetically and epidemiologically vulnerable subjects. FUNDING: This work was funded by the Hong Kong Collaborative Research Fund (CRF) 2020/21 and the CRF Coronavirus and Novel Infectious Diseases Research Exercises (reference no. C7149-20G).

Efficient Edge-AI Models for Robust ECG Abnormality Detection on Resource-Constrained Hardware.

This study introduces two models, ConvLSTM2D-liquid time-constant network (CLTC) and ConvLSTM2D-closed-form continuous-time neural network (CCfC), designed for abnormality identification using electrocardiogram (ECG) data. Trained on the Telehealth Network of Minas Gerais (TNMG) subset dataset, both models were evaluated for their performance, generalizability capacity, and resilience. They demonstrated comparable results in terms of F1 scores and AUROC values. The CCfC model achieved slightly higher accuracy, while the CLTC model showed better handling of empty channels. Remarkably, the models were successfully deployed on a resource-constrained microcontroller, proving their suitability for edge device applications. Generalization capabilities were confirmed through the evaluation on the China Physiological Signal Challenge 2018 (CPSC) dataset. The models' efficient resource utilization, occupying 70.6% of memory and 9.4% of flash memory, makes them promising candidates for real-world healthcare applications. Overall, this research advances abnormality identification in ECG data, contributing to the progress of AI in healthcare.

The relationship between social media use and psychosocial outcomes in older adults: A systematic review.

OBJECTIVES: Social isolation and loneliness are prevalent in older adults and are detrimental to physical and mental health. Social media use has been shown to be effective in maintaining social connections and improving older adults' psychosocial outcomes. This study aimed to systematically review and synthesize current research on this topic. DESIGN: Searches were conducted in November 2021 (and updated in October 2023) in PsycINFO, PubMed, and CINAHL. Inclusion criteria: (1) participants ≥ 65 years (mean, median, or minimum age) and (2) reported impact of social media use on psychosocial outcomes (including loneliness, depression, anxiety, social connectedness, wellbeing, life satisfaction, and quality of life). Quality appraisal tools were utilized, and results were synthesized using narrative synthesis. RESULTS: Sixty-four papers met inclusion criteria, including cross-sectional (n = 38), observational longitudinal (n = 6), interventional (n = 9), mixed-methods (n = 4), and qualitative (n = 7) studies. Participant numbers ranged from 6 to 16,925. While associations between social media use and positive psychosocial outcomes were generally reported in cross-sectional studies, the impact of social media use over time from longitudinal studies was mixed and inconclusive. CONCLUSIONS: While social media use is associated with positive psychosocial outcomes, casual conclusions cannot be drawn. Few longitudinal and randomized controlled trial studies existed, and these reported mixed findings. Large variations in study methodology including participants, measurement of social media use, and outcome measures contributed to the inconsistencies of findings. Addressing this heterogeneity through standardized approaches and more rigorous research may enhance understanding.

Intimate Partner Violence Against Women Before, During, and After Pregnancy: A Meta-Analysis.

Intimate partner violence (IPV) against pregnant women negatively impacts women's and infants' health. Yet inconsistent results have been found regarding whether pregnancy increases or decreases the risk of IPV. To answer this question, we systematically searched for studies that provided data on IPV against women before pregnancy, during pregnancy, and after childbirth. Nineteen studies met our selection criteria. We meta-analyzed the nineteen studies for the pooled prevalence of IPV across the three periods and examined study characteristics that moderate the prevalence. Results showed the pooled prevalence estimates of IPV were 21.2% before pregnancy, 12.8% during pregnancy and 14.7% after childbirth. Although these findings suggest a reduction in IPV during pregnancy, our closer evaluation of the prevalence of IPV after childbirth revealed that the reduction does not appear to persist. The prevalence of IPV increased from 12.8% within the first year after childbirth to 24.0% beyond the first year. Taken together, we should not assume pregnancy protects women from IPV, as IPV tends to persist across a longer-term period. Future studies are needed to investigate if IPV transits into other less obvious types of violence during pregnancy. Moderator analyses showed the prevalence estimates significantly varied across countries by income levels and regions.

The rectum, anal sphincter and puborectalis muscle show different contraction wave forms during prolonged measurement with a simulated feces.

Contractile patterns in rectum, puborectalis muscle and anal sphincter must be studied to understand defecation. Six subjects had contractile waveforms studied with Fecobionics. Symptom questionnaires, balloon expulsion test and anorectal manometry were done for reference. The Fecobionics bag was filled in rectum to urge-to-defecate volume and measurements were done for 4 h before the subjects attempted to evacuate the device. Pressures and bend angle (BA) variations were analyzed with Fast Fourier Transformation. Four normal subjects exhibited low frequency waves (< 0.06 Hz) for pressures and BA. The waves were uncoordinated between recordings, except for rear and bag pressures. Peak wave amplitudes occurred at 0.02-0.04 Hz. Pressures and the BA differed for peak 1 (p < 0.001) and peak 2 amplitudes (p < 0.005). The front pressure amplitude was bigger than the others (rear and BA, p < 0.05; bag, p < 0.005) for peak 1, and bigger than bag pressure (p < 0.005) and BA (p < 0.05) for peak 2. One subject was considered constipated with lower front pressure amplitudes compared to normal subjects and increased amplitudes for other parameters. The sixth subject was hyperreactive and differed from the other subjects. In conclusion, the rectum, anal sphincter and puborectalis muscle showed different contraction waves during prolonged measurements. The data call for larger studies to better understand normal defecation, feces-withholding patterns, and the implications on anorectal disorders.

Seeing through a robot's eyes: A cross-sectional exploratory study in developing a robotic screening technology for autism.

The present exploratory cross-sectional case-control study sought to develop a reliable and scalable screening tool for autism using a social robot. The robot HUMANE, installed with computer vision and linked with recognition technology, detected the direction of eye gaze of children. Children aged 3-8 (M = 5.52; N = 199) participated, 87 of whom had been confirmed with autism, 55 of whom were suspected to have autism, and 57 of whom were not considered to cause any concern for having autism. Before a session, a human experimenter instructed HUMANE to narrate a story to a child. HUMANE prompted the child to return his/her eye gaze to the robot if the child looked away, and praised the child when it re-established its eye gaze quickly after a prompt. The reliability of eye gaze detection was checked across all pairs of human raters and HUMANE and reached 0.90, indicating excellent interrater agreement. Using the pre-specified reference standard (Autism Spectrum Quotient), the sensitivity and specificity of the index tests (i.e., the number of robot prompts and duration of inattentiveness) reached 0.88 or above and the Diagnostic Odds Ratios were beyond 190. These results show that social robots may detect atypical eye patterns, suggesting a potential future for screening autism using social robots.

Natural history of infants with vitamin D deficiency in Hong Kong.

BACKGROUND AND OBJECTIVES: The usual recommended intake of vitamin D for healthy infants is 400 international unit (IU) daily. However, a high dose of vitamin D at 2000-3000 IU daily is needed for those with vitamin D deficiency (VDD). This study aimed to assess the natural history of a group of healthy infants with VDD and the associated factors for persistent VDD. METHODS AND STUDY DESIGN: Healthy infants detected to have VDD (25OHD <25 nmol/L) in a population study were followed, and their demographics and clinical data were collected. RESULTS: One hundred and thirty-one subjects (boys = 66%) were included. Their first serum 25OHD was taken at a median age of 87.5 days. None were treated with high-dose vitamin D supplements, but some have been given vitamin D at 400 IU daily. They were assessed again at the median age of 252.5 days when 15 remained to have VDD and 26 were in the insufficient range (25 - 49.9nmol/L). All persistent VDD children were on exclusive breastfeeding. Exclusive breastfeeding and no vitamin D supplementation were significant risk factors for persistent vitamin D insufficiency (<50nmol/L). CONCLUSIONS: Persistent VDD is common among infants exclusively breastfeeding and those who did not receive vitamin D supplementation.