Publications by authors named "Robert F Miller"

167 Publications

Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.

Emerg Infect Dis 2021 Mar;27(3):944-948

Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.
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http://dx.doi.org/10.3201/eid2703.202359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920675PMC
March 2021

Influenza vaccine community outreach: Leveraging an interprofessional healthcare student workforce to immunize marginalized populations.

Prev Med 2021 Feb 18;147:106460. Epub 2021 Feb 18.

Department of General Internal Medicine and Public Health, Vanderbilt University Medical Center (VUMC), Nashville, TN, United States of America.

Vulnerable populations such as the uninsured, unemployed, and unhoused face significant morbidity and mortality from influenza but are less likely to receive the annual vaccine and have limited access to medical care. We describe an interprofessional, student-run vaccine outreach program (VOP) in Davidson County, Tennessee that lowers barriers to vaccination through free vaccination events in nontraditional community locations. We provide this framework as a model to expand novel, seasonal, or outbreak-oriented vaccine outreach to resource-poor populations. Demographic data were collected from the patients who received an influenza vaccine between 2015 and 2019 through an optional survey to determine whether these events were reaching unhoused, uninsured, and/or unemployed individuals. Of 1,803 patients, 1,733 (96.1%) completed at least one field of the demographic form. Overall, 481 (27.8%) were individuals without homes or living in temporary housing and 673 (38.8%) were unemployed. Most patients, 1,109 (64.0%), did not have health insurance at any point during the prior two years. With the addition of a nurse practitioner student to VOP leadership, the 2018-2019 VOP reached the most unhoused or temporarily-housed (228, 32.3%), unemployed (313, 18.5%), and disabled (60, 8.5%) patients. The VOP can be adapted to meet community needs, funding, and volunteer interest. The VOP model may be applicable to a SARS-CoV-2 vaccine, especially since the economic impact of COVID-19 has increased unemployment rates and housing instability. Healthcare students serve as an eager, underutilized resource who can be leveraged to disseminate vaccines to individuals with limited access to care.
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http://dx.doi.org/10.1016/j.ypmed.2021.106460DOI Listing
February 2021

Acute D-Serine Co-Agonism of β-Cell NMDA Receptors Potentiates Glucose-Stimulated Insulin Secretion and Excitatory β-Cell Membrane Activity.

Cells 2021 Jan 7;10(1). Epub 2021 Jan 7.

Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.

Insulin-secreting pancreatic β-cells express proteins characteristic of D-serine regulated synapses, but the acute effect of D-serine co-agonism on its presumptive β-cell target, N-methyl D-aspartate receptors (NMDARs), is unclear. We used multiple models to evaluate glucose homeostasis and insulin secretion in mice with a systemic increase in D-serine (intraperitoneal injection or DAAO mutants without D-serine catabolism) or tissue-specific loss of Grin1-encoded GluN1, the D-serine binding NMDAR subunit. We also investigated the effects of D-serine ± NMDA on glucose-stimulated insulin secretion (GSIS) and β-cell depolarizing membrane oscillations, using perforated patch electrophysiology, in β-cell-containing primary isolated mouse islets. In vivo models of elevated D-serine correlated to improved blood glucose and insulin levels. In vitro, D-serine potentiated GSIS and β-cell membrane excitation, dependent on NMDAR activating conditions including GluN1 expression (co-agonist target), simultaneous NMDA (agonist), and elevated glucose (depolarization). Pancreatic GluN1-loss females were glucose intolerant and GSIS was depressed in islets from younger, but not older, βGrin1 KO mice. Thus, D-serine is capable of acute antidiabetic effects in mice and potentiates insulin secretion through excitatory β-cell NMDAR co-agonism but strain-dependent shifts in potency and age/sex-specific Grin1-loss phenotypes suggest that context is critical to the interpretation of data on the role of D-serine and NMDARs in β-cell function.
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http://dx.doi.org/10.3390/cells10010093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826616PMC
January 2021

Ambulatory management of secondary spontaneous pneumothorax: a randomised controlled trial.

Eur Respir J 2020 Dec 17. Epub 2020 Dec 17.

Academic Respiratory Unit Bristol, Westbury on Trym, United Kingdom.

Objective: Secondary spontaneous pneumothorax (SSP) is traditionally managed with an intercostal chest tube attached to an underwater seal. We investigated whether use of a one-way flutter valve shortened length of patients' stay (LoS).

Methods: This open-label randomised controlled trial enrolled patients presenting with SSP and randomised to either a chest tube and underwater seal (standard care: SC) or ambulatory care (AC) with a flutter valve. The type of flutter valve used depended on whether at randomisation the patient already had a chest tube in place: in those without a chest tube a Pleural Vent (PV) was used; in those with a chest tube in situ, an Atrium Pneumostat (AP) valve was attached. The primary end-point was LoS.

Results: Between March 2017 and March 2020, 41 patients underwent randomisation: 20 to SC and 21 to AC (13=PV, 8=AP). There was no difference in LoS in the first 30 days following treatment intervention: AC (median=6 days, IQR 14.5) and SC (median=6 days, IQR 13.3). In patients treated with PV there was a high rate of early treatment failure (6/13; 46%), compared to patients receiving SC (3/20; 15%) (p=0.11) Patients treated with AP had no (0/8 0%) early treatment failures and a median LoS of 1.5 days (IQR 23.8).

Conclusion: There was no difference in LoS between ambulatory and standard care. Pleural Vents had high rates of treatment failure and should not be used in SSP. Atrium Pneumostats are a safer alternative, with a trend towards lower LOS.
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http://dx.doi.org/10.1183/13993003.03375-2020DOI Listing
December 2020

An immunocompromised Albanian farmer with a Mediterranean menace.

Br J Hosp Med (Lond) 2020 Nov 1;81(11):1-4. Epub 2020 Dec 1.

Infectious Diseases Department, Royal Free London NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.12968/hmed.2020.0019DOI Listing
November 2020

All-cause hospitalization according to demographic group in people living with HIV in the current antiretroviral therapy era.

AIDS 2021 02;35(2):245-255

Institute for Global Health, UCL.

Objective: We investigated differences in all-cause hospitalization between key demographic groups among people with HIV in the UK in the current antiretroviral therapy (ART) era.

Design/methods: We used data from the Royal Free HIV Cohort study between 2007 and 2018. Individuals were classified into five groups: MSM, Black African men who have sex with women (MSW), MSW of other ethnicity, Black African women and women of other ethnicity. We studied hospitalizations during the first year after HIV diagnosis (Analysis-A) separately from those more than one year after diagnosis (Analysis-B). In Analysis-A, time to first hospitalization was assessed using Cox regression adjusted for age and diagnosis date. In Analysis-B, subsequent hospitalization rate was assessed using Poisson regression, accounting for repeated hospitalization within individuals, adjusted for age, calendar year, time since diagnosis.

Results: The hospitalization rate was 30.7/100 person-years in the first year after diagnosis and 2.7/100 person-years subsequently; 52% and 13% hospitalizations, respectively, were AIDS-related. Compared with MSM, MSW and women were at much higher risk of hospitalization during the first year [aHR (95% confidence interval, 95% CI): 2.7 (1.7-4.3), 3.0 (2.0-4.4), 2.0 (1.3-2.9), 3.0 (2.0-4.5) for Black African MSW; other ethnicity MSW; Black African women; other ethnicity women respectively, Analysis-A] and remained at increased risk subsequently [corresponding aIRR (95% CI): 1.7 (1.2-2.4), 2.1 (1.5-2.8), 1.5 (1.1-1.9), 1.7 (1.2-2.3), Analysis-B].

Conclusion: In this setting with universal healthcare, substantial variation exists in hospitalization risk across demographic groups, both in early and subsequent periods after HIV diagnosis, highlighting the need for targeted interventions.
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http://dx.doi.org/10.1097/QAD.0000000000002750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810421PMC
February 2021

Management of solitary fibrous tumours of the pleura: a systematic review and meta-analysis.

ERJ Open Res 2020 Jul 17;6(3). Epub 2020 Aug 17.

University of Oxford Respiratory Trials Unit, Churchill Hospital, Oxford, UK.

Background: Solitary fibrous tumours of the pleura (SFTP), or pleural fibromas, are rare tumours that generally, but not universally, follow a benign course. Surgical resection is the standard treatment, but there are no evidence-based guidelines regarding the management of these tumours.

Methods: Five databases were searched from inception to April 1, 2019 for studies reporting on SFTP management.

Results: Twenty-seven studies met the inclusion criteria (1542 patients, all non-comparative case series); 98% of these patients underwent resection and all SFTP included were pathologically diagnosed. 394 out of 1299 cases (30.5%, 95% CI 27.8-32.8%) were malignant with recurrence rates of between 0% and 42.9%. A pleural effusion was always associated with a negative outcome, but no other features were consistently reported to have negative associations. Preoperative biopsies incorrectly reported malignant histology in two studies. Over 25% of cases of recurrence occurred when a complete (R0) resection had been achieved. The first recurrence occurred >5 years after the initial resection in at least 23% of cases.

Conclusions: There is strong evidence to support long-term surveillance after surgical resection of SFTP, even where a complete (R0) resection has been achieved; however, there is no clear evidence to inform clinicians regarding the selection of patients who should undergo resection. The rates of malignant SFTP and SFTP recurrence are higher than previously reported. Only those that were pathologically diagnosed or resected were included, which may bias the data towards more aggressive tumours. Data collection on radiologically diagnosed SFTP is required to draw conclusions regarding the timing and need for intervention.
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http://dx.doi.org/10.1183/23120541.00055-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430150PMC
July 2020

Prospective validation of the RAPID clinical risk prediction score in adult patients with pleural infection: the PILOT study.

Eur Respir J 2020 11 26;56(5). Epub 2020 Nov 26.

Oxford Centre for Respiratory Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Background: Over 30% of adult patients with pleural infection either die and/or require surgery. There is no robust means of predicting at baseline presentation which patients will suffer a poor clinical outcome. A validated risk prediction score would allow early identification of high-risk patients, potentially directing more aggressive treatment thereafter.

Objectives: To prospectively assess a previously described risk score (the RAPID (Renal (urea), Age, fluid Purulence, Infection source, Dietary (albumin)) score) in adults with pleural infection.

Methods: Prospective observational cohort study that recruited patients undergoing treatment for pleural infection. RAPID score and risk category were calculated at baseline presentation. The primary outcome was mortality at 3 months; secondary outcomes were mortality at 12 months, length of hospital stay, need for thoracic surgery, failure of medical treatment and lung function at 3 months.

Results: Mortality data were available in 542 out of 546 patients recruited (99.3%). Overall mortality was 10% at 3 months (54 out of 542) and 19% at 12 months (102 out of 542). The RAPID risk category predicted mortality at 3 months. Low-risk mortality (RAPID score 0-2): five out of 222 (2.3%, 95% CI 0.9 to 5.7%); medium-risk mortality (RAPID score 3-4): 21 out of 228 (9.2%, 95% CI 6.0 to 13.7%); and high-risk mortality (RAPID score 5-7): 27 out of 92 (29.3%, 95% CI 21.0 to 39.2%). C-statistics for the scores at 3 months and 12 months were 0.78 (95% CI 0.71-0.83) and 0.77 (95% CI 0.72-0.82), respectively.

Conclusions: The RAPID score stratifies adults with pleural infection according to increasing risk of mortality and should inform future research directed at improving outcomes in this patient population.
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http://dx.doi.org/10.1183/13993003.00130-2020DOI Listing
November 2020

Ambulatory management of primary spontaneous pneumothorax: an open-label, randomised controlled trial.

Lancet 2020 07;396(10243):39-49

Oxford Respiratory Trials Unit, University of Oxford, Oxford, UK.

Background: Primary spontaneous pneumothorax occurs in otherwise healthy young patients. Optimal management is not defined and often results in prolonged hospitalisation. Data on efficacy of ambulatory options are poor. We aimed to describe the duration of hospitalisation and safety of ambulatory management compared with standard care.

Methods: In this open-label, randomised controlled trial, adults (aged 16-55 years) with symptomatic primary spontaneous pneumothorax were recruited from 24 UK hospitals during a period of 3 years. Patients were randomly assigned (1:1) to treatment with either an ambulatory device or standard guideline-based management (aspiration, standard chest tube insertion, or both). The primary outcome was total length of hospital stay including re-admission up to 30 days after randomisation. Patients with available data were included in the primary analysis and all assigned patients were included in the safety analysis. The trial was prospectively registered with the International Standard Randomised Clinical Trials Number, ISRCTN79151659.

Findings: Of 776 patients screened between July, 2015, and March, 2019, 236 (30%) were randomly assigned to ambulatory care (n=117) and standard care (n=119). At day 30, the median hospitalisation was significantly shorter in the 114 patients with available data who received ambulatory treatment (0 days [IQR 0-3]) than in the 113 with available data who received standard care (4 days [IQR 0-8]; p<0·0001; median difference 2 days [95% CI 1-3]). 110 (47%) of 236 patients had adverse events, including 64 (55%) of 117 patients in the ambulatory care arm and 46 (39%) of 119 in the standard care arm. All 14 serious adverse events occurred in patients who received ambulatory care, eight (57%) of which were related to the intervention, including an enlarging pneumothorax, asymptomatic pulmonary oedema, and the device malfunctioning, leaking, or dislodging.

Interpretation: Ambulatory management of primary spontaneous pneumothorax significantly reduced the duration of hospitalisation including re-admissions in the first 30 days, but at the expense of increased adverse events. This data suggests that primary spontaneous pneumothorax can be managed for outpatients, using ambulatory devices in those who require intervention.

Funding: UK National Institute for Health Research.
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http://dx.doi.org/10.1016/S0140-6736(20)31043-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607300PMC
July 2020

Implementation of General Surgery Care into a Student-Run Free Clinic.

J Surg Res 2020 11 15;255:71-76. Epub 2020 Jun 15.

Vanderbilt University Medical Center, Department of General Surgery, Nashville, Tennessee. Electronic address:

Background: Student-run free clinics (SRFCs) provide medical care to uninsured, and surgical issues are often outside the normal scope of care of these clinics. The Shade Tree Clinic (STC) is an SRFC serving 300 patients with complex medical conditions. This study describes the implementation and efficacy of a General Surgery Specialty Clinic in this setting.

Methods: This descriptive study examines the demographics and referral patterns of patients seen in two pilot Specialty Clinics and other patients evaluated for general surgical issues from December 2017 to January 2020. Providers were surveyed regarding their experience in clinic.

Results: Twenty patients were evaluated by six general surgeons during 22 separate encounters (n = 20). Nine patients were seen in two pilot Specialty Clinics for biliary colic, hernia, hemorrhoids, anal mass, toenail lesion, surgical weight loss, and venous insufficiency. Referrals from these clinics to affiliated Vanderbilt University Medical Center included six ultrasounds; referrals to vascular surgery and podiatry clinics; and referrals for laparoscopic cholecystectomy and anal mass excision. STC also directly referred eight patients for colonoscopies and five patients for major operations through primary care clinic. Hundred percent of care was cost-free to patients. Providers reported a median satisfaction score of five with the Specialty Clinics (Very Satisfied; [4, 5]). Hundred percent of providers felt that the concerns of patients were addressed.

Conclusions: A surgery specialty clinic in the setting of an SRFC is an effective way to provide surgical care to underserved populations with the potential to reduce unplanned hospital utilization.
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http://dx.doi.org/10.1016/j.jss.2020.05.031DOI Listing
November 2020

Thoracoscopy and talc poudrage compared with intercostal drainage and talc slurry infusion to manage malignant pleural effusion: the TAPPS RCT.

Health Technol Assess 2020 06;24(26):1-90

Academic Respiratory Unit, University of Bristol, Bristol, UK.

Background: There are around 40,000 new cases of malignant pleural effusion in the UK each year. Insertion of talc slurry via a chest tube is the current standard treatment in the UK. However, some centres prefer local anaesthetic thoracoscopy and talc poudrage. There is no consensus as to which approach is most effective.

Objective: This trial tested the hypothesis that thoracoscopy and talc poudrage increases the proportion of patients with successful pleurodesis at 3 months post procedure, compared with chest drain insertion and talc slurry.

Design: This was a multicentre, open-label, randomised controlled trial with embedded economic evaluation. Follow-up took place at 1, 3 and 6 months.

Setting: This trial was set in 17 NHS hospitals in the UK.

Participants: A total of 330 adults with a confirmed diagnosis of malignant pleural effusion needing pleurodesis and fit to undergo thoracoscopy under local anaesthetic were included. Those adults needing a tissue diagnosis or with evidence of lung entrapment were excluded.

Interventions: Allocation took place following minimisation with a random component, performed by a web-based, centralised computer system. Participants in the control arm were treated with a bedside chest drain insertion and 4 g of talc slurry. In the intervention arm, participants underwent local anaesthetic thoracoscopy with 4 g of talc poudrage.

Main Outcome Measures: The primary outcome measure was pleurodesis failure at 90 days post randomisation. Secondary outcome measures included mortality and patient-reported symptoms. A cost-utility analysis was also performed.

Results: A total of 166 and 164 patients were allocated to poudrage and slurry, respectively. Participants were well matched at baseline. For the primary outcome, no significant difference in pleurodesis failure was observed between the treatment groups at 90 days, with rates of 36 out of 161 (22%) and 38 out of 159 (24%) noted in the poudrage and slurry groups, respectively (odds ratio 0.91, 95% confidence interval 0.54 to 1.55;  = 0.74). No differences (or trends towards difference) were noted in adverse events or any of the secondary outcomes at any time point, including pleurodesis failure at 180 days [poudrage 46/161 (29%), slurry 44/159 (28%), odds ratio 1.05, 95% confidence interval 0.63 to 1.73;  = 0.86], mean number of nights in hospital over 90 days [poudrage 12 nights (standard deviation 13 nights), slurry 11 nights (standard deviation 10 nights);  = 0.35] and all-cause mortality at 180 days [poudrage 66/166 (40%), slurry 68/164 (42%);  = 0.70]. At £20,000 per quality-adjusted life-year gained, poudrage would have a 0.36 probability of being cost-effective compared with slurry.

Limitations: Entry criteria specified that patients must be sufficiently fit to undergo thoracoscopy, which may make the results less applicable to those patients presenting with a greater degree of frailty. Furthermore, the trial was conducted on an open-label basis, which may have influenced the results of patient-reported measures.

Conclusions: The TAPPS (evaluating the efficacy of Thoracoscopy And talc Poudrage versus Pleurodesis using talc Slurry) trial has robustly demonstrated that there is no additional clinical effectiveness or cost-effectiveness benefit in performing talc poudrage at thoracoscopy over bedside chest drain and talc slurry for the management of malignant pleural effusion.

Trial Registration: Current Controlled Trials ISRCTN47845793.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 26. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307272PMC
June 2020

Addressing Patients' Mental Health Needs at a Student-Run Free Clinic.

Community Ment Health J 2021 Jan 21;57(1):196-202. Epub 2020 May 21.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Student-run free clinics are uniquely positioned to understand the barriers to accessing mental health resources. We abstracted patient demographics and clinical characteristics from 355 patient charts and examined referral patterns for a subset of patients. Seventy-three (21%) of patients were found to have a psychiatric diagnosis and were more likely to have more medical comorbidities (10 versus 6, p < 0.001), total medications (8 versus 6, p < 0.001, and to be English-speaking (odds ratio: 1.97, p < 0.05). Of patients who received a referral, 37 (60%) were referred to specialty treatment, the majority to a single outside agency provider. 15 (25%) of patients were interviewed. Barriers to successful referral included transportation and medical symptoms. A facilitator of successful referral was concern for individual's health. Language, social stigma, and cost were not cited as barriers. This study describes mental health needs at a SRFC and suggests opportunities for improvement.
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http://dx.doi.org/10.1007/s10597-020-00634-3DOI Listing
January 2021

Non-necrotizing granulomatous pneumonitis and chronic pleuritis in soldiers deployed to Southwest Asia.

Histopathology 2020 Sep 2;77(3):453-459. Epub 2020 Jul 2.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.

Aims: Reports of respiratory illnesses among soldiers returning from Southwest Asia have been described. During deployment to Southwest Asia, soldiers are exposed to various respiratory hazards, including dust storms, smoke from burn pits and industrial air pollutants. A few studies have reported increased rates of constrictive bronchiolitis and asthma in these patients. We sought to expand upon the pathological findings in this cohort.

Methods And Results: Lung biopsies from veterans of Southwest Asia were identified and re-reviewed. All patients had undergone pulmonary function tests and chest high-resolution CT imaging with no significant findings. Overall, 59 patients with a history of inhalational exposure to at least one of the following were identified: smoke from burn pit, dust storm and sulphur plant fire. Samples included video-assisted thoracoscopic lung biopsies (57 of 59, 96.6%) and cryobiopsies (two of 59, 3.4%). Patients were predominantly male (54 of 59, 91.5%) with an age range of 24-55 years (mean and median = 35). Non-necrotising, poorly formed granulomas were identified in 22 cases (22 of 59, 37.2%). The granulomas were mainly bronchiolocentric and were associated with chronic lymphoplasmacytic bronchiolitis, similar to hypersensitivity pneumonitis (HP). Pleural reaction in the form of focal chronic lymphocytic pleuritis and/or focal pleural adhesions were seen in 43 of 57 (75.4%) biopsies.

Conclusions: To our knowledge, this is the first study to report pleural reaction as well as features of HP in this population, suggesting that pleural reaction and HP may be part of the spectrum of Southwest Asia deployment-related lung diseases.
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http://dx.doi.org/10.1111/his.14135DOI Listing
September 2020

Blood transcriptional biomarkers for active pulmonary tuberculosis in a high-burden setting: a prospective, observational, diagnostic accuracy study.

Lancet Respir Med 2020 04 13;8(4):407-419. Epub 2020 Mar 13.

Division of Infection and Immunity, University College London, London, UK. Electronic address:

Background: Blood transcriptional signatures are candidates for non-sputum triage or confirmatory tests of tuberculosis. Prospective head-to-head comparisons of their diagnostic accuracy in real-world settings are necessary to assess their clinical use. We aimed to compare the diagnostic accuracy of candidate transcriptional signatures identified by systematic review, in a setting with a high burden of tuberculosis and HIV.

Methods: We did a prospective observational study nested within a diagnostic accuracy study of sputum Xpert MTB/RIF (Xpert) and Xpert MTB/RIF Ultra (Ultra) tests for pulmonary tuberculosis. We recruited consecutive symptomatic adults aged 18 years or older self-presenting to a tuberculosis clinic in Cape Town, South Africa. Participants provided blood for RNA sequencing, and sputum samples for liquid culture and molecular testing using Xpert and Ultra. We assessed the diagnostic accuracy of candidate blood transcriptional signatures for active tuberculosis (including those intended to distinguish active tuberculosis from other diseases) identified by systematic review, compared with culture or Xpert MTB/RIF positivity as the standard reference. In our primary analysis, patients with tuberculosis were defined as those with either a positive liquid culture or Xpert result. Patients with missing blood RNA or sputum results were excluded. Our primary objective was to benchmark the diagnostic accuracy of candidate transcriptional signatures against the WHO target product profile (TPP) for a tuberculosis triage test.

Findings: Between Feb 12, 2016, and July 18, 2017, we obtained paired sputum and RNA sequencing data from 181 participants, 54 (30%) of whom had confirmed pulmonary tuberculosis. Of 27 eligible signatures identified by systematic review, four achieved the highest diagnostic accuracy with similar area under the receiver operating characteristic curves (Sweeney3: 90·6% [95% CI 85·6-95·6]; Kaforou25: 86·9% [80·9-92·9]; Roe3: 86·9% [80·3-93·5]; and BATF2: 86·8% [80·6-93·1]), independent of age, sex, HIV status, previous tuberculosis, or sputum smear result. At test thresholds that gave 70% specificity (the minimum WHO TPP specificity for a triage test), these four signatures achieved sensitivities between 83·3% (95% CI 71·3-91·0) and 90·7% (80·1-96·0). No signature met the optimum criteria, of 95% sensitivity and 80% specificity proposed by WHO for a triage test, or the minimum criteria (of 65% sensitivity and 98% specificity) for a confirmatory test, but all four correctly identified Ultra-positive, culture-negative patients.

Interpretation: Selected blood transcriptional signatures met the minimum WHO benchmarks for a tuberculosis triage test but not for a confirmatory test. Further development of the signatures is warranted to investigate their possible effects on clinical and health economic outcomes as part of a triage strategy, or when used as add-on confirmatory test in conjunction with the highly sensitive Ultra test for Mycobacterium tuberculosis DNA.

Funding: Royal Society Newton Advanced Fellowship, Wellcome Trust, National Institute of Health Research, and UK Medical Research Council.
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http://dx.doi.org/10.1016/S2213-2600(19)30469-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113842PMC
April 2020

Emergency Department Use Among Student-Run Free Clinic Patients: a Cross-sectional Study.

J Gen Intern Med 2021 Mar 27;36(3):830-832. Epub 2020 Feb 27.

Department of Medicine, Division of General Internal Medicine, Section of Hospital Medicine Vanderbilt University Medical Center, Nashville, TN, USA.

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http://dx.doi.org/10.1007/s11606-020-05743-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947082PMC
March 2021

Electroretinographic Abnormalities and Sex Differences Detected with Mesopic Adaptation in a Mouse Model of Schizophrenia: A and B Wave Analysis.

Invest Ophthalmol Vis Sci 2020 02;61(2):16

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Purpose: Mesopic flash electroretinography (fERG) as a tool to identify N-methyl-d-aspartate receptor (NMDAR) hypofunction in subjects with schizophrenia shows great potential. We report the first fERG study in a genetic mouse model of schizophrenia characterized by NMDAR hypofunction from gene silencing of serine racemase (SR) expression (SR-/-), an established risk gene for schizophrenia. We analyzed fERG parameters under various background light adaptations to determine the most significant variables to allow for early identification of people at risk for schizophrenia, prior to onset of psychosis. SR is a risk gene for schizophrenia, and negative and cognitive symptoms antedate the onset of psychosis that is required for diagnosis.

Methods: The scotopic, photopic, and mesopic fERGs were analyzed in male and female mice in both SR-/- and wild-type (WT) mice and also analyzed for sex differences. Amplitude and implicit time of the a- and b-wave components, b-/a-wave ratio, and Fourier transform analysis were analyzed.

Results: Mesopic a- and b-wave implicit times were significantly delayed, and b-wave amplitudes, b/a ratios, and Fourier transform were significantly decreased in the male SR-/- mice compared to WT, but not in female SR-/- mice. No significant differences were observed in photopic or scotopic fERGs between genotype.

Conclusions: The fERG prognostic capability may be improved by examination of background light adaptation, a larger array of light intensities, considering sex as a variable, and performing Fourier transform analyses of all waveforms. This should improve the ability to differentiate between controls and subjects with schizophrenia characterized by NMDAR hypofunction.
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http://dx.doi.org/10.1167/iovs.61.2.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326504PMC
February 2020

Implementation of routine interferon-gamma release assay testing in a South London HIV cohort.

Int J STD AIDS 2020 03 9;31(3):264-267. Epub 2020 Feb 9.

King's College London, London, UK.

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http://dx.doi.org/10.1177/0956462419893536DOI Listing
March 2020

Management of HIV-infected patients in the intensive care unit.

Intensive Care Med 2020 02 3;46(2):329-342. Epub 2020 Feb 3.

Medical Intensive Care Unit, Saint-Louis University Hospital, APHP, Paris, France.

The widespread use of combination antiretroviral therapies (cART) has converted the prognosis of HIV infection from a rapidly progressive and ultimately fatal disease to a chronic condition with limited impact on life expectancy. Yet, HIV-infected patients remain at high risk for critical illness due to the occurrence of severe opportunistic infections in those with advanced immunosuppression (i.e., inaugural admissions or limited access to cART), a pronounced susceptibility to bacterial sepsis and tuberculosis at every stage of HIV infection, and a rising prevalence of underlying comorbidities such as chronic obstructive pulmonary diseases, atherosclerosis or non-AIDS-defining neoplasms in cART-treated patients aging with controlled viral replication. Several patterns of intensive care have markedly evolved in this patient population over the late cART era, including a steady decline in AIDS-related admissions, an opposite trend in admissions for exacerbated comorbidities, the emergence of additional drivers of immunosuppression (e.g., anti-neoplastic chemotherapy or solid organ transplantation), the management of cART in the acute phase of critical illness, and a dramatic progress in short-term survival that mainly results from general advances in intensive care practices. Besides, there is a lack of data regarding other features of ICU and post-ICU care in these patients, especially on the impact of sociological factors on clinical presentation and prognosis, the optimal timing of cART introduction in AIDS-related admissions, determinants of end-of-life decisions, long-term survival, and functional outcomes. In this narrative review, we sought to depict the current evidence regarding the management of HIV-infected patients admitted to the intensive care unit.
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http://dx.doi.org/10.1007/s00134-020-05945-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095039PMC
February 2020

Clinically important associations of pleurodesis success in malignant pleural effusion: Analysis of the TIME1 data set.

Respirology 2020 07 17;25(7):750-755. Epub 2019 Dec 17.

University of Oxford Respiratory Trials Unit, Churchill Hospital, Oxford, UK.

Background And Objective: Chemical pleurodesis is performed for patients with MPE with a published success rate of around 80%. It has been postulated that inflammation is key in achieving successful pleural symphysis, as evidenced by higher amounts of pain or detected inflammatory response. Patients with mesothelioma are postulated to have a lower rate of successful pleurodesis due to lack of normal pleural tissue enabling an inflammatory response.

Methods: The TIME1 trial data set, in which pleurodesis success and pain were co-primary outcome measures, was used to address a number of these assumptions. Pain score, systemic inflammatory parameters as a marker of pleural inflammation and cancer type were analysed in relation to pleurodesis success.

Results: In total, 285 patients were included with an overall success rate of 81.4%. There was a significantly higher rise in CRP in the Pleurodesis Success group compared with the Pleurodesis Failure group (mean difference: 19.2, 95% CI of the difference: 6.2-32.0, P = 0.004) but no significant change in WCC. There was no significant difference in pain scores or analgesia requirements between the groups. Patients with mesothelioma had a lower rate of pleurodesis success than non-mesothelioma patients (73.3% vs 84.9%, χ = 5.1, P = 0.023).

Conclusion: Change in CRP during pleurodesis is associated with successful pleurodesis but higher levels of pain are not associated. Patients with mesothelioma appear less likely to undergo successful pleurodesis than patients with other malignancies, but there is still a significant rise in systemic inflammatory markers. The mechanisms of these findings are unclear but warrant further investigation.
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http://dx.doi.org/10.1111/resp.13755DOI Listing
July 2020

: out with the old, in with the new.

Br J Hosp Med (Lond) 2019 Dec;80(12):690

Editor in Chief, British Journal of Hospital Medicine.

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http://dx.doi.org/10.12968/hmed.2019.80.12.690DOI Listing
December 2019

Effect of Thoracoscopic Talc Poudrage vs Talc Slurry via Chest Tube on Pleurodesis Failure Rate Among Patients With Malignant Pleural Effusions: A Randomized Clinical Trial.

JAMA 2019 Dec 5. Epub 2019 Dec 5.

Academic Respiratory Unit, University of Bristol, Bristol, United Kingdom.

Importance: Malignant pleural effusion (MPE) is challenging to manage. Talc pleurodesis is a common and effective treatment. There are no reliable data, however, regarding the optimal method for talc delivery, leading to differences in practice and recommendations.

Objective: To test the hypothesis that administration of talc poudrage during thoracoscopy with local anesthesia is more effective than talc slurry delivered via chest tube in successfully inducing pleurodesis.

Design, Setting, And Participants: Open-label, randomized clinical trial conducted at 17 UK hospitals. A total of 330 participants were enrolled from August 2012 to April 2018 and followed up until October 2018. Patients were eligible if they were older than 18 years, had a confirmed diagnosis of MPE, and could undergo thoracoscopy with local anesthesia. Patients were excluded if they required a thoracoscopy for diagnostic purposes or had evidence of nonexpandable lung.

Interventions: Patients randomized to the talc poudrage group (n = 166) received 4 g of talc poudrage during thoracoscopy while under moderate sedation, while patients randomized to the control group (n = 164) underwent bedside chest tube insertion with local anesthesia followed by administration of 4 g of sterile talc slurry.

Main Outcomes And Measures: The primary outcome was pleurodesis failure up to 90 days after randomization. Secondary outcomes included pleurodesis failure at 30 and 180 days; time to pleurodesis failure; number of nights spent in the hospital over 90 days; patient-reported thoracic pain and dyspnea at 7, 30, 90, and 180 days; health-related quality of life at 30, 90, and 180 days; all-cause mortality; and percentage of opacification on chest radiograph at drain removal and at 30, 90, and 180 days.

Results: Among 330 patients who were randomized (mean age, 68 years; 181 [55%] women), 320 (97%) were included in the primary outcome analysis. At 90 days, the pleurodesis failure rate was 36 of 161 patients (22%) in the talc poudrage group and 38 of 159 (24%) in the talc slurry group (adjusted odds ratio, 0.91 [95% CI, 0.54-1.55]; P = .74; difference, -1.8% [95% CI, -10.7% to 7.2%]). No statistically significant differences were noted in any of the 24 prespecified secondary outcomes.

Conclusions And Relevance: Among patients with malignant pleural effusion, thoracoscopic talc poudrage, compared with talc slurry delivered via chest tube, resulted in no significant difference in the rate of pleurodesis failure at 90 days. However, the study may have been underpowered to detect small but potentially important differences.

Trial Registration: ISRCTN Identifier: ISRCTN47845793.
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http://dx.doi.org/10.1001/jama.2019.19997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990658PMC
December 2019

Incidence and significance of elevated platelet-to-lymphocyte and neutrophil-to-lymphocyte ratios among hospitalised HIV-positive adult patients.

Int J STD AIDS 2019 11 15;30(13):1329-1332. Epub 2019 Nov 15.

HIV Services, Royal Free London NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1177/0956462419868881DOI Listing
November 2019

Predicting No-shows at a Student-Run Comprehensive Primary Care Clinic.

Fam Med 2019 Nov;51(10):845-849

Vanderbilt University Medical Center, Nashville, TN.

Background And Objectives: Missed appointments represent a significant challenge to the efficient and effective provision of care in the outpatient setting. High no-show rates result in ineffective use of human resources and contribute to loss of follow-up. Shade Tree Clinic (STC) is a student-run, comprehensive primary care clinic that serves more than 350 Middle Tennessee residents. This study aimed to use available data to predict no-shows to improve clinic efficiency and service quality.

Methods: Data were pulled from clinic scheduling software for all appointments at STC between January 1, 2010 and December 31, 2015. Weather data were added for each appointment date using an online database. Multivariable logistic regression was used to create models from these historical data.

Results: A total of 13,499 appointments were included with an overall show rate of 69.2%. The final model contained previous show rate (OR 1.063; P<.001), day of the week (OR 1.20; P<.001), automated reminder (OR 1.40; P<.001), snow in inches (OR .33; P<.001), and high ambient temperature in degrees (OR 1.01; P<.001). Using a cutoff probability of the 25th percentile, the model had a negative predictive value of 61.0%.

Conclusions: Based on readily available data and a novel conceptual framework, we can identify the quarter of patients least likely to present for scheduled appointments and target them for interventions, allowing care providers to more effectively address community health care disparities through the clinic. This analysis is replicable at any clinic using an electronic medical record.
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http://dx.doi.org/10.22454/FamMed.2019.406053DOI Listing
November 2019

Electoretinographic evidence of retinal ganglion cell-dependent function in schizophrenia.

Schizophr Res 2020 05 12;219:34-46. Epub 2019 Oct 12.

Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, United States of America; Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States of America; Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, United States of America.

Schizophrenia is a complex disorder that is diagnosed mainly with clinical observation and evaluation. Recent studies suggest that many people with schizophrenia have abnormalities in the function of the N-methyl-d-aspartate receptor (NMDAR). The retina is part of the central nervous system and expresses the NMDAR, raising the possibility of the early detection of NMDAR-related schizophrenia by detecting differences in retinal function. As a first-step, we used two non-invasive outpatient tests of retinal function, the photopic negative response (PhNR) of the light-adapted flash-electroretinogram (PhNR-fERG) and the pattern ERG (PERG), to test individuals with schizophrenia and controls to determine if there were measurable differences between the two populations. The PhNR-fERG showed that males with schizophrenia had a significant increase in the variability of the overall response, which was not seen in the females with schizophrenia. Additionally at the brightest flash strength, there were significant increases in the PhNR amplitude in people with schizophrenia that were maximal in controls. Our results show measurable dysfunction of retinal ganglion cells (RGCs) in schizophrenia using the PhNR-fERG, with a good deal of variability in the retinal responses of people with schizophrenia. The PhNR-fERG holds promise as a method to identify individuals more at risk for developing schizophrenia, and may help understand heterogeneity in etiology and response to treatment.
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http://dx.doi.org/10.1016/j.schres.2019.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442157PMC
May 2020

Survival in patients with malignant pleural effusion undergoing talc pleurodesis.

Lung Cancer 2019 11 4;137:14-18. Epub 2019 Sep 4.

Oxford Pleural Unit, Oxford University Hospitals NHS Foundation Trust, UK; Oxford NIHR Biomedical Research Centre, Oxford, UK.

Objectives: Recent observations indicate a potential survival benefit in patients with malignant pleural effusion (MPE) who achieve successful pleurodesis in comparison to patients who experience effusion recurrence post pleurodesis. This study aimed to explore this observation using two datasets of patients with MPE undergoing talc pleurodesis.

Materials And Methods: Dataset 1 comprised patients who underwent talc pleurodesis at Oxford Pleural Unit for MPE. Dataset 2 comprised patients enrolled in the TIME1 clinical trial. Pleurodesis success was defined as absence of need for further therapeutic procedures for MPE in the three months following pleurodesis. Data on various clinical, laboratory and radiological parameters were collected and survival was compared according to pleurodesis outcome (success vs. failure) after adjusting for the aforementioned parameters.

Results: Dataset 1 comprised 60 patients with mean age 74.1±10.3 years. The most common primary malignancies were mesothelioma, breast and lung cancer. 29 patients (48.3%) achieved pleurodesis. The adjusted odds ratio (aOR) for poor survival with pleurodesis failure was 2.85 (95% CI 1.08-7.50, =p 0.034). Dataset 2 comprised 259 patients from the TIME1 trial. The mean age was 70.8±10.3 and the most common primary malignancies were mesothelioma, lung and breast cancer. Pleurodesis was successful in 205 patients (79%). aOR for poor survival was 1.62 (95% CI 1.09-2.39, p = 0.015).

Conclusion: Achieving pleurodesis seems to impart a survival benefit in patients with MPE. Further studies are required to explore factors that may contribute to this phenomenon and to address the difference in survival between pleurodesis and indwelling pleural catheter interventions.
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http://dx.doi.org/10.1016/j.lungcan.2019.09.003DOI Listing
November 2019

Sociality deficits in serine racemase knockout mice.

Brain Behav 2019 10 12;9(10):e01383. Epub 2019 Sep 12.

Department of Psychology, University of Minnesota - Twin Cities, Minneapolis, Minnesota.

Background: Studies of schizophrenia have pointed to the role of glutamate in its pathophysiology. Mice lacking D-serine show impairments in neurotransmission through NMDA receptors and display behaviors consistent with features of schizophrenia. Yet, socio-communicative deficits, a characteristic of schizophrenia, have not been reported in serine racemase knockout mice.

Methods: We use behavioral testing (the three-chambered social approach task, the dyadic interaction task, and the novel object recognition task) to examine socio-communicative behaviors in these mice.

Results: Serine racemase mice show abnormal social investigation and approach behavior, and differ from wild-type controls in the duration and number of vocalizations they emit in the presence of a conspecific. Serine racemase knockout mice were not impaired in a cognitive test (novel object recognition), although they displayed abnormal behavior in the acquisition phase of the task.

Conclusions: Serine racemase knockout mice demonstrate abnormalities in socio-communicative behaviors consistent with an impairment in sociality, a negative symptom of schizophrenia.
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http://dx.doi.org/10.1002/brb3.1383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790321PMC
October 2019

Respiratory Health after Military Service in Southwest Asia and Afghanistan. An Official American Thoracic Society Workshop Report.

Ann Am Thorac Soc 2019 08;16(8):e1-e16

Since 2001, more than 2.7 million U.S. military personnel have been deployed in support of operations in Southwest Asia and Afghanistan. Land-based personnel experienced elevated exposures to particulate matter and other inhalational exposures from multiple sources, including desert dust, burn pit combustion, and other industrial, mobile, or military sources. A workshop conducted at the 2018 American Thoracic Society International Conference had the goals of: ) identifying key studies assessing postdeployment respiratory health, ) describing emerging research, and ) highlighting knowledge gaps. The workshop reviewed epidemiologic studies that demonstrated more frequent encounters for respiratory symptoms postdeployment compared with nondeployers and for airway disease, predominantly asthma, as well as case series describing postdeployment dyspnea, asthma, and a range of other respiratory tract findings. On the basis of particulate matter effects in other populations, it also is possible that deployers experienced reductions in pulmonary function as a result of such exposure. The workshop also gave particular attention to constrictive bronchiolitis, which has been reported in lung biopsies of selected deployers. Workshop participants had heterogeneous views regarding the definition and frequency of constrictive bronchiolitis and other small airway pathologic findings in deployed populations. The workshop concluded that the relationship of airway disease, including constrictive bronchiolitis, to exposures experienced during deployment remains to be better defined. Future clinical and epidemiologic research efforts should address better characterization of deployment exposures; carry out longitudinal assessment of potentially related adverse health conditions, including lung function and other physiologic changes; and use rigorous histologic, exposure, and clinical characterization of patients with respiratory tract abnormalities.
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http://dx.doi.org/10.1513/AnnalsATS.201904-344WSDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774741PMC
August 2019

Randomised Ambulatory Management of Primary Pneumothorax (RAMPP): protocol of an open-label, randomised controlled trial.

BMJ Open Respir Res 2019 11;6(1):e000403. Epub 2019 Apr 11.

Department of Respiratory Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Introduction: Pneumothorax is a common clinical problem. Primary spontaneous pneumothorax (PSP) occurs in otherwise fit young patients, but optimal management is not clearly defined and often results in a long hospital stay. Ambulatory treatment options are available, but the existing data on their efficacy are poor. The Randomised Ambulatory Management of Primary Pneumothorax trial is a multicentre, randomised controlled trial comparing ambulatory management with standard care, specifically designed to safely and effectively reduce hospital stay.

Methods And Analysis: 236 patients with PSP will be recruited from UK hospitals. Patients will be randomised 1:1 to treatment to either the 'Intervention' arm (ambulatory device; Rocket Pleural Vent) or the 'Control' arm (aspiration ± standard chest drain insertion). Patients will be followed up for a total of 12 months to assess recurrence rates. The primary outcome is total length of stay in hospital (including readmissions) up to 30 days postrandomisation. The secondary outcomes are pain and breathlessness scores, air leak measurement and radiological evidence (on CT scanning) of emphysema-like changes, compared with short-term and long-term outcomes, respectively, and health economic analysis.

Ethics And Dissemination: The trial has received ethical approval from the National Research Ethics Service Committee South-Central Oxford A (15/SC/0240).

Trial Registration Number: ISRCTN79151659.
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http://dx.doi.org/10.1136/bmjresp-2019-000403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530507PMC
April 2020

Incidence and significance of an elevated red blood cell distribution width among hospitalised HIV-infected adult patients.

Int J STD AIDS 2019 08 3;30(9):915-918. Epub 2019 Jun 3.

1 HIV Services, Royal Free London NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1177/0956462419851903DOI Listing
August 2019

Kidney disease in Africans with HIV and tuberculosis.

AIDS 2019 06;33(7):1207-1213

King's College London.

Objective: To describe the spectrum of kidney disease in African patients with HIV and tuberculosis (TB).

Methods: We used data from three cohorts: consecutive patients with HIV/TB in South London (UK, 2004-2016; n = 95), consecutive patients with HIV/TB who underwent kidney biopsy in Cape Town (South Africa, 2014-2017; n = 70), and consecutive patients found to have HIV/TB on autopsy in Abidjan (Cote d'Ivoire, 1991; n = 100). Acute kidney injury (AKI) was ascertained using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. In the Cape Town cohort, predictors of recovery of kidney function at 6 months were assessed using Cox regression.

Results: In the London cohort, the incidence of moderate/severe AKI at 12 months was 15.1 (95% CI 8.6-26.5) per 100 person-years, and the prevalence of chronic and end-stage kidney disease (ESKD) 13.7 and 5.7%, respectively. HIV-associated nephropathy (HIVAN) was diagnosed in 6% of patients in London, and in 6% of autopsy cases in Abidjan. Evidence of renal TB was present in 60% of autopsies in Abidjan and 61% of kidney biopsies in Cape Town. HIVAN and acute tubular necrosis (ATN) were also common biopsy findings in Cape Town. In Cape Town, 40 patients were dialyzed, of whom 28 (70%) were able to successfully discontinue renal replacement therapy. Antiretroviral therapy status, CD4 cell count, estimated glomerular filtration rate (eGFR) at biopsy and renal histology, other than ATN, were not predictive of eGFR recovery.

Conclusion: Kidney disease was common in Africans with HIV/TB. Monitoring of kidney function, and provision of acute dialysis to those with severe kidney failure, is warranted.
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http://dx.doi.org/10.1097/QAD.0000000000002204DOI Listing
June 2019