HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text

Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn's disease: 3-year data from the prospective, multicentre PANTS cohort study

This is the final version. Available from Elsevier via the DOI in this record. Background We sought to report the effectiveness of infliximab and adalimumab over the first 3 years of treatment and to define the factors that predict anti-TNF treatment failure and the strategies that prevent or mitigate loss of response. Methods Personalised Anti-TNF therapy in Crohn’s disease (PANTS) is a UK-wide, multicentre, prospective observational cohort study reporting the rates of effectiveness of infliximab and adalimumab in anti-TNF-naive patients with active luminal Crohn’s disease aged 6 years and older. At the end of the first year, sites were invited to enrol participants still receiving study drug into the 2-year PANTS-extension study. We estimated rates of remission across the whole cohort at the end of years 1, 2, and 3 of the study using a modified survival technique with permutation testing. Multivariable regression and survival analyses were used to identify factors associated with loss of response in patients who had initially responded to anti-TNF therapy and with immunogenicity. Loss of response was defined in patients who initially responded to anti-TNF therapy at the end of induction and who subsequently developed symptomatic activity that warranted an escalation of steroid, immunomodulatory, or anti-TNF therapy, resectional surgery, or exit from study due to treatment failure. This study was registered with ClinicalTrials.gov, NCT03088449, and is now complete. Findings Between March 19, 2014, and Sept 21, 2017, 389 (41%) of 955 patients treated with infliximab and 209 (32%) of 655 treated with adalimumab in the PANTS study entered the PANTS-extension study (median age 32·5 years [IQR 22·1–46·8], 307 [51%] of 598 were female, and 291 [49%] were male). The estimated proportion of patients in remission at the end of years 1, 2, and 3 were, for infliximab 40·2% (95% CI 36·7–43·7), 34·4% (29·9–39·0), and 34·7% (29·8–39·5), and for adalimumab 35·9% (95% CI 31·2–40·5), 32·9% (26·8–39·2), and 28·9% (21·9–36·3), respectively. Optimal drug concentrations at week 14 to predict remission at any later timepoints were 6·1–10·0 mg/L for infliximab and 10·1–12·0 mg/L for adalimumab. After excluding patients who had primary non-response, the estimated proportions of patients who had loss of response by years 1, 2, and 3 were, for infliximab 34·4% (95% CI 30·4–38·2), 54·5% (49·4–59·0), and 60·0% (54·1–65·2), and for adalimumab 32·1% (26·7–37·1), 47·2% (40·2–53·4), and 68·4% (50·9–79·7), respectively. In multivariable analysis, loss of response at year 2 and 3 for patients treated with infliximab and adalimumab was predicted by low anti-TNF drug concentrations at week 14 (infliximab: hazard ratio [HR] for each ten-fold increase in drug concentration 0·45 [95% CI 0·30–0·67], adalimumab: 0·39 [0·22–0·70]). For patients treated with infliximab, loss of response was also associated with female sex (vs male sex; HR 1·47 [95% CI 1·11–1·95]), obesity (vs not obese 1·62 [1·08–2·42]), baseline white cell count (1·06 [1·02–1·11) per 1 × 10⁹ increase in cells per L), and thiopurine dose quartile. Among patients treated with adalimumab, carriage of the HLA-DQA1*05 risk variant was associated with loss of response (HR 1·95 [95% CI 1·17–3·25]). By the end of year 3, the estimated proportion of patients who developed anti-drug antibodies associated with undetectable drug concentrations was 44·0% (95% CI 38·1–49·4) among patients treated with infliximab and 20·3% (13·8–26·2) among those treated with adalimumab. The development of antidrug antibodies associated with undetectable drug concentrations was significantly associated with treatment without concomitant immunomodulator use for both groups (HR for immunomodulator use: infliximab 0·40 [95% CI 0·31–0·52], adalimumab 0·42 [95% CI 0·24–0·75]), and with carriage of HLA-DQA1*05 risk variant for infliximab (HR for carriage of risk variant: infliximab 1·46 [1·13–1·88]) but not for adalimumab (HR 1·60 [0·92–2·77]). Concomitant use of an immunomodulator before or on the day of starting infliximab was associated with increased time without the development of anti-drug antibodies associated with undetectable drug concentrations compared with use of infliximab alone (HR 2·87 [95% CI 2·20–3·74]) or introduction of an immunomodulator after anti-TNF initiation (1·70 [1·11–2·59]). In years 2 and 3, 16 (4%) of 389 patients treated with infliximab and 11 (5%) of 209 treated with adalimumab had adverse events leading to treatment withdrawal. Nine (2%) patients treated with infliximab and two (1%) of those treated with adalimumab had serious infections in years 2 and 3. Interpretation Only around a third of patients with active luminal Crohn’s disease treated with an anti-TNF drug were in remission at the end of 3 years of treatment. Low drug concentrations at the end of the induction period predict loss of response by year 3 of treatment, suggesting higher drug concentrations during the first year of treatment, particularly during induction, might lead to better long-term outcomes. Anti-drug antibodies associated with undetectable drug concentrations of infliximab, but not adalimumab, can be predicted by carriage of HLA-DQA1*05 and mitigated by concomitant immunomodulator use for both drugs.Guts UKCrohn’s and Colitis UKCure Crohn’s ColitisAbbVieMerck Sharp and DohmeNapp PharmaceuticalsPfizerCelltrion Healthcar

Biogenic Silver Nanoparticles from Stereospermum kunthianum Cham Stem Bark Extract: Synthesis, Characterization, In Vitro Antimicrobial Study and Cytotoxicity Effects Against Brine Shrimp Artemia

Metal nanoparticles as a category of nanomaterial are receiving interest due to their wide range of applications including in biomedical fields. Among these nanoparticles, silver nanoparticles are the most extensively studied for medical applications because they have been proven to exhibit excellent activity against a wide range of medically significant pathogenic microorganisms, including bacteria, viruses, fungi, and yeasts. In this work, silver nanoparticles were biogenically synthesized using the stem bark extract of Stereospermum kunthianum Cham as capping agent. Physicochemical properties, antioxidant activity, antimicrobial properties and in vitro cytotoxicity of the synthesized AgNPs were studied following standard procedures. UV-Vis studies show broad absorbance peak of the nanoparticles between 430 and 450 nm, SEM image shows that some of the synthesized nanoparticles are near spherical shape with many of the particles appear to have irregular shapes while the material average crystalline size from the XRD analysis was 27.878 mm. The synthesized AgNPs exhibits moderate antioxidant activity with IC50 value of 124.84 μg/mL. Among the microorganism tested, the AgNPs shows more activity against Staphylococcus aureus than Salmonella typhi and Candida albicans. Brine shrimp lethality test of the synthesized AgNPs indicates some level of cytotoxicity with LC50 of 461.850 μg/mL. using biological materials as reducing agents remains best green approach for the synthesis of silver nanoparticles

Antioxidant Activity and In Vitro Inhibition Property of Mitrocarpus hirtus Leaf Extracts Against Tinea capitis (Scalp Ringworm)

Tinea capitis or scalp ringworm is a fungal skin disorder commonly found in children below 12-year-old. The management of ringworm by mean of synthetic drugs continue to face setback as result of antibiotic resistance being exhibited by the disease-causing fungi. Mitracarpus hirtus (L) is a weed plant found on gardens, farms and fields with wide geographical distributions. Pharmacological studies of the plant show its potent antifungal potentials as it is used traditionally for the treatment of skin diseases. The aim of this preliminary study is to examine the antioxidant activities and inhibitory properties of various solvent extracts of M. hirtus leaves against Tinea capitis by standard procedures.  The in vitro antioxidant activities show that all extracts possess moderate radical scavenging properties with IC50 values of 159.12±0.48µg/mL, 832.48±64.53µg/mL, 547.68±12.3553µg/mL and 168.41±5.0 µg/mL for Aqueous Residue, n-hexane, chloroform and ethylacetate extracts respectively. Considerable inhibitory effect on the growth of Tinea capitis was observed from the zone of inhibitions of the extracts with ethylacetate fraction exhibiting highest inhibition as the concentration increases. This study shows the potential of M. hirtus to inhibit the growth of tinea capitis. An extensive research is recommended in order to isolate the compounds responsible for the observed activities of the plant

Severe acute respiratory syndrome Coronavirus-2 infection: A synopsis of the host immune responses and viral immune evasion strategies involved

The novel coronavirus designated as SARS-CoV-2 is the etiological agent of coronavirus disease 2019 (COVID-19), which rendered the care of the global health powerless and plunged the world economy into a historic decline. This disease is characterized by different clinical pictures; ranging from asymptomatic mild phase to severe illness with acute respiratory distress syndrome (ARDS), in addition to having no specific therapy. The protective immunity involving solid CD4+ T-cells, viral specific CD8+ T-cells and the neutralizing immunoglobulins have been established in most of the convalescent COVID-19 individuals. On the other hand, the host immune response to severe COVID-19 infection has been attributed to the inflammatory cytokine storm, and to influx of the activated immune cells to the lungs; leading to severe pneumonia, extensive ARDS and finally to death. Despite of this, the protective and pathogenic aspects of the human immunity have not been fully elucidated. Recent attempts conducted by several published research works have focused on information derived from the immune responses to the severe acute respiratory syndrome-related coronavirus diseases (mainly; SARS and MERS). However, these works lack sufficiency due to variations in the transmissibility, virulence, host-virus interactions and the immune evasion mechanisms. Hence, adequate understanding of the host immune response mechanisms to SARS-CoV-2 will generate the impetus towards effective control and preventive measures. The objectives of this article were to provide an overview of the host immune responses to SARS-CoV-2 infection, the viral immune evasion strategies, and to define certain knowledge gaps that require further studies

Antibiotics Resistance Pattern of Coliform Bacteria Isolated From Slaughterhouse Wastewater in Jega Town, Kebbi State, Nigeria

Wastewater is an essential reservoir of pathogenic bacteria, which include resistant strains. This study determined the antibiotics resistance pattern of Coliform bacteria isolated from slaughterhouse wastewater in Jega local government. Five different samples of wastewater from different locations of a slaughterhouse were collected using standard sample collection techniques. Coliform bacteria were isolated using the standard microbiological method. The total bacterial count was determined using plate count agar. Suspected coliforms were identified based on morphological and biochemical tests. Antimicrobial susceptibility testing was carried out using the standard disc diffusion method. The highest bacterial count (8.4x102 CFU/ml) was observed from the wastewater collection point, and the lowest bacterial (1.2x102 CFU/ml) count from the slaughtering point. Three Gram-negative bacteria, Escherichia coli, Pseudomonas aeruginosa, and Enterobacter aerogenes, were identified. Escherichia coli was the most frequently isolated in slaughterhouse wastewater 39 (45.8%). Among the antibiotics tested against isolated bacteria, Septrin was the most resistant antibiotics recorded against E. coli and E. aerogenes with 84.61% and 88.89% resistant, respectively. Pseudomonas aeruginosa was found to show higher resistance to Chloramphenicol and Septrin with 84.21% resistance each. The occurrence of antibiotic-resistant bacteria from slaughterhouse wastewater showed the risks associated with antimicrobial drug resistance transferred from food-producing animals to humans. Management concerns, such as local government health officers and community development officers, should increase the sensitization of slaughterhouse workers by organizing conferences or conducting radio talk to educates these slaughterhouse workers on the treatment of slaughterhouse wastewater and health risk associated with antimicrobial-drug resistance transferred from animals to humans

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19. Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24). Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research