Point-of-Care Diagnostic Test for Beta-Thalassemia.

Hemoglobin (Hb) disorders are among the most common monogenic diseases affecting nearly 7% of the world population. Among various Hb disorders, approximately 1.5% of the world population carries ß-thalassemia (ß-Thal), affecting 40,000 newborns every year. Early screening and a timely diagnosis are essential for ß-thalassemia patients for the prevention and management of later clinical complications. However, in Africa, Southern Europe, the Middle East, and Southeast Asia, where ß-thalassemia is most prevalent, the diagnosis and screening for ß-thalassemia are still challenging due to the cost and logistical burden of laboratory diagnostic tests. Here, we present Gazelle, which is a paper-based microchip electrophoresis platform that enables the first point-of-care diagnostic test for ß-thalassemia. We evaluated the accuracy of Gazelle for the ß-Thal screening across 372 subjects in the age range of 4-63 years at Apple Diagnostics lab in Mumbai, India. Additionally, 30 blood samples were prepared to mimic ß-Thal intermediate and ß-Thal major samples. Gazelle-detected levels of Hb A, Hb F, and Hb A2 demonstrated high levels of correlation with the results reported through laboratory gold standard high-performance liquid chromatography (HPLC), yielding a Pearson correlation coefficient = 0.99. This ability to obtain rapid and accurate results suggests that Gazelle may be suitable for the large-scale screening and diagnosis of ß-Thal.

Evaluation of a point-of-care haemozoin assay (Gazelle device) for rapid detection of Plasmodium knowlesi malaria.

Plasmodium knowlesi is the major cause of zoonotic malaria in Southeast Asia. Rapid and accurate diagnosis enables effective clinical management. A novel malaria diagnostic tool, Gazelle (Hemex Health, USA) detects haemozoin, a by-product of haem metabolism found in all Plasmodium infections. A pilot phase refined the Gazelle haemozoin identification algorithm, with the algorithm then tested against reference PCR in a larger cohort of patients with P. knowlesi mono-infections and febrile malaria-negative controls. Limit-of-detection analysis was conducted on a subset of P. knowlesi samples serially diluted with non-infected whole blood. The pilot phase of 40 P. knowlesi samples demonstrated 92.5% test sensitivity. P. knowlesi-infected patients (n = 203) and febrile controls (n = 44) were subsequently enrolled. Sensitivity and specificity of the Gazelle against reference PCR were 94.6% (95% CI 90.5-97.3%) and 100% (95% CI 92.0-100%) respectively. Positive and negative predictive values were 100% and 98.8%, respectively. In those tested before antimalarial treatment (n = 143), test sensitivity was 96.5% (95% CI 92.0-98.9%). Sensitivity for samples with ≤ 200 parasites/µL (n = 26) was 84.6% (95% CI 65.1-95.6%), with the lowest parasitaemia detected at 18/µL. Limit-of-detection (n = 20) was 33 parasites/µL (95% CI 16-65%). The Gazelle device has the potential for rapid, sensitive detection of P. knowlesi infections in endemic areas.

Multispectral imaging for MicroChip electrophoresis enables point-of-care newborn hemoglobin variant screening.

Hemoglobin (Hb) disorders affect nearly 7% of the world's population. Globally, around 400,000 babies are born annually with sickle cell disease (SCD), primarily in sub-Saharan Africa where morbidity and mortality rates are high. Screening, early diagnosis, and monitoring are not widely accessible due to technical challenges and cost. We hypothesized that multispectral imaging will allow sensitive hemoglobin variant identification in existing affordable paper-based Hb electrophoresis. To test this hypothesis, we developed the first integrated point-of-care multispectral Hb variant test: Gazelle-Multispectral. Here, we evaluated the accuracy of Gazelle-Multispectral for Hb variant newborn screening in 265 newborns with known hemoglobin variants including hemoglobin A (Hb A), hemoglobin F (Hb F), hemoglobin S (Hb S) and hemoglobin C (Hb C). Gazelle-Multispectral detected levels of Hb A, Hb F, Hb S, and Hb C/E/A2, demonstrated high correlations with the results reported by laboratory gold standard high performance liquid chromatography (HPLC) at Pearson Correlation Coefficient = 0.97, 0.97, 0.93, and 0.95. Gazelle-Multispectral demonstrated accuracy of 96.8% in subjects of 0-3 days, and 96.9% in newborns. The ability to obtain accurate results on newborn samples suggest that Gazelle-Multispectral can be suitable for large-scale newborn screening and for diagnosis of SCD in low resource settings.

Evaluation of a haemozoin-based rapid diagnostic test for diagnosis of imported malaria during the phase of prevention of reestablishment in Sri Lanka.

BACKGROUND: Sri Lanka, an island nation, has eliminated endemic malaria transmission. Maintaining elimination in the continued presence of vectors requires vigilance in screening people travelling from high malaria-risk areas and a rapid response with focal screening for infections identified in the community. Such screening requires accurate and very rapid assays that enable an immediate response. Both microscopy and rapid diagnostic tests (RDTs) have limitations including sensitivity and speed in screening large numbers, while polymerase chain reaction (PCR) is practical only as laboratory confirmation. This study assessed the utility of 'Gazelle', a novel rapid malaria assay based on magneto-optical detection of haemozoin, a by-product of malaria parasite metabolism. METHODS: Between October 2020 and March 2021, two groups of individuals were screened for malaria by four methods, namely, microscopy, Rapid Diagnostic Test (RDT), Gazelle and PCR. Passive case detection was carried out for confirmation of diagnosis amongst individuals suspected of having malaria. Individuals at high-risk of acquiring malaria, namely persons returning from malaria endemic countries, were screened by active case detection. RESULTS: Of the 440 individuals screened for malaria, nine malaria positives were diagnosed by PCR, microscopy and the HRP2 band of RDT, which included five Plasmodium falciparum infections, two Plasmodium ovale, and one each of Plasmodium vivax and Plasmodium malariae. Gazelle correctly detected the P. vivax, P. ovale and P. malariae infections within the 2 min test time, but did not detect two P. falciparum infections giving a sensitivity of 77.8%. Specificity was 100%. DISCUSSION: The Gazelle, a portable bench top device proved useful to screen a large number of blood samples for non-falciparum parasites within 5 minutes of sample input. Species differentiation, and improvement in P. falciparum detection, will be important to broaden utility.

Evaluation of Microchip-Based Point-Of-Care Device "Gazelle" for Diagnosis of Sickle Cell Disease in India.

Sickle cell disease is a major public health problem in India. Lack of rapid and reliable diagnostic methods result in many avoidable deaths in affected population. Current diagnostic tools are laboratory based, expensive and need trained manpower. Here, we evaluated the performance of a microchip-based cellulose acetate electrophoresis test, "Gazelle" in the tribal-dominated Indian states of Chhattisgarh and Madhya Pradesh. A total of 1,050 patients were screened by sickle cell solubility, hemoglobin (cellulose acetate) electrophoresis, high-performance liquid chromatography (HPLC) and Gazelle. Of the total 1,027 test results obtained, 960 tests were "Valid" (93.5%) and included in the analysis. Gazelle identified all patients with disease (HbSS and Thalassemia Major) with 100% accuracy. Gazelle demonstrated 100% sensitivity when comparing sickle cell disease (SCD) vs. sickle cell trait and SCD vs. normal. Specificity was 98.9% and 99.5% when comparing SCD vs. trait and trait vs. normal, respectively. Specificity was 99.8% when comparing SCD vs. normal and sensitivity was 99.3% when comparing trait vs. normal. Overall, Gazelle yielded a high accuracy (99.0%) compared to reference standard tests (hemoglobin electrophoresis and HPLC). Gazelle is a low-cost, rapid diagnostic test with high accuracy for detecting SCD both quantitatively and qualitatively. Gazelle can be a potential screening tool for the rapid diagnosis in resource limited settings and developing countries with high burden of hemoglobin disorders.

Efficacy and harms of convalescent plasma for treatment of hospitalized COVID-19 patients: a systematic review and meta-analysis.

INTRODUCTION: We systematically reviewed benefits and harms of convalescent plasma (CP) in hospitalized COVID-19 patients. MATERIAL AND METHODS: Randomized controlled trials (RCTs) and observational studies assessing CP effects on hospitalized, adult COVID-19 patients were searched until November 24, 2020. We assessed risk of bias (RoB) using Cochrane RoB 2.0 and ROBINS-I tools. Inverse variance random effect meta-analyses were performed. Quality of evidence was evaluated using GRADE methodology. Primary outcomes were all-cause mortality, clinical improvement, and adverse events. RESULTS: Five RCTs (n = 1067) and 6 cohorts (n = 881) were included. Three and 1 RCTs had some concerns and high RoB, respectively; and there was serious RoB in all cohorts. Convalescent plasma did not reduce all-cause mortality in RCTs of severe (RR = 0.60, 95% CI: 0.33-1.10) or moderate (RR = 0.60, 95% CI: 0.09-3.86) COVID-19 vs. standard of care (SOC); CP reduced all-cause mortality vs. SOC in cohorts (RR = 0.66, 95% CI: 0.49-0.91). Convalescent plasma did not reduce invasive ventilation vs. SOC in moderate disease (RR = 0.85, 95% CI: 0.47-1.55). In comparison to placebo + SOC, CP did not affect all-cause mortality (RR = 0.75, 95% CI: 0.48-1.16) or clinical improvement (HR = 1.07, 95% CI: 0.82-1.40) in severe patients. Adverse and serious adverse events were scarce, similar between CP and controls. Quality of evidence was low or very low for most outcomes. CONCLUSIONS: In comparison to SOC or placebo + SOC, CP did not reduce all-cause mortality in RCTs of hospitalized COVID-19 patients. Convalescent plasma did not have an effect on other clinical or safety outcomes. Until now there is no good quality evidence to recommend CP for hospitalized COVID-19 patients.

Field validation of a magneto-optical detection device (Gazelle) for portable point-of-care Plasmodium vivax diagnosis.

A major challenge for malaria is the lack of tools for accurate and timely diagnosis in the field which are critical for case management and surveillance. Microscopy along with rapid diagnostic tests are the current mainstay for malaria diagnosis in most endemic regions. However, these methods present several limitations. This study assessed the accuracy of Gazelle, a novel rapid malaria diagnostic device, from samples collected from the Peruvian Amazon between 2019 and 2020. Diagnostic accuracy was compared against microscopy and two rapid diagnostic tests (SD Bioline and BinaxNOW) using 18ssr nested-PCR as reference test. In addition, a real-time PCR assay (PET-PCR) was used for parasite quantification. Out of 217 febrile patients enrolled and tested, 180 specimens (85 P. vivax and 95 negatives) were included in the final analysis. Using nested-PCR as the gold standard, the sensitivity and specificity of Gazelle was 88.2% and 97.9%, respectively. Using a cutoff of 200 parasites/µl, Gazelle's sensitivity for samples with more than 200 p/uL was 98.67% (95%CI: 92.79% to 99.97%) whereas the sensitivity for samples lower than 200 p/uL (n = 10) was 12.5% (95%CI: 0.32% to 52.65%). Gazelle's sensitivity and specificity were statistically similar to microscopy (sensitivity = 91.8, specificity = 100%, p = 0.983) and higher than both SD Bioline (sensitivity = 82.4, specificity = 100%, p = 0.016) and BinaxNOW (sensitivity = 71.8%, specificity = 97.9%, p = 0.002). The diagnostic accuracy of Gazelle for malaria detection in P. vivax infections was comparable to light microscopy and superior to both RDTs even in the presence of low parasitemia infections. The performance of Gazelle makes it a valuable tool for malaria diagnosis and active case detection that can be utilized in different malaria-endemic regions.

Performance of a sensitive haemozoin-based malaria diagnostic test validated for vivax malaria diagnosis in Brazilian Amazon.

BACKGROUND: Vivax malaria diagnosis remains a challenge in malaria elimination, with current point of care rapid diagnostic tests (RDT) missing many clinically significant infections because of usually lower peripheral parasitaemia. Haemozoin-detecting assays have been suggested as an alternative to immunoassay platforms but to date have not reached successful field deployment. Haemozoin is a paramagnetic crystal by-product of haemoglobin digestion by malaria parasites and is present in the food vacuole of malaria parasite-infected erythrocytes. This study aimed to compare the diagnostic capability of a new haemozoin-detecting platform, the Gazelle™ device with optical microscopy, RDT and PCR in a vivax malaria-endemic region. METHODS: A comparative, double-blind study evaluating symptomatic malaria patients seeking medical care was conducted at an infectious diseases reference hospital in the western Brazilian Amazon. Optical microscopy, PCR, RDT, and Gazelle™ were used to analyse blood samples. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and Kappa values were calculated. RESULTS: Out of 300 patients, 24 test results were excluded from the final analysis due to protocol violation (6) and inconclusive and/or irretrievable results (18). Gazelle™ sensitivity was 96.1 % (91.3-98.3) and 72.1 % (65.0-78.3) when compared to optical microscopy and PCR, respectively whereas it was 83.9 % and 62.8 % for RDTs. The platform presented specificity of 100 % (97.4-100), and 99.0 % (94.8-99.9) when compared to optical microscopy, and PCR, respectively, which  was the same for RDTs. Its correct classification rate was 98.2 % when compared to optical microscopy and 82.3 % for PCR; the test's accuracy when compared to optical microscopy was 98.1 % (96.4-99.7), when compared to RDT was 95.2 % (93.0-97.5), and when compared to PCR was 85.6 % (82.1-89.1). Kappa (95 % CI) values for Gazelle™ were 96.4 (93.2-99.5), 88.2 (82.6-93.8) and 65.3 (57.0-73.6) for optical microscopy, RDT and PCR, respectively. CONCLUSIONS: The Gazelle™ device was shown to have faster, easier, good sensitivity, specificity, and accuracy when compared to microscopy and was superior to RDT, demonstrating to be an alternative for vivax malaria screening particularly in areas where malaria is concomitant with other febrile infections (including dengue fever, zika, chikungunya, Chagas, yellow fever, babesiosis).

Diagnostic accuracy of Xpert MTB/RIF for tuberculous meningitis: systematic review and meta-analysis.

OBJECTIVE: This systematic review evaluated the diagnostic accuracy of Xpert MTB/RIF to detect tuberculous meningitis (TBM). METHODS: PubMed and five other databases were systematically searched through March 2019. All studies evaluating diagnostic accuracy of Xpert MTB/RIF on cerebrospinal fluid (CSF) samples were included. Reference standards were definitive or definite plus probable TBM. The quality of studies was assessed by the QUADAS-2 tool. We performed bivariate random-effects meta-analysis and calculated summary diagnostic statistics. RESULTS: We identified 30 studies (n = 3972 participants), including 5 cohort studies and 25 cross-sectional studies. Reference standards were definite TB (n = 28 studies) or definite plus probable TBM (n = 6 studies). The pooled Xpert MTB/RIF sensitivity was 85% (95% CI, 70-93%), and specificity was 98% (95% CI, 97-99%) with a negative likelihood ratio of 0.15 (95% CI, 0.04-0.27) for definite TBM. For probable TBM cases, pooled sensitivity was 81% (95% CI, 66-90%), and specificity was 99% (95% CI, 97-99%). For both reference standard types, meta-analyses showed a C-statistic area under the curve of 0.98. The QUADAS-2 tool revealed low risk of bias as well as low concerns regarding applicability. Methodological heterogeneity was high among studies. CONCLUSIONS: Xpert MTB/RIF showed high accuracy for TBM diagnosis, but a negative Xpert MTB/RIF test does not rule out TBM. Repeat Xpert testing may be necessary. In clinical practice, Xpert MTB/RIF adds speed and sensitivity when compared to classic TBM diagnostic methods or previous commercial nucleic acid amplification techniques. More studies and better strategies for rapidly confirming a diagnosis of TBM in children are urgently needed.

OBJECTIF: Cette revue systématique a évalué la précision diagnostique de Xpert MTB/RIF pour détecter la méningite tuberculeuse (MTB). MÉTHODES: PubMed et cinq autres bases de données ont fait l'objet d'une recherche systématique jusqu'en mars 2019. Toutes les études évaluant la précision du diagnostic de Xpert MTB/RIF sur des échantillons de liquide céphalo-rachidien (LCR) ont été incluses. Les étalons de référence étaient des MTB définitives ou définitives et probables. La qualité des études a été évaluée par l'outil QUADAS-2. Nous avons effectué une méta-analyse des effets aléatoires bivariés et calculé des statistiques de résumés diagnostiques. RÉSULTATS: Nous avons identifié 30 études (n = 3.972 participants), dont 5 études de cohorte et 25 études transversales. Les étalons de référence étaient la TB définitive (n = 28 études) ou la MTB définitive et probable (n = 6 études). La sensibilité poolée Xpert MTB/RIF était de 85% (IC95%: 70-93%) et la spécificité était de 98% (IC95%: 97-99%) avec un rapport de vraisemblance négatif de 0,15 (IC95%: 0,04-0,27) pour la MTB définitive. Pour les cas probables de la MTB, la sensibilité poolée était de 81% (IC95%: 66-90%) et la spécificité était de 99% (IC95%: 97-99%). Pour les deux types d'étalons de référence, les méta-analyses ont montré une aire statistique C sous la courbe de 0,98. L'outil QUADAS-2 a révélé un faible risque de biais ainsi que de faibles préoccupations concernant l'applicabilité. L'hétérogénéité méthodologique était élevée parmi les études. CONCLUSIONS: Xpert MTB/RIF a montré une grande précision pour le diagnostic de la MTB, mais un test Xpert MTB/RIF négatif n'exclut pas la MTB. La répétition du tests Xpert peut être nécessaire. Dans la pratique clinique, Xpert MTB/RIF ajoute vitesse et sensibilité par rapport aux méthodes de diagnostic classiques de la MTB ou aux précédentes techniques d'amplification d'acide nucléique commerciales. Des études supplémentaires et de meilleures stratégies pour confirmer rapidement un diagnostic de MTB chez les enfants sont nécessaires d'urgence.

Efficacy and harms of remdesivir for the treatment of COVID-19: A systematic review and meta-analysis.

BACKGROUND: Efficacy and safety of treatments for hospitalized COVID-19 are uncertain. We systematically reviewed efficacy and safety of remdesivir for the treatment of COVID-19. METHODS: Studies evaluating remdesivir in adults with hospitalized COVID-19 were searched in several engines until August 21, 2020. Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs). Inverse variance random effects meta-analyses were performed. RESULTS: We included four randomized controlled trials (RCTs) (n = 2296) [two vs. placebo (n = 1299) and two comparing 5-day vs. 10-day regimens (n = 997)], and two case series (n = 88). Studies used intravenous remdesivir 200mg the first day and 100mg for four or nine more days. One RCT (n = 236) was stopped early due to AEs; the other three RCTs reported outcomes between 11 and 15 days. Time to recovery was decreased by 4 days with remdesivir vs. placebo in one RCT (n = 1063), and by 0.8 days with 5-days vs. 10-days of therapy in another RCT (n = 397). Clinical improvement was better for 5-days regimen vs. standard of care in one RCT (n = 600). Remdesivir did not decrease all-cause mortality (RR 0.71, 95%CI 0.39 to 1.28, I2 = 43%) and need for invasive ventilation (RR 0.57, 95%CI 0.23 to 1.42, I2 = 60%) vs. placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs vs. 10-day in one RCT (n = 397). No differences in all-cause mortality or SAEs were seen among 5-day, 10-day and standard of care. There were some concerns of bias to high risk of bias in RCTs. Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data was analyzed. CONCLUSIONS: There is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in hospitalized COVID-19 patients. Until stronger evidence emerges, we cannot conclude that remdesivir is efficacious for treating COVID-19.

First successful field evaluation of new, one-minute haemozoin-based malaria diagnostic device.

BACKGROUND: Early and accurate diagnosis of malaria is critical to the success of malaria elimination. However, the current mainstay of malaria diagnosis in the field, such as light microscopy and rapid diagnostic tests (RDTs), have limitations due to low parasite density or mutation in diagnostic markers. METHODS: We evaluated an inexpensive, robust, rapid, malaria diagnostic device, called Gazelle, that employs magneto-optical detection to identify haemozoin crystals (Hz) produced by all species of human malaria parasites in infected individuals. A beam of polarised light is passed through the lysed diluted blood sample under the influence of high (~.55T) and low magnetic fields. The difference in light transmission through the sample between the high and low magnetic fields indicates presence of Hz, suggesting possible malarial infection. A total of 300 febrile patients were screened at the malaria clinic of Indian Council of Medical Research-National Institute of Research in Tribal Health (ICMR-NIRTH), Jabalpur, India, from August 2018 to November 2018. Malaria diagnosis was done using four diagnostic methods: Gazelle, light microscopy, RDT, and malaria specific Polymerase Chain Reaction (PCR). Measures of diagnostic accuracy were compared. FINDINGS: Out of 300 febrile patients enroled and tested for the presence of malaria parasites, 262 patient samples were included in the final analysis. The sensitivity and specificity of Gazelle was 98% and 97% in comparison to light microscopy, 82% and 99% to PCR and 78% and 99% to RDT, respectively. The results of the four diagnostic methods were comparable and statistically no significant differences in sensitivity or specificity was observed between these methods. Enhanced diagnostic accuracy of Gazelle in malaria patients with no prior history of malaria treatment was observed in this study. INTERPRETATION: The diagnostic ability of Gazelle was comparable to light microscopy and better than RDTs even in low parasitemia and in presence of pfhrp2/3 deletion mutant parasites. Gazelle may be a novel valuable diagnostic tool in resource poor settings where (i) microscopy is not feasible and (ii) pfhrp2/3gene deleted parasite are present. Its speed, cost-efficiency, and alternative to lack of microscopists makes it an important adjunct in field settings. FUNDING: HemexDx, India.

Paper-based microchip electrophoresis for point-of-care hemoglobin testing.

Nearly 7% of the world's population live with a hemoglobin variant. Hemoglobins S, C, and E are the most common and significant hemoglobin variants worldwide. Sickle cell disease, caused by hemoglobin S, is highly prevalent in sub-Saharan Africa and in tribal populations of Central India. Hemoglobin C is common in West Africa, and hemoglobin E is common in Southeast Asia. Screening for significant hemoglobin disorders is not currently feasible in many low-income countries with the high disease burden. Lack of early diagnosis leads to preventable high morbidity and mortality in children born with hemoglobin variants in low-resource settings. Here, we describe HemeChip, the first miniaturized, paper-based, microchip electrophoresis platform for identifying the most common hemoglobin variants easily and affordably at the point-of-care in low-resource settings. HemeChip test works with a drop of blood. HemeChip system guides the user step-by-step through the test procedure with animated on-screen instructions. Hemoglobin identification and quantification is automatically performed, and hemoglobin types and percentages are displayed in an easily understandable, objective way. We show the feasibility and high accuracy of HemeChip via testing 768 subjects by clinical sites in the United States, Central India, sub-Saharan Africa, and Southeast Asia. Validation studies include hemoglobin E testing in Bangkok, Thailand, and hemoglobin S testing in Chhattisgarh, India, and in Kano, Nigeria, where the sickle cell disease burden is the highest in the world. Tests were performed by local users, including healthcare workers and clinical laboratory personnel. Study design, methods, and results are presented according to the Standards for Reporting Diagnostic Accuracy (STARD). HemeChip correctly identified all subjects with hemoglobin S, C, and E variants with 100% sensitivity, and displayed an overall diagnostic accuracy of 98.4% in comparison to reference standard methods. HemeChip is a versatile, mass-producible microchip electrophoresis platform that addresses a major unmet need of decentralized hemoglobin analysis in resource-limited settings.

Comparative efficacy of bone anabolic therapies in women with postmenopausal osteoporosis: A systematic review and network meta-analysis of randomized controlled trials.

OBJECTIVE: To systematically evaluate the effects of bone anabolic therapies (BATs) - specifically, drug therapy with teriparatide, abaloparatide or romosozumab - on fractures, bone mineral density (BMD), and bone metabolites in postmenopausal osteoporosis. METHODS: Six computerized engines were searched through to November 2018. We selected randomized controlled trials (RCTs) evaluating the effect of BATs on postmenopausal osteoporosis and with at least 6 months of follow-up. Controls were placebo, no treatment, or bisphosphonates. Primary outcomes were vertebral and non-vertebral fractures. Secondary outcomes were: BMD determined by dual energy X-ray absorptiometry at total hip, lumbar spine, and femoral neck; N-terminal propeptide of type I procollagen (PINP); C-terminal telopeptide of type I collagen (CTX); and severe adverse events (SAE). We followed the PRISMA guidelines for reporting, and used version 2 of the Cochrane risk-of-bias tool. Frequentist network meta-analyses were performed per outcome. Effects for dichotomous and continuous outcomes were expressed as relative risks and mean differences and their 95% confidence intervals. We used p-scores to rank best treatments per outcome. RESULTS: Sixteen RCTs (n = 18,940) were evaluated. Mean ages ranged between 61 and 74 years, and follow-up times between 6 and 30 months. Four RCTs (n = 971) excluded patients with previous fractures. In contrast to placebo/no treatment, all BATs significantly reduced the risk of vertebral fractures, but no intervention significantly reduced the risk of non-vertebral fractures; abaloparatide ranked better than other interventions for both fracture types (p-scores: 0.95, and 0.89, respectively). All BATs significantly increased BMD at all locations in comparison with placebo/no treatment; romosozumab consistently ranked better than other interventions at all BMD locations (p-scores >0.86). Teriparatide ranked better than other interventions for increasing PINP. No differences in SAE were observed among treatments. CONCLUSIONS: Abaloparatide, romosozumab, and teriparatide are the best treatments, respectively, to reduce vertebral/non-vertebral fractures, increase BMD, and increase bone formation.

Effectiveness of daily chlorhexidine bathing for reducing gram-negative infections: A meta-analysis.

OBJECTIVE: Multiple studies have demonstrated that daily chlorhexidine gluconate (CHG) bathing is associated with a significant reduction in infections caused by gram-positive pathogens. However, there are limited data on the effectiveness of daily CHG bathing on gram-negative infections. The aim of this study was to determine whether daily CHG bathing is effective in reducing the rate of gram-negative infections in adult intensive care unit (ICU) patients. DESIGN: We searched MEDLINE and 3 other databases for original studies comparing daily bathing with and without CHG. Two investigators extracted data independently on baseline characteristics, study design, form and concentration of CHG, incidence, and outcomes related to gram-negative infections. Data were combined using a random-effects model and pooled relative risk ratios (RRs), and 95% confidence intervals (CIs) were derived. RESULTS: In total, 15 studies (n = 34,895 patients) met inclusion criteria. Daily CHG bathing was not significantly associated with a lower risk of gram-negative infections compared with controls (RR, 0.89; 95% CI, 0.73-1.08; P = .24). Subgroup analysis demonstrated that daily CHG bathing was not effective for reducing the risk of gram-negative infections caused by Acinetobacter, Escherichia coli, Klebsiella, Enterobacter, or Pseudomonas spp. CONCLUSIONS: The use of daily CHG bathing was not associated with a lower risk of gram-negative infections. Further, better designed trials with adequate power and with gram-negative infections as the primary end point are needed.

Effect of low-sodium salt substitutes on blood pressure, detected hypertension, stroke and mortality.

OBJECTIVE: A systematic review and meta-analysis was conducted to assess the efficacy of low-sodium salt substitutes (LSSS) as a potential intervention to reduce cardiovascular (CV) diseases. METHODS: Five engines and ClinicalTrials.gov were searched from inception to May 2018. Randomised controlled trials (RCTs) enrolling adult hypertensive or general populations that compared detected hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), overall mortality, stroke and other CV risk factors in those receiving LSSS versus regular salt were included. Effects were expressed as risk ratios or mean differences (MD) and their 95% CIs. Quality of evidence assessment followed GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. RESULTS: 21 RCTs (15 in hypertensive (n=2016), 2 in normotensive (n=163) and 4 in mixed populations (n=5224)) were evaluated. LSSS formulations were heterogeneous. Effects were similar across hypertensive, normotensive and mixed populations. LSSS decreased SBP (MD -7.81 mm Hg, 95% CI -9.47 to -6.15, p<0.00001) and DBP (MD -3.96 mm Hg, 95% CI -5.17 to -2.74, p<0.00001) compared with control. Significant increases in urinary potassium (MD 11.46 mmol/day, 95% CI 8.36 to 14.55, p<0.00001) and calcium excretion (MD 2.39 mmol/day, 95% CI 0.52 to 4.26, p=0.01) and decreases in urinary sodium excretion (MD -35.82 mmol/day, 95% CI -57.35 to -14.29, p=0.001) were observed. Differences in detected hypertension, overall mortality, total cholesterol, triglycerides, glucose or BMI were not significant. Quality of evidence was low to very low for most of outcomes. CONCLUSIONS: LSSS significantly decreased SBP and DBP. There was no effect for detected hypertension, overall mortality and intermediate outcomes. Large, long-term RCTs are necessary to clarify salt substitute effects on clinical outcomes.

A Multicenter Randomized Trial to Determine the Effect of an Environmental Disinfection Intervention on the Incidence of Healthcare-Associated Clostridium difficile Infection.

OBJECTIVE To determine the impact of an environmental disinfection intervention on the incidence of healthcare-associated Clostridium difficile infection (CDI). DESIGN A multicenter randomized trial. SETTING In total,16 acute-care hospitals in northeastern Ohio participated in the study. INTERVENTION We conducted a 12-month randomized trial to compare standard cleaning to enhanced cleaning that included monitoring of environmental services (EVS) personnel performance with feedback to EVS and infection control staff. We assessed the thoroughness of cleaning based on fluorescent marker removal from high-touch surfaces and the effectiveness of disinfection based on environmental cultures for C. difficile. A linear mixed model was used to compare CDI rates in the intervention and postintervention periods for control and intervention hospitals. The primary outcome was the incidence of healthcare-associated CDI. RESULTS Overall, 7 intervention hospitals and 8 control hospitals completed the study. The intervention resulted in significantly increased fluorescent marker removal in CDI and non-CDI rooms and decreased recovery of C. difficile from high-touch surfaces in CDI rooms. However, no reduction was observed in the incidence of healthcare-associated CDI in the intervention hospitals during the intervention and postintervention periods. Moreover, there was no correlation between the percentage of positive cultures after cleaning of CDI or non-CDI rooms and the incidence of healthcare-associated CDI. CONCLUSIONS An environmental disinfection intervention improved the thoroughness and effectiveness of cleaning but did not reduce the incidence of healthcare-associated CDI. Thus, interventions that focus only on improving cleaning may not be sufficient to control healthcare-associated CDI. Infect Control Hosp Epidemiol 2017;38:777-783.

Are hospital floors an underappreciated reservoir for transmission of health care-associated pathogens?

In a survey of 5 hospitals, we found that floors in patient rooms were frequently contaminated with pathogens and high-touch objects such as blood pressure cuffs and call buttons were often in contact with the floor. Contact with objects on floors frequently resulted in transfer of pathogens to hands.

Insulin resistance and endometrial cancer risk: A systematic review and meta-analysis.

AIM: It has been suggested that chronic hyperinsulinemia from insulin resistance is involved in the etiology of endometrial cancer (EC). We performed a systematic review and meta-analysis to assess whether insulin resistance is associated with the risk of EC. METHODS: We searched PubMed-Medline, Embase, Scopus, and Web of Science for articles published from database inception through 30th September 2014. We included all observational studies evaluating components defining insulin resistance in women with and without EC. Quality of the included studies was assessed by Newcastle-Ottawa scale. Random-effects models and inverse variance method were used to meta-analyze the association between insulin resistance components and EC. RESULTS: Twenty-five studies satisfied our inclusion criteria. Fasting insulin levels (13 studies, n = 4088) were higher in women with EC (mean difference [MD] 33.94 pmol/L, 95% confidence interval [CI] 15.04-52.85, p = 0.0004). No differences were seen in postmenopausal versus pre- and postmenopausal subgroup analysis. Similarly, non-fasting/fasting C-peptide levels (five studies, n = 1938) were also higher in women with EC (MD 0.14 nmol/L, 95% CI 0.08-0.21, p < 0.00001). Homeostatic model assessment - insulin resistance (HOMA-IR) values (six studies, n = 1859) in EC patients were significantly higher than in women without EC (MD 1.13, 95% CI 0.20-2.06, p = 0.02). There was moderate-to-high heterogeneity among the included studies. CONCLUSION: Currently available epidemiologic evidence is suggestive of significantly higher risk of EC in women with high fasting insulin, non-fasting/fasting C-peptide and HOMA-IR values.

Antimicrobial Activity of a Novel Vascular Access Film Dressing Containing Chlorhexidine Gluconate.

BACKGROUND: Covering insertion sites with chlorhexidine impregnated dressings has been proven to be clinically effective in reducing catheter related blood stream infections (CR-BSI). Two chlorhexidine gluconate (CHG)-impregnated dressings are commercially available, a polyurethane foam disk and a film dressing containing a chlorhexidine gluconate-impregnated gel pad. While both have demonstrated efficacy in clinical settings, the major drawback of high cost and impaired IV insertion site visibility limits their usage. A new, simple film dressing containing CHG within its adhesive layer is now available. The objective of this study was to test the in vitro antimicrobial efficacy of the new dressing in comparison to the CHG-impregnated gel dressing. METHODS: Quantitative aliquots of suspensions (concentration of 1.0x106 to 5.0x106 cfu/sample) of clinically relevant challenge organisms (Staphylococcus species, gram-negative bacilli, Candida albicans) were incubated in contact with the new CHG-containing film dressing, a placebo version of the same (negative control) and the commercially available CHG-impregnated gel dressing (positive control). Serial dilutions of the surviving organisms were quantified using the pour plate after 1, 3, 5, and 7 days of incubation in order to calculate an antimicrobial log10 reduction for each organism/dressing combination at each point in time. RESULTS: The new CHG-containing film dressing delivered greater than 5.0 log10 reduction throughout the 7 days on all aerobic gram-negative bacilli and Staphylococcus species tested. As of day 1 the CHG-containing film dressing provided greater than 5.0 log10 reduction on Candida albicans. There were no statistically significant differences in the log10 reduction between the two dressings tested. CONCLUSION: The new CHG-containing film dressing was found to be as effective as the chlorhexidine gluconate-impregnated gel dressing on clinically relevant microbes.

Contamination of Health Care Personnel During Removal of Personal Protective Equipment.

IMPORTANCE: Contamination of the skin and clothing of health care personnel during removal of personal protective equipment (PPE) contributes to dissemination of pathogens and places personnel at risk for infection. OBJECTIVES: To determine the frequency and sites of contamination on the skin and clothing of personnel during PPE removal and to evaluate the effect of an intervention on the frequency of contamination. DESIGN, SETTING, AND PARTICIPANTS: We conducted a point-prevalence study and quasi-experimental intervention from October 28, 2014, through March 31, 2015. Data analysis began November 17, 2014, and ended April 21, 2015. Participants included a convenience sample of health care personnel from 4 Northeast Ohio hospitals who conducted simulations of contaminated PPE removal using fluorescent lotion and a cohort of health care personnel from 7 study units in 1 medical center that participated in a quasi-experimental intervention that included education and practice in removal of contaminated PPE with immediate visual feedback based on fluorescent lotion contamination of skin and clothing. MAIN OUTCOMES AND MEASURES: The primary outcomes were the frequency and sites of contamination on skin and clothing of personnel after removal of contaminated gloves or gowns at baseline vs after the intervention. A secondary end point focused on the correlation between contamination of skin with fluorescent lotion and bacteriophage MS2, a nonpathogenic, nonenveloped virus. RESULTS: Of 435 glove and gown removal simulations, contamination of skin or clothing with fluorescent lotion occurred in 200 (46.0%), with a similar frequency of contamination among the 4 hospitals (range, 42.5%-50.3%). Contamination occurred more frequently during removal of contaminated gloves than gowns (52.9% vs 37.8%, P = .002) and when lapses in technique were observed vs not observed (70.3% vs 30.0%, P < .001). The intervention resulted in a reduction in skin and clothing contamination during glove and gown removal (60.0% before the intervention vs 18.9% after, P < .001) that was sustained after 1 and 3 months (12.0% at both time points, P < .001 compared with before the intervention). During simulations of contaminated glove removal, the frequency of skin contamination was similar with fluorescent lotion and bacteriophage MS2 (58.0% vs 52.0%, P = .45). CONCLUSIONS AND RELEVANCE: Contamination of the skin and clothing of health care personnel occurs frequently during removal of contaminated gloves or gowns. Educational interventions that include practice with immediate visual feedback on skin and clothing contamination can significantly reduce the risk of contamination during removal of PPE.