Doppler trans-thoracic echocardiography for detection of pulmonary hypertension in adults.

BACKGROUND: Pulmonary hypertension (PH) is an important cause of morbidity and mortality, which leads to a substantial loss of exercise capacity. PH ultimately leads to right ventricular overload and subsequent heart failure and early death. Although early detection and treatment of PH are recommended, due to the limited responsiveness to therapy at late disease stages, many patients are diagnosed at a later stage of the disease because symptoms and signs of PH are nonspecific at earlier stages. While direct pressure measurement with right-heart catheterisation is the clinical reference standard for PH, it is not routinely used due to its invasiveness and complications. Trans-thoracic Doppler echocardiography is less invasive, less expensive, and widely available compared to right-heart catheterisation; it is therefore recommended that echocardiography be used as an initial diagnosis method in guidelines. However, several studies have questioned the accuracy of noninvasively measured pulmonary artery pressure. There is substantial uncertainty about the diagnostic accuracy of echocardiography for the diagnosis of PH. OBJECTIVES: To determine the diagnostic accuracy of trans-thoracic Doppler echocardiography for detecting PH. SEARCH METHODS: We searched MEDLINE, Embase, Web of Science Core Collection, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform from database inception to August 2021, reference lists of articles, and contacted study authors. We applied no restrictions on language or type of publication. SELECTION CRITERIA: We included studies that evaluated the diagnostic accuracy of trans-thoracic Doppler echocardiography for detecting PH, where right-heart catheterisation was the reference standard. We excluded diagnostic case-control studies (two-gate design), studies where right-heart catheterisation was not the reference standard, and those in which the reference standard threshold differed from 25 mmHg. We also excluded studies that did not provide sufficient diagnostic test accuracy data (true-positive [TP], false-positive [FP], true-negative [TN], and false-negative [FN] values, based on the reference standard). We included studies that provided data from which we could extract TP, FP, TN, and FN values, based on the reference standard. Two authors independently screened and assessed the eligibility based on the titles and abstracts of records identified by the search. After the title and abstract screening, the full-text reports of all potentially eligible studies were obtained, and two authors independently assessed the eligibility of the full-text reports. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias and extracted data from each of the included studies. We contacted the authors of the included studies to obtain missing data. We assessed the methodological quality of studies using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We estimated a summary receiver operating characteristic (SROC) curve by fitting a hierarchical summary ROC (HSROC) non-linear mixed model. We explored sources of heterogeneity regarding types of PH, methods to estimate the right atrial pressure, and threshold of index test to diagnose PH. All analyses were performed using the Review Manager 5, SAS and STATA statistical software. MAIN RESULTS: We included 17 studies (comprising 3656 adult patients) assessing the diagnostic accuracy of Doppler trans-thoracic echocardiography for the diagnosis of PH. The included studies were heterogeneous in terms of patient distribution of age, sex, WHO classification, setting, country, positivity threshold, and year of publication. The prevalence of PH reported in the included studies varied widely (from 6% to 88%). The threshold of index test for PH diagnosis varied widely (from 30 mmHg to 47 mmHg) and was not always prespecified. No study was assigned low risk of bias or low concern in each QUADAS-2 domain assessed. Poor reporting, especially in the index test and reference standard domains, hampered conclusive judgement about the risk of bias. There was little consistency in the thresholds used in the included studies; therefore, common thresholds contained very sparse data, which prevented us from calculating summary points of accuracy estimates. With a fixed specificity of 86% (the median specificity), the estimated sensitivity derived from the median value of specificity using HSROC model was 87% (95% confidence interval [CI]: 78% to 96%). Using a prevalence of PH of 68%, which was the median among the included studies conducted mainly in tertiary hospitals, diagnosing a cohort of 1000 adult patients under suspicion of PH would result in 88 patients being undiagnosed with PH (false negatives) and 275 patients would avoid unnecessary referral for a right-heart catheterisation (true negatives). In addition, 592 of 1000 patients would receive an appropriate and timely referral for a right-heart catheterisation (true positives), while 45 patients would be wrongly considered to have PH (false positives). Conversely, when we assumed low prevalence of PH (10%), as in the case of preoperative examinations for liver transplantation, the number of false negatives and false positives would be 13 and 126, respectively. AUTHORS' CONCLUSIONS: Our evidence assessment of echocardiography for the diagnosis of PH in adult patients revealed several limitations. We were unable to determine the average sensitivity and specificity at any particular index test threshold and to explain the observed variability in results. The high heterogeneity of the collected data and the poor methodological quality would constrain the implementation of this result into clinical practice. Further studies relative to the accuracy of Doppler trans-thoracic echocardiography for the diagnosis of PH in adults, that apply a rigorous methodology for conducting diagnostic test accuracy studies, are needed.

Small molecule TCS21311 can replace BMP7 and facilitate cell proliferation in in vitro expansion culture of nephron progenitor cells.

Several groups have developed in vitro expansion cultures for mouse metanephric nephron progenitor cells (NPCs) using cocktails of small molecules and growth factors including BMP7. However, the detailed mechanisms by which BMP7 acts in the NPC expansion remain to be elucidated. Here, by performing chemical screening for BMP substitutes, we identified a small molecule, TCS21311, that can replace BMP7 and revealed a novel inhibitory role of BMP7 in JAK3-STAT3 signaling in NPC expansion culture. Further, we found that TCS21311 facilitates the proliferation of mouse embryonic NPCs and human induced pluripotent stem cell-derived NPCs when added to the expansion culture. These results will contribute to understanding the mechanisms of action of BMP7 in NPC proliferation in vitro and in vivo and to the stable supply of NPCs for regenerative therapy, disease modeling and drug discovery for kidney diseases.

Humour-based interventions for people with schizophrenia.

BACKGROUND: Humour-based interventions are defined as any intervention that promotes health and wellness by stimulating a playful discovery, expression, or appreciation of the absurdity or incongruity of life's situations. Humour-based interventions can be implemented in different settings, including hospitals, nursing homes and day care centres. They have been posed as an adjunct to usual care for people with schizophrenia, but a summary of the evidence is lacking. OBJECTIVES: To examine the effects of humour-based interventions as an add-on intervention to standard care for people with schizophrenia. SEARCH METHODS: On 31 July 2019 and 10 February 2021 we searched the Cochrane Schizophrenia Group's study-based register of trials, which is based on CENTRAL, CINAHL, ClinicalTrials.Gov, Embase, ISRCTN, MEDLINE, PsycINFO, PubMed, and WHO ICTRP. SELECTION CRITERIA: We included all randomised controlled trials comparing humour-based interventions with active controls, other psychological interventions, or standard care for people with schizophrenia. We excluded studies fulfilling our prespecified selection criteria but without useable data from further quantitative synthesis. DATA COLLECTION AND ANALYSIS: Two review authors independently inspected citations, selected studies, extracted data and appraised study quality, following the guidance from the Cochrane Handbook for Systematic Reviews of Interventions. For binary outcomes we calculated risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous outcomes we calculated the mean differences (MDs) and their 95% CIs. We assessed risks of bias for included studies and created summary of findings tables using the GRADE approach. MAIN RESULTS: We included three studies in this review for qualitative synthesis, although one study did not report any relevant outcomes. We therefore include two studies (n = 96) in our quantitative synthesis. No data were available on the following prespecified primary outcomes: clinically-important change in general mental state, clinically-important change in negative symptoms, clinically-important change in overall quality of life, and adverse effects. As compared with active control, humour-based interventions may not improve the average endpoint score of a general mental state scale (Positive and Negative Syndrome Scale (PANSS) total score: MD -1.70, 95% CI -17.01 to 13.61; 1 study, 30 participants; very low certainty of evidence); positive symptoms (PANSS positive symptom score: MD 0.00, 95% CI -2.58 to 2.58; 1 study, 30 participants; low certainty of evidence), negative symptoms (PANSS negative symptom score: MD -0.70, 95% CI -4.22 to 2.82; 1 study, 30 participants; very low certainty of evidence) and anxiety (State-Trait Anxiety Inventory (STAI): MD -2.60, 95% CI -5.76 to 0.56; 1 study, 30 participants; low certainty of evidence). Due to the small sample size, we remain uncertain about the effect of humour-based interventions on leaving the study early as compared with active control (no event, 1 study, 30 participants; very low certainty of evidence). On the other hand, humour-based interventions may reduce depressive symptoms (Beck Depression Inventory (BDI): MD -6.20, 95% CI -12.08 to -0.32; 1 study, 30 participants; low certainty of evidence). Compared with standard care, humour-based interventions may not improve  depressive symptoms (BDI second edition: MD 0.80, 95% CI -2.64 to 4.24; 1 study, 59 participants; low certainty of evidence). We are uncertain about the effect of humour-based interventions on leaving the study early for any reason compared with standard care (risk ratio 0.38, 95% CI 0.08 to 1.80; 1 study, 66 participants; very low certainty of evidence). AUTHORS' CONCLUSIONS: We are currently uncertain whether the evidence supports the use of humour-based interventions in people with schizophrenia. Future research with rigorous and transparent methodology investigating clinically important outcomes is warranted.

Monitoring of gastric residual volume during enteral nutrition.

BACKGROUND: The main goal of enteral nutrition (EN) is to manage malnutrition in order to improve clinical outcomes. However, EN may increase the risks of vomiting or aspiration pneumonia during gastrointestinal dysfunction. Consequently, monitoring of gastric residual volume (GRV), that is, to measure GRV periodically and modulate the speed of enteral feeding according to GRV, has been recommended as a management goal in many intensive care units. Yet, there is a lack of robust evidence that GRV monitoring reduces the level of complications during EN. The best protocol of GRV monitoring is currently unknown, and thus the precise efficacy and safety profiles of GRV monitoring remain to be ascertained. OBJECTIVES: To investigate the efficacy and safety of GRV monitoring during EN. SEARCH METHODS: We searched electronic databases including CENTRAL, MEDLINE, Embase, and CINAHL for relevant studies on 3 May 2021. We also checked reference lists of included studies for additional information and contacted experts in the field. SELECTION CRITERIA: We included randomized controlled trials (RCTs), randomized cross-over trials, and cluster-RCTs investigating the effects of GRV monitoring during EN. We imposed no restrictions on the language of publication. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results for eligible studies and extracted trial-level information from each included study, including methodology and design, characteristics of study participants, interventions, and outcome measures. We assessed risk of bias for each study using Cochrane's risk of bias tool. We followed guidance from the GRADE framework to assess the overall certainty of evidence across outcomes. We used a random-effects analytical model to perform quantitative synthesis of the evidence. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous and mean difference (MD) with 95% CIs for continuous outcomes. MAIN RESULTS: We included eight studies involving 1585 participants. All studies were RCTs conducted in ICU settings. Two studies (417 participants) compared less-frequent (less than eight hours) monitoring of GRV against a regimen of more-frequent (eight hours or greater) monitoring. The evidence is very uncertain about the effect of frequent monitoring of GRV on mortality rate (RR 0.91, 95% CI 0.60 to 1.37; I² = 8%; very low-certainty evidence), incidence of pneumonia (RR 1.08, 95% CI 0.64 to 1.83; heterogeneity not applicable; very low-certainty evidence), length of hospital stay (MD 2.00 days, 95% CI -2.15 to 6.15; heterogeneity not applicable; very low-certainty evidence), and incidence of vomiting (RR 0.14, 95% CI 0.02 to 1.09; heterogeneity not applicable; very low-certainty evidence). Two studies (500 participants) compared no GRV monitoring with frequent (12 hours or less) monitoring. Similarly, the evidence is very uncertain about the effect of no monitoring of GRV on mortality rate (RR 0.87, 95% CI 0.62 to 1.23; I² = 51%; very low-certainty evidence), incidence of pneumonia (RR 0.70, 95% CI 0.43 to 1.13; heterogeneity not applicable; very low-certainty evidence), length of hospital stay (MD -1.53 days, 95% CI -4.47 to 1.40; I² = 0%; very low-certainty evidence), and incidence of vomiting (RR 1.47, 95% CI 1.13 to 1.93; I² = 0%; very low-certainty evidence). One study (322 participants) assessed the impact of GRV threshold (500 mL per six hours) on clinical outcomes. The evidence is very uncertain about the effect of the threshold for GRV at time of aspiration on mortality rate (RR 1.01, 95% CI 0.74 to 1.38; heterogeneity not applicable; very low-certainty evidence), incidence of pneumonia (RR 1.03, 95% CI 0.72 to 1.46; heterogeneity not applicable; very low-certainty evidence), and length of hospital stay (MD -0.90 days, 95% CI -2.60 to 4.40; heterogeneity not applicable; very low-certainty evidence). Two studies (140 participants) explored the effects of returning or discarding the aspirated/drained GRV. The evidence is uncertain about the effect of discarding or returning the aspirated/drained GRV on the incidence of vomiting (RR 1.00, 95% CI 0.06 to 15.63; heterogeneity not applicable; very low-certainty evidence) and volume aspirated from the stomach (MD -7.30 mL, 95% CI -26.67 to 12.06, I² = 0%; very low-certainty evidence) We found no studies comparing the effects of protocol-based EN strategies that included GRV-related criteria against strategies that did not include such criteria. AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effect of GRV on clinical outcomes including mortality, pneumonia, vomiting, and length of hospital stay.

Non-pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy.

BACKGROUND: Acute kidney injury (AKI) is a common complication amongst people who are critically ill, and it is associated with an increased risk of death. For people with severe AKI, continuous kidney replacement therapy (CKRT), which is delivered over 24 hours, is needed when they become haemodynamically unstable. When CKRT is interrupted due to clotting of the extracorporeal circuit, the delivered dose is decreased and thus leading to undertreatment. OBJECTIVES: This review assessed the efficacy of non-pharmacological measures to maintain circuit patency in CKRT. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 25 January 2021 which includes records identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) (parallel-group and cross-over studies), cluster RCTs and quasi-RCTs that examined non-pharmacological interventions to prevent clotting of extracorporeal circuits during CKRT.  DATA COLLECTION AND ANALYSIS: Three pairs of review authors independently extracted information including participants, interventions/comparators, outcomes, study methods, and risk of bias. The primary outcomes were circuit lifespan and death due to any cause at day 28. We used a random-effects model to perform quantitative synthesis (meta-analysis). We assessed risk of bias in included studies using the Cochrane Collaboration's tool for assessing risk of bias. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: A total of 20 studies involving 1143 randomised participants were included in the review. The methodological quality of the included studies was low, mainly due to the unclear randomisation process and blinding of the intervention. We found evidence on the following 11 comparisons: (i) continuous venovenous haemodialysis (CVVHD) versus continuous venovenous haemofiltration (CVVH) or continuous venovenous haemodiafiltration (CVVHDF); (ii) CVVHDF versus CVVH; (iii) higher blood flow (≥ 250 mL/minute) versus standard blood flow (< 250 mL/minute); (iv) AN69 membrane (AN69ST) versus other membranes; (v) pre-dilution versus post-dilution; (vi) a longer catheter (> 20 cm) placing the tip targeting the right atrium versus a shorter catheter (≤ 20 cm) placing the tip in the superior vena cava; (vii) surface-modified double-lumen catheter versus standard double-lumen catheter with identical geometry and flow design; (viii) single-site infusion anticoagulation versus double-site infusion anticoagulation; (ix) flat plate filter versus hollow fibre filter of the same membrane type; (x) a filter with a larger membrane surface area versus a smaller one; and (xi) a filter with more and shorter hollow fibre versus a standard filter of the same membrane type. Circuit lifespan was reported in 9 comparisons. Low certainty evidence indicated that CVVHDF (versus CVVH: MD 10.15 hours, 95% CI 5.15 to 15.15; 1 study, 62 circuits), pre-dilution haemofiltration (versus post-dilution haemofiltration: MD 9.34 hours, 95% CI -2.60 to 21.29; 2 studies, 47 circuits; I² = 13%), placing the tip of a longer catheter targeting the right atrium (versus placing a shorter catheter targeting the tip in the superior vena cava: MD 6.50 hours, 95% CI 1.48 to 11.52; 1 study, 420 circuits), and surface-modified double-lumen catheter (versus standard double-lumen catheter: MD 16.00 hours, 95% CI 13.49 to 18.51; 1 study, 262 circuits) may prolong circuit lifespan. However, higher blood flow may not increase circuit lifespan (versus standard blood flow: MD 0.64, 95% CI -3.37 to 4.64; 2 studies, 499 circuits; I² = 70%). More and shorter hollow fibre filters (versus standard filters: MD -5.87 hours, 95% CI -10.18 to -1.56; 1 study, 6 circuits) may reduce circuit lifespan. Death from any cause was reported in four comparisons We are uncertain whether CVVHDF versus CVVH, CVVHD versus CVVH or CVVHDF, longer versus a shorter catheter, or surface-modified double-lumen catheters versus standard double-lumen catheters reduced death due to any cause, in very low certainty evidence. Recovery of kidney function was reported in three comparisons. We are uncertain whether CVVHDF versus CVVH, CVVHDF versus CVVH, or surface-modified double-lumen catheters versus standard double-lumen catheters increased recovery of kidney function. Vascular access complications were reported in two comparisons. Low certainty evidence indicated using a longer catheter (versus a shorter catheter: RR 0.40, 95% CI 0.22 to 0.74) may reduce vascular access complications, however the use of surface-modified double lumen catheters versus standard double-lumen catheters may make little or no difference to vascular access complications. AUTHORS' CONCLUSIONS: The use of CVVHDF as compared with CVVH, pre-dilution haemofiltration, a longer catheter, and surface-modified double-lumen catheter may be useful in prolonging the circuit lifespan, while higher blood flow and more and shorter hollow fibre filter may reduce circuit life. The Overall, the certainty of evidence was assessed to be low to very low due to the small sample size of the included studies. Data from future rigorous and transparent research are much needed in order to fully understand the effects of non-pharmacological interventions in preventing circuit coagulation amongst people with AKI receiving CKRT.

A model six-month workshop for developing systematic review protocols at teaching hospitals: action research and scholarly productivity.

BACKGROUND: Research engagement contributes to the improvement of patient care. A systematic review is a suitable first scholarly activity because it entails summarization of publicly available data and usually requires neither rigorous ethical review nor research funding. METHODS: This study aimed to develop a model workshop for healthcare staff to acquire skills in creating systematic review protocols based on their own clinical questions at teaching hospitals. We used an action research method to create a model workshop at four hospitals in Japan from April 2015 to March 2017. To improve the program, we solicited reflections using participant questionnaires for each lecture and examined the quality of homework submitted by participants after each lecture. We administered a revised final version of the workshop at five hospitals from April 2016 to March 2017. We evaluated the participants' scholarly productivity related to these workshops. The observation period was a minimum of 2 years following the workshops. RESULTS: Most participants had never developed a formal clinical research protocol and voluntarily participated in the workshop. The action research was developed and implemented at nine teaching hospitals in Japan, including one university hospital. The study developed a model nine-step workshop curriculum: 1) Research question development, 2) Search strategy development, 3) Search strategy brush-up, 4) Exclusion and inclusion criteria development, 5) Risk of bias assessment planning, 6) Meta-analysis planning, 7) Subgroup and sensitivity analysis planning, 8) Planning the presentation of results, and 9) Presentation protocols. A total of 233 participants, including medical doctors and other health professionals, produced 414 research questions. Seventy-nine participants (34%) completed the workshop, and 47 review teams accomplished systematic review protocols. The participants published 13 peer-reviewed articles as a result of the workshop. CONCLUSIONS: We developed a structured scholarly productive model workshop for healthcare staff working at hospitals. We found healthcare staff with clinical subspecialties were able to develop an unexpectedly high number of research questions through this workshop. Medical teachers at hospitals with prior systematic review experience could teach how to develop systematic review protocols using this model. Further research is needed to increase the academic productivity of such workshops. TRIAL REGISTRATION: UMIN (https://www.umin.ac.jp/ctr/), UMIN000017107 (4/15/2015), UMIN000025580 (1/10/2017).

Diagnostic test accuracy of jolt accentuation for headache in acute meningitis in the emergency setting.

BACKGROUND: Meningitis is inflammation of the meninges, the layers that protect the brain and spinal cord. Acute meningitis is an emergent disease that develops over the course of hours to several days. Delay in treatment can lead to serious outcomes. Inflammation of the meninges is assessed by analysing cerebrospinal fluid. Identifying the pathogen in cerebrospinal fluid is another way to diagnose meningitis. Cerebrospinal fluid is collected by doing a lumbar puncture, which is an invasive test, and can be avoided if a physical examination excludes the diagnosis of meningitis. However, most physical examinations, such as nuchal rigidity, Kernig's test, and Brudzinski's test, are not sufficiently sensitive to exclude meningitis completely. Jolt accentuation of headache is a new and less well-recognised physical examination, which assesses meningeal irritation. It is judged as positive if the headache is exacerbated by rotating the head horizontally two or three times per second. A 1991 observational study initially reported high sensitivity of this examination to predict pleocytosis. Pleocytosis, an abnormally high cerebrospinal fluid sample white cell count, is an accepted indicator of nervous system infection or inflammation. Jolt accentuation of headache may therefore accurately rule out meningitis without the use of lumbar puncture. However, more recent cross-sectional studies have reported variable diagnostic accuracy. OBJECTIVES: To estimate the diagnostic accuracy of jolt accentuation of headache for detecting acute meningitis in emergency settings. Secondary objectives: to investigate the sources of heterogeneity, including study population, patient condition, and types of meningitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), and Embase (Elsevier) to 27 April 2020. We searched ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and Ichushi-Web Version 5.0 to 28 April 2020. SELECTION CRITERIA: We included cross-sectional studies that assessed the diagnostic accuracy of jolt accentuation of headache for people with suspected meningitis in emergency settings. We included participants of any age and any severity of illness. Meningitis should be diagnosed with any reference standard, such as cerebrospinal fluid pleocytosis, proof of causative agents, or autopsy. DATA COLLECTION AND ANALYSIS: Two review authors independently collated study data. We assessed methodological quality of studies using QUADAS-2 criteria. We used a bivariate random-effects model to determine summary estimates of sensitivity and specificity where meta-analysis was possible. We performed sensitivity analyses to validate the robustness of outcomes. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included nine studies (1161 participants). Five studies included only adults. Four studies included both adults and children; however, the proportion was not reported in three of these studies. The youngest child reported in the studies was aged 13 years. There was no study including only children. The reference standard was pleocytosis in eight studies, and the combination of pleocytosis and increased protein in the cerebrospinal fluid in one study. Two studies also used smear or positive culture of cerebrospinal fluid. Risk of bias and concern about applicability was high in the participant selection domain for all included studies and the consciousness subgroup. Overall, pooled sensitivity was 65.3% (95% confidence interval (CI) 37.3 to 85.6), and pooled specificity was 70.4% (95% CI 47.7 to 86.1) (very low-certainty evidence). We established the possibility of heterogeneity from visual inspection of forest plots. However, we were unable to conduct further analysis for study population, types of meningitis, and participants' condition, other than disturbance of consciousness (a secondary outcome). Amongst participants whose consciousness was undisturbed (8 studies, 921 participants), pooled sensitivity and specificity were 75.2% (95% CI 54.3 to 88.6) and 60.8% (95% CI 43.4 to 75.9), respectively (very low-certainty evidence). AUTHORS' CONCLUSIONS: Jolt accentuation for headache may exclude diagnoses of meningitis in emergency settings, but high-quality evidence to support use of this test is lacking. Even where jolt accentuation of headache is negative, there is still the possibility of acute meningitis. This review identified the possibility of heterogeneity. However, factors that contribute to heterogeneity are incompletely understood, and should be considered in future research.

Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy.

BACKGROUND: Acute kidney injury (AKI) is a major comorbidity in hospitalised patients. Patients with severe AKI require continuous renal replacement therapy (CRRT) when they are haemodynamically unstable. CRRT is prescribed assuming it is delivered over 24 hours. However, it is interrupted when the extracorporeal circuits clot and the replacement is required. The interruption may impair the solute clearance as it causes under dosing of CRRT. To prevent the circuit clotting, anticoagulation drugs are frequently used. OBJECTIVES: To assess the benefits and harms of pharmacological interventions for preventing clotting in the extracorporeal circuits during CRRT. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We selected randomised controlled trials (RCTs or cluster RCTs) and quasi-RCTs of pharmacological interventions to prevent clotting of extracorporeal circuits during CRRT. DATA COLLECTION AND ANALYSIS: Data were abstracted and assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) with 95% confidence intervals (CI). The primary review outcomes were major bleeding, successful prevention of clotting (no need of circuit change in the first 24 hours for any reason), and death. Evidence certainty was determined using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. MAIN RESULTS: A total of 34 completed studies (1960 participants) were included in this review. We identified seven ongoing studies which we plan to assess in a future update of this review. No included studies were free from risk of bias. We rated 30 studies for performance bias and detection bias as high risk of bias. We rated 18 studies for random sequence generation,ààsix studies for the allocation concealment, three studies for performance bias, three studies for detection bias,à nine studies for attrition bias,à14 studies for selective reporting and nine studies for the other potential source of bias, as having low risk of bias. We identified eight studies (581 participants) that compared citrate with unfractionated heparin (UFH). Compared to UFH, citrate probably reduces major bleeding (RR 0.22, 95% CI 0.08 to 0.62; moderate certainty evidence) and probably increases successful prevention of clotting (RR 1.44, 95% CI 1.10 to 1.87; moderate certainty evidence). Citrate may have little or no effect on death at 28 days (RR 1.06, 95% CI 0.86 to 1.30, moderate certainty evidence). Citrate versus UFH may reduce the number of participants who drop out of treatment due to adverse events (RR 0.47, 95% CI 0.15 to 1.49; low certainty evidence). Compared to UFH, citrate may make little or no difference to the recovery of kidney function (RR 1.04, 95% CI 0.89 to 1.21; low certainty evidence). Compared to UFH, citrate may reduceàthrombocytopenia (RR 0.39, 95% CI 0.14 to 1.03; low certainty evidence). It was uncertain whether citrate reduces a cost to health care services because of inadequate data. For low molecular weight heparin (LMWH) versus UFH, six studies (250 participants) were identified. Compared to LMWH, UFH may reduce major bleeding (0.58, 95% CI 0.13 to 2.58; low certainty evidence). It is uncertain whether UFH versus LMWH reduces death at 28 days or leads to successful prevention of clotting. Compared to LMWH, UFH may reduce the number of patient dropouts from adverse events (RR 0.29, 95% CI 0.02 to 3.53; low certainty evidence). It was uncertain whether UFH versus LMWH leads to the recovery of kidney function because no included studies reported this outcome. It was uncertain whether UFH versus LMWH leads to thrombocytopenia. It was uncertain whether UFH reduces a cost to health care services because of inadequate data. For the comparison of UFH to no anticoagulation, one study (10 participants) was identified. It is uncertain whether UFH compare to no anticoagulation leads to more major bleeding. It is uncertain whether UFH improves successful prevention of clotting in the first 24 hours, death at 28 days, the number of patient dropouts due to adverse events, recovery of kidney function, thrombocytopenia, or cost to health care services because no study reported these outcomes. For the comparison ofàcitrate to no anticoagulation,àno completed study was identified. AUTHORS' CONCLUSIONS: Currently,àavailable evidence does not support the overall superiority of any anticoagulant to another. Compared to UFH, citrate probably reduces major bleeding and prevents clotting and probably has little or no effect on death at 28 days. For other pharmacological anticoagulation methods, there is no available data showing overall superiority to citrate or no pharmacological anticoagulation. Further studies are needed to identify patient populations in which CRRT should commence with no pharmacological anticoagulation or with citrate.

Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy.

BACKGROUND: Acute kidney injury (AKI) is a major comorbidity in hospitalised patients. Patients with severe AKI require continuous renal replacement therapy (CRRT) when they are haemodynamically unstable. CRRT is prescribed assuming it is delivered over 24 hours. However, it is interrupted when the extracorporeal circuits clot and the replacement is required. The interruption may impair the solute clearance as it causes under dosing of CRRT. To prevent the circuit clotting, anticoagulation drugs are frequently used. OBJECTIVES: To assess the benefits and harms of pharmacological interventions for preventing clotting in the extracorporeal circuits during CRRT. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We selected randomised controlled trials (RCTs or cluster RCTs) and quasi-RCTs of pharmacological interventions to prevent clotting of extracorporeal circuits during CRRT. DATA COLLECTION AND ANALYSIS: Data were abstracted and assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) with 95% confidence intervals (CI). The primary review outcomes were major bleeding, successful prevention of clotting (no need of circuit change in the first 24 hours for any reason), and death. Evidence certainty was determined using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. MAIN RESULTS: A total of 34 completed studies (1960 participants) were included in this review. We identified seven ongoing studies which we plan to assess in a future update of this review. No included studies were free from risk of bias. We rated 30 studies for performance bias and detection bias as high risk of bias. We rated 18 studies for random sequence generation,  six studies for the allocation concealment, three studies for performance bias, three studies for detection bias,  nine studies for attrition bias, 14 studies for selective reporting and nine studies for the other potential source of bias, as having low risk of bias. We identified eight studies (581 participants) that compared citrate with unfractionated heparin (UFH). Compared to UFH, citrate probably reduces major bleeding (RR 0.22, 95% CI 0.08 to 0.62; moderate certainty evidence). Citrate may have little or no effect on death at 28 days (RR 1.06, 95% CI 0.86 to 1.30, moderate certainty evidence), while citrate versus UFH may have little or no effect on successful prevention of clotting (RR 1.01, 95% CI 0.77 to 1.32; moderate certainty evidence). Citrate versus UFH may reduce the number of participants who drop out of treatment due to adverse events (RR 0.47, 95% CI 0.15 to 1.49; low certainty evidence). Compared to UFH, citrate may make little or no difference to the recovery of kidney function (RR 0.95, 95% CI 0.66 to 1.36; low certainty evidence). Compared to UFH, citrate may reduce thrombocytopenia (RR 0.39, 95% CI 0.14 to 1.03; low certainty evidence). It was uncertain whether citrate reduces a cost to health care services because of inadequate data. For low molecular weight heparin (LMWH) versus UFH, six studies (250 participants) were identified. Compared to LMWH, UFH may reduce major bleeding (0.58, 95% CI 0.13 to 2.58; low certainty evidence). It is uncertain whether UFH versus LMWH reduces death at 28 days or leads to successful prevention of clotting. Compared to LMWH, UFH may reduce the number of patient dropouts from adverse events (RR 0.29, 95% CI 0.02 to 3.53; low certainty evidence). It was uncertain whether UFH versus LMWH leads to the recovery of kidney function because no included studies reported this outcome. It was uncertain whether UFH versus LMWH leads to thrombocytopenia. It was uncertain whether UFH reduces a cost to health care services because of inadequate data. For the comparison of UFH to no anticoagulation, one study (10 participants) was identified. It is uncertain whether UFH compare to no anticoagulation leads to more major bleeding. It is uncertain whether UFH improves successful prevention of clotting in the first 24 hours, death at 28 days, the number of patient dropouts due to adverse events, recovery of kidney function, thrombocytopenia, or cost to health care services because no study reported these outcomes. For the comparison of citrate to no anticoagulation, no completed study was identified. AUTHORS' CONCLUSIONS: Currently, available evidence does not support the overall superiority of any anticoagulant to another. Compared to UFH, citrate probably reduces major bleeding and probably has little or no effect on preventing clotting or death at 28 days. For other pharmacological anticoagulation methods, there is no available data showing overall superiority to citrate or no pharmacological anticoagulation. Further studies are needed to identify patient populations in which CRRT should commence with no pharmacological anticoagulation or with citrate.

Correction to: Voice rehabilitation for laryngeal cancer after radiotherapy: a systematic review and meta-analysis.

In the original publication of the article, the reference 14 was published incorrectly. The correct reference is given below.

Videolaryngoscopy for transesophageal echocardiography probe insertion: a systematic review and meta-analysis of randomized controlled trials.

Transesophageal echocardiography (TEE) is a well-established procedure, but serious complications may occur. This systematic review and meta-analysis assessed the utility of videolaryngoscopy-assisted technique in TEE probe insertion. We performed a systematic search in MEDLINE, EMBASE, CENTRAL, and ICTRP. We included RCTs comparing TEE probe insertion techniques assisted with videolaryngoscopy and with any other insertion technique in adult patients. Primary outcome measures were (1) the number of attempts before successful TEE probe insertion, and (2) the risk of any procedural injury to related structures. The secondary outcome measure was time to TEE probe insertion. In total, three studies (n = 266) were included in this systematic review. Overall, a significantly less number of attempts were required with videolaryngoscopy-assisted insertion (mean difference [MD] - 0.60; 95% confidence interval [CI] - 0.73, - 0.46; low quality of evidence). Videolaryngoscopy-assisted technique was also associated with smaller risk of complications (risk ratio [RR] 0.17; 95% CI 0.05, 0.62; low quality of evidence). There was no significant difference in time to probe insertion (MD - 8.57; 95% CI - 26.31, 9.16; very low quality of evidence). The use of videolaryngoscopy for TEE probe insertion is associated with a significant reduction in the number of attempts and complication rate.

Dialysate temperature reduction for intradialytic hypotension for people with chronic kidney disease requiring haemodialysis.

BACKGROUND: Intradialytic hypotension (IDH) is a common complication of haemodialysis (HD), and a risk factor of cardiovascular morbidity and death. Several clinical studies suggested that reduction of dialysate temperature, such as fixed reduction of dialysate temperature or isothermal dialysate using a biofeedback system, might improve the IDH rate. OBJECTIVES: This review aimed to evaluate the benefits and harms of dialysate temperature reduction for IDH among patients with chronic kidney disease requiring HD, compared with standard dialysate temperature. SEARCH METHODS: We searched Cochrane Kidney and Transplant's Specialised Register up to 14 May 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs), cross-over RCTs, cluster RCTs and quasi-RCTs were included in the review. DATA COLLECTION AND ANALYSIS: Two authors independently extracted information including participants, interventions, outcomes, methods of the study, and risks of bias. We used a random-effects model to perform quantitative synthesis of the evidence. We assessed the risks of bias for each study using the Cochrane 'Risk of bias' tool. We assessed the certainty of evidence using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). MAIN RESULTS: We included 25 studies (712 participants). Three studies were parallel RCTs and the others were cross-over RCTs. Nineteen studies compared fixed reduction of dialysate temperature (below 36°C) and standard dialysate temperature (37°C to 37.5°C). Most studies were of unclear or high risk of bias. Compared with standard dialysate, it is uncertain whether fixed reduction of dialysate temperature improves IDH rate (8 studies, 153 participants: rate ratio 0.52, 95% CI 0.34 to 0.80; very low certainty evidence); however, it might increase the discomfort rate compared with standard dialysate (4 studies, 161 participants: rate ratio 8.31, 95% CI 1.86 to 37.12; very low certainty evidence). There were no reported dropouts due to adverse events. No study reported death, acute coronary syndrome or stroke.Three studies compared isothermal dialysate and thermoneutral dialysate. Isothermal dialysate might improve the IDH rate compared with thermoneutral dialysate (2 studies, 133 participants: rate ratio 0.68, 95% CI 0.60 to 0.76; I2 = 0%; very low certainty evidence). There were no reports of discomfort rate (1 study) or dropouts due to adverse events (2 studies). No study reported death, acute coronary syndrome or stroke. AUTHORS' CONCLUSIONS: Reduction of dialysate temperature may prevent IDH, but the conclusion is uncertain. Larger studies that measure important outcomes for HD patients are required to assess the effect of reduction of dialysate temperature. Six ongoing studies may provide much-needed high quality evidence in the future.

Voice rehabilitation for laryngeal cancer after radiotherapy: a systematic review and meta-analysis.

PURPOSE: We aimed to determine whether voice rehabilitation after radiotherapy improves the quality of life (QOL), voice function, and self-rated voice function in patients with laryngeal cancer. METHODS: We searched CENTRAL, MEDLINE, EMBASE, PEDro, and World Health Organization International Clinical Trials Registry Platform for randomized controlled trials published between inception and October 2018. The primary outcome was QOL, adverse events and mortality. Secondary outcomes included voice function and self-rated voice function. The quality of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: Three trials (enrolling 122 patients) compared voice rehabilitation to usual care or no intervention after radiotherapy. Voice rehabilitation did not significantly improve any QOL scores. Data on adverse events and mortality were not available in any of the trials. Voice rehabilitation did not improve any voice function scores, such as jitter (mean difference: - 0.48 [- 1.27 to 0.32]), shimmer (mean difference: - 0.04 [- 0.27 to 0.19]), maximum phonation time (mean difference: 1.54 [- 1.13 to 4.22]), and the grade, roughness, breathiness, asthenia, and strain scale (mean difference: - 0.39 [- 2.59 to 1.80]). Voice rehabilitation also did not improve the voice handicap index, which was used as a self-rated voice function score (mean difference: 5.54 [- 2.07 to 13.16]). The certainty of the evidence was graded as low for primary and secondary outcomes. CONCLUSION: Voice rehabilitation for patients with laryngeal cancer after radiotherapy might not improve QOL, voice function, and self-rated voice function. Pre-specified voice rehabilitation programs may not be necessary for all patients with laryngeal cancer after radiotherapy.

Generation of branching ureteric bud tissues from human pluripotent stem cells.

Recent progress in kidney regeneration research is noteworthy. However, the selective and robust differentiation of the ureteric bud (UB), an embryonic renal progenitor, from human pluripotent stem cells (hPSCs) remains to be established. The present study aimed to establish a robust induction method for branching UB tissue from hPSCs towards the creation of renal disease models. Here, we found that anterior intermediate mesoderm (IM) differentiates from anterior primitive streak, which allowed us to successfully develop an efficient two-dimensional differentiation method of hPSCs into Wolffian duct (WD) cells. We also established a simplified procedure to generate three-dimensional WD epithelial structures that can form branching UB tissues. This system may contribute to hPSC-based regenerative therapies and disease models for intractable disorders arising in the kidney and lower urinary tract.

Ultrasonography for confirmation of gastric tube placement.

BACKGROUND: Gastric tubes are commonly used for the administration of drugs and tube feeding for people who are unable to swallow. Feeding via a tube misplaced in the trachea can result in severe pneumonia. Therefore, the confirmation of tube placement in the stomach after tube insertion is important. Recent studies have reported that ultrasonography provides good diagnostic accuracy estimates in the confirmation of appropriate tube placement. Hence, ultrasound could provide a promising alternative to X-rays in the confirmation of tube placement, especially in settings where X-ray facilities are unavailable or difficult to access. OBJECTIVES: To assess the diagnostic accuracy of ultrasound for gastric tube placement confirmation. SEARCH METHODS: We searched the Cochrane Library (2016, Issue 3), MEDLINE (to March 2016), Embase (to March 2016), National Institute for Health Research (NIHR) PROSPERO Register (to May 2016), Aggressive Research Intelligence Facility Databases (to May 2016), ClinicalTrials.gov (to May 2016), ISRCTN registry (May 2016), World Health Organization International Clinical Trials Registry Platform (to May 2016) and reference lists of articles, and contacted study authors. SELECTION CRITERIA: We included studies that evaluated the diagnostic accuracy of naso- and orogastric tube placement confirmed by ultrasound visualization using X-ray visualization as the reference standard. We included cross-sectional studies, and case-control studies. We excluded case series or case reports. Studies were excluded if X-ray visualization was not the reference standard or if the tube being placed was a gastrostomy or enteric tube. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias and extracted data from each of the included studies. We contacted authors of the included studies to obtain missing data. MAIN RESULTS: We identified 10 studies (545 participants and 560 tube insertions) which met our inclusion criteria.No study was assigned low risk of bias or low concern in every QUADAS-2 domain. We judged only three (30%) studies to have low risk of bias in the participant selection domain because they performed ultrasound after they confirmed correct position by other methods.Few data (43 participants) were available for misplacement detection (specificity) due to the low incidence of misplacement. We did not perform a meta-analysis because of considerable heterogeneity of the index test such as the difference of echo window, the combination of ultrasound with other confirmation methods (e.g. saline flush visualization by ultrasound) and ultrasound during the insertion of the tube. For all settings, sensitivity estimates for individual studies ranged from 0.50 to 1.00 and specificity estimates from 0.17 to 1.00. For settings where X-ray was not readily available and participants underwent gastric tube insertion for drainage (four studies, 305 participants), sensitivity estimates of ultrasound in combination with other confirmatory tests ranged from 0.86 to 0.98 and specificity estimates of 1.00 with wide confidence intervals.For the studies using ultrasound alone (four studies, 314 participants), sensitivity estimates ranged from 0.91 to 0.98 and specificity estimates from 0.67 to 1.00. AUTHORS' CONCLUSIONS: Of 10 studies that assessed the diagnostic accuracy of gastric tube placement, few studies had a low risk of bias. Based on limited evidence, ultrasound does not have sufficient accuracy as a single test to confirm gastric tube placement. However, in settings where X-ray is not readily available, ultrasound may be useful to detect misplaced gastric tubes. Larger studies are needed to determine the possibility of adverse events when ultrasound is used to confirm tube placement.

Selective induction of human renal interstitial progenitor-like cell lineages from iPSCs reveals development of mesangial and EPO-producing cells.

Recent regenerative studies using human pluripotent stem cells (hPSCs) have developed multiple kidney-lineage cells and organoids. However, to further form functional segments of the kidney, interactions of epithelial and interstitial cells are required. Here we describe a selective differentiation of renal interstitial progenitor-like cells (IPLCs) from human induced pluripotent stem cells (hiPSCs) by modifying our previous induction method for nephron progenitor cells (NPCs) and analyzing mouse embryonic interstitial progenitor cell (IPC) development. Our IPLCs combined with hiPSC-derived NPCs and nephric duct cells form nephrogenic niche- and mesangium-like structures in vitro. Furthermore, we successfully induce hiPSC-derived IPLCs to differentiate into mesangial and erythropoietin-producing cell lineages in vitro by screening differentiation-inducing factors and confirm that p38 MAPK, hypoxia, and VEGF signaling pathways are involved in the differentiation of mesangial-lineage cells. These findings indicate that our IPC-lineage induction method contributes to kidney regeneration and developmental research.

An open competition involving thousands of competitors failed to construct useful abstract classifiers for new diagnostic test accuracy systematic reviews.

There are currently no abstract classifiers, which can be used for new diagnostic test accuracy (DTA) systematic reviews to select primary DTA study abstracts from database searches. Our goal was to develop machine-learning-based abstract classifiers for new DTA systematic reviews through an open competition. We prepared a dataset of abstracts obtained through database searches from 11 reviews in different clinical areas. As the reference standard, we used the abstract lists that required manual full-text review. We randomly splitted the datasets into a train set, a public test set, and a private test set. Competition participants used the training set to develop classifiers and validated their classifiers using the public test set. The classifiers were refined based on the performance of the public test set. They could submit as many times as they wanted during the competition. Finally, we used the private test set to rank the submitted classifiers. To reduce false exclusions, we used the Fbeta measure with a beta set to seven for evaluating classifiers. After the competition, we conducted the external validation using a dataset from a cardiology DTA review. We received 13,774 submissions from 1429 teams or persons over 4 months. The top-honored classifier achieved a Fbeta score of 0.4036 and a recall of 0.2352 in the external validation. In conclusion, we were unable to develop an abstract classifier with sufficient recall for immediate application to new DTA systematic reviews. Further studies are needed to update and validate classifiers with datasets from other clinical areas.

Current status and future directions of clinical applications using iPS cells-focus on Japan.

Regenerative medicine using iPS cell technologies has progressed remarkably in recent years. In this review, we summarize these technologies and their clinical application. First, we discuss progress in the establishment of iPS cells, including the HLA-homo iPS cell stock project in Japan and the advancement of low antigenic iPS cells using genome-editing technology. Then, we describe iPS cell-based therapies in or approaching clinical application, including those for ophthalmological, neurological, cardiac, hematological, cartilage, and metabolic diseases. Next, we introduce disease models generated from patient iPS cells and successfully used to identify therapeutic agents for intractable diseases. Clinical medicine using iPS cells has advanced safely and effectively by making full use of current scientific standards, but tests on cell safety need to be further developed and validated. The next decades will see the further spread of iPS cell technology-based regenerative medicine.

In vitro methods to ensure absence of residual undifferentiated human induced pluripotent stem cells intermingled in induced nephron progenitor cells.

Cell therapies using human induced pluripotent stem cell (hiPSC)-derived nephron progenitor cells (NPCs) are expected to ameliorate acute kidney injury (AKI). However, using hiPSC-derived NPCs clinically is a challenge because hiPSCs themselves are tumorigenic. LIN28A, ESRG, CNMD and SFRP2 transcripts have been used as a marker of residual hiPSCs for a variety of cell types undergoing clinical trials. In this study, by reanalyzing public databases, we found a baseline expression of LIN28A, ESRG, CNMD and SFRP2 in hiPSC-derived NPCs and several other cell types, suggesting LIN28A, ESRG, CNMD and SFRP2 are not always reliable markers for iPSC detection. As an alternative, we discovered a lncRNA marker gene, MIR302CHG, among many known and unknown iPSC markers, as highly differentially expressed between hiPSCs and NPCs, by RNA sequencing and quantitative RT-PCR (qRT-PCR) analyses. Using MIR302CHG as an hiPSC marker, we constructed two assay methods, a combination of magnetic bead-based enrichment and qRT-PCR and digital droplet PCR alone, to detect a small number of residual hiPSCs in NPC populations. The use of these in vitro assays could contribute to patient safety in treatments using hiPSC-derived cells.