Expanding Access to HIV Viral Load Testing: A Systematic Review of RNA Stability in EDTA Tubes and PPT beyond Current Time and Temperature Thresholds

Background: HIV viral load (VL) testing is the gold standard for antiretroviral treatment monitoring, but many barriers exist to VL testing in resource-limited settings, including storage and transport limitations for whole blood and plasma. Data from various studies indicate that HIV RNA is stable beyond current recommendations. We conducted a systematic review to assess stability data of HIV RNA in whole blood and plasma across times and temperatures. Methods and Findings: Using a pre-defined protocol, five databases were searched for studies where blood samples from HIV patients were stored at time and temperature points that exceeded manufacturer recommendations. RNA stability, the primary outcome, was measured by the difference in means compared to samples stored within established thresholds. RNA stability was defined as ≤0.5 log degradation. The search identified 10,716 titles, of which nine full-text articles were included for review. HIV RNA maintained stability in EDTA whole blood and plasma at all measured time points up to 168 hours when stored at 4°C, while stability was detected at 72 hours (95% confidence) in whole blood at 25°C, with data points before and beyond 72 hours suggesting stability but not reaching statistical significance. For EDTA plasma stored at 30°C, stability was maintained up to 48 hours (95% confidence), with OLS linear regression estimates up to 127 hours, suggesting stability. Overall, quality of studies was moderate. Limitations included small sample sizes, few studies meeting inclusion criteria, and no studies examining RNA stability in low viremia (<3,000 copies/mL) environments. Conclusions: Whole blood and plasma samples in EDTA may remain stable under conditions exceeding current manufacturer recommendations for HIV VL testing. However, given the limited number of studies addressing this question, especially at low levels of viremia, additional evaluations on HIV RNA stability in EDTA tubes and PPT in field conditions are needed

Effectiveness of Transmitted Drug Resistance Testing Before Initiation of Antiretroviral Therapy in HIV-Positive Individuals

BACKGROUND For people living with HIV, major guidelines in high-income countries recommend testing for transmitted drug resistance (TDR) to guide the choice of first-line antiretroviral therapy (ART). However, individuals who fail a first-line regimen can now be switched to one of several effective regimens. Therefore, the virological and clinical benefit of TDR testing needs to be evaluated. METHODS We included individuals from the HIV-CAUSAL Collaboration who enrolled <6 months of HIV diagnosis between 2006 and 2015, were ART-naive, and had measured CD4 count and HIV-RNA. Follow-up started at the date when all inclusion criteria were first met (baseline). We compared 2 strategies: (1) TDR testing within 3 months of baseline versus (2) no TDR testing. We used inverse probability weighting to estimate the 5-year proportion and hazard ratios (HRs) of virological suppression (confirmed HIV-RNA <50 copies/mL), and of AIDS or death under both strategies. RESULTS Of 25,672 eligible individuals (82% males, 52% diagnosed in 2010 or later), 17,189 (67%) were tested for TDR within 3 months of baseline. Of these, 6% had intermediate- or high-level TDR to any antiretroviral drug. The estimated 5-year proportion virologically suppressed was 77% under TDR testing and 74% under no TDR testing; HR 1.06 (95% confidence interval: 1.03 to 1.19). The estimated 5-year risk of AIDS or death was 6% under both strategies; HR 1.03 (95% confidence interval: 0.95 to 1.12). CONCLUSIONS TDR prevalence was low. Although TDR testing improved virological response, we found no evidence that it reduced the incidence of AIDS or death in first 5 years after diagnosis

Subacromial decompression surgery for adults with shoulder pain : a clinical practice guideline

Clinical question Do adults with atraumatic shoulder pain for more than 3 months diagnosed as subacromial pain syndrome (SAPS), also labelled as rotator cuff disease, benefit from subacromial decompression surgery? This guideline builds on to two recent high quality trials of shoulder surgery. Current practice SAPS is the common diagnosis for shoulder pain with several first line treatment options, including analgesia, exercises, and injections. Surgeons frequently perform arthroscopic subacromial decompression for prolonged symptoms, with guidelines providing conflicting recommendations. Recommendation The guideline panel makes a strong recommendation against surgery. How this guideline was created A guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines and the GRADE system. The recommendation is based on two linked systematic reviews on (a) the benefits and harms of subacromial decompression surgery and (b) the minimally important differences for patient reported outcome measures. Recommendations are made actionable for clinicians and their patients through visual overviews. These provide the relative and absolute benefits and harms of surgery in multilayered evidence summaries and decision aids available in MAGIC (www.magicapp.org) to support shared decisions and adaptation. The evidence Surgery did not provide important improvements in pain, function, or quality of life compared with placebo surgery or other options. Frozen shoulder may be more common with surgery. Understanding the recommendation The panel concluded that almost all informed patients would choose to avoid surgery because there is no benefit but there are harms and it is burdensome. Subacromial decompression surgery should not be offered to patients with SAPS. However, there is substantial uncertainty in what alternative treatment is best.Peer reviewe

Low intensity pulsed ultrasound (LIPUS) for bone healing: A clinical practice guideline

Does low intensity pulsed ultrasound (LIPUS) accelerate recovery in adults and children who have experienced bone fractures or osteotomy (cutting of a bone)? An expert panel rapidly produced these recommendations based on a linked systematic review triggered by a large multi-centre randomised trial in adults with tibial fracture

Systematic reviews of observational studies of risk of thrombosis and bleeding in urological surgery (ROTBUS) : introduction and methodology

Abstract Background Pharmacological thromboprophylaxis in the peri-operative period involves a trade-off between reduction in venous thromboembolism (VTE) and an increase in bleeding. Baseline risks, in the absence of prophylaxis, for VTE and bleeding are known to vary widely between urological procedures, but their magnitude is highly uncertain. Systematic reviews and meta-analyses addressing baseline risks are uncommon, needed, and require methodological innovation. In this article, we describe the rationale and methods for a series of systematic reviews of the risks of symptomatic VTE and bleeding requiring reoperation in urological surgery. Methods/design We searched MEDLINE from January 1, 2000 until April 10, 2014 for observational studies reporting on symptomatic VTE or bleeding after urological procedures. Additional studies known to experts and studies cited in relevant review articles were added. Teams of two reviewers, independently assessed articles for eligibility, evaluated risk of bias, and abstracted data. We derived best estimates of risk from the median estimates among studies rated at the lowest risk of bias. The primary endpoints were 30-day post-operative risk estimates of symptomatic VTE and bleeding requiring reoperation, stratified by procedure and patient risk factors. Discussion This series of systematic reviews will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding. Our work advances standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at best estimates of risk (including modeling of timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate certainty in estimates of risk. The results will be incorporated in the upcoming European Association Urology Guideline on Thromboprophylaxis. Systematic review registration PROSPERO CRD42014010342

Atraumatic (pencil-point) versus conventional needles for lumbar puncture:a clinical practice guideline

Is the needle tip configuration important when performing a lumbar puncture for any indication? A systematic review published in the Lancet in December 2017 suggests that it is. The review found that using atraumatic (pencil-point) lumbar puncture needles instead of conventional lumbar puncture needles reduced the risk of post-dural-puncture headache and of return to hospital for additional pain control.1 This guideline recommendation aims to promptly and transparently translate this evidence to a clinical recommendation, following standards for GRADE methodology and trustworthy guidelines.2 The BMJ Rapid Recommendations panel makes a strong recommendation for the use of atraumatic needles for lumbar puncture in all patients regardless of age (adults and children) or indication instead of conventional needles.3 4 Box 1 shows the article and evidence linked to this Rapid Recommendation. The main infographic provides an overview of the absolute benefits and harms (although none were present here) of atraumatic needles. Table 1 below shows any evidence that has emerged since the publication of this guideline.publishedVersio

The persisting burden of invasive pneumococcal disease in HIV patients: an observational cohort study

<p>Abstract</p> <p>Background</p> <p>The increasing use of highly active antiretroviral therapy (HAART) and pneumococcal immunization along with shifting community exposures may have altered the burden of <it>Streptococcus pneumoniae </it>disease in HIV-infected persons. We describe the burden and risk factors for pneumococcal disease in the modern era of HIV care and evaluate the use of a 23-valent pneumococcal polysaccharide vaccine (PPV-23).</p> <p>Methods</p> <p>The incidence of invasive pneumococcal disease (IPD) between January 1^st, 2000 and January 1^st, 2010 in a regional HIV population in Southern Alberta, Canada was determined by linking comprehensive laboratory and hospital surveillance data. Clinical and epidemiologic data including risk factors for <it>S. pneumoniae</it>, history of pneumococcal immunization, serotypes of infections, and length of any hospitalizations for pneumococcal disease were evaluated with multivariate analysis. CD4 count and viral load at immunization were evaluated with a nested case-control analysis.</p> <p>Results</p> <p>In 1946 HIV-patients with 11,099 person-years of follow up, there were 68 distinct episodes of pneumococcal disease occurring in 50 patients. Increased risk was seen if female, age >60, Aboriginal ethnicity, lower education, injection drug use, smoking, nadir CD4 <200/μL, chronic obstructive pulmonary disease, and hepatitis C. Overall, the incidence of IPD was 342/100,000 person-years and was reduced to 187/100,000 within three years of PPV-23 immunization (P < 0.01). Although 78% of patients received PPV-23, 74% of IPD episodes were caused by PPV-23 serotypes. In a case-control analysis, HIV viral load at immunization was significantly predictive of PPV-23 failure, while CD4 count was not. 80% of IPD cases required hospitalization: median length of stay was 7 days (range: 1-71); four patients died.</p> <p>Conclusions</p> <p>Despite universal access to intensive measures to prevent pneumococcal disease including the widespread use of HAART and PPV-23 immunization, the incidence of IPD remains high in HIV patients with its associated morbidity and mortality.</p

Comparative efficacy and safety of alternative glucocorticoids regimens in patients with ANCA-associated vasculitis: a systematic review.

OBJECTIVE: To compare the efficacy and safety of alternative glucocorticoids (GCs) regimens as induction therapy for patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. DESIGN: Systematic review of randomised controlled trials (RCTs). DATA SOURCES: Medline, Embase, Clinicaltrials.gov and Cochrane Central Register of Controlled Trials up to 10 April 2020. STUDY SELECTION AND REVIEW METHODS: RCTs comparing two (or more) different dose regimens of GC in ANCA-associated vasculitis during induction of remission, regardless of other therapies. Pairs of reviewers independently screened records, extracted data and assessed risk of bias. Two reviewers rated certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: Of 3912 records identified, the full texts of two records met the eligibility criteria. Due to the heterogeneity of population and dose regimen of GCs between the two trials, we descriptively presented the two trials and did not combine the results using meta-analysis. Compared with the standard-dose regimen, the reduced-dose regimen of GC may reduce death risk difference (RD): from -1.7% to -2.1%, low certainty), while not increasing end-stage kidney disease (ESKD) (RD: from -1.5% to 0.4%, moderate certainty). The reduced-dose regimen probably has an important reduction in serious infections at 1 year (RD: from -12.8% to -5.9%, moderate certainty). Reduced-dose regimen of GCs probably has trivial or no effect in disease remission, relapse or health-related quality of life (moderate to high certainty). CONCLUSIONS: The reduced-dose regimen of GC may reduce death at the follow-up of 6 months to longer than 1 year and serious infections while not increasing ESKD. PROSPERO REGISTRATION NUMBER: CRD42020179087

PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations.

CLINICAL QUESTION In adults with low density lipoprotein (LDL) cholesterol levels >1.8 mmol/L (>70 mg/dL) who are already taking the maximum dose of statins or are intolerant to statins, should another lipid-lowering drug be added, either a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor or ezetimibe, to reduce the risk of major cardiovascular events? If so, which drug is preferred? Having decided to use one, should we add the other lipid-lowering drug? CURRENT PRACTICE Most guidelines emphasise LDL cholesterol targets in their recommendations for prescribing PCSK9 inhibitors and/or ezetimibe in adults at high risk of experiencing a major adverse cardiovascular event. However, to achieve these goals in very high risk patients with statins alone is almost impossible, so physicians are increasingly considering other lipid-lowering drugs solely for achieving LDL cholesterol treatment goals rather than for achieving important absolute cardiovascular risk reduction. Most guidelines do not systematically assess the cardiovascular benefits of adding PCSK9 inhibitors and/or ezetimibe for all risk groups across primary and secondary prevention, nor do they report, in accordance with explicit judgments of assumed patients' values and preferences, absolute benefits and harms and potential treatment burdens. RECOMMENDATIONS The guideline panel provided mostly weak recommendations, which means we rely on shared decision making when applying these recommendations. For adults already using statins, the panel suggests adding a second lipid-lowering drug in people at very high and high cardiovascular risk but recommends against adding it in people at low cardiovascular risk. For adults who are intolerant to statins, the panel recommends using a lipid-lowering drug in people at very high and high cardiovascular risk but against adding it in those at low cardiovascular risk. When choosing to add another lipid-lowering drug, the panel suggests ezetimibe in preference to PCSK9 inhibitors. The panel suggests further adding a PCSK9 inhibitor to ezetimibe for adults already taking statins at very high risk and those at very high and high risk who are intolerant to statins. HOW THIS GUIDELINE WAS CREATED An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified four risk groups of patients (low, moderate, high, and very high cardiovascular risk) and primarily applied an individual patient perspective in moving from evidence to recommendations, though societal issues were a secondary consideration. The panel considered the balance of benefits and harms and burdens of starting a PCSK9 inhibitor and/or ezetimibe, making assumptions of adults' average values and preferences. Interactive evidence summaries and decision aids accompany multi-layered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that also allows re-use and adaptation. THE EVIDENCE A linked systematic review and network meta-analysis (14 trials including 83 660 participants) of benefits found that PCSK9 inhibitors or ezetimibe probably reduce myocardial infarctions and stroke in patients with very high and high cardiovascular risk, with no impact on mortality (moderate to high certainty evidence), but not in those with moderate and low cardiovascular risk. PCSK9 inhibitors may have similar effects to ezetimibe on reducing non-fatal myocardial infarction or stroke (low certainty evidence). These relative benefits were consistent, but their absolute magnitude varied based on cardiovascular risk in individual patients (for example, for 1000 people treated with PCSK9 inhibitors in addition to statins over five years, benefits ranged from 2 fewer strokes in the lowest risk to 21 fewer in the highest risk). Two systematic reviews on harms found no important adverse events for these drugs (moderate to high certainty evidence). PCSK9 inhibitors require injections that sometimes result in injection site reactions (best estimate 15 more per 1000 in a 5 year timeframe), representing a burden and harm that may matter to patients. The MATCH-IT decision support tool allows you to interact with the evidence and your patients across the alternative options: https://magicevidence.org/match-it/220504dist-lipid-lowering-drugs/. UNDERSTANDING THE RECOMMENDATIONS The stratification into four cardiovascular risk groups means that, to use the recommendations, physicians need to identify their patient's risk first. We therefore suggest, specific to various geographical regions, using some reliable risk calculators that estimate patients' cardiovascular risk based on a mix of known risk factors. The largely weak recommendations concerning the addition of ezetimibe or PCSK9 inhibitors reflect what the panel considered to be a close balance between small reductions in stroke and myocardial infarctions weighed against the burdens and limited harms.Because of the anticipated large variability of patients' values and preferences, well informed choices warrant shared decision making. Interactive evidence summaries and decision aids linked to the recommendations can facilitate such shared decisions. The strong recommendations against adding another drug in people at low cardiovascular risk reflect what the panel considered to be a burden without important benefits. The strong recommendation for adding either ezetimibe or PCSK9 inhibitors in people at high and very high cardiovascular risk reflect a clear benefit.The panel recognised the key uncertainty in the evidence concerning patient values and preferences, namely that what most people consider important reductions in cardiovascular risks, weighed against burdens and harms, remains unclear. Finally, availability and costs will influence decisions when healthcare systems, clinicians, or people consider adding ezetimibe or PCSK9 inhibitors