Cordova: web-based management of genetic variation data.

UNLABELLED: Cordova is an out-of-the-box solution for building and maintaining an online database of genetic variations integrated with pathogenicity prediction results from popular algorithms. Our primary motivation for developing this system is to aid researchers and clinician-scientists in determining the clinical significance of genetic variations. To achieve this goal, Cordova provides an interface to review and manually or computationally curate genetic variation data as well as share it for clinical diagnostics and the advancement of research. AVAILABILITY AND IMPLEMENTATION: Cordova is open source under the MIT license and is freely available for download at https://github.com/clcg/cordova.

Exploration of microstructural characteristics, mechanical properties, andin vitrobiocompatibility of biodegradable porous magnesium scaffolds for orthopaedic implants.

In this study, porous magnesium (Mg) scaffolds were investigated with varying strontium (Sr) and constant zinc (Zn) concentrations through the powder metallurgy process. All samples were examined at room temperature to evaluate their microstructure, mechanical andin-vitrodegradation behaviour and biological properties. Results indicated that adding Sr was associated with fine average grain size, increased mechanical strength, and a decreased corrosion rate. All samples show tiny isolated and open interconnected pores (porosities: 18%-30%, pores: 127-279 µm) with a suitable surface roughness of less than 0.5 µm. All the provided samples possess mechanical and hemocompatible properties that closely resemble natural bone. Mg-4Zn-2Sr has the highest hardness (102.61 ± 15.1 HV) and compressive strength (24.80 MPa) than Mg-4Zn-0.5Sr (85 ± 8.5 HV, 22.14 MPa) and Mg-4Zn-1Sr (97.71 ± 11.2 HV, 18.06 MPa). Immersion results revealed that samples in phosphate-buffered saline solutions have excellent degradability properties, which makes them a promising biodegradable material for orthopaedic applications. The scaffold with the highest Sr concentration shows the best optimised mechanical and degradation behaviour out of the three porous scaffolds, with a 2.7% hemolysis rate.

Biodegradable implant application: Electrodeposition of HA/TiO2/ZrO2 coating onto Zn-composite substrates.

Zinc has currently emerged as a promising biodegradable metal due to its good biocompatible property and promising degradation behaviour. Additionally, inadequate mechanical strength and a lower cell viability value fall short of what is needed for biodegradable implants. In this work, we used the stir-casting process to create a biodegradable Zn-1Mg-1Cu-1HA (ZHA) and Zn-1Mg-1Cu-1ZrO2 (ZZR) composite onto which ceramics composite coating is done by electrodeposition technique to enhance the biocompatibility. The as-cast sample has uniformly distributed fine MgZn2 and CuZn2 phases in a α-Zn matrix, according to microstructural analysis. The mechanical test confirms that ZZR composite exhibited high tensile and compressive properties, including compressive yield strength of 369.562 MPa, a yield tensile strength of 88.725 MPa and ultimate tensile strength of 116.21 MPa. The result of potentiodynamic polarization test shows that the coated ZZR composite sample gives a corrosion rate value of 0.112 mm/year. From immersion tests, the degradation rate obtained a much lower value after immersing the sample in PBS solution for 55 days (0.067 mm/year). Moreover, an extract of coated ZZR composite shows good cell viability in comparison to the uncoated sample at a concentration of 25%, 50% and 75%. Also, the hemolysis percentage for coated ZZR sample is lower than the other prepared uncoated sample (3.072%) Overall, the result obtained proves that the coated ZZR composite sample can be expected as a capable material for implant application.

SCAPS study on the effect of various hole transport layer on highly efficient 31.86% eco-friendly CZTS based solar cell.

Copper Zinc Tin Sulphide (CZTS) is a propitious semiconductor for active absorber material in thin-film solar cells (SCs). Here, SC architecture comprising FTO/ZnS/CZTS/variable HTLs/Au is discussed. Fluorine-doped tin oxide (FTO) and gold (Au) are used as front and back contacts, respectively. Zinc sulphide (ZnS) is used as an active electron transport layer (ETL), while different Cu-based materials (Cu2O, CuO, CuI, and CuSCN) are used as hole transport layers (HTL). A one-dimensional solar cell capacitance simulator (SCAPS-1D) is utilized to simulate the SC structure. Among different Cu-based HTLs, Cu2O is preferred as a potential candidate for high cell performance of CZTS-based SC. The effects of various layer parameters such as thickness, doping density, and carrier concentrations, electron affinity of HTL and absorber, respectively, are also discussed. After optimization of the device, variation of operating temperature and the effect of series and shunt resistance are also taken into consideration. The optimized results of thickness and acceptor concentration (NA) of absorber material are 1.5 µm and approx. 1.0 × 1019 cm-3, respectively. In addition, the function of HTL (with and without) in the designed SC structure is also studied. Capacitance-voltage (C-V) characteristics are also discussed to get an insight of built-in potential. We have achieved cell performances viz. efficiency = 31.86%, short circuit current density = 32.05 mA/cm2, open circuit voltage = 1.19 V, and fill factor = 83.37%.

Neutralising antibody responses against SARS-CoV-2 Omicron BA.4/5 and wild-type virus in patients with inflammatory bowel disease following three doses of COVID-19 vaccine (VIP): a prospective, multicentre, cohort study.

Background: Patients with inflammatory bowel disease (IBD) receiving anti-TNF and JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the Omicron BA.4/5 variant. Methods: In this multicentre cohort study, we prospectively recruited 340 adults (69 healthy controls and 271 IBD) at nine UK hospitals between May 28, 2021 and March 29, 2022. The IBD study population was established (>12 weeks therapy) on either thiopurine (n = 63), infliximab (n = 45), thiopurine and infliximab combination therapy (n = 48), ustekinumab (n = 45), vedolizumab (n = 46) or tofacitinib (n = 24). Patients were excluded if they were being treated with any other immunosuppressive therapies. Participants had two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccines, followed by a third dose of either BNT162b2 or mRNA1273. Pseudo-neutralisation assays against SARS-CoV-2 wild-type and BA.4/5 were performed. The half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARS-CoV-2 neutralising response against wild-type virus and Omicron BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, vaccine type, age, and interval between vaccination and blood collection. This study is registered with ISRCTN (No. 13495664). Findings: Both heterologous (first two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both wild-type SARS-CoV-2 virus and the Omicron BA.4/5 variant in healthy participants and patients with IBD. Antibody titres against BA.4/5 were significantly lower than antibodies against wild-type virus in both healthy participants and patients with IBD (p < 0.0001). Multivariable models demonstrated that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in patients with IBD on infliximab (Geometric Mean Ratio (GMR) 0.19 [0.10, 0.36], p < 0.0001), infliximab and thiopurine combination (GMR 0.25 [0.13, 0.49], p < 0.0001) or tofacitinib (GMR 0.43 [0.20, 0.91], p = 0.028), but not in patients on thiopurine monotherapy, ustekinumab, or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against wild-type (p = 0.037) and BA.4/5 (p = 0.045). Interpretation: A third dose of a COVID-19 mRNA vaccine based on the wild-type spike glycoprotein significantly boosts neutralising antibody titres in patients with IBD. However, responses are lower against the Omicron variant BA.4/5, particularly in patients taking anti-TNF and JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed patients with IBD may receive additional benefit from bivalent vaccine boosters which target Omicron variants. Funding: Pfizer.

Evaluation of biodegradable Zn-1Mg-1Mn and Zn-1Mg-1Mn-1HA composites with a polymer-ceramics coating of PLA/HA/TiO2 for orthopaedic applications.

Zn is a promising biodegradable metal that shows huge potential as bioresorbable implant material as it possesses outstanding biocompatibility and high corrosion resistance than Mg. However, the low value of mechanical strength and hardness has hugely restricted its application. Moreover, incorporating alloying elements have typically magnified its mechanical properties. In the current study, the effect of the alloying component Mn and HA on the Zn-Mg composite and also the effect of polymer-ceramics nanofiber coating on the composite sample was studied. The result shows that the current studied samples were mainly comprised of a primary Zn matrix and a secondary phase of Mg2Zn11. The prepared sample shows very high compressive yield strength (CYS 228 MPa) and hardness (83 HV). The value of corrosion rates of the as-cast Zn-1Mg-1Mn-1HA sample was higher in comparison to that of the as-cast Zn-1Mg-1Mn sample, but after the polymer-ceramics nanofiber coating formation of PLA/HA/TiO2, the values were reduced to a more significant extent and achieved values of 0.01484 mm/year from 0.01892 mm/year in electrochemical tests. Moreover, the coated and uncoated sample shows outstanding hemocompatibility for both samples, but the minimum value is obtained for coated Zn-1Mg-1Mn-1HA sample (2.251%). The viability of MG63 cells cultured in different diluted extracts (25% and 50% extract) of the coated Zn-1Mg-1Mn-1HA sample reached a value greater than 90%, which displayed no possible cytotoxicity for biomedical applications.

COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study.

BACKGROUND: COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to assess whether immunosuppressive treatments were associated with reduced antibody and T-cell responses in patients with IBD after a third vaccine dose. METHODS: VIP was a multicentre, prospective, case-control study done in nine centres in the UK. We recruited immunosuppressed patients with IBD and non-immunosuppressed healthy individuals. All participants were aged 18 years or older. The healthy control group had no diagnosis of IBD and no current treatment with systemic immunosuppressive therapy for any other indication. The immunosuppressed patients with IBD had an established diagnosis of Crohn's disease, ulcerative colitis, or unclassified IBD using standard definitions of IBD, and were receiving established treatment with one of six immunosuppressive regimens for at least 12 weeks at the time of first dose of SARS-CoV-2 vaccination. All participants had to have received three doses of an approved COVID-19 vaccine. SARS-CoV-2 spike antibody binding and T-cell responses were measured in all participant groups. The primary outcome was anti-SARS-CoV-2 spike (S1 receptor binding domain [RBD]) antibody concentration 28-49 days after the third vaccine dose, adjusted by age, homologous versus heterologous vaccine schedule, and previous SARS-CoV-2 infection. The primary outcome was assessed in all participants with available data. FINDINGS: Between Oct 18, 2021, and March 29, 2022, 352 participants were included in the study (thiopurine n=65, infliximab n=46, thiopurine plus infliximab combination therapy n=49, ustekinumab n=44, vedolizumab n=50, tofacitinib n=26, and healthy controls n=72). Geometric mean anti-SARS-CoV-2 S1 RBD antibody concentrations increased in all groups following a third vaccine dose, but were significantly lower in patients treated with infliximab (2736·8 U/mL [geometric SD 4·3]; p<0·0001), infliximab plus thiopurine (1818·3 U/mL [6·7]; p<0·0001), and tofacitinib (8071·5 U/mL [3·1]; p=0·0018) compared with the healthy control group (16 774·2 U/mL [2·6]). There were no significant differences in anti-SARS-CoV-2 S1 RBD antibody concentrations between the healthy control group and patients treated with thiopurine (12 019·7 U/mL [2·2]; p=0·099), ustekinumab (11 089·3 U/mL [2·8]; p=0·060), or vedolizumab (13 564·9 U/mL [2·4]; p=0·27). In multivariable modelling, lower anti-SARS-CoV-2 S1 RBD antibody concentrations were independently associated with infliximab (geometric mean ratio 0·15 [95% CI 0·11-0·21]; p<0·0001), tofacitinib (0·52 [CI 0·31-0·87]; p=0·012), and thiopurine (0·69 [0·51-0·95]; p=0·021), but not with ustekinumab (0·64 [0·39-1·06]; p=0·083), or vedolizumab (0·84 [0·54-1·30]; p=0·43). Previous SARS-CoV-2 infection (1·58 [1·22-2·05]; p=0·0006) was independently associated with higher anti-SARS-CoV-2 S1 RBD antibody concentrations and older age (0·88 [0·80-0·97]; p=0·0073) was independently associated with lower anti-SARS-CoV-2 S1 RBD antibody concentrations. Antigen-specific T-cell responses were similar in all groups, except for recipients of tofacitinib without evidence of previous infection, where T-cell responses were significantly reduced relative to healthy controls (p=0·021). INTERPRETATION: A third dose of COVID-19 vaccine induced a boost in antibody binding in immunosuppressed patients with IBD, but these responses were reduced in patients taking infliximab, infliximab plus thiopurine, and tofacitinib. Tofacitinib was also associated with reduced T-cell responses. These findings support continued prioritisation of immunosuppressed groups for further vaccine booster dosing, particularly patients on anti-TNF and JAK inhibitors. FUNDING: Pfizer.

Pressure: the politechnics of water supply in Mumbai.

In Mumbai, most all residents are delivered their daily supply of water for a few hours every day, on a water supply schedule. Subject to a more precarious supply than the city's upper-class residents, the city's settlers have to consistently demand that their water come on "time" and with "pressure." Taking pressure seriously as both a social and natural force, in this article I focus on the ways in which settlers mobilize the pressures of politics, pumps, and pipes to get water. I show how these practices not only allow settlers to live in the city, but also produce what I call hydraulic citizenship­a form of belonging to the city made by effective political and technical connections to the city's infrastructure. Yet, not all settlers are able to get water from the city water department. The outcomes of settlers' efforts to access water depend on a complex matrix of socionatural relations that settlers make with city engineers and their hydraulic infrastructure. I show how these arrangements describe and produce the cultural politics of water in Mumbai. By focusing on the ways in which residents in a predominantly Muslim settlement draw water despite the state's neglect, I conclude by pointing to the indeterminacy of water, and the ways in which its seepage and leakage make different kinds of politics and publics possible in the city.

Predicting the Spread of COVID-19 Using SIR Model Augmented to Incorporate Quarantine and Testing.

India imposed a nationwide lockdown from 25th March 2020 onwards to combat the spread of COVID-19 pandemic. To model the spread of a disease and to predict its future course, epidemiologists make use of compartmental models such as the SIR model. In order to address some of the assumptions of the standard SIR model, a new modified version of SIR model is proposed in this paper that takes into account the percentage of infected individuals who are tested and quarantined. This approach helps overcome the assumption of homogenous mixing of population which is inherent to the conventional SIR model. Using the available data of the number of COVID-19 positive cases reported in the state of Kerala, and in India till 26th April, 2020 and 12th May 2020, respectively, the parameter estimation problem is converted into an optimization problem with the help of a least squared cost function. The optimization problem is then solved using differential evolution optimizer. The impact of lockdown is quantified by comparing the rising trend in infections before and during the lockdown. Using the estimated set of parameters, the model predicts that in the state of Kerala, by using certain interventions the pandemic can be successfully controlled latest by the first week of July, whereas the R0 value for India is still greater than 1, and hence lifting of lockdown from all regions of the country is not advisable.

Pericentral hydroxychloroquine retinopathy in a Caucasian female.

PURPOSE: To report a rare presentation of the pericentral pattern of hydroxychloroquine (HCQ) retinal toxicity in a Caucasian female. OBSERVATIONS: The patient presented with 20 years of exposure to HCQ, at a daily dose of 5.2mg/kg of actual body weight, and manifested a pericentral-only phenotype of HCQ toxicity, as demonstrated with detailed structural and functional testing. CONCLUSIONS AND IMPORTANCE: Although rare, the pericentral pattern of HCQ toxicity may occur in Caucasian patients in the absence of paracentral changes.