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Abstract Background At the onset of the Coronavirus disease (COVID-19) pandemic when pharmaceutical interventions were not readily available, governments relied on public health mandates and social distancing measures to counter rising infection rates. In order to address the dearth of longitudinal studies, this study sought to identify factors associated with continued adherence to COVID-19 preventive behaviours in Singapore. Methods Data were from a two-wave longitudinal cohort study; baseline study was conducted from May 2020 to June 2021 and follow-up study from October 2021 to September 2022. Participants (n = 858) were Singapore residents, aged 18 and above, and able to speak English, Chinese or Malay. Weighted multivariable logistic regressions were conducted to identify factors associated with adherence to the COVID-19 measures. Results Adherence rates of ‘avoid dining out’, ‘crowded places’, ‘people with flu symptoms’ and ‘small group gatherings’ at baseline were 39.41%, 60.82%, 79.82%, and 44.82% respectively. All measures had a decrease in adherence rates across the two-waves. Older age groups were associated with greater adherence to ‘avoid dining out’ and ‘avoid crowded places’. Having high trust in local public health experts was associated with greater adherence to ‘avoid crowded places’ and ‘avoid people with flu symptoms’. Fear of family and friends getting infected with COVID-19 was associated with ‘avoid dining out’ and ‘avoid crowded places’. Conclusions Soft interventions like nudges can be implemented at crowded places to remind the public of the ease of transmitting the virus to their loved ones. Increasing media presence of public health experts can be a viable alternative to improve adherence.

Abstract Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated with a lower proliferative history than the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

Abstract Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.

Few studies have examined the genetic population structure of vector-borne microparasites in wildlife, making it unclear how much these systems can reveal about the movement of their associated hosts. This study examined the complex host–vector–microbe interactions in a system of bats, wingless ectoparasitic bat flies (Nycteribiidae), vector-borne microparasitic bacteria (Bartonella) and bacterial endosymbionts of flies (Enterobacterales) across an island chain in the Gulf of Guinea, West Africa. Limited population structure was found in bat flies and Enterobacterales symbionts compared to that of their hosts. Significant isolation by distance was observed in the dissimilarity of Bartonella communities detected in flies from sampled populations of Eidolon helvum bats. These patterns indicate that, while genetic dispersal of bats between islands is limited, some non-reproductive movements may lead to the dispersal of ectoparasites and associated microbes. This study deepens our knowledge of the phylogeography of African fruit bats, their ectoparasites and associated bacteria. The results presented could inform models of pathogen transmission in these bat populations and increase our theoretical understanding of community ecology in host–microbe systems.

As the world’s population increases, the growing demand for food intensifies the generation of agricultural waste, leading to several environmental issues. Intensive research indicates black soldier fly (BSF) larvae Hermetia illucens (Linnaeus, 1758) as efficient converters of organic waste into nutrient-rich biomass suitable for animal feed. Using a structured questionnaire and volunteer farmers (N = 595), we investigated the potential for adoption of BSF larvae composting technology for sustainable agricultural waste management in Greater Ahafo-Ano. Almost all surveyed farmers declared they generated a significant amount of biowaste on their farms and were willing to learn how to use the BSF-based technology to transform it into value-added products. The waste generated was mainly disposed of in pits at Ahafo-Ano South-East (56.2%), by composting at Ahafo-Ano South-West (34.9%) and by sale at Ahafo-Ano North (34.4%). Across the three districts, awareness of the BSF was very low – 14.5% in Ahafo-Ano South-East, 14.1% in Ahafo-Ano South-West and 0.5% in Ahafo-Ano North. However, high acceptance of the technology was recorded. It was found that about 8% of farmers surveyed in Ahafo-Ano South-East had already tried BSF farming on a small scale. Indicating this district as a good entry point to introduce the technology into Greater Ahafo-Ano.

Abstract Extremophile organisms are known that can metabolize at temperatures down to − 25 °C (psychrophiles) and up to 122 °C (hyperthermophiles). Understanding viability under extreme conditions is relevant for human health, biotechnological applications, and our search for life elsewhere in the universe. Information about the stability and dynamics of proteins under environmental extremes is an important factor in this regard. Here we compare the dynamics of small Fe-S proteins – rubredoxins – from psychrophilic and hyperthermophilic microorganisms, using three different nuclear techniques as well as molecular dynamics calculations to quantify motion at the Fe site. The theory of ‘corresponding states’ posits that homologous proteins from different extremophiles have comparable flexibilities at the optimum growth temperatures of their respective organisms. Although ‘corresponding states’ would predict greater flexibility for rubredoxins that operate at low temperatures, we find that from 4 to 300 K, the dynamics of the Fe sites in these homologous proteins are essentially equivalent.

Abstract Background Dental cone beam computed tomography (CBCT) is commonly used to evaluate cancellous bone density before dental implant surgery. However, to our knowledge, no measurement approach has been standardized yet. This study aimed to evaluate the relationship between three different regions of interest (ROI) methods on cancellous bone density at the dental implant site using dental CBCT images. Methods Patients’ dental CBCT images (n = 300) obtained before dental implant surgery were processed using Mimics (Materialise, Leuven, Belgium). At the potential implant sites, the rectangle, cylinder, and surrounding cylinder ROI methods were used to measure bone density. Repeated measures one-way analysis of variance was performed to compare the three ROI methods in terms of measurement results. Pearson correlation analysis was performed to identify the likely pair-wise correlations between the three ROI methods. Results The density value obtained using the surrounding cylinder approach (grayscale value [GV],523.56 ± 228.03) was significantly higher than the values obtained using the rectangle (GV, 497.04 ± 236.69) and cylinder (GV,493 ± 231.19) ROI methods in terms of results. Furthermore, significant correlations were noted between the ROI methods (r > 0.965; p

Abstract Modulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures and are practical for chronic daily home use are desirable for a variety of therapeutic applications. Repetitive audio-visual stimulation, or sensory flicker, is an accessible approach that modulates hippocampus in mice, but its effects in humans are poorly defined. We therefore quantified the neurophysiological effects of flicker with high spatiotemporal resolution in patients with focal epilepsy who underwent intracranial seizure monitoring. In this interventional trial (NCT04188834) with a cross-over design, subjects underwent different frequencies of flicker stimulation in the same recording session with the effect of sensory flicker exposure on local field potential (LFP) power and interictal epileptiform discharges (IEDs) as primary and secondary outcomes, respectively. Flicker focally modulated local field potentials in expected canonical sensory cortices but also in the medial temporal lobe and prefrontal cortex, likely via resonance of stimulated long-range circuits. Moreover, flicker decreased interictal epileptiform discharges, a pathological biomarker of epilepsy and degenerative diseases, most strongly in regions where potentials were flicker-modulated, especially the visual cortex and medial temporal lobe. This trial met the scientific goal and is now closed. Our findings reveal how multi-sensory stimulation may modulate cortical structures to mitigate pathological activity in humans.

Abstract Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of antigens. In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface antigens that could be targeted by antibodies and chimeric antigen receptor-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas) and 9166 normal tissue samples (from the Genotype-Tissue Expression project), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN, which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative antigens. Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.

Recently, we demonstrated self-consistent formation of strongly-magnetized quasar accretion disks (QADs) from cosmological radiation-magnetohydrodynamic-thermochemical galaxy-star formation simulations, including the full STARFORGE physics shown previously to produce a reasonable IMF under typical ISM conditions. Here we study star formation and the stellar IMF in QADs, on scales from 100 au to 10 pc from the SMBH. We show it is critical to include physics often previously neglected, including magnetic fields, radiation, and (proto)stellar feedback. Closer to the SMBH, star formation is suppressed, but the (rare) stars that do form exhibit top-heavy IMFs. Stars can form only in special locations (e.g. magnetic field switches) in the outer QAD. Protostars accrete their natal cores rapidly but then dynamically decouple from the gas and 'wander,' ceasing accretion on timescales ~100 yr. Their jets control initial core accretion, but the ejecta are 'swept up' into the larger-scale QAD flow without much dynamical effect. The strong tidal environment strongly suppresses common-core multiplicity. The IMF shape depends sensitively on un-resolved dynamics of protostellar disks (PSDs), as the global dynamical times can become incredibly short (< yr) and tidal fields are incredibly strong, so whether PSDs can efficiently transport angular momentum or fragment catastrophically at

Wild boars have a worldwide distribution and also have major economic, veterinary, and medical importance. Due to a small amount of data on the parasitic fauna of wild boars in the Russian Far East, especially in Prymorye territory, a post-mortem parasitic examination of 20 wild boars was provided. The general prevalence was 25%, and a total of six helminth species, including one larva stage, were found. The most prevalent helminth species were Gnathostoma doloresi (25%) and Metastrongylus elongatus (20%). Followed by Trichuris suis and Ascaris suum (15%). The lowest prevalence was registered for Cysticercus tenuicollis (the larvae stage of T. hydatigena). Parasites were found in each region, with the highest prevalence registered in the Chuguevskii region. Totally 100% of adult boars were positive for helminth infections, instead of 60% of young specimens. Some helminthes found (G. doloresi, T. suis, A. suum) have zoonotic potential and can be involved in the circulation of human parasitic diseases, especially in rural areas. Further research work on parasitic infections in wild boars in Prymorye is necessary due to the high prevalence of helminthes in wild boars.

Despite success in the treatment of some blood cancers and melanoma, positive response to immunotherapies remains disappointingly low in the treatment of solid tumors. The context of the molecular crosstalk within the tumor microenvironment can result in dysfunctional immune cell activation, leading to tumor tolerance and progression. Although modulating these protein–protein interactions (PPIs) is vital for appropriate immune cell activation and recognition, targeting nonenzymatic PPIs has proven to be fraught with challenges. To address this, a synthetic, multivalent molecular modality comprised of small interfering peptides precisely hybridized to a semirigid DNA scaffold is introduced. Herein, a prototype of this modality that targets the IL‐33/ST2 signaling axis, which is associated with tumor tolerance and immunotherapy treatment failure is described. Using peptides that mimic the specific high‐energy “hotspot” residues with which the IL‐33/ST2 coreceptor, IL‐1RAcP, interacts with the initial binary complex, this platform is shown to effectively bind IL‐33/ST2 with a KD of 110 nm. Additionally, this molecule effectively abrogates signal transduction in cell models at high nanomolar concentrations and is exquisitely selective for this complex over structurally similar PPIs within the same cytokine superfamily.

Summary: Background: The UN warns that Myanmar faces the ‘triple crises’ of mass conflict, uncontrolled COVID-19, and economic collapse. Therefore, we aimed to assess the population mental health burden, healthcare needs, and the associated risk factors in Myanmar. Methods: We established a nationwide random sample and recruited 1038 adults via random digit dialling from July 3–Aug 9, 2021, during the ongoing conflict since Feb 1, 2021, and surge in SARS-CoV-2 infections. Probable post-traumatic stress disorder (PTSD) was assessed using the PTSD Checklist—Civilian Version. Probable depression and anxiety were assessed using the Patient Health Questionnaire-2 and the Generalized Anxiety Disorder-2. We calculated population attributable fractions for probable mental disorders using multivariable logistic regression models. Based on the mental health burden and healthcare-seeking patterns, we projected the need for mental health services. Findings: During the ‘triple crises’, a third of adults in Myanmar (34.9%, 95% CI 32.0–37.7) reported a probable mental disorder. Prevalence of probable PTSD, depression, and anxiety were 8.1% (6.6–9.7), 14.3% (12.0–16.6), and 22.2% (19.7–24.7), respectively. We estimated that up to 79.9% (43.8–97.9) of probable PTSD was attributable to political stress. This corresponds to 2.1 million (1.1–3.2 million) fewer adults with probable PTSD if political stress was removed from the population. The mental health burden could translate into roughly 5.9 million adults seeking mental health services. Interpretation: The mental health burden in Myanmar is substantial, and population mental health might only be restored when the three crises have ended. An accelerated peace process is critical to protecting Myanmar’s population mental health. Funding: This research was supported the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. HKU 17606122) and the Michele Tansella Award.

Splicing factor 3b subunit 1 (SF3B1) is the largest subunit and core component of the spliceosome. Inhibition of SF3B1 was associated with an increase in broad intron retention (IR) on most transcripts, suggesting that IR can be used as a marker of spliceosome inhibition in chronic lymphocytic leukemia (CLL) cells. Furthermore, we separately analyzed exonic and intronic mapped reads on annotated RNA-sequencing transcripts obtained from B cells (n = 98 CLL patients) and healthy volunteers (n = 9). We measured intron/exon ratio to use that as a surrogate for alternative RNA splicing (ARS) and found that 66% of CLL-B cell transcripts had significant IR elevation compared with normal B cells (NBCs) and that correlated with mRNA downregulation and low expression levels. Transcripts with the highest IR levels belonged to biological pathways associated with gene expression and RNA splicing. A >2-fold increase of active pSF3B1 was observed in CLL-B cells compared with NBCs. Additionally, when the CLL-B cells were treated with macrolides (pladienolide-B), a significant decrease in pSF3B1, but not total SF3B1 protein, was observed. These findings suggest that IR/ARS is increased in CLL, which is associated with SF3B1 phosphorylation and susceptibility to SF3B1 inhibitors. These data provide additional support to the relevance of ARS in carcinogenesis and evidence of pSF3B1 participation in this process.

To investigate how host and pathogen diversity govern immunity against Mycobacterium tuberculosis (Mtb), we performed a large-scale screen of vaccine-mediated protection against aerosol Mtb infection using three inbred mouse strains [C57BL/6 (B6), C3HeB/FeJ (C3H), Balb/c x 129/SvJ (C129F1)] and three Mtb strains (H37Rv, CDC1551, SA161) representing two lineages and distinct virulence properties. We compared three protective modalities, all of which involve inoculation with live mycobacteria: Bacillus Calmette-Guérin (BCG), the only approved TB vaccine, delivered either subcutaneously or intravenously, and concomitant Mtb infection (CoMtb), a model of pre-existing immunity in which a low-level Mtb infection is established in the cervical lymph node following intradermal inoculation. We examined lung bacterial burdens at early (Day 28) and late (Day 98) time points after aerosol Mtb challenge and histopathology at Day 98. We observed substantial heterogeneity in the reduction of bacterial load afforded by these modalities at Day 28 across the combinations and noted a strong positive correlation between bacterial burden in unvaccinated mice and the degree of protection afforded by vaccination. Although we observed variation in the degree of reduction in bacterial burdens across the nine mouse/bacterium strain combinations, virtually all protective modalities performed similarly for a given strain-strain combination. We also noted dramatic variation in histopathology changes driven by both host and bacterial genetic backgrounds. Vaccination improved pathology scores for all infections except CDC1551. However, the most dramatic impact of vaccination on lesion development occurred for the C3H-SA161 combination, where vaccination entirely abrogated the development of the large necrotic lesions that arise in unvaccinated mice. In conclusion, we find that substantial TB heterogeneity can be recapitulated by introducing variability in both host and bacterial genetics, resulting in changes in vaccine-mediated protection as measured both by bacterial burden as well as histopathology. These differences can be harnessed in future studies to identify immune correlates of vaccine efficacy.

Abstract Manipulating thermal properties of materials can be interpreted as the control of how vibrations of atoms (known as phonons) scatter in a crystal lattice. Compared to a perfect crystal, crystalline solids with defects are expected to have shorter phonon mean free paths caused by point defect scattering, leading to lower lattice thermal conductivities than those without defects. While this is true in many cases, alloying can increase the phonon mean free path in the Cd‐doped AgSnSbSe3 system to increase the lattice thermal conductivity from 0.65 to 1.05 W m−1 K−1 by replacing 18% of the Sb sites with Cd. It is found that the presence of lone pair electrons leads to the off‐centering of cations from the centrosymmetric position of a cubic lattice. X‐ray pair distribution function analysis reveals that this structural distortion is relieved when the electronic configuration of the dopant element cannot produce lone pair electrons. Furthermore, a decrease in the Grüneisen parameter with doping is experimentally confirmed, establishing a relationship between the stereochemical activity of lone pair electrons and the lattice anharmonicity. The observed “harmonic” behavior with doping suggests that lone pair electrons must be preserved to effectively suppress phonon transport in these systems.

Dendritic cells (DCs) play a central role in the orchestration of effective T cell responses against tumors. However, their functional behavior is context-dependent. DC type, transcriptional program, location, intratumoral factors, and inflammatory milieu all impact DCs with regard to promoting or inhibiting tumor immunity. The following review introduces important facets of DC function, and how subset and phenotype can affect the interplay of DCs with other factors in the tumor microenvironment. It will also discuss how current cancer treatment relies on DC function, and survey the myriad ways with which immune therapy can more directly harness DCs to enact antitumor cytotoxicity.

Abstract Background Acute kidney injury is a common disorder that is associated with significant morbidity and mortality. Point-of-care ultrasonography (PoCUS) is an imaging modality performed at the bedside and is used to assess for obstructive causes of acute kidney injury. Little is known about the test characteristics of PoCUS in patients with acute kidney injury. Objective Our primary objective was to describe the test characteristics of PoCUS for the detection of hydronephrosis in patients presenting with acute kidney injury at our centre. Our secondary objective was to describe the current rate of use of PoCUS for this indication. Results In total, 7873 patients were identified between June 1, 2019 and April 30, 2021, with 4611 meeting inclusion criteria. Of these, 94 patients (2%) underwent PoCUS, and 65 patients underwent both PoCUS and reference standard, for a total of 124 kidneys included in our diagnostic accuracy analysis. The prevalence of hydronephrosis in our cohort was 33% (95% CI 25–41%). PoCUS had a sensitivity of 85% (95% CI 71–94%) and specificity of 78% (95% CI 68–87%) for the detection of hydronephrosis. Conclusion We describe the test characteristics of PoCUS for the detection of hydronephrosis in a cohort of patients with acute kidney injury. The low uptake of this test presents an opportunity for quality improvement work to increase its use for this indication.

Abstract BRAF mutations are associated with a small number of hematologic malignancies, including hairy cell leukemia and histiocytic disorders. In addition, BRAF mutations have also been detected in low frequency in other B‐cell lymphomas, such as chronic lymphocytic leukemia and diffuse large B‐cell lymphoma, but never in mantle cell lymphoma (MCL). We present a case of a 69‐year‐old female with classic MCL harboring a BRAFN581S mutation. To our knowledge, this is the first reported case of any BRAF mutation in MCL.

Abstract The global rollout of COVID-19 vaccines faces a significant barrier in the form of vaccine hesitancy. This study adopts a dynamic and network perspective to explore the determinants of COVID-19 vaccine uptake in Hong Kong, focusing on multi-level determinants and their interconnections. Following the framework proposed by the Strategic Advisory Group of Experts (SAGE), the study used repeated cross-sectional surveys to map these determinants at multiple levels and investigates their interconnections simultaneously in a sample of 15,179 over two years. The results highlight the dynamic nature of COVID-19 vaccine hesitancy in an evolving pandemic. The findings suggest that vaccine confidence attitudes play crucial roles in vaccination uptake, with their importance shifting over time. The initial emphasis on vaccine safety gradually transitioned to heightened consideration of vaccine effectiveness at a later stage. The study also highlights the impact of chronic condition, age, COVID-19 case numbers, and non-pharmaceutical preventive behaviours on vaccine uptake. Higher educational attainment and being married were associated with primary and booster vaccine uptake and it may be possible to leverage these groups as early innovation adopters. Trust in government acts as a crucial bridging factor linking various variables in the networks with vaccine confidence attitudes, which subsequently closely linked to vaccine uptake. This study provides insights for designing future effective vaccination programmes for changing circumstances.

Abstract Background Mesenchymal stem cells in the adult corneal stroma (named corneal stromal stem cells, CSSCs) inhibit corneal inflammation and scarring and restore corneal clarity in pre-clinical corneal injury models. This cell therapy could alleviate the heavy reliance on donor materials for corneal transplantation to treat corneal opacities. Herein, we established Good Manufacturing Practice (GMP) protocols for CSSC isolation, propagation, and cryostorage, and developed in vitro quality control (QC) metric for in vivo anti-scarring potency of CSSCs in treating corneal opacities. Methods A total of 24 donor corneal rims with informed consent were used—18 were processed for the GMP optimization of CSSC culture and QC assay development, while CSSCs from the remaining 6 were raised under GMP-optimized conditions and used for QC validation. The cell viability, growth, substrate adhesion, stem cell phenotypes, and differentiation into stromal keratocytes were assayed by monitoring the electric impedance changes using xCELLigence real-time cell analyzer, quantitative PCR, and immunofluorescence. CSSC’s conditioned media were tested for the anti-inflammatory activity using an osteoclastogenesis assay with mouse macrophage RAW264.7 cells. In vivo scar inhibitory outcomes were verified using a mouse model of anterior stromal injury caused by mechanical ablation using an Algerbrush burring. Results By comparatively assessing various GMP-compliant reagents with the corresponding non-GMP research-grade chemicals used in the laboratory-based protocols, we finalized GMP protocols covering donor limbal stromal tissue processing, enzymatic digestion, primary CSSC culture, and cryopreservation. In establishing the in vitro QC metric, two parameters—stemness stability of ABCG2 and nestin and anti-inflammatory ability (rate of inflammation)—were factored into a novel formula to calculate a Scarring Index (SI) for each CSSC batch. Correlating with the in vivo scar inhibitory outcomes, the CSSC batches with SI 10 were ineffective to inhibit scarring. Conclusions We established a full GMP-compliant protocol for donor CSSC cultivation, which is essential toward clinical-grade cell manufacturing. A novel in vitro QC–in vivo potency correlation was developed to predict the anti-scarring efficacy of donor CSSCs in treating corneal opacities. This method is applicable to other cell-based therapies and pharmacological treatments.

Laparoscopic anterior lumbar interbody fusion (L-ALIF), which employs laparoscopic cameras to facilitate a less invasive approach, originally gained traction during the 1990s but has subsequently fallen out of favor. As the envelope for endoscopic approaches continues to be pushed, a recurrence of interest in laparoscopic and/or endoscopic anterior approaches seems possible. Therefore, evaluating the current evidence base in regard to this approach is of much clinical relevance. To this end, a systematic literature search was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the following keywords: “(laparoscopic OR endoscopic) AND (anterior AND lumbar).” Out of the 441 articles retrieved, 22 were selected for quantitative analysis. The primary outcome of interest was the radiographic fusion rate. The secondary outcome was the incidence of perioperative complications. Meta-analysis was performed using RStudio’s “metafor” package. Of the 1,079 included patients (mean age, 41.8±2.9 years), 481 were males (44.6%). The most common indication for L-ALIF surgery was degenerative disk disease (reported by 18 studies, 81.8%). The mean follow-up duration was 18.8±11.2 months (range, 6–43 months). The pooled fusion rate was 78.9% (95% confidence interval [CI], 68.9–90.4). Complications occurred in 19.2% (95% CI, 13.4–27.4) of L-ALIF cases. Additionally, 7.2% (95% CI, 4.6–11.4) of patients required conversion from L-ALIF to open surgery. Although L-ALIF does not appear to be supported by studies available in the literature, it is important to consider the context from which these results have been obtained. Even if these results are taken at face value, the failure of endoscopy to have a role in the ALIF approach does not mean that it should not be incorporated in posterior approaches.

Amphiboreal taxa are often composed of vicariant phylogroups and species complexes whose divergence and phylogeographic affinities reflect a shared history of chronic isolation and episodic trans-Arctic dispersal. Ecological filters and shifting selective pressures may also promote selective sweeps, niche shifts and ecological speciation during colonization, but these are seldom considered at biogeographical scales. Here we integrate genetic data and Ecologic Niche Models (ENMs) to investigate the historical biogeography and cohesion of the polymorphic rockweed Fucus distichus throughout its immense amphiboreal range, focusing on trans-Arctic asymmetries, glacial/interglacial dynamics, and integrity of sympatric eco-morphotypes. Populations were sampled throughout the Pacific and the Atlantic, from southern rear-edges to the high-Arctic. They were genotyped for seven microsatellites and an mtDNA spacer, and genetic diversity and structure were assessed from global to local scales. ENMs were used to compare niche divergence and magnitude of post-glacial range shifts in Pacific versus Atlantic sub-ranges. Haplotypic and genotypic data revealed distinct and seemingly isolated Pacific vs Arctic/Atlantic gene-pools, with finer-scale regional sub-structuring pervasive in the Pacific. MtDNA diversity was highly structured and overwhelmingly concentrated in the Pacific. Regionally, Alaska showed the highest intra-population diversity but the lowest levels of endemism. Some sympatric/parapatric ecotypes exhibited distinct genotypic/haplotypic compositions. Strikingly, niche models revealed higher Pacific tolerance to maximum temperatures and predicted a much more consolidated presence in the NE Atlantic. Glacial and modern ranges overlapped extensively in the Pacific, whereas the modern Atlantic range was largely glaciated or emerged during the Last Glacial Maximum. Higher genetic and ecogeographic diversity supports a primary Pacific diversification and secondary Atlantic colonization, also likely reflecting the much larger and more stable climatic refugia in the Pacific. The relic distribution and reduced ecological/morphological plasticity in the NE Atlantic are hypothesized to reflect functional trans-Arctic bottlenecks, recent colonization or competition with congeners. Within the Pacific, Alaska showed signatures of a post-glacial melting pot of eastern and southern populations. Genetic/ecotypic variation was generally not sufficiently discontinuous or consistent to justify recognizing multiple taxonomic entities, but support a separate species in the eastern Pacific, at the southern rear-edge. We predict that layered patterns of phylogeographic structure, incipient speciation and niche differences might be common among widespread low-dispersal amphiboreal taxa.

Abstract Introduction Ventricular septal defect (VSD) is one of the most common congenital cardiac anomalies. Patients with perimembranous VSD may have aortic regurgitation (AR) secondary to prolapse of the aortic cusp. Case presentation We present a case of 23-year-old White man with VSD, AR and ascending aortic aneurysm. The patient presented to outpatient clinic with weakness and gradual worsening shortness of breath for the past 5 years. Clinical examination revealed regular heart rhythm and loud continuous systolic-diastolic murmur (Lewin’s grade 6/6), heard all over the precordium, associated with a palpable thrill. The ECG showed right axis deviation, fractionated QRS in V1 and signs of biventricular hypertrophy. The chest X-ray showed cardiomegaly. Transthoracic and transesophageal echocardiograms showed a perimembranous VSD with moderate restrictive shunt (Qp/Qs = 1.6), aortic regurgitation (AR), and ascending aortic aneurysm. Other clinical and laboratory findings were within normal limits. Conclusions Perimembranous VSD, may be associated with aortic regurgitation and ascending aortic aneurysm as secondary phenomenon if it is not early diagnosed and successfully treated.

Abstract Background Singapore and Osaka in Japan have comparable population sizes and prehospital management; however, the frequency of ECPR differs greatly for out-of-hospital cardiac arrest (OHCA) patients with initial shockable rhythm. Given this disparity, we hypothesized that the outcomes among the OHCA patients with initial shockable rhythm in Singapore were different from those in Osaka. The aim of this study was to evaluate the outcomes of OHCA patients with initial shockable rhythm in Singapore compared to the expected outcomes derived from Osaka data using machine learning-based prediction models. Methods This was a secondary analysis of two OHCA databases: the Singapore PAROS database (SG-PAROS) and the Osaka-CRITICAL database from Osaka, Japan. This study included adult (18–74 years) OHCA patients with initial shockable rhythm. A machine learning-based prediction model was derived and validated using data from the Osaka-CRITICAL database (derivation data 2012–2017, validation data 2018–2019), and applied to the SG-PAROS database (2010–2016 data), to predict the risk-adjusted probability of favorable neurological outcomes. The observed and expected outcomes were compared using the observed–expected ratio (OE ratio) with 95% confidence intervals (CI). Results From the SG-PAROS database, 1,789 patients were included in the analysis. For OHCA patients who achieved return of spontaneous circulation (ROSC) on hospital arrival, the observed favorable neurological outcome was at the same level as expected (OE ratio: 0.905 [95%CI: 0.784–1.036]). On the other hand, for those who had continued cardiac arrest on hospital arrival, the outcomes were lower than expected (shockable rhythm on hospital arrival, OE ratio: 0.369 [95%CI: 0.258–0.499], and nonshockable rhythm, OE ratio: 0.137 [95%CI: 0.065–0.235]). Conclusion This observational study found that the outcomes for patients with initial shockable rhythm but who did not obtain ROSC on hospital arrival in Singapore were lower than expected from Osaka. We hypothesize this is mainly due to differences in the use of ECPR.

The KOSovan Acute Coronary Syndrome (KOS-ACS) Registry is established as a prospective, continuous, nationwide, web-based registry that is operated online. The KOS-ACS registry is designed with the following objectives: (1) to obtain data on the demographic, clinical, and laboratory characteristics of ACS patients treated in Kosovo; (2) to create a national database with information on health care in ACS patients treated in Kosovo; (3) to identify the national features of associations between ACS characteristics and clinical outcomes, including mortality, complications, the length of hospital stay, and the quality of clinical care; and (4) to propose a practical guide for improving the quality and efficiency of ACS treatment in Kosovo. The Kosovo Society of Cardiology and University of Prishtina will be responsible for the development of the KOS-ACS registry and centralized data analysis at the national level. The KOS-ACS Registry will enroll all patients admitted, at any of the registered clinical centers, with the diagnosis of ACS and who will be clinically managed at any of the Kosovo hospitals. Data on patient demographics, clinical characteristics, previous and hospital drug treatment, and reperfusion therapy will be collected. The type of ACS (unstable angina, NSTEMI, or STEMI) will also be clearly defined. The time from first medical contact to balloon inflation (FMC-to-balloon) and door-to-ballon time will be registered. In-hospital death and complications will be registered. Data on the post-hospital primary outcome (MACE: cardiac death, all-cause mortality, hospitalization, stroke, need for coronary revascularization) of patients, at 30 days and 1 year, will be included in the registry.

Background: An increasing proportion of heart failure (HF) patients progress to the advanced stage (AdHF) with high event rates and limited treatment options. Echocardiography, particularly Speckle Tracking-derived myocardial work (MW), is useful for HF diagnosis and prognosis. We aimed to assess MW’s feasibility in the prognostic stratification of AdHF. Methods: We retrospectively screened patients with AdHF who accessed our hospital in 2018–2022. We excluded subjects with inadequate acoustic windows; unavailable brachial artery cuff pressure at the time of the echocardiography; atrial fibrillation; and mitral or aortic regurgitation. We measured standard parameters and left ventricular (LV) strain (LS) and MW. The population was followed up to determine the composite outcomes of all-cause mortality, left ventricular assist device implantation and heart transplantation (primary endpoint), as well as unplanned HF hospitalization (secondary endpoint). Results: We enrolled 138 patients, prevalently males (79.7%), with a median age of 58 years (IQR 50–62). AdHF etiology was predominantly non-ischemic (65.9%). Thirty-five patients developed a composite event during a median follow-up of 636 days (IQR 323–868). Diastolic function, pulmonary pressures, and LV GLS and LV MW indices were not associated with major events. Contrarily, for the secondary endpoint, the hazard ratio for each increase in global work index (GWI) by 50 mmHg% was 0.90 (p = 0.025) and for each increase in global constructive work (GCW) by 50 mmHg% was 0.90 (p = 0.022). Kaplan–Meier demonstrated better endpoint-free survival, with an LV GWI ≥ 369 mmHg%. Conclusions: GWI and GCW, with good feasibility, can help in the better characterization of patients with AdHF at higher risk of HF hospitalization and adverse events, identifying the need for closer follow-up or additional HF therapy.

Abstract Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the FADS locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of P 9 Mb region on chromosome 11 (57.5 Mb ~ 67.1 Mb). Among these novel signals, we found associations unique to Hispanic Americans, including rs28364240, a POLD4 missense variant for AA that is common in CHARGE Hispanic Americans but absent in other race/ancestry groups. Our study sheds light on the genetics of PUFAs and the value of investigating complex trait genetics across diverse ancestry populations.

Abstract Background Point-of-Care-Ultrasound (POCUS) curricula have rapidly expanded in undergraduate medical education (UME). However, the assessments used in UME remain variable without national standards. This scoping review characterizes and categorizes current assessment methods using Miller’s pyramid for skills, performance, and competence of POCUS in UME. A structured protocol was developed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR). A literature search of MEDLINE was performed from January 1, 2010, to June 15, 2021. Two independent reviewers screened all titles and abstracts for articles that met inclusion criteria. The authors included all POCUS UME publications in which POCUS-related knowledge, skills, or competence were taught and objectively assessed. Articles were excluded if there were no assessment methods used, if they exclusively used self-assessment of learned skills, were duplicate articles, or were summaries of other literature. Full text analysis and data extraction of included articles were performed by two independent reviewers. A consensus-based approach was used to categorize data and a thematic analysis was performed. Results A total of 643 articles were retrieved and 157 articles met inclusion criteria for full review. Most articles (n = 132; 84%) used technical skill assessments including objective structured clinical examinations (n = 27; 17%), and/or other technical skill-based formats including image acquisition (n = 107; 68%). Retention was assessed in n = 98 (62%) studies. One or more levels of Miller’s pyramid were included in 72 (46%) articles. A total of four articles (2.5%) assessed for students’ integration of the skill into medical decision making and daily practice. Conclusions Our findings demonstrate a lack of clinical assessment in UME POCUS that focus on integration of skills in daily clinical practice of medical students corresponding to the highest level of Miller’s Pyramid. There exists opportunities to develop and integrate assessment that evaluate higher level competencies of POCUS skills of medical students. A mixture of assessment methods that correspond to multiple levels of Miller’s pyramid should be used to best assess POCUS competence in UME.

Abstract Background Although mRNA vaccines have overall efficacy preventing morbidity/mortality from SARS-CoV-2 infection, immunocompromised persons remain at risk. Antibodies mostly prevent early symptomatic infection, but cellular immunity, particularly the virus-specific CD8+ T cell response, is protective against disease. Defects in T cell responses to vaccination have not been well characterized in immunocompromised hosts; persons with lung transplantation are particularly vulnerable to vaccine failure with severe illness. Methods Comparison groups included persons with lung transplantation and no history of COVID-19 (21 and 19 persons after initial mRNA vaccination and a third booster vaccination respectively), 8 lung transplantation participants recovered from COVID-19, and 22 non-immunocompromised healthy control individuals after initial mRNA vaccination (without history of COVID-19). Anti-spike T cell responses were assayed by stimulating peripheral blood mononuclear cells (PBMCs) with pooled small overlapping peptides spanning the SARS-CoV-2 spike protein, followed by intracellular cytokine staining (ICS) and flow cytometry for release of cytokines in response to stimulation, including negative controls (no peptide stimulation) and positive controls (phorbol myristate acetate [PMA] and ionomycin stimulation). To evaluate for low frequency memory responses, PBMCs were cultured in the presence of the mRNA-1273 vaccine for 14 days before this evaluation. Results Ionophore stimulation of PBMCs revealed a less inflammatory milieu in terms of interleukin (IL)-2, IL-4, and IL-10 profiling in lung transplantation individuals, reflecting the effect of immunosuppressive treatments. Similar to what we previously reported in healthy vaccinees, spike-specific responses in lung transplantation recipients were undetectable (

Background Effective therapies for reducing cardiovascular disease (CVD) risk in people with elevated lipoprotein(a) are lacking, especially for primary prevention. Because of the potential association of lipoprotein(a) with thrombosis, we evaluated the relationship between aspirin use and CVD events in people with elevated lipoprotein(a). Methods and Results We used data from the MESA (Multi‐Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of baseline cardiovascular disease. Due to potential confounding by indication, we matched aspirin users to nonusers using a propensity score based on CVD risk factors. We then evaluated the association between aspirin use and coronary heart disease (CHD) events (CHD death, nonfatal myocardial infarction) stratified by baseline lipoprotein(a) level (threshold of 50 mg/dL) using Cox proportional hazards models with adjustment for CVD risk factors. After propensity matching, the study cohort included 2183 participants, including 1234 (57%) with baseline aspirin use and 423 (19%) with lipoprotein(a) >50 mg/dL. Participants with lipoprotein(a) >50 mg/dL had a higher burden of CVD risk factors, more frequent aspirin use (61.7% versus 55.3%, P=0.02), and higher rate of incident CHD events (13.7% versus 8.9%, P50 mg/dL and aspirin use had similar CHD risk as those with lipoprotein(a) ≤50 mg/dL regardless of aspirin use. Conclusions Aspirin use was associated with a significantly lower risk for CHD events in participants with lipoprotein(a) >50 mg/dL without baseline CVD. The results of this observational propensity‐matched study require confirmation in studies with randomization of aspirin use.

Risk stratification of cardiovascular death and treatment strategies in patients with heart failure (HF), the optimal timing for valve replacement, and the selection of patients for implantable cardioverter defibrillators are based on an echocardiographic calculation of left ventricular ejection fraction (LVEF) in most guidelines. As a marker of systolic function, LVEF has important limitations being affected by loading conditions and cavity geometry, as well as image quality, thus impacting inter- and intra-observer measurement variability. LVEF is a product of shortening of the three components of myocardial fibres: longitudinal, circumferential, and oblique. It is therefore a marker of global ejection performance based on cavity volume changes, rather than directly reflecting myocardial contractile function, hence may be normal even when myofibril's systolic function is impaired. Sub-endocardial longitudinal fibers are the most sensitive layers to ischemia, so when dysfunctional, the circumferential fibers may compensate for it and maintain the overall LVEF. Likewise, in patients with HF, LVEF is used to stratify subgroups, an approach that has prognostic implications but without a direct relationship. HF is a dynamic disease that may worsen or improve over time according to the underlying pathology. Such dynamicity impacts LVEF and its use to guide treatment. The same applies to changes in LVEF following interventional procedures. In this review, we analyze the clinical, pathophysiological, and technical limitations of LVEF across a wide range of cardiovascular pathologies.

Summary: Background: Despite the early demonstrated safety and effectiveness of COVID-19 vaccines in children, uptake was slow throughout the pandemic and remains low globally. Understanding vaccine refusal could provide insights to improving vaccine uptake in future pandemics. Methods: In a population-wide registry of all COVID-19 paediatric vaccination appointments, we used interrupted time series analysis to evaluate the impact of public policies. In a population-based cohort of adults, we used population attributable fractions to assess the individual and joint contributions of potential determinants to paediatric COVID-19 vaccination, and used mediation analysis to identify modifiable mediators between political views and paediatric vaccination. Findings: School vaccination requirements were associated with an increase in vaccination appointments by 278.7% (95% CI 85.3–673.9) in adolescents aged 12–17 and 112.8% (27.6–255.0) in children aged 5–11. Government-mandated vaccine pass, required for entry into restaurants, shopping malls and supermarkets, was associated with increased vaccination appointments by 108.7% (26.6–244.0) in adolescents. The following four determinants may explain 82.5% (63.5–100.0) of the reasons why children were unvaccinated: familial political views, vaccine hesitancy for children, mistrust in doctors and academics, and vaccine misconceptions. The influence of political views may be mitigated since 95.9% (76.4–100.0) of its association with vaccine reluctance for adolescents was mediated by modifiable factors such as mistrust in health authorities and low vaccine confidence. Interpretation: School vaccination requirements and vaccine passes were associated with increased vaccine uptake. Clinicians should recognise that factors beyond health, such as political views, can influence paediatric vaccine uptake to a significant extent. Nonetheless, such influences could be mitigated by targeted interventions and public policies. Funding: Hong Kong Jockey Club Charities Trust, Research Grants Council, University Grants Committee, and Health Bureau.

Introduction: Spondylodiscitis (SD) is an infection of the intervertebral disc with involvement of the adjacent vertebral bodies. Diagnostic tests with CT-guided biopsy only provide a positive yield in 14%–48% of cases. Percutaneous endoscopic debridement and drainage (PEDD) has recently shown promise in the treatment of spondylodiscitis. Research question: The purpose of this study is to determine differences in pathogen identification and clinical outcomes for PEDD versus CT-guided needle biopsy in SD patients. Materials and methods: We conducted a systematic review of the literature using PRISMA guidelines to determine differences in positive microbiology results, perioperative complications, pain control, and long-term clinical outcomes for PEDD vs. CT-guided needle biopsy in SD patients. Results: 1078 studies were evaluated, 87 of which underwent full review. 15 studies met the inclusion and exclusion criteria, including 7 PEDD, 7 CT-guided biopsy, and 1 CT-guided biopsy vs. PEDD article, for a total of 192 PEDD patients and 604 CT-guided biopsy patients. We found 36.59% of CT-guided biopsy patients had positive microbiology results, compared to 84.38% of PEDD patients. No major perioperative complications occurred as a result of the PEDD procedure. Of the five PEDD studies that reported pain outcomes, greater than 80% of patients experienced relief after intervention. Discussion and conclusion: These results suggest that PEDD may improve pathogen identification while simultaneously reducing pain compared to CT-guided needle biopsy in SD. Although current treatment guidelines recommend CT-guided biopsy, in patients with severe back pain and suspected SD, PEDD can be considered an alternative intervention.

Abstract Abrupt sunlight reduction scenarios such as a nuclear winter caused by the burning of cities in a nuclear war, an asteroid/comet impact or an eruption of a large volcano inject large amounts of particles in the atmosphere, which limit sunlight. This could decimate agriculture as it is practiced today. We therefore need resilient food sources for such an event. One promising candidate is seaweed, as it can grow quickly in a wide range of environmental conditions. To explore the feasibility of seaweed after nuclear war, we simulate the growth of seaweed on a global scale using an empirical model based on Gracilaria tikvahiae forced by nuclear winter climate simulations. We assess how quickly global seaweed production could be scaled to provide a significant fraction of global food demand. We find seaweed can be grown in tropical oceans, even after nuclear war. The simulated growth is high enough to allow a scale up to an equivalent of 45% of the global human food demand (spread among food, animal feed, and biofuels) in around 9–14 months, while only using a small fraction of the global ocean area. The main limiting factor being the speed at which new seaweed farms can be built. The results also show that the growth of seaweed increases with the severity of the nuclear war, as more nutrients become available due to increased vertical mixing. This means that seaweed has the potential to be a viable resilient food source for abrupt sunlight reduction scenarios.

When a detailed model of a stellar population is unavailable, it is most common to assume that stellar masses are independently and identically distributed according to some distribution: the universal initial mass function (IMF). However, stellar masses resulting from causal, long-ranged physics cannot be truly random and independent, and the IMF may vary with environment. To compare stochastic sampling with a physical model, we run a suite of 100 STARFORGE radiation magnetohydrodynamics simulations of low-mass star cluster formation in $2000M_\odot$ clouds that form $\sim 200$ stars each on average. The stacked IMF from the simulated clouds has a sharp truncation at $\sim 28 M_\odot$, well below the typically-assumed maximum stellar mass $M_{\rm up} \sim 100-150M_\odot$ and the total cluster mass. The sequence of star formation is not totally random: massive stars tend to start accreting sooner and finish later than the average star. However, final cluster properties such as maximum stellar mass and total luminosity have a similar amount of cloud-to-cloud scatter to random sampling. Therefore stochastic sampling does not generally model the stellar demographics of a star cluster as it is forming, but may describe the end result fairly well, if the correct IMF -- and its environment-dependent upper cutoff -- are known.

Summary: Background: Maternal lipidomic profiling offers promise for characterizing lipid metabolites during pregnancy, but longitudinal data are limited. This study aimed to examine associations of longitudinal lipidomic profiles during pregnancy with multiple neonatal anthropometry using data from a multiracial cohort. Methods: We measured untargeted plasma lipidome profiles among 321 pregnant women from the NICHD Fetal Growth Study-Singletons using plasma samples collected longitudinally during four study visits at gestational weeks (GW) 10–14, 15–26, 23–31, and 33–39, respectively. We evaluated individual lipidomic metabolites at each study visit in association with neonatal anthropometry. We also evaluated the associations longitudinally by constructing lipid networks using weighted correlation network analysis and common networks using consensus network analysis across four visits using linear mixed-effects models with the adjustment of false discover rate. Findings: Multiple triglycerides (TG) were positively associated with birth weight (BW), BW Z-score, length and head circumference, while some cholesteryl ester (CE), phosphatidylcholine (PC), sphingomyelines (SM), phosphatidylethanolamines (PE), and lysophosphatidylcholines (LPC 20:3) families were inversely associated with BW, length, abdominal and head circumference at different GWs. Longitudinal trajectories of TG, PC, and glucosylcermides (GlcCer) were associated with BW, and CE (18:2) with BW z-score, length, and sum of skinfolds (SS), while some PC and PE were significantly associated with abdominal and head circumference. Modules of TG at GW 10–14 and 15–26 mainly were associated with BW. At GW 33–39, two networks of LPC (20:3) and of PC, TG, and CE, showed inverse associations with abdominal circumference. Distinct trajectories within two consensus modules with changes in TG, CE, PC, and LPC showed significant differences in BW and length. Interpretation: The results demonstrated that longitudinal changes of TGs during early- and mid-pregnancy and changes of PC, LPC, and CE during late-pregnancy were significantly associated with neonatal anthropometry. Funding: National Institute of Child Health and Human Development intramural funding.

ABSTRACTBackground This article addresses the impact of the novel SARS-CoV-2 virus (COVID-19) on dental care for patients with intellectual and developmental disabilities (IDD).Public Health Issues The authors discuss public health issues affected, including the limited number of providers and the decreased access to hospital operating rooms that resulted in a backlog of patients needing care.Practical Implications Recommendations are presented for continuity of care during a pandemic in traditional clinical care settings and, if needed, with general anesthesia. Desensitization, noninvasive and minimally invasive techniques are discussed as methods to support continuity of care. The first responder's supportive role as a vaccination educator and administrator is also addressed as an opportunity to increase access to care for those with IDD.

Kappaphycus malesianus is a red seaweed farmed primarily for its carrageenan, a polysaccharide important in the food and pharmaceutical industries. Among the commercially cultivated Kappaphycus species, only K. malesianus has no mitogenome data available. Here, we assembled the mitochondrial genome of K. malesianus from next-generation sequencing data. The circular mitogenome consisted of 25,250 base pairs (bp) with a GC content of 30.25%. These values were comparable to previously sequenced solieriacean mitogenomes. Structural features, such as the stem-loop and hairpin, which were previously reported in other rhodophytes mitochondrial DNA, were also identified. The annotated genes (24 protein-coding genes, 24 tRNA genes, and 2 rRNA genes) were arranged in an order similar to the other available solieriacean mitogenomes. Lastly, phylogenetic analysis using 23 predicted protein domains showed the sister relationship of K. malesianus with other Kappaphycus species.

Abstract Background Time to diagnosis and treatment is a major factor in determining the likelihood of tuberculosis (TB) transmission and is an important area of intervention to reduce the reservoir of TB infection and prevent disease and mortality. Although Indigenous peoples experience an elevated incidence of TB, prior systematic reviews have not focused on this group. We summarize and report findings related to time to diagnosis and treatment of pulmonary TB (PTB) among Indigenous peoples, globally. Methods A Systematic review was performed using Ovid and PubMed databases. Articles or abstracts estimating time to diagnosis, or treatment of PTB among Indigenous peoples were included with no restriction on sample size with publication dates restricted up to 2019. Studies that focused on outbreaks, solely extrapulmonary TB alone in non-Indigenous populations were excluded. Literature was assessed using the Hawker checklist. Registration Protocol (PROSPERO): CRD42018102463. Results Twenty-four studies were selected after initial assessment of 2021 records. These included Indigenous groups from five of six geographical regions outlined by the World Health Organization (all except the European Region). The range of time to treatment (24–240 days), and patient delay (20 days–2.5 years) were highly variable across studies and, in at least 60% of the studies, longer in Indigenous compared to non-Indigenous peoples. Risk factors associated with longer patient delays included poor awareness of TB, type of health provider first seen, and self-treatment. Conclusion Time to diagnosis and treatment estimates for Indigenous peoples are generally within previously reported ranges from other systematic reviews focusing on the general population. However among literature examined in this systematic review that stratified by Indigenous and non-Indigenous peoples, patient delay and time to treatment were longer compared to non-Indigenous populations in over half of the studies. Studies included were sparse and highlight an overall gap in literature important to interrupting transmission and preventing new TB cases among Indigenous peoples. Although, risk factors unique to Indigenous populations were not identified, further investigation is needed as social determinants of health among studies conducted in medium and high incidence countries may be shared across both population groups. Trial registration N/a.

Abstract While there is an expanding body of literature on Point-of-Care Ultrasound (POCUS) pedagogy, administrative elements that are necessary for the widespread adoption of POCUS in the clinical environment have received little attention. In this short communication, we seek to address this gap by sharing our institutional experience with POCUS program development and implementation. The five pillars of our program, selected to tackle local barriers to POCUS uptake, are education, workflow, patient safety, research, and sustainability. Our program logic model outlines the inputs, activities, and outputs of our program. Finally, key indicators for the monitoring of program implementation efforts are presented. Though designed for our local context, this approach may readily be adapted toward other clinical environments. We encourage others leading the integration of POCUS at their centers to adopt this approach not only to achieve sustainable change but also to ensure that quality safeguards are in place.

Percutaneous endoscopic lumbar discectomy (PELD) presents a challenging learning curve, and the correlation between surgeon experience and clinical outcomes remains contentious. This retrospective study aimed to compare the outcomes of PELD performed by a single surgeon at beginner and experienced stages. Propensity score matching selected 150 patients (75 per group) with a minimum 3-year follow-up. Clinical and radiological outcomes, perioperative complications, and adverse events were assessed. Baseline characteristics, pain improvement, patient satisfaction, and radiological outcomes did not differ between the groups. However, operation time was longer in the beginner group than in the experienced group (57.5 min [IQR, 50.0–70.0] versus 50.0 min [IQR, 45.0–55.0], p < 0.001). The beginner group had higher perioperative complication rates (eight patients [10.7%] versus one patient [1.3%], with a hazard ratio of 8.836 [95% CI, 1.077–72.514], p = 0.034) and lower 3-year survival without adverse events (19 patients [25.3%] in the beginner group and 10 patients [13.3%] in the experienced group, p = 0.045). Our findings indicate that the clinical outcomes were more favorable in patients operated on at the experienced stage compared to those treated at the beginner stage.

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10−8) and suggestive (p < 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals).Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue.Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

Introduction The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations.Methods Here, we examined how ancestrally diverse studies could clarify Lp(a)’s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations.Results Fourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R2=15% in East Asians) to high (R2=50% in Europeans) accuracy. For all populations, PRS showed promise as a ‘rule out’ for elevated Lp(a) because certainty of assignment to the low-risk threshold was high (88.0%–99.9%) across PRS thresholds (80th–99th percentile). Causal effects of increased Lp(a) with increased glycated haemoglobin were estimated for Europeans (p value =1.4×10−6), although inverse effects in Africans and East Asians suggested the potential for heterogeneous causal effects. Finally, Hispanic/Latinos were the only population in which known associations with coronary atherosclerosis and ischaemic heart disease were identified in external testing of Lp(a) PRS phenotypic effects.Conclusions Our results emphasise the merits of prioritising ancestral diversity when addressing Lp(a) evidence gaps.

Abstract Bartonella are rodent-borne bacteria that cause varied human etiologies. Studies on synanthropic rodents are rare, causing gaps in epidemiological knowledge. We tested bloodclot samples from 79 rats from an urban slum in Salvador, Brazil through PCR targeting gltA gene. Nine samples (11.4%) were positive: six had 100% identity with Bartonella sp. isolate JF429580 and 99.5% with B. queenslandensis strain AUST/NH8; three were 100% identical to isolate JF429532 and 99.7% to B. tribocorum. This is the second report on urban rat Bartonella indicating bacterial circulation at detectable rates. Its presence in rats from vulnerable human settlements demands public health attention.

Abstract Epithelial-to-mesenchymal transition (EMT) is associated with tumor initiation, metastasis, and drug resistance. However, the mechanisms underlying these associations are largely unknown. We studied several tumor types to identify the source of EMT gene expression signals and a potential mechanism of resistance to immuno-oncology treatment. Across tumor types, EMT-related gene expression was strongly associated with expression of stroma-related genes. Based on RNA sequencing of multiple patient-derived xenograft models, EMT-related gene expression was enriched in the stroma versus parenchyma. EMT-related markers were predominantly expressed by cancer-associated fibroblasts (CAFs), cells of mesenchymal origin which produce a variety of matrix proteins and growth factors. Scores derived from a 3-gene CAF transcriptional signature (COL1A1, COL1A2, COL3A1) were sufficient to reproduce association between EMT-related markers and disease prognosis. Our results suggest that CAFs are the primary source of EMT signaling and have potential roles as biomarkers and targets for immuno-oncology therapies.

Abstract C-reactive protein (CRP) is an acute-phase protein involved in inflammation. Furthermore, CRP is an important biomarker used in diagnostics to predict risk of cardiovascular disease (CVD) in addition to monitoring bacterial and viral infections. To measure plasma CRP, venipuncture is still necessitated and has to be performed by trained phlebotomists. As a solution, dried blood spots (DBS) are used for minimally invasive at-home sampling of blood and can be send to diagnostic laboratories by regular mail. In this study, we included 53 patients that presented to the outpatient clinic of the University Medical Center Utrecht. Capillary finger stick was used to spot blood on a filter paper card and allowed to dry. After extraction of DBS, CRP was analyzed on an automated high-throughput chemistry analyzer. Additional validation steps regarding stability, effect of hematocrit, precision, and limits of blank and quantitation were conducted according to corresponding Clinical and Laboratory Standards Institute standards. An excellent regression analysis of R2 (95% confidence interval) = 0.986 (0.982–0.989) was found. This enabled correct classification for high CVD risk of all 25 cases with sensitivity (95% CI) of 1.00 (1.00–1.00) and specificity (95% CI) of 0.96 (0.89–1.03) and correct diagnosis of inflammation of 12/13 cases with sensitivity (95% CI) of 0.92 (0.77–1.07) and specificity (95% CI) of 1.00 (1.00–1.00). Furthermore, CRP was found to be stable for 31 days and observed hematocrit variation amongst patients was clinically acceptable. CRP from DBS can be accurately measured on an automated high-throughput chemistry analyzer and used to diagnose inflammation and classify high CVD risk. This method enables individuals to engage in at-home sampling of blood on DBS for (tele)diagnostics, screening programs, patient follow-up, and medication management.