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The efficacy of acupuncture and moxibustion in the treatment of depression has been fully recognized internationally. However, its central mechanism is still not developed into a unified standard, and it is generally believed that the central mechanism is regulation of the cortical striatum thalamic neural pathway of the limbic system. In recent years, some scholars have applied functional magnetic resonance imaging (fMRI) to study the central mechanism and the associated brain effects of acupuncture and moxibustion treatment for depression. This study reviews the acupuncture and moxibustion treatment of depression from two aspects: (1) fMRI study of the brain function related to the acupuncture treatment of depression: different acupuncture and moxibustion methods are summarized, the fMRI technique is elaborately explained, and the results of fMRI study of the effects of acupuncture are analyzed in detail, and (2) fMRI associated “brain functional network” effects of acupuncture and moxibustion on depression, including the effects on the hippocampus, the amygdala, the cingulate gyrus, the frontal lobe, the temporal lobe, and other brain regions. The study of the effects of acupuncture on brain imaging is not adequately developed and still needs further improvement and development. The brain function networks associated with the acupuncture treatment of depression have not yet been adequately developed to provide a scientific and standardized mechanism of the effects of acupuncture. For this purpose, this study analyzes in-depth the clinical studies on the treatment of anxiety and depression by acupuncture and moxibustion, by depicting how the employment of fMRI technology provides significant imaging changes in the brain regions. Therefore, the study also provides a reference for future clinical research on the treatment of anxiety and depression.

Introduction: EGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion of exon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations. Methods: Patients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed. Results: A total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n = 18), G719X (28%, n = 14), and exon 20 insertion (14%, n = 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5–12.9 mo) overall and 10.7 months (95% CI: 3.2–18.1 mo) in the first-line setting (n = 20). The objective response rate was 31.7% (95% CI: 18.1%–48.1%) overall and 41.2% (95% CI: 18.4%–67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations. Conclusions: Osimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR-activating mutation.

Abstract Background Systematic reviews (SRs) synthesise the best evidence of effectiveness and safety on Chinese herbal medicine (CHM). Decision-making should be supported by the high-quality evidence of prudently conducted SRs, but the trustworthiness of conclusions may be limited by poor methodological rigour. Methods This survey aimed to examine the methodological quality of a representative sample of SRs on CHM published during January 2018 to March 2020. We conducted literature search in Cochrane Database of Systematic Reviews, MEDLINE via Ovid, and EMBASE via Ovid. Eligible SRs must be in Chinese or English with at least one meta-analysis on the treatment effect of any CHM documented in the 2015 Chinese Pharmacopoeia. Two reviewers extracted the bibliographical characteristics of SRs and appraised their methodological quality using AMSTAR 2 (Assessing the Methodological Quality of Systematic Reviews 2). The associations between bibliographical characteristics and methodological quality were investigated using Kruskal-Wallis tests and Spearman’s rank correlation coefficients. Results We sampled and appraised one hundred forty-eight SRs. Overall, one (0.7%) was of high methodological quality; zero (0%), four (2.7%), and one-hundred forty-three (96.6%) SRs were of moderate, low, and critically-low quality. Only thirteen SRs (8.8%) provided a pre-defined protocol; none (0%) provided justifications for including particular primary study designs; six (4.1%) conducted a comprehensive literature search; two (1.4%) provided a list of excluded studies; nine (6.1%) undertook meta-analysis with appropriate methods; and seven (4.7%) reported funding sources of included primary studies. Cochrane reviews had higher overall quality than non-Cochrane reviews (P

Background Diabetes is a risk factor for postoperative complications. Previous meta-analyses have shown that elevated glycated hemoglobin (HbA1c) levels are associated with postoperative complications in various surgical populations. However, this is the first meta-analysis to investigate the association between preoperative HbA1c levels and postoperative complications in patients undergoing elective major abdominal surgery. Methods PRISMA guidelines were adhered to for this study. Six databases were searched up to April 1, 2020. Primary studies investigating the effect of HbA1c levels on postoperative complications after elective major abdominal surgery were included. Risk of bias and quality of evidence assessments were performed. Data were pooled using a random effects model. Meta-regression was performed to evaluate different HbA1c cut-off values. Results Twelve observational studies (25,036 patients) were included. Most studies received a ‘good’ and ‘moderate quality’ score using the NOS and GRADE, respectively. Patients with a high HbA1c had a greater risk of anastomotic leaks (odds ratio [OR]: 2.80, 95% CI [1.63, 4.83], P < 0.001), wound infections (OR: 1.21, 95% CI [1.08, 1.36], P = 0.001), major complications defined as Clavien-Dindo [CD] 3–5 (OR: 2.16, 95% CI [1.54, 3.01], P < 0.001), and overall complications defined as CD 1–5 (OR: 2.12, 95% CI [1.48, 3.04], P < 0.001). Conclusions An HbA1c between 6% and 7% is associated with higher risks of anastomotic leaks, wound infections, major complications, and overall postoperative complications. Therefore, guidelines with an HbA1c threshold > 7% may be putting pre-optimized patients at risk. Future randomized controlled trials are needed to explore causation before policy changes are made.

In cancer, associations between mutational signatures and driver mutations have been proposed but not fully explored. Here, the authors develop sigDriver to find associations between mutational signatures and mutation hotspots in order to predict coding and non-coding driver mutations in pan-cancer genomics data.

Abstract Background Prokinetic is the first-line conventional treatment for functional dyspepsia (FD) in Asia despite potential adverse events. Chinese herbal medicine (CHM) may be an effective and safe substitution. This network meta-analysis (NMA) aimed to evaluate the comparative effectiveness of different CHM formulae for FD against prokinetics. Methods Seven international and Chinese databases were searched from their inception to July 2020 for randomised controlled trials (RCTs) on CHM versus prokinetics. Data from each RCT were first pooled using random-effect pairwise meta-analyses and illustrated as risk difference (RD) or standardised mean difference (SMD) with 95% confidence interval (CI). Random-effect NMAs were then performed to evaluate the comparative effectiveness of CHM formulae and displayed as RD with 95% CI or SMD with 95% credible interval (CrI). The GRADE partially contextualised framework was applied for NMA result interpretation. Results Twenty-six unique CHM formulae were identified from twenty-eight RCTs of mediocre quality. Pairwise meta-analyses indicated that CHM was superior to prokinetics in alleviating global symptoms at 4-week follow-up (pooled RD: 0.14; 95% CI: 0.10–0.19), even after trim and fill adjustment for publication bias. NMAs demonstrated that Modified Zhi Zhu Decoction may have a moderate beneficial effect on alleviating global symptoms at 4-week follow-up (RD: 0.28; 95% CI: − 0.03 to 0.75). Xiao Pi Kuan Wei Decoction may have a large beneficial effect on alleviating postprandial fullness (SMD: − 2.14; 95% CI: − 2.76 to 0.70), early satiety (SMD: − 3.90; 95% CI: − 0.68 to − 0.42), and epigastric pain (SMD: − 1.23; 95% CI: − 1.66 to − 0.29). No serious adverse events were reported. Conclusion Modified Zhi Zhu Decoction and Xiao Pi Kuan Wei Decoction may be considered as an alternative for patients unresponsive to prokinetics. Confirmatory head-to-head trials should be conducted to investigate their comparative effectiveness against prokinetics.

ObjectiveTo culturally adapt and examine the psychometric properties of the Chinese (Cantonese) version of the Upper Extremity Functional Index (C-UEFI) in people with chronic stroke.DesignCross-sectional study.SettingsUniversity-affiliated neurorehabilitation research laboratory.ParticipantsThe participants (N = 151) were people with chronic stroke (N = 101) and healthy controls (n = 50).Main outcome measuresWe assessed the C-UEFI, Fugl-Meyer Assessment for Upper Extremity (FMA-UE), Wolf Motor Function Test (WMFT), Six-Minute Walk Test (6MWT), Motor Activity Log (MAL), Activity-Specific Balance Confidence (ABC) scale, Lawton Instrumental Activities of Daily Living (IADL) scale, Survey of Activities and Fear of Falling in the Elderly (SAFFE), Stroke Impact Scale (SIS) and Community Integration Measure (CIM) as outcome measures.ResultsThe C-UEFI items demonstrated good test–retest reliability (intraclass correlation coefficient [ICC]3, 1 = 0.872) and excellent internal consistency (Cronbach's α = 0.922). People with chronic stroke had poorer C-UEFI scores than the healthy controls. The overall C-UEFI mean score of 101 people with stroke was significantly correlated with the mean scores of the FMA-UE, WMFT, MAL, ABC scale, IADL scale, SAFFE, SIS and CIM and the distance covered in the 6MWT. The C-UEFI cut-off score to distinguish between people with chronic stroke and healthy older adults according to upper extremity function was 57.5 out of 59 (sensitivity: 88.1%; specificity: 84%). The C-UEFI had good content validity, with an acceptable fit to the two-factor structure model.ConclusionsThe C-UEFI is reliable and valid for assessing functional recovery of upper extremity activity in Chinese people with chronic stroke.

Aim: To examine benefits of corticosteroids for Duchenne muscular dystrophy (DMD) by age and disease progression. Methods: Data from daily steroid users (placebo-treated) were pooled from four phase 2b/3 trials in DMD. Outcomes assessed overall and among subgroups included changes from baseline to 48 weeks in six-minute walk distance (6MWD), timed function tests and North Star Ambulatory Assessment total score. Results: Among 231 patients receiving deflazacort (n = 127) or prednisone (n = 104), observed differences in 6MWD favoring deflazacort over prednisone were significant for patients with relatively older age (≥8-years-old), greater disease progression (baseline timed stand from supine ≥5 s), or longer corticosteroid use (>3 years). Conclusion: Daily deflazacort had greater benefits than daily prednisone particularly among older/more progressed patients.

BackgroundAlthough older adults are at an increased risk of atherosclerotic cardiovascular disease (ASCVD), the effect of an integrated exercise and cardiovascular health education programme based on self-efficacy theory has not been well investigated among older adults. This study aims at examining the effect of this programme on community-dwelling older adults at risk of ASCVD concerning physical activity level, exercise self-efficacy and ASCVD risk profile.MethodsA parallel two-arm randomised controlled trial with pretest-posttest design will be performed among 190 Chinese community-dwelling adults aged 60 or above in elderly community centres of the Guangdong-Hong Kong-Macao Greater Bay Area. Eligible participants will be randomised by computerised generation. Experimental group will receive a 12-week integrated exercise and cardiovascular health education programme, which comprises a one-hour group-based health education talk conducted at Week 1, a booklet, a lecture video, a tailor-made exercise video, and a booster intervention by text messaging starting from Week 1 to Week 12. Control group will receive placebo intervention including a talk on basic health issues, a lecture video and corresponding leaflet. The outcomes will be investigated through self-report questionnaires and physiological evaluations at baseline, Week 12, Week 24, and Week 36. Physical activity level, exercise self-efficacy and ASCVD risk profile will be assessed, with physical activity level at Week 24 considered the primary outcome. The main intervention effect (group differences on continuous outcome variables) will be examined via Generalized Estimating Equations with identity link.DiscussionThis study findings will provide clues to the effect of the integrated exercise and cardiovascular health education programme, which is theoretically underpinned with self-efficacy theory, in older adults at risk of ASCVD. It will also enhance the quality of community health education by providing insight into the effective teaching strategies targeting older adults.Trial registrationThis study has been registered on ChinicalTrial.gov (Trial ID: NCT05434273).

IntroductionThe aim of our study was to assess the initial impact of COVID-19 on total publicly-funded direct healthcare costs and health services use in two Canadian provinces, Ontario and British Columbia (BC).MethodsThis retrospective repeated cross-sectional study used population-based administrative datasets, linked within each province, from January 1, 2018 to December 27, 2020. Interrupted time series analysis was used to estimate changes in the level and trends of weekly resource use and costs, with March 16-22, 2020 as the first pandemic week. Also, in each week of 2020, we identified cases with their first positive SARS-CoV-2 test and estimated their healthcare costs until death or December 27, 2020.ResultsThe resources with the largest level declines (95% confidence interval) in use in the first pandemic week compared to the previous week were physician services [Ontario: -43% (-49%,-37%); BC: -24% (-30%,-19%) (both pConclusionsReduced utilization of healthcare services in the overall population outweighed utilization by COVID-19 patients in 2020. Meeting the needs of all patients across all services is essential to maintain resilient healthcare systems.

Abstract Background Low‐density neutrophils (LDN) are a distinct subset of neutrophils rarely detected in healthy people but appear in the blood of patients with autoimmune diseases, including systemic lupus erythematosus (SLE), and are mobilised in response to granulocyte colony‐stimulating factor (G‐CSF). The aim of this study was to identify novel mechanisms responsible for the pathogenic capacity of LDN in SLE. Methods Neutrophils were isolated from donors treated with G‐CSF, and whole‐cell proteomic analysis was performed on LDN and normal‐density neutrophils. Results CD98 is significantly upregulated in LDN from G‐CSF donors and defines a subset of LDN within the blood of SLE patients. CD98 is a transmembrane protein that dimerises with L‐type amino acid transporters. We show that CD98 is responsible for the increased bioenergetic capacity of LDN. CD98 on LDN mediates the uptake of essential amino acids that are used by mitochondria to produce adenosine triphosphate, especially in the absence of glucose. Inhibition of CD98 reduces the metabolic flexibility of this population, which may limit their pathogenic capacity. CD98+ LDN produce more proinflammatory cytokines and chemokines than their normal density counterparts and are resistant to apoptosis, which may also contribute to tissue inflammation and end organ damage in SLE. Conclusions CD98 provides a phenotypic marker for LDN that facilitates identification of this population without density‐gradient separation and represents a novel therapeutic target to limit its pathogenic capacity.

A previous study investigated robustness of manual flash (MF) and robust optimized (RO) volumetric modulated arc therapy plans for breast radiotherapy based on five patients in 2020 and indicated that the RO was more robust than the MF, although the MF is still current standard practice. The purpose of this study was to compare their plan robustness in terms of dose variation to clinical target volume (CTV) and organs at risk (OARs) based on a larger sample size. This was a retrospective study involving 34 female patients. Their plan robustness was evaluated based on measured volume/dose difference between nominal and worst scenarios (ΔV/ΔD) for each CTV and OARs parameter, with a smaller difference representing greater robustness. Paired sample t-test was used to compare their robustness values. All parameters (except CTV ΔD98%) of the RO approach had smaller ΔV/ΔD values than those of the MF. Also, the RO approach had statistically significantly smaller ΔV/ΔD values (p < 0.001–0.012) for all CTV parameters except the CTV ΔV95% and ΔD98% and heart ΔDmean. This study’s results confirm that the RO approach was more robust than the MF in general. Although both techniques were able to generate clinically acceptable plans for breast radiotherapy, the RO could potentially improve workflow efficiency due to its simpler planning process.

The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has completely transformed the functioning of health care facilities. These changes have also significantly affected the work of dental health professionals. Due to the high infectivity of the virus and the fact that transmission occurs primarily through respiratory droplets, both dental patients and professionals are particularly exposed to coronavirus infection. In order to reduce the risk of COVID-19 transmission, a number of medical societies have issued recommendations for the provision of health care services during the pandemic. The article is based mainly on the recommendations of the Polish Ministry of Health, since WHO recommendations underline that following updated local guidelines is of highest importance. It is impossible to outline uniform guidelines for all dental specialists in the world, as the pandemic develops at differing rates in different countries and each country requires guidelines adapted to the current local epidemiological situation. The publication features an additional review of foreign literature and guidelines proposed by individual dental societies. The article presents an overview of guidelines related to the functioning of dental offices, dental treatment procedures and recommended personal protective equipment, as well as underlines the overriding principle that both physicians and dental practitioners should first and foremost take care of their own health in order to be able to protect others. Med Pr. 2021;72(5):561–8

Abstract Background Many patients with polymyositis (PM) or dermatomyositis (DM) have circulating myositis-specific antibodies (MSAs). Interstitial lung disease (ILD) is a common manifestation of PM/DM, and it can even precede the onset of characteristic muscle or skin manifestations. Furthermore, there appear to be some patients with ILD and circulating MSAs who do not develop muscle or skin disease even after prolonged follow-up. We sought to determine whether ILD is equally or more common than myositis or dermatitis at the time of initial detection of MSAs. Methods We identified all patients found to have circulating MSAs at our institution over a 4-year period and assessed for the presence of lung, muscle, and skin disease at the time of initial detection of MSAs. Among those found to have ILD, we compared demographic and clinical features, chest CT scan findings, and outcomes between those with PM/DM-associated ILD and those with ILD but no muscle or skin disease. Results A total of 3078 patients were tested for MSAs, and of these 40 were positive. Nine different MSAs were detected, with anti-histidyl tRNA synthetase (anti-Jo-1) being the most common (35% of MSAs). Among patients with positive MSAs, 86% were found to have ILD, compared to 39% and 28% with muscle and skin involvement, respectively (p

Abstract Background While well-conducted systematic reviews (SRs) can provide the best evidence on the potential effectiveness of acupuncture, limitations on the methodological rigour of SRs may impact the trustworthiness of their conclusions. This cross-sectional study aimed to evaluate the methodological quality of a representative sample of SRs on acupuncture effectiveness. Methods Cochrane Database of Systematic Reviews, MEDLINE, and EMBASE were searched for SRs focusing on the treatment effect of manual acupuncture or electro-acupuncture published during January 2018 and March 2020. Eligible SRs must contain at least one meta-analysis and be published in English language. Two independent reviewers extracted the bibliographical characteristics of the included SRs with a pre-designed questionnaire and appraised the methodological quality of the studies with the validated AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews 2). The associations between bibliographical characteristics and methodological quality ratings were explored using Kruskal-Wallis rank tests and Spearman’s rank correlation coefficients. Results A total of 106 SRs were appraised. Only one (0.9%) SR was of high overall methodological quality, zero (0%) was of moderate-quality, six (5.7%) and 99 (93.4%) were of low-quality and critically low-quality respectively. Among appraised SRs, only ten (9.4%) provided an a priori protocol, four (3.8%) conducted a comprehensive literature search, five (4.7%) provided a list of excluded studies, and six (5.7%) performed meta-analysis appropriately. Cochrane SRs, updated SRs, and SRs that did not search non-English databases had relatively higher overall quality. Conclusions Methodological quality of SRs on acupuncture is unsatisfactory. Future reviewers should improve critical methodological aspects of publishing protocols, performing comprehensive search, providing a list of excluded studies with justifications for exclusion, and conducting appropriate meta-analyses. These recommendations can be implemented via enhancing the technical competency of reviewers in SR methodology through established education approaches as well as quality gatekeeping by journal editors and reviewers. Finally, for evidence users, skills in SR critical appraisal remain to be essential as relevant evidence may not be available in pre-appraised formats.

MeCP2 mutations can cause Rett syndrome, a severe childhood neurological disorder. Here the authors show that MeCP2 mediates the higher-order assembly of a large splicing complex Rbfox/LASR, which is disrupted in the mouse models of Rett syndrome.

Globally, there are about a billion people comprising of about 95 million children who experience disability. The number of people in Africa living with disability is about 80 million people; out of which 10%−15% are children of school age. The causes of disability among these children include epilepsy, vision loss, or hearing loss, cerebral palsy, poliomyelitis, tetanus, cerebrospinal meningitis and malaria. However, these causes of disability are preventable and can be managed with proper care. The aim of this article is to propose the establishment of childhood disability clinics in Africa in order to help prevent or reduce the incidence/ prevalence of disability among children. Some of the mandates of the clinics will be to carry out routine assessment of children for disability, to provide education on disability and strategies for disability prevention to parents and caregivers, to promptly prevent and manage disability or its causes. However, establishing these clinics requires shared commitment of all the stakeholders.

Microsatellite instability (MSI) is a molecular signature of mismatch repair deficiency (dMMR), a predictive marker of immune checkpoint inhibitor therapy response. Despite its recognized pan-cancer value, most methods only support detection of this signature in colorectal cancer. In addition to the tissue-specific differences that impact the sensitivity of MSI detection in other tissues, the performance of most methods is also affected by patient ethnicity, tumor content, and other sample-specific properties. These limitations are particularly important when only tumor samples are available and restrict the performance and adoption of MSI testing. Here we introduce MSIdetect, a novel solution for NGS-based MSI detection. MSIdetect models the impact of indel burden and tumor content on read coverage at a set of homopolymer regions that we found are minimally impacted by sample-specific factors. We validated MSIdetect in 139 Formalin-Fixed Paraffin-Embedded (FFPE) clinical samples from colorectal and endometrial cancer as well as other more challenging tumor types, such as glioma or sebaceous adenoma or carcinoma. Based on analysis of these samples, MSIdetect displays 100% specificity and 96.3% sensitivity. Limit of detection analysis supports that MSIdetect is sensitive even in samples with relatively low tumor content and limited microsatellite instability. Finally, the results obtained using MSIdetect in tumor-only data correlate well (R=0.988) with what is obtained using tumor-normal matched pairs, demonstrating that the solution addresses the challenges posed by MSI detection from tumor-only data. The accuracy of MSI detection by MSIdetect in different cancer types coupled with the flexibility afforded by NGS-based testing will support the adoption of MSI testing in the clinical setting and increase the number of patients identified that are likely to benefit from immune checkpoint inhibitor therapy.

Cystic Fibrosis (CF) results from over 400 different disease-causing mutations in the CF Transmembrane Conductance Regulator (CFTR) gene. These CFTR mutations lead to numerous defects in CFTR protein function. A novel class of targeted therapies (CFTR modulators) have been developed that can restore defects in CFTR folding and gating. This study aimed to characterize the functional and structural defects of S945L-CFTR and interrogate the efficacy of modulators with two modes of action: gating potentiator [ivacaftor (IVA)] and folding corrector [tezacaftor (TEZ)]. The response to these modulators in vitro in airway differentiated cell models created from a participant with S945L/G542X-CFTR was correlated with in vivo clinical outcomes of that participant at least 12 months pre and post modulator therapy. In this participants' airway cell models, CFTR-mediated chloride transport was assessed via ion transport electrophysiology. Monotherapy with IVA or TEZ increased CFTR activity, albeit not reaching statistical significance. Combination therapy with TEZ/IVA significantly (p = 0.02) increased CFTR activity 1.62-fold above baseline. Assessment of CFTR expression and maturation via western blot validated the presence of mature, fully glycosylated CFTR, which increased 4.1-fold in TEZ/IVA-treated cells. The in vitro S945L-CFTR response to modulator correlated with an improvement in in vivo lung function (ppFEV1) from 77.19 in the 12 months pre TEZ/IVA to 80.79 in the 12 months post TEZ/IVA. The slope of decline in ppFEV1 significantly (p = 0.02) changed in the 24 months post TEZ/IVA, becoming positive. Furthermore, there was a significant improvement in clinical parameters and a fall in sweat chloride from 68 to 28 mmol/L. The mechanism of dysfunction of S945L-CFTR was elucidated by in silico molecular dynamics (MD) simulations. S945L-CFTR caused misfolding of transmembrane helix 8 and disruption of the R domain, a CFTR domain critical to channel gating. This study showed in vitro and in silico that S945L causes both folding and gating defects in CFTR and demonstrated in vitro and in vivo that TEZ/IVA is an efficacious modulator combination to address these defects. As such, we support the utility of patient-derived cell models and MD simulations in predicting and understanding the effect of modulators on CFTR function on an individualized basis.

BackgroundWhile the efficacy of immune checkpoint inhibitors (ICIs) is increasingly recognized in advanced gastric cancer (aGC), overall survival (OS) has not been consistently improved across the different randomized controlled trials (RCTs). This meta-analysis aimed to quantify the efficacy and safety of ICI and explore potential predictive tumor tissue biomarkers in aGC.MethodsA random-effect pairwise meta-analysis was used to evaluate the primary outcome of OS. Sensitivity analysis was performed to investigate the effects of ICIs on PD-L1 status, TMB, MSI-H, and the Asian patient population. We extracted the OS Kaplan–Meier curves from the included trials to compare the effect of PD-L1 status on response to ICIs using DigitizeIt 2.5 and Guyot’s algorithm.ResultsA pairwise meta-analysis of seven RCTs included in this study showed that ICIs were more effective than the comparator in improving OS (pooled HR: 0.84). We demonstrated that PD-1 ICIs were additive when combined with the comparator arm (pooled HR: 0.79). A sensitivity analysis showed that PD-1 ICIs were associated with better OS outcomes in the Asian patient population as monotherapy (pooled HR: 0.66) or in combination with chemotherapy (pooled HR: 0.83). We demonstrated that tumors with PD-L1 ≥1 (P = 0.02) and PD-L1 ≥10 (P = 0.006) derived OS benefit from ICI monotherapy. Equally, MSI-H (P

Advances in Next Generation Sequencing (NGS) technologies have enabled the accurate detection and quantification of circulating tumor-derived (ct)DNA in most gastrointestinal (GI) cancers. The prognostic and predictive utility of ctDNA in patiets with different stages of colorectal (CRC), gastro-esophageal (GEC) and pancreaticobiliary cancers (PBC) are currently under active investigation. The most mature clinical data to date are derived from studies in the prognostic utility of personalized ctDNA-based NGS assays in the detection of minimal residual disease (MRD) and early recurrence after surgery in CRC and other GI cancers. These findings are being validated in several prospective studies which are designed to test if ctDNA could outperform conventional approaches in guiding adjuvant chemotherapy, and in post-operative surveillance in some GI cancers. Several adaptive studies using ctDNA as a screening platform are also being used to identify patients with actionable genomic alterations for clinical trials of targeted therapies. In the palliative setting, ctDNA monitoring during treatment has shown promise in the detection and tracking of clonal variants associated with acquired resistance to targeted therapies and immune-checkpoint inhibitors (ICI). Moreover, ctDNA may help to guide the therapeutic re-challenge of targeted therapies in patients who have prior exposure to such treatment. This review will examine the most updated research findings on ctDNA as a biomarker in CRC, GEC and PBCs. It aims to provide insights into how the unique strengths of this biomarker could be optimally leveraged in improving the management of these GI cancers.

The role of amphiphilicity in polysaccharide-based superabsorbent polymers is paramount in determining material properties. While the performance of freeze-dried polymers is improved by maximizing hydrophilicity, this may not be the case for evaporative-dried polymers. In this study, four diglycidyl ether crosslinkers, with varying chain lengths and amphiphilicities, were used to synthesize a series of evaporative-dried carboxymethyl cellulose-based superabsorbent films. Through structural and physiochemical characterization, the effect of amphiphilicity on swelling and mechanical properties was established. Contrary to freeze-dried polymers, it was found that the addition of hydrophobic moieties by crosslinking with novel poly(propylene glycol) diglycidyl ether crosslinkers increased the swelling performance of evaporative-dried polymers. By adding hydrophobic functional groups, a reduction in inter-chain hydrogen bonding occurs during evaporative-drying, reducing the degree of hornification and decreasing the entropy requirement for water uptake. By optimizing the amphiphilic ratio, a poly(propylene glycol)-carboxymethyl cellulose polymer achieved a swelling capacity of 182 g/g which is competitive with freeze-dried cellulose-based hydrogels. The mechanical properties of these films improved with the addition of the crosslinkers, with glycerol-carboxymethyl cellulose polymers achieving a tensile strength of 39 MPa and a Young’s Modulus of 4.0 GPa, indicating their potential application as low-cost, swellable films.

Imitation is an important daily activity involved in social interactions, motor learning, and is commonly used for rehabilitation after stroke. Moreover, deficits in imitation of novel movements commonly occur after left hemisphere stroke (LCVA) in the syndrome of limb apraxia. In the current study, we used a novel virtual reality (VR) imitation paradigm to assess two factors that have remained underexplored in novel movement imitation: the imitation of complex, dynamic full-arm movements, and the effect of spatial perspective. VR holds promise as a tool for a number of clinical assessments and treatments, but has very rarely been studied in the context of imitation or diagnosis of apraxia. Thirty participants (18 with LCVA and 12 age- and education-matched controls) wore a VR headset and observed and imitated an instructor avatar demonstrating arm movements. Three spatial perspectives were examined within-subjects: first-person, third-person mirror, and third-person anatomical. Movements of the ipsilesional (left) arm were recorded and qualitatively coded for accuracy compared to the instructor avatar. Participants also completed embodiment questionnaires, a measure of limb apraxia (imitation of video-recorded meaningless movements), and three computerized background tasks that were hypothesized to evoke some of the same processing requirements of each of the three perspective conditions: a block-matching task, a block-mirroring task, and a mental rotation task. Imitation accuracy was highest in the first-person perspective, consistent with predictions, but did not differ between third-person mirror and anatomical. Surprisingly, patients and controls performed similarly on the imitation task for all spatial perspectives, with overall modest accuracy in both groups, and both patients and controls felt a moderate level of embodiment of their own avatar. Higher imitation accuracy related to quicker block-matching reaction times and higher mental rotation accuracy, regardless of perspective, but was unrelated to imitation of video-recorded meaningless movements. In sum, virtual reality provides advantages in terms of experimental manipulation and control but may present challenges in detecting clinical imitation deficits (limb apraxia).

In the field of wall painting conservation, photogrammetric surveys are an increasingly common documentation tool. The outputs from these surveys, including captured images, orthophotos, and three-dimensional models, are used by conservators to monitor and record condition phenomena and conservation treatments. To serve these conservation needs, the outputs should have visual fidelity, meaning they are a close representation of the subject based on their spatial resolution, overall focus, even lighting and color accuracy. However, wall paintings present unique technical challenges for photogrammetry considering their often large scale, irregular topography, range of surface attributes, and access issues. As a documentation technique more commonly applied to capture the geometry of buildings and objects, using photogrammetry to record both the topography and fine surface details of a wall painting requires thorough planning. This paper examines specific challenges in documenting wall paintings and how collaboration between conservators and heritage-recording specialists has improved practice and maximized the value of photogrammetric surveys for conservation.

Abstract Background Interest in the application of machine learning (ML) to the design, conduct, and analysis of clinical trials has grown, but the evidence base for such applications has not been surveyed. This manuscript reviews the proceedings of a multi-stakeholder conference to discuss the current and future state of ML for clinical research. Key areas of clinical trial methodology in which ML holds particular promise and priority areas for further investigation are presented alongside a narrative review of evidence supporting the use of ML across the clinical trial spectrum. Results Conference attendees included stakeholders, such as biomedical and ML researchers, representatives from the US Food and Drug Administration (FDA), artificial intelligence technology and data analytics companies, non-profit organizations, patient advocacy groups, and pharmaceutical companies. ML contributions to clinical research were highlighted in the pre-trial phase, cohort selection and participant management, and data collection and analysis. A particular focus was paid to the operational and philosophical barriers to ML in clinical research. Peer-reviewed evidence was noted to be lacking in several areas. Conclusions ML holds great promise for improving the efficiency and quality of clinical research, but substantial barriers remain, the surmounting of which will require addressing significant gaps in evidence.

Abstract With the onset and increasing frequency of multiple disturbances, the recovery potential of critical ecosystem-building species and their mutual symbionts is threatened. Similar effects to both hosts and their symbionts following disturbances have been assumed. However, we report unequal declines between hosts and symbionts throughout multiple climate-driven disturbances in reef-building Acropora corals and cryptobenthic coral-dwelling Gobiodon gobies. Communities were surveyed before and after consecutive cyclones (2014, 2015) and heatwaves (2016, 2017). After cyclones, coral diameter and goby group size (i.e., the number of gobies within each coral) decreased similarly by 28–30%. After heatwave-induced bleaching, coral diameter decreased substantially (47%) and gobies mostly inhabited corals singly. Despite several coral species persisting after bleaching, all goby species declined, leaving 78% of corals uninhabited. These findings suggest that gobies, which are important mutual symbionts for corals, are unable to cope with consecutive disturbances. This disproportionate decline could lead to ecosystem-level disruptions through loss of key symbiont services to corals.

Abstract Background Chinese medicine (CM) modalities, including acupuncture and Chinese herbal medicine (CHM), are popular palliative interventions among patients with cancer, but further clinical research is required to assess their effectiveness and safety. Objective To prioritize top ten important CM clinical research questions from patients with cancer, cancer survivors and caregivers’ perspectives via a face‐to‐face prioritization workshop in Hong Kong. Methods A list of 25 CM clinical research questions for cancer palliative care, which were identified from existing systematic reviews (SRs) and overview of SRs, was presented to 17 participants (patients with cancer [n = 5], cancer survivors [n = 6] and caregivers [n = 6]). The participants were then invited to establish consensus on prioritizing top ten research questions. Results Among the top ten priorities, five (50%) focused on acupuncture and related therapies, while five (50%) were on CHM. The three most important research priorities were (i) manual acupuncture plus opioids for relieving pain; (ii) CHM for improving quality of life among patients receiving chemotherapy; and (iii) concurrent use of CHM plus loperamide for reducing stomatitis. Conclusion The top ten participant‐endorsed CM clinical research priorities for cancer palliative care can guide local researchers on future direction. They can also inform local research funders on patient‐centred allocation of limited funding. Under limited research funding, the most important co‐prioritized research question from professional and patient perspectives may be addressed first. Patient or Public Contribution Patients with cancer, cancer survivors and caregivers participated in conduct of the study to prioritize CM clinical research questions.

The engineering of 5′ UTRs that modulate protein expression remains a great challenge. Here we leverage synthetic biology and computational design to develop a high-throughput strategy to design, screen, and optimize 5′ UTRs that enhance protein expression for non-viral gene therapies.

Background/Objective: To date, a validated Chinese (Mandarin) six-minute walk test (6MWT) translated instruction is not available. Translation of the Chinese 6MWT instruction is done in an ad hoc manner within the Chinese-speaking populations. This study aimed to develop a set of valid and reliable Chinese (Mandarin) instructions of the 6MWT. Methods: Translation was performed from the original English instruction via the recommended “Process of translation and adaptation of instruments” by the World Health Organization to generate the Chinese instructions. The Chinese instructions were tested with 52 healthy adult participants for its validity. Each participant underwent three 6MWTs and a cardiopulmonary exercise test. Randomization allowed participants to undergo the walk test in both the original English and the new Chinese instructions. Face and content validity, intra-rater and inter-rater reliability of the Chinese instructions of the 6MWT were established through the translation process. Criterion validity was established by analyzing the results of the 6MWT and cardiopulmonary exercise test. Results: Intraclass correlation coefficient for inter-rater reliability was excellent (ICC=0.999, 95% confidence interval=0.996–1.000). Similarly, the intra-rater reliability across the three raters was high (R1: ICC=0.996, 95% confidence interval (CI)=0.812–1.000; R2: ICC=1.000, 95% CI=0.994–1.000; R3: ICC=1.000, 95% CI=0.998–1.000). The 6-min walk distances collected from the Chinese and English instructed trials correlated positively with the maximal oxygen consumption (r=0.315, p=0.023; r=0.309, p=0.026). Conclusion: This is the first study to develop and validate the Chinese (Mandarin) instructions of the 6MWT, and the translation is as reliable and valid as the original English instructions.

Abstract People with obstructive sleep apnea (OSA) often have psychological symptoms including depression and anxiety, which are commonly treated with anti-depression or anti-anxiety interventions. Psychological stress is a related symptom with different intervention targets that may also improve mental state, but this symptom is not well characterized in OSA. We therefore aimed to describe stress in relation to other psychological symptoms. We performed a prospective cross-sectional study of 103 people, 44 untreated OSA (mean ± s.d. age: 51.2 ± 13.9 years, female/male 13/31) and 57 healthy control participants (age: 46.3 ± 13.8 years, female/male 34/23). We measured stress (Perceived Stress Scale; PSS), excessive daytime sleepiness (Epworth Sleepiness Scale; ESS), depressive symptoms (Patient Health Questionnaire; PHQ-9), and anxiety symptoms (General Anxiety Disorder; GAD-7). We compared group means with independent samples t-tests and calculated correlations between variables. Mean symptom levels were higher in OSA than control, including PSS (mean ± s.d.: OSA = 15.3 ± 6.9, control = 11.4 ± 5.5; P = 0.002), GAD-7 (OSA = 4.8 ± 5.0, control = 2.1 ± 3.9; P = 0.02), PHQ-9 (OSA = 6.9 ± 6.1, control = 2.6 ± 3.8; P = 0.003) and ESS (OSA = 8.1 ± 5.3, control = 5.0 ± 3.3; P = 0.03). Similar OSA-vs-control differences appeared in males, but females only showed significant differences in PHQ-9 and ESS, not PSS or GAD-7. PSS correlated strongly with GAD-7 and PHQ-9 across groups (R = 0.62–0.89), and moderately with ESS. Perceived stress is high in OSA, and closely related to anxiety and depressive symptoms. The findings support testing stress reduction in OSA.

Abstract Background There is a paucity of studies describing the incidence and risk factors for late‐occurring (≥1 year) infectious complications in contemporary survivors of hematopoietic cell transplantation (HCT). Methods This was a retrospective cohort study of 641 1‐year survivors of HCT, transplanted between 2010 and 2013 as adults, and in remission from their primary disease. Standardized definitions were used to characterize viral, fungal, and bacterial infections. Cumulative incidence of infections was calculated, with relapse/progression considered as a competing risk event. Fine‐Gray subdistribution hazard ratio estimates and 95% confidence intervals (CI) were obtained, adjusted for relevant covariates. Results Median age at HCT was 55.2 years (range 18.1–78.1 years); 54.0% were survivors of allogeneic HCT. The 5‐year cumulative incidence of a late‐occurring infection for the entire cohort was 31.6%; the incidence of polymicrobial (≥2) infections was 10.1%. In survivors who developed at least one infection, the 5‐year incidence of a subsequent infection was 45.3%. Among allogeneic HCT survivors, patients with acute lymphoblastic (HR = 1.82 95% CI [1.12–2.96]) or myeloid (HR = 1.50 95% CI [1.02–2.20]) leukemia, and those with an elevated HCT‐Comorbidity index score (HR = 1.09 95% CI [1.01–1.17]) were more likely to develop late‐occurring infections; there was an incremental risk associated with severity of graft versus host disease (GVHD) at 1‐year post‐HCT (mild: HR = 2.17, 95% CI [1.09–4.33]; moderate/severe: HR = 3.78, 95% CI [1.90–7.53]; reference: no GVHD). Conclusions The burden of late‐occurring infections in HCT survivors is substantial, and there are important patient‐ and HCT‐related modifiers of risk over time. These findings may help guide personalized screening and prevention strategies to improve outcomes after HCT.

Abstract The high-energy release of plutonium (Pu) and uranium (U) during the Maralinga nuclear trials (1955–1963) in Australia, designed to simulate high temperature, non-critical nuclear accidents, resulted in wide dispersion µm-sized, radioactive, Pu–U-bearing ‘hot’ particles that persist in soils. By combining non-destructive, multi-technique synchrotron-based micro-characterization with the first nano-scale imagining of the composition and textures of six Maralinga particles, we find that all particles display intricate physical and chemical make-ups consistent with formation via condensation and cooling of polymetallic melts (immiscible Fe–Al–Pu–U; and Pb ± Pu–U) within the detonation plumes. Plutonium and U are present predominantly in micro- to nano-particulate forms, and most hot particles contain low valence Pu–U–C compounds; these chemically reactive phases are protected by their inclusion in metallic alloys. Plutonium reworking was observed within an oxidised rim in a Pb-rich particle; however overall Pu remained immobile in the studied particles, while small-scale oxidation and mobility of U is widespread. It is notoriously difficult to predict the long-term environmental behaviour of hot particles. Nano-scale characterization of the hot particles suggests that long-term, slow release of Pu from the hot particles may take place via a range of chemical and physical processes, likely contributing to on-going Pu uptake by wildlife at Maralinga.