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Background: Development of secondary esophageal cancer after hematopoietic stem cell transplantation has been described; however, there is little consensus on treatment and surveillance for these patients. The objective of this study was to describe our experience treating patients with secondary esophageal cancer. Methods: A retrospective chart review of prospectively collected data was performed to identify patients who underwent hematopoietic stem cell transplantation from 1997 to 2012 and in whom esophageal cancer developed later. Results: A total of 5066 patients underwent hematopoietic stem cell transplantation, and esophageal cancer developed in 11 (0.2%) of these patients. The median time to diagnosis of esophageal cancer after hematopoietic stem cell transplantation was 11 years (interquartile range, 8.5 to 14 years). Four patients received a diagnosis of stage III or IV disease. Seven patients underwent esophagectomy, 6 patients after neoadjuvant treatment. Three patients experienced adverse events postoperatively, all grades II and IIIa. Two surgical patients died of distant recurrence 2 years and 3 years, respectively, after their esophageal cancer diagnosis. The other 5 surgical patients have not experienced recurrence of their esophageal cancer. Conclusions: For patients with secondary esophageal cancer, esophagectomy after neoadjuvant treatment has acceptable morbidity and may be a viable option for this cohort.

Abstract Background Enterovirus 71 (EV-A71) causes Hand, Foot and Mouth Disease (HFMD) in children and has been associated with neurological complications. The molecular mechanisms involved in EV-A71 pathogenesis have remained elusive. Methods A siRNA screen in EV-A71 infected-motor neurons was performed targeting 112 genes involved in intracellular membrane trafficking, followed by validation of the top four hits using deconvoluted siRNA. Downstream approaches including viral entry by-pass, intracellular viral genome quantification by qPCR, Western blot analyses, and Luciferase reporter assays allowed determine the stage of the infection cycle the top candidate, RAB11A was involved in. Proximity ligation assay, co-immunoprecipitation and multiplex confocal imaging were employed to study interactions between viral components and RAB11A. Dominant negative and constitutively active RAB11A constructs were used to determine the importance of the protein’s GTPase activity during EV-A71 infection. Mass spectrometry and protein interaction analyses were employed for the identification of RAB11A’s host interacting partners during infection. Results Small GTPase RAB11A was identified as a novel pro-viral host factor during EV-A71 infection. RAB11A and RAB11B isoforms were interchangeably exploited by strains from major EV-A71 genogroups and by Coxsackievirus A16, another major causative agent of HFMD. We showed that RAB11A was not involved in viral entry, IRES-mediated protein translation, viral genome replication, and virus exit. RAB11A co-localized with replication organelles where it interacted with structural and non-structural viral components. Over-expression of dominant negative (S25N; GDP-bound) and constitutively active (Q70L; GTP-bound) RAB11A mutants had no effect on EV-A71 infection outcome, ruling out RAB11A’s involvement in intracellular trafficking of viral or host components. Instead, decreased ratio of intracellular mature viral particles to viral RNA copies and increased VP0:VP2 ratio in siRAB11-treated cells supported a role in provirion maturation hallmarked by VP0 cleavage into VP2 and VP4. Finally, chaperones, not trafficking and transporter proteins, were found to be RAB11A’s top interacting partners during EV-A71 infection. Among which, CCT8 subunit from the chaperone complex TRiC/CCT was further validated and shown to interact with viral structural proteins specifically, representing yet another novel pro-viral host factor during EV-A71 infection. Conclusions This study describes a novel, unconventional role for RAB11A during viral infection where it participates in the complex process of virus morphogenesis by recruiting essential chaperone proteins.

Summary: RNA degradation is a central process required for transcriptional regulation. Eventually, this process degrades diribonucleotides into mononucleotides by specific diribonucleases. In Escherichia coli, oligoribonuclease (Orn) serves this function and is unique as the only essential exoribonuclease. Yet, related organisms, such as Pseudomonas aeruginosa, display a growth defect but are viable without Orn, contesting its essentiality. Here, we take advantage of P. aeruginosa orn mutants to screen for suppressors that restore colony morphology and identified yciV. Purified YciV (RNase AM) exhibits diribonuclease activity. While RNase AM is present in all γ-proteobacteria, phylogenetic analysis reveals differences that map to the active site. RNase AMPa expression in E. coli eliminates the necessity of orn. Together, these results show that diribonuclease activity prevents toxic diribonucleotide accumulation in γ-proteobacteria, suggesting that diribonucleotides may be utilized to monitor RNA degradation efficacy. Because higher eukaryotes encode Orn, these observations indicate a conserved mechanism for monitoring RNA degradation.

Abstract Large population-based cohort studies utilizing device-based measures of physical activity are crucial to close important research gaps regarding the potential protective effects of physical activity on chronic diseases. The present study details the quality control processes and the derivation of physical activity metrics from 100 Hz accelerometer data collected in the German National Cohort (NAKO). During the 2014 to 2019 baseline assessment, a subsample of NAKO participants wore a triaxial ActiGraph accelerometer on their right hip for seven consecutive days. Auto-calibration, signal feature calculations including Euclidean Norm Minus One (ENMO) and Mean Amplitude Deviation (MAD), identification of non-wear time, and imputation, were conducted using the R package GGIR version 2.10-3. A total of 73,334 participants contributed data for accelerometry analysis, of whom 63,236 provided valid data. The average ENMO was 11.7 ± 3.7 mg (milli gravitational acceleration) and the average MAD was 19.9 ± 6.1 mg. Notably, acceleration summary metrics were higher in men than women and diminished with increasing age. Work generated in the present study will facilitate harmonized analysis, reproducibility, and utilization of NAKO accelerometry data. The NAKO accelerometry dataset represents a valuable asset for physical activity research and will be accessible through a specified application process.

Abstract Fractional charges are one of the wonders of the fractional quantum Hall effect. Such objects are also anticipated in two-dimensional hexagonal lattices under time reversal symmetry—emerging as bound states of a rotating bond texture called a Kekulé vortex. However, the physical mechanisms inducing such topological defects remain elusive, preventing experimental realization. Here, we report the observation of Kekulé vortices in the local density of states of graphene under time reversal symmetry. The vortices result from intervalley scattering on chemisorbed hydrogen adatoms. We uncover that their 2π winding is reminiscent of the Berry phase π of the massless Dirac electrons. We can also induce a Kekulé pattern without vortices by creating point scatterers such as divacancies, which break different point symmetries. Our local-probe study thus confirms point defects as versatile building blocks for Kekulé engineering of graphene’s electronic structure.

Abstract Horizontal gene transfer (HGT) and gene duplication are often considered as separate mechanisms driving the evolution of new functions. However, the mobile genetic elements (MGEs) implicated in HGT can copy themselves, so positive selection on MGEs could drive gene duplications. Here, we use a combination of modeling and experimental evolution to examine this hypothesis and use long-read genome sequences of tens of thousands of bacterial isolates to examine its generality in nature. Modeling and experiments show that antibiotic selection can drive the evolution of duplicated antibiotic resistance genes (ARGs) through MGE transposition. A key implication is that duplicated ARGs should be enriched in environments associated with antibiotic use. To test this, we examined the distribution of duplicated ARGs in 18,938 complete bacterial genomes with ecological metadata. Duplicated ARGs are highly enriched in bacteria isolated from humans and livestock. Duplicated ARGs are further enriched in an independent set of 321 antibiotic-resistant clinical isolates. Our findings indicate that duplicated genes often encode functions undergoing positive selection and horizontal gene transfer in microbial communities.

Intravesical therapy (IVT) is the standard of care to decrease risk of recurrence and progression for high‐grade nonmuscle‐invasive bladder cancer. However, post‐IVT recurrence remains common and the ability to risk‐stratify patients before or after IVT is limited. In this prospectively designed and accrued cohort study, we examine the utility of urinary comprehensive genomic profiling (uCGP) for predicting recurrence risk following transurethral resection of bladder tumor (TURBT) and evaluating longitudinal IVT response. Urine was collected before and after IVT instillation and uCGP testing was done using the UroAmp™ platform. Baseline uCGP following TURBT identified patients with high (61%) and low (39%) recurrence risk. At 24 months, recurrence‐free survival (RFS) was 100% for low‐risk and 45% for high‐risk patients with a hazard ratio (HR) of 9.3. Longitudinal uCGP classified patients as minimal residual disease (MRD) Negative, IVT Responder, or IVT Refractory with 24‐month RFS of 100%, 50%, and 32%, respectively. Compared with MRD Negative patients, IVT Refractory patients had a HR of 10.5. Collectively, uCGP enables noninvasive risk assessment of patients following TURBT and induction IVT. uCGP could inform surveillance cystoscopy schedules and identify high‐risk patients in need of additional therapy.

BackgroundThrombotic microangiopathy (TMA) associated with hematopoietic stem cell transplantation (HSCT-TMA) is a serious post-transplant complication. Diagnosis is difficult due to overlapping symptoms with other conditions and a lack of universally adopted diagnostic criteria.MethodsThis retrospective, observational study investigated HSCT-TMA incidence between July 2009–August 2020 using the TriNetX US Electronic Medical Record database. Patients who underwent autologous or allogeneic HSCT procedures and had conditioning agents were stratified as follows: confirmed TMA (≥1 hemolytic uremic syndrome (HUS)/TMA diagnosis code), suspected TMA [no HUS/TMA code but met modified published Cho (adult) or Jodele (pediatric) diagnostic criteria (further information in main text), and non-TMA (met neither criteria). Baseline demographics, clinical characteristics and outcomes, and all-cause unadjusted healthcare resource utilization (HCRU) within 12-months of HSCT, were assessed. Statistical comparisons were against the non-TMA cohort (p

TIN-X (Target Importance and Novelty eXplorer) is an interactive visualization tool for illuminating associations between diseases and potential drug targets and is publicly available at newdrugtargets.org. TIN-X uses natural language processing to identify disease and protein mentions within PubMed content using previously published tools for named entity recognition (NER) of gene/protein and disease names. Target data is obtained from the Target Central Resource Database (TCRD). Two important metrics, novelty and importance, are computed from this data and when plotted as log(importance) vs. log(novelty), aid the user in visually exploring the novelty of drug targets and their associated importance to diseases. TIN-X Version 3.0 has been significantly improved with an expanded dataset, modernized architecture including a REST API, and an improved user interface (UI). The dataset has been expanded to include not only PubMed publication titles and abstracts, but also full-text articles when available. This results in approximately 9-fold more target/disease associations compared to previous versions of TIN-X. Additionally, the TIN-X database containing this expanded dataset is now hosted in the cloud via Amazon RDS. Recent enhancements to the UI focuses on making it more intuitive for users to find diseases or drug targets of interest while providing a new, sortable table-view mode to accompany the existing plot-view mode. UI improvements also help the user browse the associated PubMed publications to explore and understand the basis of TIN-X’s predicted association between a specific disease and a target of interest. While implementing these upgrades, computational resources are balanced between the webserver and the user’s web browser to achieve adequate performance while accommodating the expanded dataset. Together, these advances aim to extend the duration that users can benefit from TIN-X while providing both an expanded dataset and new features that researchers can use to better illuminate understudied proteins.

Abstract Background Continuous loss of muscle mass and strength are the consequences of the ageing process, which increase the risk of falls among older people. Falls can lead to severe consequences such as bone fractures and hampered physical and psychological well-being. Regular exercise is the key to reversing muscle atrophy and relieving sarcopenia. However, the frailty of older people and the recent COVID-19 pandemic may affect their confidence to leave home to attend classes in the community. A feasible and effective alternative should be explored. Methods The primary objective is to evaluate the effectiveness of tele-exercise (TE) in relation to physical functioning and exercise adherence among community-dwelling older people at risk of falls in comparison with a community-based group (CB). The secondary objective includes evaluating older people’s experience with tele-exercise, emphasizing their psychological welfare, social well-being, and acceptance of the telehealth approach. The design, conduct, and report follow the SPIRIT guidelines (Standard Protocol Items: recommended items to address in a Clinical Trial Protocol and Related Documents). Older people will be recruited from 10 local community centres in Hong Kong and randomly allocated into two groups. All participants will attend the exercise training 3 days per week for 3 months but the mode of delivery will differ, either online as the tele-exercise group (TE) or face-to-face as the community-based group (CB). The outcome measures include muscle strength, physical function, exercise adherence and dropout rate, psychological and social well-being will be assessed at the baseline, and the 3rd, 6th and 12th month. Some participants will be invited to attend focus group interviews to evaluate their overall experience of the tele-exercise training. Discussion Tele-exercise reduces the barriers to exercise, such as time constraints, inaccessibility to facilities, and the fear of frail older people leaving their homes. Promoting an online home-based exercise programme for older people can encourage them to engage in regular physical activity and increase their exercise adherence even when remaining at home. The use of telehealth can potentially result in savings in cost and time. The final findings will provide insights on delivering exercise via telehealth to older people and propose an exercise delivery and maintenance model for future practice. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/hvshowprojectEN.html?id=219002&v=1.1 ), registration number: ChiCTR2200063370. Registered on 5 September 2022.

Objectives We identified profiles of wake-time movement behaviours (sedentary behaviours, light intensity physical activity and moderate-to-vigorous physical activity) based on accelerometer-derived features among older adults and then examined their association with all-cause mortality.Methods Data were drawn from a prospective cohort of 3991 Whitehall II accelerometer substudy participants aged 60–83 years in 2012–2013. Daily movement behaviour profiles were identified using k-means cluster analysis based on 13 accelerometer-assessed features characterising total duration, frequency, bout duration, timing and activity intensity distribution of movement behaviour. Cox regression models were used to assess the association between derived profiles and mortality risk.Results Over a mean follow-up of 8.1 (SD 1.3) years, a total of 410 deaths were recorded. Five distinct profiles were identified and labelled as ‘active’ (healthiest), ‘active sitters’, ‘light movers’, ‘prolonged sitters’, and ‘most sedentary’ (most deleterious). In model adjusted for sociodemographic, lifestyle, and health-related factors, compared with the ‘active’ profile, ‘active sitters’ (HR 1.57, 95% CI 1.01 to 2.44), ‘light movers’ (HR 1.75, 95% CI 1.17 to 2.63), ‘prolonged sitters’ (HR 1.67, 95% CI 1.11 to 2.51), ‘most sedentary’ (HR 3.25, 95% CI 2.10 to 5.02) profiles were all associated with a higher risk of mortality.Conclusion Given the threefold higher mortality risk among those with a ‘most sedentary’ profile, public health interventions may target this group wherein any improvement in physical activity and sedentary behaviour might be beneficial.

Acute Myeloid Leukemia (AML) is the prototype of cancer genomics as it was the first published cancer genome. Large-scale next generation/massively parallel sequencing efforts have identified recurrent alterations that inform prognosis and have guided the development of targeted therapies. Despite changes in the frontline and relapsed standard of care stemming from the success of small molecules targeting FLT3, IDH1/2, and apoptotic pathways, allogeneic stem cell transplantation (alloHSCT) and the resulting graft-versus-leukemia (GVL) effect remains the only curative path for most patients. Advances in conditioning regimens, graft-vs-host disease prophylaxis, anti-infective agents, and supportive care have made this modality feasible, reducing transplant related mortality even among patients with advanced age or medical comorbidities. As such, relapse has emerged now as the most common cause of transplant failure. Relapse may occur after alloHSCT because residual disease clones persist after transplant, and develop immune escape from GVL, or such clones may proliferate rapidly early after alloHSCT, and outpace donor immune reconstitution, leading to relapse before any GVL effect could set in. To address this issue, genomically informed therapies are increasingly being incorporated into pre-transplant conditioning, or as post-transplant maintenance or pre-emptive therapy in the setting of mixed/falling donor chimerism or persistent detectable measurable residual disease (MRD). There is an urgent need to better understand how these emerging therapies modulate the two sides of the GVHD vs. GVL coin: 1) how molecularly or immunologically targeted therapies affect engraftment, GVHD potential, and function of the donor graft and 2) how these therapies affect the immunogenicity and sensitivity of leukemic clones to the GVL effect. By maximizing the synergistic action of molecularly targeted agents, immunomodulating agents, conventional chemotherapy, and the GVL effect, there is hope for improving outcomes for patients with this often-devastating disease.

Management of cutaneous malignancies can be particularly challenging when they are located in the periocular region. The standard of care for localized disease is complete surgical excision, but this may not be possible without significant disruption to visual structures and facial appearance. Definitive radiation may be an option for some patients who cannot or do not wish to undergo surgery. Advances in systemic treatment options for locally advanced and metastatic skin cancers in the past 10 years have prompted investigation into neoadjuvant treatment of periocular cancers. The use of chemotherapy, immune checkpoint inhibitors, and targeted therapies have all been reported with varying degrees of success. For many patients, targeted therapies or immune checkpoint inhibitors should be considered depending on the cancer type, symptoms, and goals with the input of a multidisciplinary cancer care team. In this article, we systematically review the latest updates in surgical, radiotherapeutic, and medical management of periocular malignancies.

Abstract Background Health literacy is essential in the promotion of healthy lifestyle habits and chronic disease prevention. Objective To assess the health literacy level among Hong Kong adolescents; to evaluate the association between access of an online health information platform (GoSmart Channel) and health literacy level; and to examine the association between health literacy level and various unhealthy behaviours. Design This study recruited students from 10 local secondary schools in Hong Kong to assess the health literacy level among adolescents. Settings and Participants Participants were required to complete a self‐administered questionnaire on health behaviours and health literacy using the Health Literacy Measure for Adolescents (HELMA). Main Outcome Measure Data were analysed using descriptive statistics and multivariate regression modelling. Results A total of 777 responses were collected. Overall, most (74.4%) of the adolescents in Hong Kong have limited health literacy (HELMA score

The COVID-19 pandemic remains a serious public health problem globally. During winter influenza seasons, more aggressive SARS-CoV-2 infections and fatalities have been documented, indicating that influenza co-infections may significantly impact the disease outcome of COVID-19. Both influenza and SARS-CoV-2 viruses share many similarities in their transmission and their cellular tropism for replication in the human respiratory tract. However, the complex intricacies and multi-faceted dynamics of how the two pathogens interact to ensure their survival in the same lung microenvironment are still unclear. In addition, clinical studies on influenza co-infections in COVID-19 patients do not provide conclusive evidence of how influenza co-infection mechanistically modifies disease outcomes of COVID-19. This review discusses various viral as well as host factors that potentially influence the survival or synergism of these two respiratory pathogens in the infected lung microenvironment.

Introduction and aim of studyMetachronous upper tract urothelial carcinoma (UTUC) is a rare yet aggressive malignancy that is often multifocal and invasive at the time of diagnosis. Unfortunately, the rarity of metachronous UTUC results in a paucity of targeted data, as current literature and clinical management of this tumor is largely extrapolated from that of bladder cancer. Urinary comprehensive genomic profiling with the UroAmp assay identifies six general classes of tumor-mutations present in the urine and thus, may aid in detecting UTUC when the limitations of current tools impede definitive diagnosis. We describe the utility of urinary comprehensive genomic profiling in confirming the provider’s suspicion for metachronous UTUC and recommending radical nephroureterectomy.Patient caseA 68-year-old male with a history of recurrent carcinoma in situ (CIS) of the bladder presented to the urology clinic in 2022 for continued surveillance. Abnormal soft tissue thickening surrounding the proximal right ureter, revealed on computerized tomography urography, prompted further evaluation. Selective right upper tract cytology was indeterminate, and urinary comprehensive genomic profiling was ordered to adjudicate. No tumor was visualized on ureteroscopy however the cytologic brush biopsy of the renal pelvis and proximal ureter were positive for urothelial carcinoma (UC) and/or CIS. UroAmp testing identified genomic features associated with high-grade UC, risk of invasion, and a high genomic disease burden.ResultsThe patient underwent a right kidney and ureter nephroureterectomy in September 2022. Surgical pathology confirmed non-invasive multifocal urothelial CIS. A postoperative urinary comprehensive genomic profiling in February and May of 2023 detected no evidence of residual disease, consistent with complete resection of the tumor. The provider will continue intensive urinary comprehensive genomic profile monitoring coupled with conventional surveillance.ConclusionUrinary measurement of mutated UC genes correlate with disease burden, pathologic grade, and invasion risk and provide clinical utility when reliance on visual confirmation and cytology were not definitive or feasible.

Abstract Objective High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. Research design and methods HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. Results Over median (IQR) 5.2 (5.0–5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate

Objective Hip fractures are associated with significant morbidity and mortality. Ultrasound-guided peripheral nerve blocks are a safe method to manage pain and decrease opioid usage. The pericapsular nerve group (PENG) block is a novel, potentially superior block because of its motor-sparing effects. Through training, simulation, and supervision, we aim to determine whether it is feasible to perform the PENG block in the emergency department. Methods Phase 1 consisted of emergency physicians attending a workshop to demonstrate ultrasound proficiency, anatomical understanding, and procedural competency using a low-fidelity model. Phase 2 consisted of a prospective, observational, feasibility study of 10 patients with hip fractures. Pain scores, side effects, and opioid usage data were collected. Results The median pain score at time 0 (time of block) was 9 (interquartile range [IQR], 6.5–9). The median pain score at 30 minutes was 4 (IQR, 2.0–6.8) and 3.5 (IQR, 1.0–4.8) at 4 hours. All 10 patients required narcotics prior to the initiation of the PENG block with a median dosage of 6.25 morphine milligram equivalents (MME; IQR, 4.25–7.38 MME). After the PENG block, only 30% of the patients required further narcotics with a median dosage of 0 MME (IQR, 0–0.6 MME) until operative fixation. Conclusion In this feasibility study, PENG blocks were safely administered by trained emergency physicians under supervision. We demonstrated data suggesting a trend of pain relief and decreased opiate requirements, and further investigation is necessary to measure efficacy.

Abstract Background Accurate accelerometer-based methods are required for assessment of 24-h physical behavior in young children. We aimed to summarize evidence on measurement properties of accelerometer-based methods for assessing 24-h physical behavior in young children. Methods We searched PubMed (MEDLINE) up to June 2021 for studies evaluating reliability or validity of accelerometer-based methods for assessing physical activity (PA), sedentary behavior (SB), or sleep in 0–5-year-olds. Studies using a subjective comparison measure or an accelerometer-based device that did not directly output time series data were excluded. We developed a Checklist for Assessing the Methodological Quality of studies using Accelerometer-based Methods (CAMQAM) inspired by COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). Results Sixty-two studies were included, examining conventional cut-point-based methods or multi-parameter methods. For infants (0—12 months), several multi-parameter methods proved valid for classifying SB and PA. From three months of age, methods were valid for identifying sleep. In toddlers (1—3 years), cut-points appeared valid for distinguishing SB and light PA (LPA) from moderate-to-vigorous PA (MVPA). One multi-parameter method distinguished toddler specific SB. For sleep, no studies were found in toddlers. In preschoolers (3—5 years), valid hip and wrist cut-points for assessing SB, LPA, MVPA, and wrist cut-points for sleep were identified. Several multi-parameter methods proved valid for identifying SB, LPA, and MVPA, and sleep. Despite promising results of multi-parameter methods, few models were open-source. While most studies used a single device or axis to measure physical behavior, more promising results were found when combining data derived from different sensor placements or multiple axes. Conclusions Up to age three, valid cut-points to assess 24-h physical behavior were lacking, while multi-parameter methods proved valid for distinguishing some waking behaviors. For preschoolers, valid cut-points and algorithms were identified for all physical behaviors. Overall, we recommend more high-quality studies evaluating 24-h accelerometer data from multiple sensor placements and axes for physical behavior assessment. Standardized protocols focusing on including well-defined physical behaviors in different settings representative for children’s developmental stage are required. Using our CAMQAM checklist may further improve methodological study quality. PROSPERO Registration number CRD42020184751.

Alloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT), chronic graft-versus-host disease (cGVHD), a B cell–associated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B cell receptor (BCR) activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells in allo-HCT, we performed scRNA-Seq analysis on high numbers of purified B cells from patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation, and memory. Within the memory B cell compartment, we found striking transcriptional differences in allo-HCT patients compared with healthy or infected individuals, including potentially pathogenic atypical B cells (ABCs) that were expanded in active cGVHD. To identify intrinsic alterations in potentially pathological B cells, we interrogated all clusters for differentially expressed genes (DEGs) in active cGVHD versus patients who never had signs of immune tolerance loss (no cGVHD). Active cGVHD DEGs occurred in both naive and BCR-activated B cell clusters. Remarkably, some DEGs occurred across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides understanding of altered B cell memory during chronic alloantigen stimulation.

Abstract In rod-shaped bacteria, morphological plasticity occurs in response to stress, which blocks cell division to promote filamentation. We demonstrate here that overexpression of the patatin-like phospholipase variant CapVQ329R, but not CapV, causes pronounced sulA-independent pyridoxine-inhibited cell filamentation in the Escherichia coli K-12-derivative MG1655 associated with restriction of flagella production and swimming motility. Conserved amino acids in canonical patatin-like phospholipase A motifs, but not the nucleophilic serine, are required to mediate CapVQ329R phenotypes. Furthermore, CapVQ329R production substantially alters the lipidome and colony morphotype including rdar biofilm formation with modulation of the production of the biofilm activator CsgD, and affects additional bacterial traits such as the efficiency of phage infection and antimicrobial susceptibility. Moreover, genetically diverse commensal and pathogenic E. coli strains and Salmonella typhimurium responded with cell filamentation and modulation in colony morphotype formation to CapVQ329R expression. In conclusion, this work identifies the CapV variant CapVQ329R as a pleiotropic regulator, emphasizes a scaffold function for patatin-like phospholipases, and highlights the impact of the substitution of a single conserved amino acid for protein functionality and alteration of host physiology.

Tertiary lymphoid structures (TLS) are associated with a reduced risk of cancer recurrence and improved response to immune checkpoint blockade in several tumor types. Here the authors identify L1CAM as a marker for mature TLS and show that the presence of TLS is associated with favorable prognosis in patients with endometrial cancer from the PORTEC-3 trial.

Influenza is a highly contagious respiratory illness that commonly causes outbreaks among human communities. Details about the exact nature of the droplets produced by human respiratory activities such as breathing, and their potential to carry and transmit influenza A and B viruses is still not fully understood. The objective of our study was to characterize and quantify influenza viral shedding in exhaled aerosols from natural patient breath, and to determine their viral infectivity among participants in a university cohort in tropical Singapore. Using the Gesundheit-II exhaled breath sampling apparatus, samples of exhaled breath of two aerosol size fractions (“coarse” > 5 µm and “fine” ≤ 5 µm) were collected and analyzed from 31 study participants, i.e., 24 with influenza A (including H1N1 and H3N2 subtypes) and 7 with influenza B (including Victoria and Yamagata lineages). Influenza viral copy number was quantified using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Infectivity of influenza virus in the fine particle fraction was determined by culturing in Madin–Darby canine kidney cells. Exhaled influenza virus RNA generation rates ranged from 9 to 1.67 × 105 and 10 to 1.24 × 104 influenza virus RNA copies per minute for the fine and coarse aerosol fractions, respectively. Compared to the coarse aerosol fractions, influenza A and B viruses were detected more frequently in the fine aerosol fractions that harbored 12-fold higher viral loads. Culturable virus was recovered from the fine aerosol fractions from 9 of the 31 subjects (29%). These findings constitute additional evidence to reiterate the important role of fine aerosols in influenza transmission and provide a baseline range of influenza virus RNA generation rates.

The transition time during which a virus leaves its host and infects the next susceptible host is critical for virus survival. Enterovirus 71 (EV71) is stable in aqueous environments, but its molecular interactions with bacteria and their biofilms are not well-established. Helicobacter pylori is a highly successful gut bacterial pathogen, with its capacity to form biofilms being linked to its transmission. Given that both are gut-associated microbes, we hypothesized that biofilms formed by H. pylori may play a significant role in the survival of EV71 in the external environment. In this study, we examine the interactions of EV71 with the preformed biofilm of H. pylori to mimic its natural state in the environment. Immunofluorescence confocal microscopy and scanning electron microscopy revealed that EV71 particles persisted for up to 10 days when incubated with the H. pylori biofilm. Furthermore, the presence of the H. pylori biofilm significantly augmented viral viability, as verified through virus plaque assays. Interestingly, the viability of EV71 was dependent on the quantity of H. pylori biofilm formation. Thus, two H. pylori strains able to generate large amounts of biofilm could facilitate EV71 viability for up to 17 days, whereas two other H. pylori strains that produced moderate or low quantities of biofilm could not prolong virus viability. It is interesting that biofilm contains N-acetyl-glucosamine and glycosaminoglycan, and that EV71 has binding affinity to cell-surface heparan sulfate glycosaminoglycan, which acts as an EV71 attachment receptor. The synergistic ability of H. pylori biofilm to promote EV71 viability for extended periods implies that H. pylori biofilm may serve as an additional pathway of EV71 transmission.

Fourteen sulfide-linked 3,4,5-trimethoxyphenyl-thiosemicarbazide/triazole hybrid derivatives containing a variety of structural modifications on the thiosemicarbazide moiety were synthesized. Structure-activity correlations were investigated to determine the influence of structural variations on the antioxidant, antiglycation and DNA cleavage activities. Antioxidant activity was determined using the DPPH radical scavenging and CUPRAC assays. The majority of the derivatives displayed moderate to weak DPPH radical scavenging activity (IC50 = 20.96 to 106.7 μM) compared to ascorbic acid (IC50 = 13.72 μM), with derivatives having π-donating substituents being the most effective. A similar trend was observed for the CUPRAC assay. All derivatives containing electron-donating substituents were more effective than Trolox at reducing copper(II) ion, with Trolox Equivalent Antioxidant Capacity (TEAC) values ranging from 1.44 to 2.45. However, only the nitro derivative was found to be a promising antiglycation agent, inhibiting the formation of advanced glycation end products (AGEs) by 75 % compared to 27 % for the aminoguanidine control. In addition, the majority of the derivatives cleaved pBR322 plasmid DNA in the presence of copper(II) acetate. The interaction of the derivatives with DNA was confirmed by molecular docking studies, which revealed that all of the derivatives bind favorably in the minor groove of DNA.

Summary: Background: Identification of new physical activity (PA) and sedentary behaviour (SB) features relevant for health at older age is important to diversify PA targets in guidelines, as older adults rarely adhere to current recommendations focusing on total duration. We aimed to identify accelerometer-derived dimensions of movement behaviours that predict mortality risk in older populations. Methods: We used data on 21 accelerometer-derived features of daily movement behaviours in 3991 participants of the UK-based Whitehall II accelerometer sub-study (25.8% women, 60–83 years, follow-up: 2012–2013 to 2021, mean = 8.3 years). A machine-learning procedure was used to identify core PA and SB features predicting mortality risk and derive a composite score. We estimated the added predictive value of the score compared to traditional sociodemographic, behavioural, and health-related risk factors. External validation in the Switzerland-based CoLaus study (N = 1329, 56.7% women, 60–86 years, follow-up: 2014–2017 to 2021, mean = 3.8 years) was conducted. Findings: In total, 11 features related to overall activity level, intensity distribution, bouts duration, frequency, and total duration of PA and SB, were identified as predictors of mortality in older adults and included in a composite score. Both in the derivation and validation cohorts, the score was associated with mortality (hazard ratio = 1.10 (95% confidence interval = 1.05–1.15) and 1.18 (1.10–1.26), respectively) and improved the predictive value of a model including traditional risk factors (increase in C-index = 0.007 (0.002–0.014) and 0.029 (0.002–0.055), respectively). Interpretation: The identified accelerometer-derived PA and SB features, beyond the currently recommended total duration, might be useful for screening of older adults at higher mortality risk and for diversifying PA and SB targets in older populations whose adherence to current guidelines is low. Funding: National Institute on Aging; UK Medical Research Council; British Heart Foundation; Wellcome Trust; French National Research Agency; GlaxoSmithKline; Lausanne Faculty of Biology and Medicine; Swiss National Science Foundation.

Abstract Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a life-threatening syndrome that occurs in adult and pediatric patients after hematopoietic stem cell transplantation. Nonspecific symptoms, heterogeneity within study populations, and variability among current diagnostic criteria contribute to misdiagnosis and underdiagnosis of this syndrome. Hematopoietic stem cell transplantation and associated risk factors precipitate endothelial injury, leading to HSCT-TMA and other endothelial injury syndromes such as hepatic veno-occlusive disease/sinusoidal obstruction syndrome, idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, capillary leak syndrome, and graft-versus-host disease. Endothelial injury can trigger activation of the complement system, promoting inflammation and the development of endothelial injury syndromes, ultimately leading to organ damage and failure. In particular, the lectin pathway of complement is activated by damage-associated molecular patterns (DAMPs) on the surface of injured endothelial cells. Pattern-recognition molecules such as mannose-binding lectin (MBL), collectins, and ficolins—collectively termed lectins—bind to DAMPs on injured host cells, forming activation complexes with MBL-associated serine proteases 1, 2, and 3 (MASP-1, MASP-2, and MASP-3). Activation of the lectin pathway may also trigger the coagulation cascade via MASP-2 cleavage of prothrombin to thrombin. Together, activation of complement and the coagulation cascade lead to a procoagulant state that may result in development of HSCT-TMA. Several complement inhibitors targeting various complement pathways are in clinical trials for the treatment of HSCT-TMA. In this article, we review the role of the complement system in HSCT-TMA pathogenesis, with a focus on the lectin pathway.

Nearly one-third of the global coastline is vegetated. Incorporating these vegetation belts in coastal protection strategies would result in more sustainable and financially-attractive designs to mitigate the impacts of extreme coastal storms.

Dilhara Karunaratne,1 Nisal Karunaratne,2 Jade Wilmot,3 Tim Vincent,2 Juliet Wright,2 Nadia Mahmood,4 Alice Tang,5 Amir H Sam,5 Malcolm Reed,2 David Howlett1 1Eastbourne District General Hospital, Eastbourne, BN21 2UD, UK; 2Brighton and Sussex Medical School, Brighton, BN1 9PX, UK; 3Warwick Medical School, Coventry, CV4 7HL, UK; 4Royal Sussex County Hospital, Brighton, BN2 5BE, UK; 5Imperial College London, Charing Cross Campus, London, W6 8RP, UKCorrespondence: Dilhara KarunaratneEastbourne District General Hospital, King’s Drive, Eastbourne, BN21 2UD, UKTel +44 300 151 4500Fax +44 1323 43579Email diliekaru@yahoo.co.ukAbstract: This paper describes the development and use of the bespoke digital learning resource CAPSULE (Clinical and Professional Studies Unique Learning Environment) which was launched UK wide in May 2020 to facilitate the delivery of core learning content for UK medical students during the COVID-19 pandemic. CAPSULE is a digital learning resource comprising case-based scenarios and multiple-choice questions, encompassing all undergraduate medical specialities and supported by a pan-speciality editorial board. Following the COVID-19 pandemic lockdown and loss of face-to-face learning opportunities, CAPSULE was made available to all UK medical schools in May 2020. Following a global content review and edit and UK wide rollout, over 41,000 medical students and 3200 faculty registered as users. Approximately 1.5 million cases were completed in the first 12 months of use by up to 4500 distinct monthly users. Feedback from both students and faculty has been highly positive. CAPSULE continues to be used within UK medical schools and has allowed an entire cohort of medical students to access core curriculum content and progress their studies during the COVID-19 pandemic. Future directions may include further integration into UK medical school curricula, enhancement of platform functionality and potential expansion on an international scale.Keywords: CAPSULE, COVID-19, digital learning platform, UK medical school

Abstract SARS-CoV-2 is a newly identified member of the coronavirus family that has caused the Coronavirus disease 2019 (COVID-19) pandemic. This rapidly evolving and unrelenting SARS-CoV-2 has disrupted the lives and livelihoods of millions worldwide. As of 23 August 2021, a total of 211,373,303 COVID-19 cases have been confirmed globally with a death toll of 4,424,341. A strong understanding of the infection pathway of SARS-CoV-2, and how our immune system responds to the virus is highly pertinent for guiding the development and improvement of effective treatments. In this review, we discuss the current understanding of neutralising antibodies (NAbs) and their implications in clinical practice. The aspects include the pathophysiology of the immune response, particularly humoral adaptive immunity and the roles of NAbs from B cells in infection clearance. We summarise the onset and persistence of IgA, IgM and IgG antibodies, and we explore their roles in neutralising SARS-CoV-2, their persistence in convalescent individuals, and in reinfection. Furthermore, we also review the applications of neutralising antibodies in the clinical setting—from predictors of disease severity to serological testing to vaccinations, and finally in therapeutics such as convalescent plasma infusion.

Abstract Plant invasions have been linked to displacement of native vegetation and altering of fire regimes and might influence vector mosquito populations by altering habitats or nutrient inputs. Whereas wildfire effects on terrestrial ecosystems are relatively well‐studied, ash depositions into aquatic ecosystems and effects on semi‐aquatic taxa such as mosquitoes have remained overlooked. Here, we investigated mosquito colonization in water treated with ash from native plants [quinine tree (Rauvolfia caffra), Transvaal milk plum (Englerophytum magalismontanum), apple leaf (Philenoptera violacea)] and invasive alien plants [i.e., lantana (Lantana camara), guava (Psidium guajava), red river gum (Eucalyptus camaldulensis)] in containers at two ash concentrations (i.e., 1, 2 g/L). Overall, there was no statistically clear difference in colonization between ash from native and alien species. We recorded colonization by two mosquito genera (Culex spp. and Anopheles spp.), with Culex generally much more abundant than Anopheles. Few differences were identified among the plants, with statistically clear effects of ash type and concentration on larval and pupal stages. High Culex egg and larval abundances were shown in lantana and apple leaf treatments compared to controls, and milkplum versus controls for pupae of both genera. Further research is required to elucidate the influence of nutrient inputs from different ash species on vector mosquito population dynamics.

Abstract Due to rising sea levels and projected socio‐economic change, global coastal flood risk is expected to increase in the future. To reduce this increase in risk, one option is to reduce the probability or magnitude of the hazard through the implementation of structural, Nature‐based or hybrid adaptation measures. Nature‐based Solutions in coastal areas have the potential to reduce impacts of climate change and can provide a more sustainable and cost‐effective alternative to structural measures. In this paper, we present the first global scale assessment of the benefits of conserving foreshore vegetation as a means of adaptation to future projections of change in coastal flood risk. In doing so, we extend the current knowledge on the economic feasibility of implementing global scale Nature‐based Solutions. We show that globally foreshore vegetation can contribute to a large decrease in both absolute and relative flood risk (13% of present‐day and 8.5% of future conditions in 2080 of global flood risk). Although this study gives a first proxy of the flood risk reduction benefits of conserving foreshore vegetation at the global scale, it shows promising results for including Nature‐based and hybrid adaptation measures in coastal adaptation schemes.

High physical activity levels during wake are beneficial for health, while high movement levels during sleep are detrimental to health. Our aim was to compare the associations of accelerometer-assessed physical activity and sleep disruption with adiposity and fitness using standardized and individualized wake and sleep windows. People (N = 609) with type 2 diabetes wore an accelerometer for up to 8 days. Waist circumference, body fat percentage, Short Physical Performance Battery (SPPB) test score, sit-to-stands, and resting heart rate were assessed. Physical activity was assessed via the average acceleration and intensity distribution (intensity gradient) over standardized (most active 16 continuous hours (M16h)) and individualized wake windows. Sleep disruption was assessed via the average acceleration over standardized (least active 8 continuous hours (L8h)) and individualized sleep windows. Average acceleration and intensity distribution during the wake window were beneficially associated with adiposity and fitness, while average acceleration during the sleep window was detrimentally associated with adiposity and fitness. Point estimates for the associations were slightly stronger for the standardized than for individualized wake/sleep windows. In conclusion, standardized wake and sleep windows may have stronger associations with health due to capturing variations in sleep durations across individuals, while individualized windows represent a purer measure of wake/sleep behaviors.

Abstract Background Moderate-to-vigorous physical activity (MVPA) is proposed as key for cardiovascular diseases (CVD) prevention. At older ages, the role of sedentary behaviour (SB) and light intensity physical activity (LIPA) remains unclear. Evidence so far is based on studies examining movement behaviours as independent entities ignoring their co-dependency. This study examines the association between daily composition of objectively-assessed movement behaviours (MVPA, LIPA, SB) and incident CVD in older adults. Methods Whitehall II accelerometer sub-study participants free of CVD at baseline (N = 3319, 26.7% women, mean age = 68.9 years in 2012–2013) wore a wrist-accelerometer from which times in SB, LIPA, and MVPA during waking period were extracted over 7 days. Compositional Cox regression was used to estimate the hazard ratio (HR) for incident CVD for daily compositions of movement behaviours characterized by 10 (20 or 30) minutes greater duration in one movement behaviour accompanied by decrease in another behaviour, while keeping the third behaviour constant, compared to reference composition. Analyses were adjusted for sociodemographic, lifestyle, cardiometabolic risk factors and multimorbidity index. Results Of the 3319 participants, 299 had an incident CVD over a mean (SD) follow-up of 6.2 (1.3) years. Compared to daily movement behaviour composition with MVPA at recommended 21 min per day (150 min/week), composition with additional 10 min of MVPA and 10 min less SB was associated with smaller risk reduction – 8% (HR, 0.92; 95% CI, 0.87–0.99) – than the 14% increase in risk associated with a composition of similarly reduced time in MVPA and more time in SB (HR, 1.14; 95% CI, 1.02–1.27). For a given MVPA duration, the CVD risk did not differ as a function of LIPA and SB durations. Conclusions Among older adults, an increase in MVPA duration at the expense of time in either SB or LIPA was found associated with lower incidence of CVD. This study lends support to public health guidelines encouraging increase in MVPA or at least maintain MVPA at current duration.

Barrett’s esophagus is a pro-oncogenic lesion in the proximal gastrointestinal tract, but with a distal colon-like morphology. Here the authors report that the distal HOX gene HOXA13 is expressed in Barrett’s esophagus and in single cells of the physiological esophagus, and may underlie the phenotypic aspects of metaplasia and increase proliferation.

BackgroundStandard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma followed by nivolumab single-agent maintenance therapy. While many patients receive less than 4 doses due to immune-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and assess if fewer doses of I/N can lead to similar survival outcomes.MethodsWe performed a retrospective analysis on a cohort of patients with advanced melanoma who w0ere treated with standard I/N. Cox regression of progression-free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 1 or 2 vs 3 or 4 doses of I/N adjusted by known prognostic variables in advanced melanoma.Results199 patients were evaluated. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.16, 95% CI 0.08-0.33; p

Background Responses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell–based therapy is a promising modality to treat post-HCT relapse.Methods We initiated this ongoing phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5 to 10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High-resolution profiling with mass cytometry and single-cell RNA sequencing characterized the expanding and persistent NK cell subpopulations in a longitudinal manner after infusion.Results In the first 6 enrolled patients on the trial, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Expansion of NK cells was distinct from IL-2 effects on endogenous post-HCT NK cells, and not dependent on CMV viremia. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires.Conclusion Given their rapid expansion and long-term persistence in an immune-compatible environment, CIML NK cells serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies.Trial Registration ClinicalTrials.gov NCT04024761.Funding Dunkin’ Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society.

Sleep dysregulation has been linked to dementia, but it is unknown whether sleep duration earlier in life is associated with dementia risk. Here, the authors show higher dementia risk associated with short sleep duration (six hours or less) in a longitudinal study of middle and older age adults.

In this paper we consider a retained digits Cantor set \(T\) based on digit expansions with Gaussian integer base. Let \(F\) be the set all \(x\) such that the intersection of \(T\) with its translate by \(x\) is non-empty and let \(F_{\beta}\) be the subset of \(F\) consisting of all \(x\) such that the dimension of the intersection of \(T\) with its translate by \(x\) is \(\beta\) times the dimension of \(T\). We find conditions on the retained digits sets under which \(F_{\beta}\) is dense in \(F\) for all \(0\leq\beta\leq 1\). The main novelty in this paper is that multiplication the Gaussian integer base corresponds to an irrational (in fact transcendental) rotation in the complex plane.

Rewatching a series using video-on-demand (VOD) platforms is becoming increasingly popular. Based on semi-structured interviews with 20 Quebecers aged 18 to 34, this study aims at investigating young adults rewatching practices and their meaning. The results highlight a variety of rewatching practices, most often individual, which are reinforced by the use of connected viewing devices. Marketing strategies of VoD providers as well as platform interfaces offer several incentives to rewatch series and provide users with increased opportunity to control serial text and viewing context.

Abstract Background The clinical utility of personal genomic information in identifying individuals at increased risks for dyslipidemia and cardiovascular diseases remains unclear. Methods We used data from Biobank Japan (n = 70,657–128,305) and developed novel East Asian-specific genome-wide polygenic risk scores (PRSs) for four lipid traits. We validated (n = 4271) and subsequently tested associations of these scores with 3-year lipid changes in adolescents (n = 620), carotid intima-media thickness (cIMT) in adult women (n = 781), dyslipidemia (n = 7723), and coronary heart disease (CHD) (n = 2374 cases and 6246 controls) in type 2 diabetes (T2D) patients. Results Our PRSs aggregating 84–549 genetic variants (0.251

Abstract The incidence of malignant melanoma has rapidly increased in the last two decades. There are many challenges associated with the current conventional therapies, including tumour size and location, the specificity of treatments, tumour resistance, non-mutually exclusive mutations, drug resistance, and many adverse side effects. Due to conventional therapies having several limitations, we have explored an alternative therapy such as nano-clays; nano-sized natural materials originating from clay fraction of the soil. Recently, clay nanoparticles have increasingly been used as a drug carrier for cancer treatment due to their high absorption, ability to engulf microbes, and low toxicity. In this study, we evaluated the effects of a nano-clays mix on melanoma cell proliferation and cell viability in vitro and melanoma growth in vivo xenograft animal model. The in vitro study revealed that nano-clay treatments significantly reduced melanoma cell proliferation and cell viability in a dosage-dependent manner. The in vivo tumour xenograft model demonstrated that nano-clay mix treatment led to significantly reduced tumour size and weight, decreased tumour cell mitosis, and induced tumour necrosis. These processes owe to the most probable changes in the membrane potential of the cancer cells once nano-clays bind with the former through the high non-specific adhesion characteristic of the cancer cells. As the data suggest an important role of nano-clays as an inhibitor of melanoma cell proliferation and survival, these prove to be a natural and effective medicine for the treatment of melanoma. The proven compatibility of nano-clays with the human cells with little side-effects makes them a highly preferred choice for the treatment of melanoma and probably other types of cancers.

Our previous study revealed that prolonged human rhinovirus (HRV) infection rapidly induces antiviral interferons (IFNs) and chemokines during the acute stage of infection. It also showed that expression levels of RIG-I and interferon-stimulated genes (ISGs) were sustained in tandem with the persistent expression of HRV RNA and HRV proteins at the late stage of the 14-day infection period. Some studies have explored the protective effects of initial acute HRV infection on secondary influenza A virus (IAV) infection. However, the susceptibility of human nasal epithelial cells (hNECs) to re-infection by the same HRV serotype, and to secondary IAV infection following prolonged primary HRV infection, has not been studied in detail. Therefore, the aim of this study was to investigate the effects and underlying mechanisms of HRV persistence on the susceptibility of hNECs against HRV re-infection and secondary IAV infection. We analyzed the viral replication and innate immune responses of hNECs infected with the same HRV serotype A16 and IAV H3N2 at 14 days after initial HRV-A16 infection. Prolonged primary HRV infection significantly diminished the IAV load of secondary H3N2 infection, but not the HRV load of HRV-A16 re-infection. The reduced IAV load of secondary H3N2 infection may be explained by increased baseline expression levels of RIG-I and ISGs, specifically MX1 and IFITM1, which are induced by prolonged primary HRV infection. As is congruent with this finding, in those cells that received early and multi-dose pre-treatment with Rupintrivir (HRV 3C protease inhibitor) prior to secondary IAV infection, the reduction in IAV load was abolished compared to the group without pre-treatment with Rupintrivir. In conclusion, the antiviral state induced from prolonged primary HRV infection mediated by RIG-I and ISGs (including MX1 and IFITM1) can confer a protective innate immune defense mechanism against secondary influenza infection.

The COVID-19 pandemic caused by SARS-CoV-2 is associated with a lower fatality rate than its SARS and MERS counterparts. However, the rapid evolution of SARS-CoV-2 has given rise to multiple variants with varying pathogenicity and transmissibility, such as the Delta and Omicron variants. Individuals with advanced age or underlying comorbidities, including hypertension, diabetes and cardiovascular diseases, are at a higher risk of increased disease severity. Hence, this has resulted in an urgent need for the development of better therapeutic and preventive approaches. This review describes the origin and evolution of human coronaviruses, particularly SARS-CoV-2 and its variants as well as sub-variants. Risk factors that contribute to disease severity and the implications of co-infections are also considered. In addition, various antiviral strategies against COVID-19, including novel and repurposed antiviral drugs targeting viral and host proteins, as well as immunotherapeutic strategies, are discussed. We critically evaluate strategies of current and emerging vaccines against SARS-CoV-2 and their efficacy, including immune evasion by new variants and sub-variants. The impact of SARS-CoV-2 evolution on COVID-19 diagnostic testing is also examined. Collectively, global research and public health authorities, along with all sectors of society, need to better prepare against upcoming variants and future coronavirus outbreaks.

Abstract Accurate and low-cost sleep measurement tools are needed in both clinical and epidemiological research. To this end, wearable accelerometers are widely used as they are both low in price and provide reasonably accurate estimates of movement. Techniques to classify sleep from the high-resolution accelerometer data primarily rely on heuristic algorithms. In this paper, we explore the potential of detecting sleep using Random forests. Models were trained using data from three different studies where 134 adult participants (70 with sleep disorder and 64 good healthy sleepers) wore an accelerometer on their wrist during a one-night polysomnography recording in the clinic. The Random forests were able to distinguish sleep-wake states with an F1 score of 73.93% on a previously unseen test set of 24 participants. Detecting when the accelerometer is not worn was also successful using machine learning ( $$\hbox {F1-score} > 93.31\%$$ F1-score > 93.31 % ), and when combined with our sleep detection models on day-time data provide a sleep estimate that is correlated with self-reported habitual nap behaviour ( $$\hbox {r}=.60$$ r = . 60 ). These Random forest models have been made open-source to aid further research. In line with literature, sleep stage classification turned out to be difficult using only accelerometer data.

AbstractMigraine is a chronic neurologic disease estimated to affect approximately 50 million Americans. It is associated with a range of symptoms, which contribute to disability and substantial negative impacts on quality of life for many patients. Still, migraine continues to be underdiagnosed, undertreated, and optimising treatment for individual patients has proven difficult. As many migraine patients will be seen first in primary care settings, internists and other primary care providers are ideally positioned to improve diagnosis and migraine management for many patients. In this review, we discuss some of the challenges in diagnosing migraine and suggest strategies to overcome them, summarise the current understanding of migraine pathophysiology and clinical evidence on acute and preventive treatment options, and offer practical approaches to diagnosis and contemporary management of migraine in the primary care setting.Key messagesMigraine is a prevalent disease with substantial impact. Primary care providers are ideally positioned to improve care for migraine patients with streamlined approaches to diagnosis and management.A stepwise diagnostic approach to migraine involves taking a thorough headache history, excluding secondary headache, and identifying primary headache disorder using screening tools or ICHD-3 criteria.The FDA approved seven new migraine therapies from 2018 to 2020 (four monoclonal antibodies, two gepants, one ditan), expanding acute and preventive therapeutic options.