Immunogenicity and safety of heterologous Omicron BA.1 and bivalent SARS-CoV-2 recombinant spike protein booster vaccines: a phase 3, randomized, clinical trial.

BACKGROUND: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone, or as a bivalent preparation in combination with the prototype vaccine (NVX-CoV2373), to assess antibody responses to SARS-CoV-2. METHODS: Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed. RESULTS: Of participants who received trial vaccine (N = 829), those administered NVX-CoV2515 (n = 286) demonstrated superior neutralizing antibody response to BA.1 versus NVX-CoV2373 (n = 274) at Day 14 (geometric mean titer ratio [95% CI]: 1.6 [1.33, 2.03]). Seroresponse rates [n/N; 95% CI] were 73.4% [91/124; 64.7, 80.9] for NVX-CoV2515 versus 50.9% [59/116; 41.4, 60.3] for NVX-CoV2373. All formulations were similarly well-tolerated. CONCLUSIONS: NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373.

Sea ice variability and trends in the Indian Ocean sector of Antarctica: Interaction with ENSO and SAM.

Antarctic sea ice variability is primarily associated with ocean-atmospheric forcing driven by anomalous conditions over the tropical regions of the Pacific and Indian Oceans. The ice-ocean-atmosphere dynamics in the Indian Ocean Sector (IOS) of Antarctica have been studied using monthly satellite and reanalysis observations over four decades (1979-2019). In this study, we revealed that the annual sea ice extent (SIE) in the IOS increases at a rate of 0.7 ± 0.9% decade-1, with a maximum increase in austral summer (5.9 ± 3.7% decade-1). The wavelet approach was used to determine the variability in IOS sea ice caused by the El Niño/Southern Oscillation (ENSO) and southern annular mode (SAM). The SIE has a significant association with both indices during the summer and autumn. In comparison to ENSO, the sea ice variability associated with SAM is typically seasonal in nature and lacks distinct patterns. The wavelet coherence analysis revealed a relatively weak relationship between ENSO and SAM but a highly significant coherence between climatic indices and SIE. We observed that sea ice in the IOS is influenced significantly by climatic oscillations during their negative SAM/El Niño or positive SAM/La Niña phases. Furthermore, the study demonstrated a substantial impact of climatic disturbances in determining the sea ice variability in the IOS.

Epidural blood patch for post-dural puncture headaches in adult and paediatric patients with malignancies: a review.

Many anaesthetists are hesitant to perform epidural blood patch in patients with cancer because of the potential risk of seeding the CNS with malignant cells. Recent evidence suggests that anaesthetists may view malignancy as a relative contraindication to epidural blood patch rather than an absolute contraindication. This review article summarises the clinical dilemma, reviews the existing literature, and proposes a treatment algorithm that includes the utilisation of for the management of post-dural puncture headache in the oncology population.

Awareness of the Harms of Continued Smoking Among Cancer Survivors.

BACKGROUND: Smoking cessation is an integral part of cancer survivorship. To help improve survivorship education, clinicians need an understanding of patient awareness of the harms of continued smoking. METHODS: Cancer survivors from Princess Margaret Cancer Centre (Toronto, ON) were surveyed on their awareness of the harms of continued smoking on cancer-related outcomes. Multivariable logistic regression models assessed factors associated with awareness and whether awareness was associated with subsequent cessation among smokers at diagnosis. RESULTS: Among 1118 patients, 23% were current smokers pre-diagnosis and 54% subsequently quit; 25% had lung and 30% head and neck cancers. Many patients reported being unaware that continued smoking results in greater cancer surgical complications (53%), increased radiation side effects (62%), decreased quality of life during chemotherapy (51%), decreased chemotherapy or radiation efficacy (57%), increased risk of death (40%), and increased development of second primaries (38%). Being a current smoker was associated with greater lack of awareness of some of these smoking harms (aORs = 1.53-2.20, P < 0.001-0.02), as was exposure to any second-hand smoke (aORs = 1.45-1.53, P = 0.006-0.04) and being diagnosed with early stage cancer (aORs = 1.38-2.31, P < 0.001-0.06). Among current smokers, those with fewer pack-years, being treated for cure, or had a non-tobacco-related cancer were more likely unaware. Awareness that continued tobacco use worsen quality of life after chemotherapy was associated with subsequent cessation (aOR = 2.26, P = 0.006). CONCLUSIONS: Many cancer survivors are unaware that continued smoking can negatively impact cancer-related outcomes. The impact of educating patients about the potential harms of continued smoking when discussing treatment plans should be further evaluated.

Spatio-temporal changes and prediction of Amery ice shelf, east Antarctica: A remote sensing and statistics-based approach.

The Amery ice shelf (AIS) dynamics and mass balance play key role to decipher changes in the global climate scenario. The spatio-temporal changes in morphology of the AIS were studied into a number of transects at 5 km uniform intervals using multi-dated Moderate Resolution Imaging Spectro-radiometer (MODIS) satellite data (2001-2016) of the austral summer months (January-March). Past ice shelf extents have been reconstructed and future ice shelf extents were estimated for 5- and 10-year time periods. The rate changes of AIS extent were estimated using the linear regression analysis and cross-validated with the coefficient of determination (R2) and root-mean-square error (RMSE) methods. Further, the changes in shelf extent were linked to prevailing factors viz. mass changes, Southern Annular Mode (SAM) index, and ocean-air temperatures. The study reveals that the AIS extent has been prograded at the rate of 994 m/year with an average 14.5 km increase in the areal extents during 2001-2016, as compared to the year 2001, whereas, the maximum advancement in ice shelf extent was recorded during the 2006-2016 period. Based on the linear regression analysis, the predicted ice shelf extents (i.e., the summer 2021 and 2016) show progradation in all the transects. About 52% of transects exhibit ±200 m RMSE values, indicating better agreement between the estimated and satellite-based ice-shelf position. The recent changes (2017-2019) observed in the ice shelf are cross validated with predicted ice self-extent rates. The eastern part of Mackenzie Bay to Ingrid Christensen coast recorded advancement in the ice shelf extents and mass which is the feedback of positive SAM along with a decrease in the temperatures (air temperature and sea surface temperature). The present study demonstrates that the combined use of satellite imagery and statistical techniques can be useful in quantifying and predicting ice shelf morphological variability.

Predicting gene expression in massively parallel reporter assays: A comparative study.

In many human diseases, associated genetic changes tend to occur within noncoding regions, whose effect might be related to transcriptional control. A central goal in human genetics is to understand the function of such noncoding regions: given a region that is statistically associated with changes in gene expression (expression quantitative trait locus [eQTL]), does it in fact play a regulatory role? And if so, how is this role "coded" in its sequence? These questions were the subject of the Critical Assessment of Genome Interpretation eQTL challenge. Participants were given a set of sequences that flank eQTLs in humans and were asked to predict whether these are capable of regulating transcription (as evaluated by massively parallel reporter assays), and whether this capability changes between alternative alleles. Here, we report lessons learned from this community effort. By inspecting predictive properties in isolation, and conducting meta-analysis over the competing methods, we find that using chromatin accessibility and transcription factor binding as features in an ensemble of classifiers or regression models leads to the most accurate results. We then characterize the loci that are harder to predict, putting the spotlight on areas of weakness, which we expect to be the subject of future studies.

An unusual case of primary tuberculosis of the patella and patellar tendon masquerading as gout.

Tuberculosis (TB), an infection caused by Mycobacterium tuberculosis, accounts for significant morbidity and mortality worldwide. While primary TB predominantly involves the respiratory system, approximately 10-19% patients have musculoskeletal involvement. We present a case of a 54-year-old year gentleman with insidious onset of anterior knee pain. Imaging demonstrated a soft tissue lesion involving the patellar tendon and eroding the inferior pole of the patella. The imaging features, particularly ultrasound, resembled those that are typically seen with gout. Ultrasound guided biopsy revealed this to be TB of the patella. The patient was successfully treated with antitubercular therapy. Musculoskeletal TB, while usually not a primary form of TB, is an important consideration particularly in patients with risk factors for the disease. Its imaging features can mimic other forms of arthropathy such as gout. Moreover, while the knee is a relatively common site for TB infection, isolated involvement of the patella and patellar tendon is extremely rare. The case highlights the possibility of rare musculoskeletal manifestation of TB as a well as a potential imaging pitfall of TB infection mimicking gout, which is an important consideration in clinical practice.

Cantilever Failure of Modular Uncemented Femoral Revision Stem in Patients with Poor Proximal Femoral Support; How to avoid it?

Objectives: Revision hip arthroplasty is a major surgical challenge and is even more difficult in cases with a deficient proximal femur. Modular uncemented cone body revision femoral stems were introduced as a solution. They have the advantage of optimising joint kinematics by allowing the variable degrees of version, offset and leg length. However, we noticed cantilever failure of such stems, particularly in patients with deficient proximal femoral support. Fatigue fracture of the revision femoral stems should raise questions about its use in patients with insufficient proximal femoral bone support. Methods: We present a case series of five patients with the cantilever failure of Stryker restoration modular stem conical distal femur prosthesis. These cases were identified during a retrospective review of revision hip surgeries performed at our trust. Results: The stem failed after an average of 22.6 months post-revision surgery. Primarily, poor proximal femur bone support with a well-fixed distal stem and secondarily high BMI led to this catastrophic failure in the absence of trauma. All five cases were re-revised to Stanmore proximal femoral replacement and achieved good functional outcomes after an average follow-up of seven years. Conclusion: Proximal femoral bone support should be restored to prevent early cantilever failure of distally fixed proximal modular revision femoral stems. Consider a proximal femoral replacement if we cannot ensure proximal bone support.

Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial.

BACKGROUND: SARS-CoV-2 variants evade immunity despite vaccination with prototype COVID-19 vaccines or previous infection. The 2019nCoV-311 (part 2) study is evaluating immune responses after two booster doses of a vaccine containing the omicron BA.5 subvariant spike protein in adults previously vaccinated with a prototype mRNA vaccine. This interim analysis reports on day 28 immunogenicity and safety outcomes after one booster dose. METHODS: In this phase 3, randomised, observer-blinded study conducted at 35 sites in Australia, medically stable, previously COVID-19-vaccinated (mRNA-based; ≥three doses) adults aged 18 years or older were enrolled and randomly allocated (1:1:1; via an interactive web response system) to receive two doses of bivalent (NVX-CoV2373 + NVX-CoV2540; bivalent group), authorised prototype (NVX-CoV2373; prototype group), or BA.5 (NVX-CoV2540; BA.5 group) vaccine. Only blinded personnel performed study assessments or had participant contact to collect data after study vaccination. Participants received vaccines containing 5 µg SARS-CoV-2 recombinant spike protein and 50 µg Matrix-M adjuvant, administered via a 0·5 mL intramuscular injection (2·5 µg of NVX-CoV2373 plus 2·5 µg of NVX-CoV2540 for the bivalent vaccine, prepared on-site as a 1:1 mixture). The coprimary endpoints include day 28 neutralising antibody geometric mean titre (GMT) ratios (GMTRs) to omicron BA.5 and the ancestral strain, and seroresponse rates to BA.5, in the bivalent and prototype groups. These endpoints were calculated in the per-protocol analysis set, which was defined as participants who had received a vaccine dose, had baseline and day 28 immunogenicity data, and were PCR-negative for SARS-CoV-2, with no major protocol deviations. The primary objective was to determine the primary outcome (antibody responses), which consisted of three comparisons: superiority of the bivalent versus prototype vaccine for neutralising antibody GMT to BA.5 (ie, lower bound of the GMTR 95% CI >1·0); non-inferiority of neutralising antibody seroresponse rate to BA.5 (ie, lower bound of the seroresponse rate 95% CI >-5%); and non-inferiority of neutralising antibody GMT to the ancestral strain (ie, lower bound of GMTR 95% CI >0·67). This trial was registered at ClinicalTrials.gov, number NCT05372588. FINDINGS: Between March 22, 2023 and May 2, 2023, 837 participants were screened for eligibility and 766 were randomly allocated to receive the BA.5 (n=255), prototype (n=252), or bivalent (n=259) vaccine. After accounting for exclusions due to participants being baseline SARS-CoV-2-positive, having previous infection, or protocol deviations, the per-protocol analysis set included 694 participants (236 in BA.5 group, 227 in prototype group, and 231 in bivalent group). In this interim analysis (maximum follow-up 35 days after the first dose), the bivalent group, compared with the prototype group, had superior neutralising antibody responses to BA.5 (GMT 1017·8 [95% CI 891·0-1162·6] vs 515·1 [450·4-589·0]; GMTR 2·0 [1·69-2·33]) and a non-inferior seroresponse rate to BA.5 at day 28 (39·8% [33·5-46·5] vs 12·3% [8·4-17·3]; difference 27·5% [19·8-35·0]). The bivalent group also had non-inferior neutralising antibody responses to the ancestral strain (GMTR 1·0 [0·84-1·20]), compared with the prototype group. All vaccines were similarly well tolerated. INTERPRETATION: All three coprimary endpoints were met in part 2 of the ongoing 2019nCoV-311 study. These data support the development of monovalent and/or bivalent vaccines for the most currently circulating variants, to optimise protection. With no new safety findings, further investigation of omicron-based subvariant vaccines is supported by the evidence. FUNDING: Novavax.

Spatiotemporal evolution of sea ice and its teleconnections with large-scale climate indices over Antarctica.

Sea ice variability patterns are highly influenced by several large-scale ocean-atmospheric oscillations. We analysed both statistical and wavelet coherence methods to examine sea ice's interannual and interdecadal variability. During the past 42-year, the total Southern Ocean sea ice extent (SIE) has expanded, while the Amundsen-Bellingshausen Sea SIE has decreased. A wavelet coherence analysis (WCA) of El Niño Southern Oscillation (ENSO) and the SIE in various sectors revealed an out-of-phase correlation between the Indian Ocean and the Ross Sea. There are significant out-of-phase correlations between sea ice variability and Indian Ocean Dipole (IOD) on an interannual scale. A consistent phase relationship was seen between SIE and Southern Annular Mode (SAM) over the past decade, with in-phase relationships advancing to out-of-phase relationships. The Interdecadal Pacific Oscillation (IPO) shifted from positive to negative after the 1990s. In recent years, SAM has had a stronger impact on sea ice variability than ENSO.

Cohort study of short-term outcomes after ACL-reconstruction using autograft with internal brace reinforcement versus isolated autograft demonstrating no significant difference.

Background: The gold standard treatment for Anterior Cruciate Ligament injury is reconstruction (ACL-R). Graft failure is the concern and ensuring a durable initial graft with rapid integration is crucial. Graft augmentation with implantable devices (internal brace reinforcement) is a technique purported to reduce the risk of rupture and hasten recovery. Few studies have examined these techniques, in particular when compared to non-augmented grafts. This study assesses the short-term outcome of ACL-R using augmented and non-augmented hamstring tendon autografts. Methods: This was a retrospective cohort study comparing augmented and non-augmented ACL-R. All procedures were performed in a single centre using the same technique. The Knee injury and Osteoarthritis Outcome Score [KOOS] was used to assess patient-reported outcomes. Results: There were 70 patients in the augmented and 111 patients in the control group. Mean graft diameter in the augmented group was 8.82 mm versus 8.44 mm in the non-augmented. Six strand graft was achievable in 73.5% of the augmented group compared to 33% in the non-augmented group. Two graft failures were reported in the non-augmented group and none in the augmented group. Patient satisfaction rates were higher in the augmented group. There was a statistically insignificant improvement in the postoperative KOOS in the augmented group compared to the non-augmented group (p 0.6). Irrespective of augmentation status, no correlation was found between the functional score and age, or femoral tunnel width. Conclusion: No statistically significant difference was demonstrated in the short-term functional outcome of ACL reconstruction using an augmented or non-augmented hamstring graft. Augmented ACL-R may achieve superior graft diameters, failure rates and patient reported outcomes when compared to nonaugmented ACL-R. Prospective trials are needed to examine this further.

A Novel Inhibitor against the Biofilms of Non-Tuberculous Mycobacteria.

Non-tuberculous Mycobacteria (NTM), previously classified as environmental microbes, have emerged as opportunistic pathogens causing pulmonary infections in immunocompromised hosts. The formation of the biofilm empowers NTM pathogens to escape from the immune response and antibiotic action, leading to treatment failures. NF1001 is a novel thiopeptide antibiotic first-in-class compound with potent activity against planktonic/replicating and biofilm forms of various NTM species. It is potent against both drug-sensitive and -resistant NTM. It has demonstrated a concentration-dependent killing of replicating and intracellularly growing NTM, and has inhibited and reduced the viability of NTM in biofilms. Combination studies using standard-of-care (SoC) drugs for NTM exhibited synergetic/additive effects, but no antagonism against both planktonic and biofilm populations of Mycobacterium abscessus and Mycobacterium avium. In summary, the activity of NF1001 alone or in combination with SoC drugs projects NF1001 as a promising candidate for the treatment of difficult-to-treat NTM pulmonary diseases (NTM-PD) and cystic fibrosis (CF) in patients.

Therapeutic Potential of Cannabis: A Comprehensive Review of Current and Future Applications.

Historically, cannabis has been valued for its pain-relieving, anti-inflammatory, and calming properties. Ancient civilizations like the Egyptians, Greeks, and Chinese medicines recognized their therapeutic potential. The discovery of the endocannabinoid system, which interacts with cannabis phytoconstituents, has scientifically explained how cannabis affects the human immune system, including the central nervous system (CNS). This review explores the evolving world of cannabis-based treatments, spotlighting its diverse applications. By researching current research and clinical studies, we probe into how cannabinoids like Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) help to manage conditions ranging from chronic pain, persistent inflammation, cancer, inflammatory bowel disease, and neurological disorders to even viral diseases such as Human Immunodeficiency virus (HIV), SARS-CoV-2. and the emerging monkeypox. The long-term recreational use of cannabis can develop into cannabis use disorder (CUD), and therefore, understanding the factors contributing to the development and maintenance of cannabis addiction, including genetic predisposition, neurobiological mechanisms, and environmental influences, will be timely. Shedding light on the adverse impacts of CUD underscores the importance of early intervention, effective treatment approaches, and public health initiatives to address this complex issue in an evolving landscape of cannabis policies and perceptions.

Malformation in coccolithophores in low pH waters: evidences from the eastern Arabian Sea.

Oceanic calcifying plankton such as coccolithophores is expected to exhibit sensitivity to climate change stressors such as warming and acidification. Observational studies on coccolithophore communities along with carbonate chemistry provide important perceptions of possible adaptations of these organisms to ocean acidification. However, this phytoplankton group remains one of the least studied in the northern Indian Ocean. In 2017, the biogeochemistry group at the Council for Scientific and Industrial Research-National Institute of Oceanography (CSIR-NIO) initiated a coccolithophore monitoring study in the eastern Arabian Sea (EAS). Here, we document for the first time a detailed spatial and seasonal distribution of coccolithophores and their controlling factors from the EAS, which is a well-known source of CO2 to the atmosphere. To infer the seasonality, data collected at three transects (Goa, Mangalore, and Kochi) during the Southwest Monsoon (SWM) of 2018 was compared with that of the late SWM of 2017. Apart from this, the abundance of coccolithophores was studied at the Candolim Time Series (CaTS) transect, off Goa during the Northeast Monsoon (NEM). The most abundant coccolithophore species found in the study region was Gephyrocapsa oceanica. A high abundance of G. oceanica (1800 × 103cells L-1) was observed at the Mangalore transect during the late SWM despite experiencing low pH and can be linked to nitrogen availability. The high abundance of G. oceanica at Mangalore was associated with high dimethylsulphide (DMS). Particulate inorganic carbon (PIC) and scattering coefficient retrieved from satellites also indicated a high abundance of coccolithophores off Mangalore during the late SWM of 2017. Interestingly, G. oceanica showed malformation during the late SWM in low pH waters. Malformation in coccolithophores could have a far-reaching impact on the settling fluxes of organic matter and also on the emissions of climatically important gases such as DMS and CO2, thus influencing atmospheric chemistry. The satellite data for PIC in the EAS indicates a high abundance of coccolithophore in recent years, especially during the warm El Nino years (2015 and 2018). This warrants the need for a better assessment of the fate of coccolithophores in high-CO2 and warmer oceans.

Are children who play a sport or a musical instrument better at motor imagery than children who do not?

OBJECTIVE: Playing a sport or a musical instrument is presumed to improve motor ability. One would therefore predict that children who play a sport or music are better at motor imagery tasks, which rely on an intact cortical proprioceptive representation and precise motor planning, than children who do not. The authors tested this prediction. METHODS: This study involved an online questionnaire and then a motor imagery task. The task measured the reaction time (RT) and the accuracy for left/right-hand judgements in children aged 5 to 17 years. Forty pictured hands (20 left), held in various positions and rotated zero, 90°, 180° or 270°, were displayed on a screen. Participants indicated whether the displayed hands were left or right by pressing keys on a keyboard. RESULTS: Fifty-seven children (30 boys; mean±SD age=10±3.3 years) participated. The mean±SD RT was 3015.4±1330.0 ms and the accuracy was 73.9±16.6%. There was no difference in RT between children who played sport, music, neither or both (four-level one-way analysis of variance, p=0.85). There was no difference in accuracy between groups either (Kruskal-Wallis, p=0.46). In a secondary analysis, participants whose parents rated them as being 'clumsy' were no slower (n.s.) but were about 25% less accurate than those rated coordinated or very coordinated (p<0.05). CONCLUSION: The authors conclude against the intuitively sensible and widely held view that participation in a sport or music is associated with better cortical proprioceptive representation and motor planning. Secondary analyses suggest that parent-rated clumsiness is negatively related to motor imagery performance.

Liver Outcome in Renal Transplant Recipients Who Acquired Hepatitis C Infection From an Infected Graft: Study Based on Liver Biopsy Findings.

Long-term liver outcome in hepatitis C virus (HCV)-negative kidney recipients who acquired HCV infection from viremic donors is of intense interest in the transplant community. We evaluated the incidence of fibrosis in liver biopsy specimens of recipients who were transplanted with HCV-infected grafts. Methods: Patients were evaluated in the hepatology clinic, and 29 patients agreed to undergo liver biopsy. The liver histology was scored by the meta-analysis of histological data in viral hepatitis scoring system and was assessed by hepatopathologists. The fibrosis score was compared between patients who initiated direct-acting antiviral (DAA) within 6 wk (n = 6) and after 6 wk (n = 29). Results: Eighty-nine aviremic patients were transplanted with HCV-infected grafts between March 2018 and October 2019. All patients developed HCV infection and were treated with DAA treatment after kidney transplantation (median, 70 d; interquartile range, 55-85 d). All patients (n = 89) achieved sustained virologic response with DAA. The median follow-up time from kidney transplant to liver biopsy was 28 mo (interquartile range, 26-30 mo). Twenty-five patients (86%) had F0, and 4 patients (14%) had F1 fibrosis. No patient had advanced fibrosis (F3-F4). Grade 1 inflammation was present in 6 (21%) patients, whereas 26 (90%) patients had iron accumulation in the hepatocytes and reticuloendothelial cells. There was no difference in the fibrosis score between patients who received treatment within 6 wk versus after 6 wk (P = 0.55). Conclusions: Kidney transplantation of HCV-infected graft to HCV-negative recipients is safe and has no long-term liver-related complications with successful eradication of HCV. In our cohort, delayed treatment did not affect sustained virologic response or liver histology.

Identifying disease-critical cell types and cellular processes by integrating single-cell RNA-sequencing and human genetics.

Genome-wide association studies provide a powerful means of identifying loci and genes contributing to disease, but in many cases, the related cell types/states through which genes confer disease risk remain unknown. Deciphering such relationships is important for identifying pathogenic processes and developing therapeutics. In the present study, we introduce sc-linker, a framework for integrating single-cell RNA-sequencing, epigenomic SNP-to-gene maps and genome-wide association study summary statistics to infer the underlying cell types and processes by which genetic variants influence disease. The inferred disease enrichments recapitulated known biology and highlighted notable cell-disease relationships, including γ-aminobutyric acid-ergic neurons in major depressive disorder, a disease-dependent M-cell program in ulcerative colitis and a disease-specific complement cascade process in multiple sclerosis. In autoimmune disease, both healthy and disease-dependent immune cell-type programs were associated, whereas only disease-dependent epithelial cell programs were prominent, suggesting a role in disease response rather than initiation. Our framework provides a powerful approach for identifying the cell types and cellular processes by which genetic variants influence disease.

Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. Here, we construct a high-resolution molecular landscape of the cellular subtypes and spatial communities that compose PDAC using single-nucleus RNA sequencing and whole-transcriptome digital spatial profiling (DSP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment naive. We uncovered recurrent expression programs across malignant cells and fibroblasts, including a newly identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities with distinct contributions from malignant, fibroblast and immune subtypes: classical, squamoid-basaloid and treatment enriched. Our refined molecular and cellular taxonomy can provide a framework for stratification in clinical trials and serve as a roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions.

Spatio-temporal change and variability of Barents-Kara sea ice, in the Arctic: Ocean and atmospheric implications.

The reduction in Arctic sea-ice in recent decades has been a significant indicator of climate change and is related to weather pattern changes across the Arctic regions. In this study, for the period 1979-2018, we addressed the processes controlling the sea-ice cover in the Barents-Kara Sea (BKS). The inter-annual variability of the sea-ice extent (SIE) in BKS was analyzed using passive microwave satellite observations. The ocean-atmospheric forcing variables which including air temperature (AT), sea surface temperature (SST) and outgoing long-wave radiation (OLR) were derived from ERA-Interim reanalysis data. The spatial correlation analysis was performed for the year 2016 and 1998, where sea ice concentration (SIC) in BKS is recorded as a minimum and maximum respectively. The long-term analysis (1979-2018) shows negative trends of the Arctic SIE (-4.7 ± 0.3% decade-1) with the largest decrease in the Barents Sea (-23 ± 2.5% decade-1) and Kara Sea (-7.3 ± 0.9% decade-1). However, the sea-ice decline in the Barents Sea was recorded very high during the winter (-17.6 ± 2.2% decade-1) compared to the Kara Sea (-0.8 ± 0.2% decade-1). Sea-ice cover in the Barents Sea is more likely to recede during the summers -4.1 ± 0.7 x 103 km2yr-1 due to warm inflow of Atlantic waters. Correlation analysis using statistically significant trend values with p-values ≤ 0.01 was performed from 1982 to 2018, the SIC of BKS showing significant negative correlation analyses with SST (-0.75; p-value = 0.01), SAT (-0.84; p-value = 0.00) and OLR (-0.76; p-value = 0.00). In recent years, Atlantic Multi-decadal Oscillation (AMO) index has become positive due to an increase in SST anomalies, while, AMO does not reflect the cooling events in the BKS. During recent Arctic climate change, caused by atmospheric heat transport, the loss of sea-ice at BKS is becoming a major factor. In this study, new perspectives of the complex processes associated with Arctic warming and the declining sea-ice in the BKS region are demonstrated.

Hallux varus: A literature review.

Hallux varus is a rare foot deformity due to iatrogenic, post-traumatic, idiopathic, inflammatory, spontaneous, or congenital pathologies. Acquired hallux varus, in particular, iatrogenic type, is the commonest. The primary pathology is the abnormal musculotendinous forces secondary to soft tissue or bony imbalance exerting varus deforming force. Understanding the anatomy of the hallux stabilisers and the pathophysiology of hallux varus is vital in its management. It would be helpful to understand the potential surgical pitfalls leading to iatrogenic hallux varus. This literature review summarises all the published facts about hallux varus, focussing on anatomy, pathophysiology, clinical and radiological assessment, and management.