Prevalence of frailty in patients with lower extremity peripheral arterial disease: A systematic review and meta-analysis

BackgroundIncreasing studies have reported on the prevalence of frailty in patients with peripheral artery disease (PAD). The aim of this systematic review and meta-analysis was to estimate the pooled prevalence of frailty in patients with lower extremity PAD.MethodsTwo authors systematically searched PubMed and Embase databases from their inception to August 8, 2022. Original articles that reported the prevalence of frailty in patients with lower extremity PAD were included. The prevalence of frailty in patients with lower extremity PAD was pooled using a random-effect model. Meta-regression, subgroup, and sensitivity analyses were conducted to explore the heterogeneity.ResultsEighteen studies reported on 17 articles involving 1,726,343 patients with lower extremity PAD were identified. The pooled prevalence of frailty in patients with lower extremity PAD was 49 % (95 % confidence interval [CI] 37–61 %), with significant heterogeneity between studies (I ² = 100 %, p < 0.001). Multivariable meta-regression showed that only the severity of PAD (coefficient 0.270; 95 % CI 0.017–0.523, p = 0.039) was significantly associated with the heterogeneity. In subgroup analysis, the pooled prevalence of frailty was higher in critical limb ischemia or chronic limb-threatening ischemia (54 %) than all PAD (48 %); the pooled prevalence of frailty was 64 %, 51 %, and 54 % for Modified Frailty Index-5, Modified Frailty Index-11, and Clinical Frailty Scale, respectively. The pooled prevalence of frailty appeared to be lower in male (39 %) than the female patients (47 %).ConclusionsThe prevalence of frailty was higher in patients with lower extremity PAD, suggesting frailty is a common condition. This finding highlights the significance of assessing frailty in patients with lower extremity PAD.     

Non-Myeloablative Allogeneic Transplantation with Post-Transplant Cyclophosphamide after Immune Checkpoint Inhibition for Classic Hodgkin Lymphoma: A Retrospective Cohort Study

Immune checkpoint inhibitors (ICIs) are approved in relapsed classic Hodgkin lymphoma (cHL). The safety and effectiveness of allogeneic blood or marrow transplantation (alloBMT) in ICI-pretreated patients with cHL remain unclear. The aim of this study is to assess outcomes of patients with cHL receiving ICIs before alloBMT using post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis.We performed a retrospective study of relapsed/refractory patients with cHL undergoing alloBMT with PTCy at Johns Hopkins between November 2004 and September 2019. Engraftment, GVHD incidence, nonrelapse mortality, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving pre-alloBMT ICI or standard salvage chemotherapy.We identified 105 consecutive relapsed/refractory patients with cHL, of whom 37 (35.2%) received ICIs and 68 (64.7%) received chemotherapy without ICIs (no-ICI) before alloBMT. ICI and no-ICI patients experienced a 3-year estimated OS of 94% versus 78% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.08 to 1.56; P = .17) and a 3-year estimated PFS of 90% and 65% (HR, 0.3; 95% CI, 0.09 to 1; P = .05), respectively. We observed no statically significant difference in the 12-month cumulative incidence of acute grade II to IV GVHD or in the 24-month incidence of chronic GVHD.ICIs do not increase acute or chronic GVHD incidence compared with salvage chemotherapy. Patients with cHL receiving ICIs prior to alloBMT experienced outstanding PFS and OS. Thus, ICI therapy is safe in patients with cHL when undergoing alloBMT with PTCy and may improve post-alloBMT disease progression and survival.     

Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

BackgroundPathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study.MethodsInformation was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age.ResultsAt time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5–3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1–2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1–3.5), with trends up to 2–4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3–0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4–0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2.ConclusionThe PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants.     

National case fatality rates of the COVID-19 pandemic

ObjectivesThe case fatality rate (CFR) of coronavirus disease 2019 (COVID-19) varies significantly between countries. We aimed to describe the associations between health indicators and the national CFRs of COVID-19.MethodsWe identified for each country health indicators potentially associated with the national CFRs of COVID-19. We extracted data for 18 variables from international administrative data sources for 34 member countries of the Organization for Economic Cooperation and Development (OECD). We excluded the collinear variables and examined the 16 variables in multivariable analysis. A dynamic web-based model was developed to analyse and display the associations for the CFRs of COVID-19. We followed the Guideline for Accurate and Transparent Health Estimates Reporting (GATHER).ResultsIn multivariable analysis, the variables significantly associated with the increased CFRs were percentage of obesity in ages >18 years (β = 3.26; 95%CI = 1.20, 5.33; p 0.003), tuberculosis incidence (β = 3.15; 95%CI = 1.09, 5.22; p 0.004), duration (days) since first death due to COVID-19 (β = 2.89; 95%CI = 0.83, 4.96; p 0.008), and median age (β = 2.83; 95%CI = 0.76, 4.89; p 0.009). The COVID-19 test rate (β = –3.54; 95%CI = –5.60, –1.47; p 0.002), hospital bed density (β = –2.47; 95%CI = –4.54, –0.41; p 0.021), and rural population ratio (β = –2.19; 95%CI = –4.25, –0.13; p 0.039) decreased the CFR.ConclusionsThe pandemic hits population-dense cities. Available hospital beds should be increased. Test capacity should be increased to enable more effective diagnostic tests. Older patients and patients with obesity and their caregivers should be warned about a potentially increased risk.     

The performance of human papillomavirus DNA detection with type 16/18 genotyping by hybrid capture in primary test of cervical cancer screening: a cross-sectional study in 10,669 Chinese women

ObjectivesWe aimed to assess the performance of DH3 human papillomavirus (HPV) assay, a newly developed hybrid capture technique that detects 14 high-risk HPVs with type 16/18 genotyping, as a primary test in cervical cancer screening.MethodsIn total 11,356 Chinese women aged 21–65 years participated in a cervical cancer screening programme using cytology (Thinprep, Hologic) and HPV testing (Cobas 4800 Test, Roche). Residual samples were used to detect HPV by DH3 HPV.ResultsIn total 10,669 women with valid results were included in the study. Of those, 135 were diagnosed as CIN2+, and 83 were diagnosed as CIN3+; 1056 women (9.9%) were DH3 HPV-positive and 255 (2.4%) of those were 16/18-positive, while 990 (9.3%) women were Cobas HPV-positive and 243 (2.3%) of those were 16/18-positive. DH3 HPV was non-inferior to Cobas HPV in identifying CIN1− and CIN2+ using predetermined thresholds (both p < 0.001). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of DH3 HPV were 93.3% (95% confidence interval [CI] = 87.7–96.9), 91.2% (95%CI = 90.6–91.7), 12.0% (95%CI = 10.1–14.1) and 99.9% (95%CI = 99.8–100), respectively, similar to those of Cobas HPV (91.1%, 95%CI = 85.0–5.3; 91.8%, 95%CI = 91.2–92.3; 12.5%, 95%CI = 10.5–14.7; and 99.9%, 95%CI = 99.8–99.9, respectively), in identifying CIN2+ (all p > 0.05). When DH3 HPV and Cobas HPV were respectively used as primary testing in screening strategy, the performance of two strategies were similar in identifying CIN2+. The results were similar in identifying CIN3+.ConclusionOur data suggest that DH3 HPV performs similarly to Cobas HPV in identifying high-grade CIN in cervical cancer screening.     

Immune checkpoint inhibitor-induced myositis,the earliest and most lethal complication among rheumatic and musculoskeletal toxicities

BackgroundIn addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI.Patients MethodsWe performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC₀₂₅ (lower end of the IC 95% credibility interval) >0 is deemed significant.ResultsWe identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 [11.6–18.4], IC₀₂₅ = 3.34), sarcoidosis (n = 94; ROR = 9.6 [7.9–11.9]; IC₀₂₅ = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 [5.2–9.2]; IC₀₂₅ = 2.24), myositis (n = 465; ROR = 4.9 [4.5–5.4]; IC₀₂₅ = 2.12), arthritis (n = 606; ROR = 1.4 [1.3–1.5]; IC₀₂₅ = 0.34) and scleroderma (n = 17; ROR = 2.0 [1.2–3.2]; IC₀₂₅ = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6–2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1–4.4, p < .05). Median time to onset occurred early for myositis (31 days [19.2–57.8]) and was the most delayed for scleroderma (395 days [323.8–457.2], p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to [0–6.7%] for other RMS-irAE (p < .0001).ConclusionsClinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.     

The effects of acupressure on postoperative nausea and vomiting among patients undergoing laparoscopic surgery: A meta-analysis of randomized controlled trials

Background and objectiveLaparoscopic surgery is one of the most commonly performed surgeries in general surgery, with fewer side effects and rapid recovery. Postoperative nausea and vomiting (PONV) remains the main challenge that confronts the prognosis of this minimally invasive surgery. We aimed to evaluate the effect of acupressure, a nonpharmacological non-invasive method, on the incidence of nausea and vomiting following laparoscopic surgery within the early phase (first six hours postoperatively) and the extended phase (for at least 24 h postoperatively).MethodsWe searched PubMed, Cochran, Scopus, Web of Science, Google scholar, and Wiley for randomized controlled trials that evaluated the effect of acupressure on PONV in patients undergoing laparoscopy. Data were extracted and analyzed in a random model, and pooled risk ratios (RRs) with their respective 95% confidence intervals (CIs) were calculated.ResultsEleven trials were included in the meta-analysis, comprising 941 patients. Most of the included patients were females undergoing gynecological laparoscopy or laparoscopic cholecystectomy. Acupressure significantly lowered the incidence of nausea and vomiting, within the early phase (RR = 0.62, 95% CI [0.44 to 0.88]; p = 0.008), (RR = 0.5, 95% CI [0.30 to 0.84]; p = 0.008), and the extended phase (RR = 0.65, 95% CI [0.52 to 0.83]; p = 0.0003), (RR = 0.44, 95% CI [0.32 to 0.61]; p < 0.00001), respectively. Moreover, acupressure significantly reduced the need for rescue antiemetic drugs in both phases (p < 0.05).ConclusionAcupressure is an effective procedure for reducing nausea, vomiting, and the need for antiemetic drugs after laparoscopic surgery.     

Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis

BackgroundHydroxychloroquine or chloroquine with or without azithromycin have been widely promoted to treat coronavirus disease 2019 (COVID-19) following early in vitro antiviral effects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).ObjectiveThe aim of this systematic review and meta-analysis was to assess whether chloroquine or hydroxychloroquine with or without azithromycin decreased COVID-19 mortality compared with the standard of care.Data sourcesPubMed, Web of Science, Embase Cochrane Library, Google Scholar and MedRxiv were searched up to 25 July 2020.Study eligibility criteriaWe included published and unpublished studies comparing the mortality rate between patients treated with chloroquine or hydroxychloroquine with or without azithromycin and patients managed with standard of care.ParticipantsPatients ≥18 years old with confirmed COVID-19.InterventionsChloroquine or hydroxychloroquine with or without azithromycin.MethodsEffect sizes were pooled using a random-effects model. Multiple subgroup analyses were conducted to assess drug safety.ResultsThe initial search yielded 839 articles, of which 29 met our inclusion criteria. All studies except one were conducted on hospitalized patients and evaluated the effects of hydroxychloroquine with or without azithromycin. Among the 29 articles, three were randomized controlled trials, one was a non-randomized trial and 25 were observational studies, including 11 with a critical risk of bias and 14 with a serious or moderate risk of bias. After excluding studies with critical risk of bias, the meta-analysis included 11 932 participants for the hydroxychloroquine group, 8081 for the hydroxychloroquine with azithromycin group and 12 930 for the control group. Hydroxychloroquine was not significantly associated with mortality: pooled relative risk (RR) 0.83 (95% CI 0.65–1.06, n = 17 studies) for all studies and RR = 1.09 (95% CI 0.97–1.24, n = 3 studies) for randomized controlled trials. Hydroxychloroquine with azithromycin was associated with an increased mortality (RR = 1.27; 95% CI 1.04–1.54, n = 7 studies). We found similar results with a Bayesian meta-analysis.ConclusionHydroxychloroquine alone was not associated with reduced mortality in hospitalized COVID-19 patients but the combination of hydroxychloroquine and azithromycin significantly increased mortality.     

Impact of frailty on all-cause mortality or major amputation in patients with lower extremity peripheral artery disease: A meta-analysis

BackgroundFrailty has been increasingly identified as a risk factor of adverse outcomes in vascular disease. However, its impact on the survival and amputation in patients with lower extremity peripheral artery disease (PAD) remains controversial. This meta-analysis aimed to examine the value of frailty in predicting all-cause mortality or major amputation in patients with lower extremity PAD.MethodsPubMed, Embase, Web of Sciences, and Scopus databases (up to April 7, 2022) were comprehensively searched to identify relevant studies that investigated the association between frailty and all-cause mortality or major amputation in patients with lower extremity PAD. The impact of frailty on adverse outcomes was summarized by pooling the fully adjusted hazard ratio (HR) with 95% confidence intervals (CI) using a random effect (DerSimonian-Laird) model.ResultsSeven studies reporting on eight articles that involved 122,892 patients were included. The prevalence of frailty ranged from 42% to 80% based on the frailty tool used. Meta-analysis showed that frailty was associated with an increased risk of 30-day all-cause mortality (HR 2.11; 95% CI 1.41–3.15; I² =47.6%, p = 0.148, Tau-squared=0.058) and long-term all-cause mortality (HR 1.86; 95% CI 1.25–2.76; I² =76.1%, p = 0.002, Tau-squared=0.118). However, no clear association was observed between frailty and major amputation (HR 1.07; 95% CI 0.83–1.36; I² =23.0%, p = 0.273, Tau-squared=0.019).ConclusionFrailty independently predicts short and long-term all-cause mortality but not major amputation in patients with lower extremity PAD. Frailty status may play an important role in risk stratification of lower extremity PAD.     

Vitamin D and risk of ankylosing spondylitis: A two-sample mendelian randomization study

ObjectivesTo study whether Vitamin D levels are causally associated with ankylosing spondylitis (AS).MethodsTwo-sample Mendelian randomization (TSMR) analysis was performed by employing MR-Egger regression, weighted median (WM¹), inverse-variance weighted (IVW), and weight mode (WM²) methods. The odds ratio (OR) with 95% confidence intervals (CIs) was used to evaluate this association.ResultsThe results of IVW show that no causal association between vitamin D and AS (OR = 0.999, 95%CI = 0.997, 1.002, P = 0.724). The MR-Egger regression results show that genetic pleiotropy does not bias the results (intercept = ?4.474E-05, SE = 2.830E-05, P = 0.255). The MR-Egger method no supported causal association between vitamin D and AS (OR = 1.000, 95%CI = 0.996, 1.005, P = 0.879). WM¹ (OR = 1.002, 95%CI = 0.999, 1.005, P = 0.837) and WM² (OR = 0.998, 95%CI = 0.996, 1.002, P = 0.910) approach also not found a causal relationship between vitamin D levels and AS. The significant heterogeneity was not observed by Cochran's Q test. The “leave-one-out” analysis also proved lack of a single SNP affected the robustness of our results.ConclusionBased on our analysis, there is lack of a strong evidence to support a causal inverse association between vitamin D levels and ankylosing spondylitis.     

Response to SARS-CoV-2 vaccination in immune mediated inflammatory diseases: Systematic review and meta-analysis

ObjectivesThe treatment for COVID-19 often utilizes immune-modulating drugs. These drugs are also used in immune mediated inflammatory diseases (IMIDs). We performed a systematic review about seroconversion after SARS-CoV-2 vaccination in patients with IMIDs and impact of various drugs on seroconversion rates.MethodsElectronic databases were searched to identify relevant studies reporting seroconversion rates following SARS-CoV-2 vaccination in IMIDs. We calculated the pooled seroconversion rates after a single or two doses of vaccination, pooled seroconversion rates in patients with specific IMIDs, and rates in patients on various drugs/drug classes.ResultsTwenty-five studies were included in the systematic review. The pooled seroconversion rates after two doses of mRNA vaccination were higher (83.1, 95%CI: 74.9–89.0, I² = 90%) as compared to a single dose (69.3, 52.4–82.3, I² = 95%). The odds of seroconversion were lower in IMIDs as compared to healthy controls (0.05, 0.02–0.13, I² = 21%). The seroconversion rates in patients with inflammatory bowel disease (95.2, 95%CI: 92.6–96.9, I² = 0%), spondyloarthropathy (95.6, 95% CI: 83.4–98.9, I² = 35%), and systemic lupus erythematosus (90.7, 95%CI: 85.4–94.2, I² = 0%) were higher as compared to rheumatoid arthritis (79.5, 95% CI: 65.1–88.9, I² = 85%), and vasculitis (70.5, 95% CI: 52.9–83.5, I² = 51%). The seroconversion rates following double dose of mRNA were excellent (>90%) in those on anti-tumour necrosis factor (TNF), anti-integrin (vedolizumab), anti-IL 17 (secukinumab), anti-IL6 (Tocilizumab) and anti-IL12/23 (Ustekinumab) therapies but attenuated (<70%) in patients on anti-CD20 (Rituximab) or anti-cytotoxic T lymphocyte associated antigen (CTLA-4) therapies (Abatacept). The seroconversion rates were good (70–90%) with steroids, hydroxychloroquine, JAK inhibitors, mycophenolate mofetil and leflunomide. Combination of anti-TNF with immunomodulators (azathioprine, 6-meracptopurine, methotrexate) resulted in an attenuated vaccine response as compared to anti-TNF monotherapy.ConclusionSeroconversion rates after SARS-CoV-2 vaccination are lower in patients with IMIDs. Certain therapies (anti-TNF, anti-integrin, anti-IL 17, anti-IL6, anti-12/23) do not impact seroconversion rates while others (anti-CD20, anti-CTLA-4) result in poorer responses.     

Rheumatic immune-related adverse events associated with cancer immunotherapy: A nationwide multi-center cohort

ObjectiveAlthough immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, their use is associated with immune toxicities referred to as immune-related adverse events (irAE). Here we describe the clinical presentation and management of rheumatic immune-related adverse events (Rh-irAE) in a national multi-center cohort.MethodsAll patients presenting with Rh-irAE at 9 academic sites across Canada between January 2013 and January 2019 were identified and included in this retrospective cohort study. Standardized data were extracted by chart review.Results117 patients who developed 136 Rh-irAE were identified. The most frequent Rh-irAE was symmetric polyarthritis (n = 45). Other Rh-irAE included non-inflammatory musculoskeletal symptoms (n = 18), polymyalgia rheumatica (n = 17) and myositis (n = 9).Prednisone was the most commonly used treatment (n = 76) with a mean maximum dose of 60 ± 74 mg/d and duration of treatment of 8.4 ± 11 months. Forty-two patients required conventional synthetic disease-modifying anti-rheumatic drugs (DMARD) and two required biologic DMARD to control the Rh-irAE. ICI was discontinued due to the Rh-irAE in 22 patients. There were no deaths related to Rh-irAE.Treatment of the Rh-irAE did not appear to negatively impact the tumor response to immunotherapy with 23 patients experiencing tumor progression prior to treatment of the Rh-irAE and 13 following treatment.ConclusionIn this largest multi-center cohort of Rh-irAE described to date, symmetric polyarthritis was the most common Rh-irAE. There was considerable heterogeneity of treatment, although this did not appear to negatively impact the anti-tumor response. This study can inform the development of evidence-based recommendations to optimize Rh-irAE and cancer outcomes in patients treated with ICI.     

Immune checkpoint inhibitors-induced autoimmunity: The impact of gender

ObjectiveTo evaluate prevalence and clinical features of immune-related adverse events (irAEs) to immune checkpoint inhibitors (ICIs) in accordance with the gender of treated cancer patients.MethodsA systematic review of the medical literature was conducted by searching all available clinical data up to December 2019 in several databases using a combination of MESH terms related to immune checkpoint inhibitors, autoimmunity, and gender. Analyzed data were related to all FDA approved ICIs and respective indications in cancer.ResultsAccording to data from the literature, male display a slightly lower frequencies of ICIs-related endocrinopathies compared with females, specifically thyroid dysfunction. On the contrary, ICIs-hypophysitis has been reported at higher rates among males compared with females. ICI-induced Sicca/Sjogren’s syndrome showed a more frequent occurrence in men than the idiopathic primary form. No differences in gender distribution seem to arise in hematologic and gastrointestinal-irAEs. Interestingly, the gender distribution of neurologic and vascular ICIs-irAEs appears male-dominant.ConclusionsThe present systematic review highlights for the first time that the distribution of patients experiencing irAEs associated with ICIs changes among the genders according to the specific drug used, the frequency of the cancer and of the autoimmune conditions in the general population.     

Four-year safety follow-up of the tetravalent dengue vaccine efficacy randomized controlled trials in Asia and Latin America

ObjectiveOur objective was to describe the risk of hospital admission for virologically confirmed dengue (VCD) and the risk of clinically severe hospitalized VCD occurring up to 4 years after the first dose (years 1 to 4) in three randomized clinical trials comparing tetravalent dengue vaccine with placebo.MethodsThe relative risks (RR) for hospitalized VCD from first dose to year 4 were estimated by year and age-group in individual and combined studies.ResultsOverall, from Year 1 to Year 4, 233 and 228 participants had at least one episode of hospitalized VCD in the vaccinated (n = 22 603) and placebo (n = 11 301) groups, respectively (RR = 0.511, 95% CI 0.42–0.62). Among these, 48 and 47 cases, respectively, were classified as clinically severe. In children aged ≥9 years, 88 and 136 participants had at least one episode of hospitalized VCD in the vaccinated (n = 17 629) and placebo (n = 8821) groups, respectively (RR = 0.324; 95% CI 0.24–0.43). In vaccinated participants aged <9 years, particularly in those aged 2–5 years, there were more hospitalized VCD cases compared with the control participants in Year 3 but not in Year 4. The overall RR in those aged <9 years for Year 1 to Year 4 was 0.786 (95% CI 0.60–1.03), with a higher protective effect in the 6–8 year olds than in the 2–5 year olds.ConclusionsThe overall benefit-risk remained positive in those aged ≥9 years up to year 4, although the protective effect was lower in years 3 and 4 than in years 1 and 2.     

Association of PTPN22 rs2476601 and EGFR rs17337023 Gene polymorphisms and rheumatoid arthritis in Zahedan,Southeast Iran

In this study we aimed to evaluate the possible association of PTPN22 rs2476601 as well as epidermal growth factor receptor (EGFR) rs17337023 gene polymorphism and rheumatoid arthritis (RA) in a sample of Iranian population. This case‐control study was performed on 120 patients with RA and 120 healthy subjects. Genomic DNA was extracted from whole blood and PTPN22 rs2476601 and EGFR rs17337023 polymorphisms were determined using tetra amplification refractory mutation system–polymerase chain reaction (T‐ARMS‐PCR). The results showed that PTPN22 rs2476601 CT genotype as well as rs2476601 T allele was a risk factor for susceptibility to RA (OR=5.89 95%CI = 1.78–19.48, P = 0.004 and OR = 4.78, 95%CI = 1.59–14.35, P = 0.003, respectively). We also found that EGFR rs17337023 AT and rs17337023 TT genotypes were risk factor for susceptibility to RA (OR = 9.94 95%CI = 3.65–26.73, P < 0.001 and OR = 3.66, 95%CI = 1.46–9.15, P = 0.005, respectively). In addition the EGFR rs17337023 T allele was a risk for predisposition to RA (OR = 1.56, 95%CI=1.06‐2.30, P = 0.030). In conclusion, we found an association between PTPN22 rs2476601 and EGFR rs17337023 polymorphisms and the risk of RA in a sample of Iranian population.     

Co-seasonality and co-detection of respiratory viruses and bacteraemia in children: a retrospective analysis

ObjectivesThe aim of this study was to assess the co-seasonality and co-detection of respiratory viral infections and bacteraemia in children since the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13).MethodsChildren <18 years old were eligible for inclusion if they had a respiratory infection and a positive PCR-based assay for respiratory viruses as well as a positive blood culture between 2010 and 2018 at a single referral centre in the United States, regardless of their underlying medical condition or antibiotic treatment history. Monthly incidence rates of respiratory viruses and bacteraemia were analysed with a seasonal-trend decomposition procedure based on loess (STL) and cross-correlation functions using time series regression modelling.ResultsWe identified 7415 unique positive respiratory virus tests, including 2278 respiratory syncytial virus (RSV) (31%), 1825 influenza viruses (24%), 1036 parainfluenza viruses (14%), 1017 human metapneumovirus (hMPV) (14%), 677 seasonal coronaviruses (9%), and 582 adenoviruses (8%), together with a total of 11 827 episodes of bacteraemia. Significant co-seasonality was found between all-cause bacteraemia and RSV (OR = 1.76, 95%CI 1.50–2.06, p < 0.001), influenza viruses (OR = 1.38, 95%CI 1.13–1.68, p 0.002), and seasonal coronaviruses (OR = 1.18, 95%CI 1.09–1.28, p < 0.001), respectively. Analysis of linked viral–bacterial infections in individual children indicated that the rate ratio (RR) of bacteraemia associated with hMPV (RR = 2.73, 95%CI 1.12–6.85, p 0.019) and influenza (RR = 2.61, 95%CI 1.21–6.11, p 0.013) were more than double that of RSV. Staphylococcus aureus and Streptococcus pneumoniae were the most commonly identified pathogens causing bacteraemia.ConclusionsThere is a significant association between hMPV and influenza viruses and bacteraemia of all causes in hospitalized children at a single paediatric centre in the United States. Large multicentre studies are needed to confirm these findings and to elucidate the mechanisms by which hMPV potentiates the virulence and invasive capacity of diverse bacteria.     

Detection and characterization of male sex chromosome abnormalities in the UK Biobank study

PurposeThe study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome [KS]) and 47,XYY, and characterize their risks of adverse health outcomes.MethodsWe analyzed genotyping array or exome sequence data in 207,067 men of European ancestry aged 40 to 70 years from the UK Biobank and related these to extensive routine health record data.ResultsOnly 49 of 213 (23%) of men whom we identified with KS and only 1 of 143 (0.7%) with 47,XYY had a diagnosis of abnormal karyotype on their medical records or self-report. We observed expected associations for KS with reproductive dysfunction (late puberty: risk ratio [RR] = 2.7; childlessness: RR = 4.2; testosterone concentration: RR = –3.8 nmol/L, all P < 2 × 10^–8), whereas XYY men appeared to have normal reproductive function. Despite this difference, we identified several higher disease risks shared across both KS and 47,XYY, including type 2 diabetes (RR = 3.0 and 2.6, respectively), venous thrombosis (RR = 6.4 and 7.4, respectively), pulmonary embolism (RR = 3.3 and 3.7, respectively), and chronic obstructive pulmonary disease (RR = 4.4 and 4.6, respectively) (all P < 7 × 10^–6).ConclusionKS and 47,XYY were mostly unrecognized but conferred substantially higher risks for metabolic, vascular, and respiratory diseases, which were only partially explained by higher levels of body mass index, deprivation, and smoking.     

Midterm follow-up results of two different types of implants in opening wedge high tibia osteotomy

BackgroundThis retrospective study investigated the midterm results of medial opening wedge high tibia osteotomy, with a monoplanar or a biplanar osteotomy using two types of implant system.MethodsOsteotomies were performed on 241 knees (231 patients). The mean follow-up period was 6.0 years (SD 3.0, range 0.2–12.8 years). Two types of implant system were used, a precountered non-locking plate (PP) (n = 74) and a precountered locking plate (LP) (n = 167). A Kaplan-Meier cumulative survival curve and a Cox regression model were used to analyse and revise survival and risk factors.ResultsCumulative survival estimates for LP were 80% at 5 years, and 64% at 10 years (SE = 0.4, CI 95%: 9.0–10.5), and for PP, they were 68% at 5 years and 49% at 10 years (SE = 0.5, CI: 95% 6.3–8.2) (p = 0.024). The revision rate was 26% (44/167) for the LP group, and 47% (35/74) for the PP group (p = 0.001). Reoperations on LP osteotomies occurred for the tibial monoplanar cut and biplanar cut groups, in 19/52 (37%) and 25/167 (16%) osteotomies, respectively (p = 0.04). Our Cox regression model showed that PP had a higher risks (RR = 1.7; CI: 95% 1.1–2.6) of revision, when compared with LP (p = 0.026).ConclusionsThe risk of revision for any reason and that of early conversion to total knee arthroplasty (TKA) after high tibia osteotomy were significantly increased for PP, when compared with LP.     

Efficacy and safety of intravenous and subcutaneous immunoglobulin therapy in idiopathic inflammatory myopathy: A systematic review and meta-analysis

ObjectiveTo perform a systematic review and meta-analysis on the efficacy and safety of intravenous (IVIg) and subcutaneous (SCIg) immunoglobulin (Ig) therapy in the treatment of idiopathic inflammatory myopathy (IIM) and juvenile dermatomyositis (JDM).MethodsPubMed, Embase and SCOPUS were searched to identify studies on Ig therapy in patients with IIM and/or JDM (2010?2020). Outcome measures were complete response (CR) or partial response (PR) in terms of muscle power and extramuscular disease activity measures on the International Myositis Assessment and Clinical Studies Group (IMACS) core set domains.ResultsTwenty-nine studies were included (n = 576, 544 IIM, 32 JDM). Muscle power PR with pooled Ig therapy was 88.5% (95% confidence interval (CI): 80.6–93.5, n = 499) and PR with SCIg treatment was 96.61% (95% CI: 87.43–99.15, n = 59). Pooled PR with first-line use of IVIg was 77.07% (95% CI: 61.25–92.89, n = 80). Overall, mean time to response was 2.9 months (95% CI: 1.9–4.1). Relapse was seen in 22.76% (95% CI: 14.9–33). Studies on cutaneous disease activity and dysphagia showed significant treatment responses. Glucocorticoid and immunosuppressant sparing effect was seen in 40.9% (95% CI: 20–61.7) and 42.2% (95% CI: 20.4–64.1) respectively. Ig therapy was generally safe with low risk of infection (1.37%, 95% CI: 0.1–2.6).ConclusionsAdd-on Ig therapy improves muscle strength in patients with refractory IIM, but evidence on Ig therapy in new-onset disease and extramuscular disease activity is uncertain.     

Novel point-of-care biomarker combination tests to differentiate acute bacterial from viral respiratory tract infections to guide antibiotic prescribing: a systematic review

BackgroundAcute respiratory tract infections (RTIs) are the most common reason to seek medical care, with many patients receiving inappropriate antibiotics. Novel testing approaches to identify aetiology at the point-of-care are required to accurately guide antibiotic treatment.ObjectiveTo assess the diagnostic accuracy of biomarker combinations to rapidly differentiate between acute bacterial or viral RTI aetiology.Data sourcesMEDLINE, Embase and Web of Science databases were searched to February 2021.Study eligibility criteriaDiagnostic accuracy studies comparing accuracy of point-of-care and rapid diagnostic tests in primary or secondary care, consisting of biomarker combinations, to identify bacterial or viral aetiology of RTI.MethodsRisk of bias was assessed using the QUADAS-2 tool. Sensitivity and specificity of tests reported by more than one study were meta-analysed using a random effects model.ResultsTwenty observational studies (3514 patients) were identified. Eighteen were judged at high risk of bias. For bacterial aetiologies, sensitivity ranged from 61% to 100% and specificity from 18% to 96%. For viral aetiologies, sensitivity ranged from 59% to 97% and specificity from 74% to 100%. Studies evaluating two commercial tests were meta-analysed. For ImmunoXpert, the summary sensitivity and specificity were 85% (95% CI 75%–91%, k = 4) and 86% (95% CI 73%–93%, k = 4) for bacterial infections, and 90% (95% CI 79%–96%, k = 3) and 92% (95% CI 83%–96%, k = 3) for viral infections, respectively. FebriDx had pooled sensitivity and specificity of 84% (95% CI 75%–90%, k = 4) and 93% (95% CI 90%–95%, k = 4) for bacterial infections, and 87% (95% CI 72%–95%; k = 4) and 82% (95% CI 66%–86%, k = 4) for viral infections, respectively.ConclusionCombinations of biomarkers show potential clinical utility in discriminating the aetiology of RTIs. However, the limitations in the evidence base, due to a high proportion of studies with high risk of bias, preclude firm conclusions. Future research should be in primary care and evaluate patient outcomes and cost-effectiveness with experimental study designs.Clinical trialPROSPERO registration number: CRD42020178973.