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Background Delirium affects > 15% of hospitalised patients but is grossly underdetected, contributing to poor care. The 4 ‘A’s Test (4AT, www.the4AT.com ) is a short delirium assessment tool designed for routine use without special training. The primary objective was to assess the accuracy of the 4AT for delirium detection. The secondary objective was to compare the 4AT with another commonly used delirium assessment tool, the Confusion Assessment Method (CAM). Methods This was a prospective diagnostic test accuracy study set in emergency departments or acute medical wards involving acute medical patients aged ≥ 70. All those without acutely life-threatening illness or coma were eligible. Patients underwent (1) reference standard delirium assessment based on DSM-IV criteria and (2) were randomised to either the index test (4AT, scores 0–12; prespecified score of > 3 considered positive) or the comparator (CAM; scored positive or negative), in a random order, using computer-generated pseudo-random numbers, stratified by study site, with block allocation. Reference standard and 4AT or CAM assessments were performed by pairs of independent raters blinded to the results of the other assessment. Results Eight hundred forty-three individuals were randomised: 21 withdrew, 3 lost contact, 32 indeterminate diagnosis, 2 missing outcome, and 785 were included in the analysis. Mean age was 81.4 (SD 6.4) years. 12.1% (95/785) had delirium by reference standard assessment, 14.3% (56/392) by 4AT, and 4.7% (18/384) by CAM. The 4AT had an area under the receiver operating characteristic curve of 0.90 (95% CI 0.84–0.96). The 4AT had a sensitivity of 76% (95% CI 61–87%) and a specificity of 94% (95% CI 92–97%). The CAM had a sensitivity of 40% (95% CI 26–57%) and a specificity of 100% (95% CI 98–100%). Conclusions The 4AT is a short, pragmatic tool which can help improving detection rates of delirium in routine clinical care. Trial registration International standard randomised controlled trial number (ISRCTN) 53388093 . Date applied 30/05/2014; date assigned 02/06/2014.

Background Spillover of effect, whether positive or negative, from intervention to control group patients invalidates the Stable Unit Treatment Variable Assumption (SUTVA). SUTVA is critical to valid causal inference from randomized concurrent controlled trials (RCCT). Spillover of infection prevention is an important population level effect mediating herd immunity. This herd effect, being additional to any individual level effect, is subsumed within the overall effect size (ES) estimate derived by contrast-based techniques from RCCT’s. This herd effect would manifest only as increased dispersion among the control group infection incidence rates above background. Methods and results The objective here is to explore aspects of spillover and how this might be visualized and diagnosed. I use, for illustration, data from 190 RCCT’s abstracted in 13 Cochrane reviews of various antimicrobial versus non-antimicrobial based interventions to prevent pneumonia in ICU patients. Spillover has long been postulated in this context. Arm-based techniques enable three approaches to identify increased dispersion, not available from contrast-based techniques, which enable the diagnosis of spillover within antimicrobial versus non-antimicrobial based infection prevention RCCT’s. These three approaches are benchmarking the pneumonia incidence rates versus a clinically relevant range, comparing the dispersion in pneumonia incidence among the control versus the intervention groups and thirdly, visualizing the incidence dispersion within summary receiver operator characteristic (SROC) plots. By these criteria there is harmful spillover effects to concurrent control group patients. Conclusions Arm-based versus contrast-based techniques lead to contrary inferences from the aggregated RCCT’s of antimicrobial based interventions despite similar summary ES estimates. Moreover, the inferred relationship between underlying control group risk and ES is ‘flipped’.

Tuberculosis (TB) remains a significant public health challenge, particularly in rural areas of high-burden countries like China. Active case finding (ACF) and timely treatment have been proven effective in reducing TB prevalence, but the impact on the TB epidemic when employing new technologies in ACF is still unknown. This study aims to evaluate the effectiveness of a comprehensive ACF package utilizing mobile vans equipped with artificial intelligence (AI)-aided radiology and GeneXpert testing in reducing TB prevalence among high-risk populations in rural Guangxi, China. A pragmatic cluster randomized controlled trial will be conducted in two counties of Guangxi, China. The trial will randomize 23 townships to intervention or control groups at approximately 1:1 ratio. The intervention group will receive an ACF campaign in Year 1 among high-risk populations, incorporating visited by mobile vans equipped with AI-based digital X-ray screening, symptom assessment, and sputum collection for GeneXpert testing. Control group participants receive usual care. TB patients identified in Year 1 will complete their treatment in Year 2. The primary outcome is the prevalence rate of bacteriologically confirmed TB among high-risk populations in Year 3. Process evaluation will explore acceptability, feasibility and adaptation of the intervention. We will conduct incremental costing study to inform future scale-up of the intervention in other settings. This study will provide valuable insights into the effectiveness and feasibility of utilizing AI-equipped mobile vans and GeneXpert for TB ACF to reduce TB prevalence in rural settings. If successful, this model will contribute to possible solutions to achieve the WHO End TB Strategy by 2035. ClinicalTrials.gov NCT06702774.

Background As a widely accepted field standard diagnostic tool for malaria, microscopic examination is often difficult to perform in resource-poor settings. The immunochromatographic HRP2/pLDH (Pf/Pan) Rapid Diagnostic Tests (RDTs) serve as alternatives to microscopic examination for falciparum and non-falciparum malaria in co-endemic areas by detecting the histidine-rich protein 2 (HRP2) and pan-plasmodial lactate dehydrogenase (pLDH) antigen. However, Pf/Pan RDTs do not directly quantify parasitaemia. In this study, the diagnostic performance of Pf/Pan RDT and its association with parasite density was examined. Methods Blood smears from patients who were screened for PRIMA Clinical Trial (Trial Registration Number: NCT03916003) conducted in East Sumba, Indonesia, and enrolled to its sub-study, ACROSS, were examined for microscopic examination and RDT using CareStart ™ Malaria HRP2/pLDH (Pf/PAN) Combo (CareStart ™ Pf/Pan RDT). Results were analysed for both diagnostic performance of RDT and its relationship with parasite density using a logistic regression model. Results 317 participants were included in this study and 158 (49.8%) were malaria positive by microscopy. Among all malaria-positive participants, Plasmodium falciparum infections accounted for 149 (94.3%) cases. The sensitivity and specificity of HRP2 band were 97.3% (95% CI 93.3–99.2) and 97.6% (95% CI 94.0–99.4), respectively, while that of pLDH band were 87.3% (95% CI 81.1–92.0) and 100% (95% CI 97.7–100). For each ten-fold increase in parasite density, the RDT had 12 times the odds of returning Pf/Pan-positive results (n = 126) compared to Pf-positive (n = 19) (OR: 12.1; 95% CI 5.18 to 34.8; p < 0.001). Conclusions CareStart ™ Pf/Pan RDT is reliable in diagnosing falciparum malaria and Pf/Pan-positive results indicate higher parasite density. Pf/Pan-positive results should alert the clinical staff of the increased risk of poor clinical outcome, and should be prioritized for microscopic examination compared to Pf-positive results.

Background Progress towards malaria elimination has stagnated, partly because infections persisting at low parasite densities comprise a large reservoir contributing to ongoing malaria transmission and are difficult to detect. This study compared the performance of an ultrasensitive rapid diagnostic test (uRDT) designed to detect low density infections to a conventional RDT (cRDT), expert microscopy using Giemsa-stained thick blood smears (TBS), and quantitative polymerase chain reaction (qPCR) during a controlled human malaria infection (CHMI) study conducted in malaria exposed adults (NCT03590340). Methods Blood samples were collected from healthy Equatoguineans aged 18–35 years beginning on day 8 after CHMI with 3.2 × 10 3 cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ Challenge, strain NF54) administered by direct venous inoculation. qPCR (18s ribosomal DNA), uRDT (Alere™ Malaria Ag P.f.), cRDT [Carestart Malaria Pf/PAN (PfHRP2/pLDH)], and TBS were performed daily until the volunteer became TBS positive and treatment was administered. qPCR was the reference for the presence of Plasmodium falciparum parasites. Results 279 samples were collected from 24 participants; 123 were positive by qPCR. TBS detected 24/123 (19.5% sensitivity [95% CI 13.1–27.8%]), uRDT 21/123 (17.1% sensitivity [95% CI 11.1–25.1%]), cRDT 10/123 (8.1% sensitivity [95% CI 4.2–14.8%]); all were 100% specific and did not detect any positive samples not detected by qPCR. TBS and uRDT were more sensitive than cRDT (TBS vs. cRDT p = 0.015; uRDT vs. cRDT p = 0.053), detecting parasitaemias as low as 3.7 parasites/µL (p/µL) (TBS and uRDT) compared to 5.6 p/µL (cRDT) based on TBS density measurements. TBS, uRDT and cRDT did not detect any of the 70/123 samples positive by qPCR below 5.86 p/µL, the qPCR density corresponding to 3.7 p/µL by TBS. The median prepatent periods in days (ranges) were 14.5 (10–20), 18.0 (15–28), 18.0 (15–20) and 18.0 (16–24) for qPCR, TBS, uRDT and cRDT, respectively; qPCR detected parasitaemia significantly earlier (3.5 days) than the other tests. Conclusions TBS and uRDT had similar sensitivities, both were more sensitive than cRDT, and neither matched qPCR for detecting low density parasitaemia. uRDT could be considered an alternative to TBS in selected applications, such as CHMI or field diagnosis, where qualitative, dichotomous results for malaria infection might be sufficient.

Inappropriate treatment of malaria is widely reported particularly in areas where there is poor access to health facilities and self-treatment of fevers with anti-malarial drugs bought in shops is the most common form of care-seeking. The main objective of the study was to examine the impact of introducing rapid diagnostic tests for malaria (mRDTs) in registered drug shops in Uganda, with the aim to increase appropriate treatment of malaria with artemisinin-based combination therapy (ACT) in patients seeking treatment for fever in drug shops. A cluster-randomized trial of introducing mRDTs in registered drug shops was implemented in 20 geographical clusters of drug shops in Mukono district, central Uganda. Ten clusters were randomly allocated to the intervention (diagnostic confirmation of malaria by mRDT followed by ACT) and ten clusters to the control arm (presumptive treatment of fevers with ACT). Treatment decisions by providers were validated by microscopy on a reference blood slide collected at the time of consultation. The primary outcome was the proportion of febrile patients receiving appropriate treatment with ACT defined as: malaria patients with microscopically-confirmed presence of parasites in a peripheral blood smear receiving ACT or rectal artesunate, and patients with no malaria parasites not given ACT. A total of 15,517 eligible patients (8672 intervention and 6845 control) received treatment for fever between January-December 2011. The proportion of febrile patients who received appropriate ACT treatment was 72·9% versus 33·7% in the control arm; a difference of 36·1% (95% CI: 21·3 - 50·9), p<0·001. The majority of patients with fever in the intervention arm accepted to purchase an mRDT (97·8%), of whom 58·5% tested mRDT-positive. Drug shop vendors adhered to the mRDT results, reducing over-treatment of malaria by 72·6% (95% CI: 46·7- 98·4), p<0·001) compared to drug shop vendors using presumptive diagnosis (control arm). Diagnostic testing with mRDTs compared to presumptive treatment of fevers implemented in registered drug shops substantially improved appropriate treatment of malaria with ACT. ClinicalTrials.gov NCT01194557.

Background The declining effectiveness of Intermittent Preventive Treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) due to the emergence of Plasmodium falciparum resistance highlights the need for alternative malaria prevention strategies in pregnant women. A novel approach was proposed: screening with an ultra-sensitive rapid diagnostic test and treating positive with pyronaridine-artesunate (ISTp-uRDT-PA). This trial compared the impact of both strategies on maternal malaria and anaemia, abortion, intrauterine death, birth weight, preterm delivery. Methods This non-inferiority trial, conducted in Kinshasa, enrolled pregnant women in their second and third trimesters. Participants in the IPTp-SP arm (n = 124) received SP at monthly antenatal visit as per guidelines, while those in the ISTp-uRDT-PA arm (n = 126) were screened monthly with an uRDT and treated with PA if positive. Primary outcomes included asymptomatic parasitaemia (uRDT positive without fever) or symptomatic parasitaemia (uRDT positive with fever or history of fever, and parasite density by microscopy during pregnancy. Results Asymptomatic parasitaemia by uRDT during pregnancy was similar in both arms (20.8% in IPTp-SP vs 21.0% in ISTp-uRDT-PA). At delivery, asymptomatic parasitaemia was 51% higher in ISTp-uRDT-PA arm compared to IPTp-SP (cRR = 1.51 [95% CI 0.76–3.00], p = 0.24). Symptomatic parasitaemia by uRDT at delivery showed no significant difference. Malaria by microscopy at enrolment was detected in 34.4% of women. Malaria by microscopy during pregnancy was 9.6% in IPTp-SP and 10.1%. ISTp-uRDT-PA (p = 0.19), decreasing to 3.2% and 0.9%, respectively, at delivery (p = 0.24). Mean haemoglobin concentration at enrolment was 10.1 g/dl in the IPTp-SP and 9.8 g/dl in the ISTp-uRDT-PA with no significant difference in maternal anaemia at delivery (7%; cRR = 1.07 [95% CI 0.87–1.31], p = 0.52). No significant differences were found for spontaneous abortions and in utero death in both arms. The risk of a premature newborn declined by 14% in ISTp-uRDT-PA compared to the IPTp-SP arm (cRR = 0.86 [95% CI 0.29–2.85], p = 0.79) while low-birth-weight was not significantly higher (cRR = 1.74 [95% CI 0.86–3.53], p = 0.12). Conclusion ISTp-uRDT-PA was non inferior to IPTp-SP and can be considered as a future alternative for IPTp-SP in case this intervention can no longer be used due to high SP resistance. Clinical trials registration: NCT04783051.

Background Urgent care centers (UCCs) are a growing segment of healthcare with high rates of inappropriate antibiotic use. MeMed BV® (MMBV) is a blood test that differentiates bacterial from viral infections. Between April 2022 and March 2023, we introduced MMBV into routine care at ten UCCs. The primary objective was to assess MMBV’s impact on antibiotic use; the secondary objective was to assess whether MMBV aided in patient management. Methods A pragmatic prospective cohort study. Physicians who ordered MMBV reported electronically (in real-time) whether they intended to prescribe antibiotics before ordering the test and upon UCC discharge whether MMBV aided in patient management. Hospitalizations were recorded for 7 days post-UCC discharge. Results During implementation, 3920 MMBV tests were ordered for adults (age ≥ 18) by 144 physicians. The study cohort had 59% female patients and the median age was 42 years (IQR 31–58). For the primary objective, 3262 cases were included. MMBV indicated 629/3262 (19.3%) cases of potentially unwarranted antibiotics, of which physicians avoided prescriptions in 397/629 (63.1%). MMBV indicated 405/3262 (12.4%) cases of potentially missed bacterial infections. Physicians prescribed antibiotics to 283/405 (69.9%). MMBV adherence was associated with fewer hospitalizations (7.8% vs. 30.3%, p  < 0.001). For the secondary objective, 2901 cases were included. Physicians reported MMBV aided patient management in 2494/2901 (86.0%) cases and contributed to avoiding emergency department referrals in 595/2901 (20.5%). Conclusions Implementing MMBV aided urgent care center physicians in their clinical decision-making and may have contributed to appropriate antibiotic use, better resource utilization, and patient management.

Background Men who have sex with men (MSM) bear a high burden of syphilis infection. Expanding syphilis testing to improve timely diagnosis and treatment is critical to improve syphilis control. However, syphilis testing rates remain low among MSM, particularly in low- and middle-income countries. We describe the protocol for a randomised controlled trial (RCT) to assess whether provision of syphilis self-testing services can increase the uptake of syphilis testing among MSM in China. Methods Four hundred forty-four high-risk MSM will be recruited online and randomized in a 1:1:1 ratio to (1) standard syphilis self-testing arm; (2) a self-testing arm program enhanced with crowdsourcing and a lottery-based incentive, and (3) a standard of care (control). Self-testing services include a free syphilis self-test kit through the mail at monthly intervals. Participants in the lottery incentive arm will additionally receive health promotion materials generated from an open crowdsourcing contest and be given a lottery draw with a 10% chance to win 100 RMB (approximately 15 US Dollars) upon confirmed completion of syphilis testing. Syphilis self-test kits have step-by-step instructions and an instructional video. This is a non-blinded, open-label, parallel RCT. Participants in each arm will be followed-up at three and 6 months through WeChat (a social media app like Facebook messenger). Confirmation of syphilis self-test use will be determined by requiring participants to submit a photo of the used test kit to study staff via secure data messaging. Both self-testing and facility-based testing will be ascertained by sending a secure photographic image of the completed kit through an existing digital platform. The primary outcome is the proportion of participants who tested for syphilis in the past 3 months. Discussion Findings from this study will provide much needed insight on the impact of syphilis self-testing on promoting routine syphilis screening among MSM. The findings will also contribute to our understanding of the safety, effectiveness and acceptability of syphilis self-testing. These findings will have important implications for self-testing policy, both in China and internationally. Trial registration ChiCTR1900022409 (10 April, 2019).

Early diagnosis and prompt, effective treatment of uncomplicated malaria is critical to prevent severe disease, death and malaria transmission. We assessed the impact of rapid malaria diagnostic tests (RDTs) by community health workers (CHWs) on provision of artemisinin-based combination therapy (ACT) and health outcome in fever patients. Twenty-two CHWs from five villages in Kibaha District, a high-malaria transmission area in Coast Region, Tanzania, were trained to manage uncomplicated malaria using RDT aided diagnosis or clinical diagnosis (CD) only. Each CHW was randomly assigned to use either RDT or CD the first week and thereafter alternating weekly. Primary outcome was provision of ACT and main secondary outcomes were referral rates and health status by days 3 and 7. The CHWs enrolled 2930 fever patients during five months of whom 1988 (67.8%) presented within 24 hours of fever onset. ACT was provided to 775 of 1457 (53.2%) patients during RDT weeks and to 1422 of 1473 (96.5%) patients during CD weeks (Odds Ratio (OR) 0.039, 95% CI 0.029-0.053). The CHWs adhered to the RDT results in 1411 of 1457 (96.8%, 95% CI 95.8-97.6) patients. More patients were referred on inclusion day during RDT weeks (10.0%) compared to CD weeks (1.6%). Referral during days 1-7 and perceived non-recovery on days 3 and 7 were also more common after RDT aided diagnosis. However, no fatal or severe malaria occurred among 682 patients in the RDT group who were not treated with ACT, supporting the safety of withholding ACT to RDT negative patients. RDTs in the hands of CHWs may safely improve early and well-targeted ACT treatment in malaria patients at community level in Africa. ClinicalTrials.gov NCT00301015.