Western Institutional Review Board Research Articles

Umbilical Cord Mesenchymal Stem Cells for COVID-19 ARDS: A Double Blind, Phase 1/2a, Randomized Controlled Trial

Background: Acute Respiratory Distress Syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal Stem Cells (MSC) are potent immunomodulatory cells. The aim of this study was to determine safety and explore efficacy of Umbilical Cord (UC)-MSC infusions in COVID-19 ARDS.Methods: A double-blind, phase 1/2a, randomized, controlled trial was performed in subjects with ARDS secondary to COVID-19, at a single institution in Miami, Florida, USA. Randomization and stratification by ARDS severity was used to foster balance among groups. Participants received two intravenous infusions of 100x106 UC-MSC, or vehicle, at day 0 and 3. The primary endpoint was safety, defined by occurrence of pre-specified infusion associated adverse events, along with adverse events during 28 day follow-up. All subjects were analyzed under an intention to treat design. Exploratory efficacy endpoints included survival at 28 days and time to recovery.Findings: 24 subjects (12 per group) were recruited between April 25 and July 21 2020. At 28 days post last infusion, patient survival was 91% and 42% in the UC-MSC and Control groups, respectively (p=0.015). No serious adverse events (SAEs) were observed related to UC-MSC infusions. There was no observed difference in number of subjects experiencing infusion-associated adverse events. Treatment unrelated SAEs were reported in 2 and 8 patients in the UC-MSC and Control groups, respectively (p=0.04). UC-MSC treatment was associated with increased SAE-free survival (p=0.008) and decreased time to recovery (p=0.03) compared to controls.Interpretation: UC-MSC infusions in COVID-19 subjects with ARDS were safe and associated with fewer SAEs, compared to control. Further, exploratory efficacy analyses provide preliminary evidence of reduction in mortality and time to recovery. Notwithstanding sample size limitations of this trial, the observed findings strongly support further investigation in a larger trial designed to estimate and test for efficacy.Trial Registration: (ClinicalTrials.gov NCT04355728).Funding Statement: The trial was funded by the Barilla Group and Family, The Cure Alliance, the Fondazione Silvio Tronchetti Provera, the Simkins Family Foundation, the North America’s Building Trades Unions, and the Diabetes Research Institute Foundation. This publication was supported by the Clinical Translational Research Site Grants Number UL1TR000460 and UL1TR002736 from the National Center for Advancing Translational Sciences (NCATS).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: Ethics Committee Approval by the regulatory and institutional review boards were obtained by the Western Institutional Review Board (WIRB) and UM Human Subject Research Office/Institutional Review Board, in accordance with local institutional requirements.

The Role of Patients in Alopecia Areata Endpoint Development: Understanding Physical Signs and Symptoms.

Meaningful patient input to understand disease experience and patient expectations for improvement with treatment is essential for the selection and development of outcome measures for alopecia areata (AA) clinical trials. This study explored the physical signs and symptoms of AA through 30 semistructured interviews with adult (n= 25) and adolescent (n= 5) patients experienced with severe or very severe AA. Scalp hair loss was overwhelmingly the most important sign and symptom of AA. Nearly all patients (90%) considered scalp hair loss in their top three most bothersome physical signs and symptoms of AA, with 77% (n= 23) naming scalp hair loss as the most bothersome symptom. Other identified signs and symptoms in the top three most bothersome included eyebrow, eyelash, nose, body, and facial hair loss, as well as eye irritation and nail damage and/or appearance. Eyebrow (16%, n= 4), eyelash (4%, n= 1), nasal (4%, n= 1), and body (4%, n= 1) hair loss were identified by seven adult patients as the most bothersome signs and symptoms of AA. Conceptual saturation confirmed that a comprehensive understanding of this patient population's physical AA-related signs and symptoms was obtained. These findings indicate that the primary objective for new AA treatments for this patient population should be meaningful improvement in scalp hair growth to address the most troubling unmet need.

Abstract PO-009: Cancer-related distress among multiple myeloma patients during the COVID-19 pandemic

Abstract Background: The rapid outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the delay of non-urgent or routine medical appointments, placing tremendous burden on cancer patients. Meanwhile, the emotional effect of the novel coronavirus (COVID-19) on high-risk groups, such as multiple myeloma (MM) patients, remains unclear. The purpose of this project was to understand psychosocial distress and unmet needs among patients with active MM during the acute phase of social distancing and COVID-19 impact in the United States. Methods: We utilized HealthTree (healthtree.org) and invited patients with active MM cancer or precursor conditions to participate in an online survey curated through a partnership with the Cancer Support Community (CSC). Participants were asked to rate their level of concern (Not at All to Very Seriously) on 12 items assessing psychosocial, practical, and physical needs (selected from CSC’s CancerSupportSource® distress screening tool) during the COVID-19 pandemic. De-identified responses were aggregated and reviewed. The survey was determined to be exempt by the Western Institutional Review Board. Results: 1,079 MM pts participated in the survey between April 15, 2020 and June 8, 2020. The percentages of patients responding moderately to very seriously concerned are reported here. Eating and nutrition (71%), sleep problems (49%), pain and/or physical discomfort (46%), and feeling too tired to do the things you need or want to do (44%) made up the physical/health concerns. Psychosocial/emotional concerns included worrying about the future and what lies ahead (46%), worry about family, children, and/or friends (44%), feeling irritable (37%), feeling sad or depressed (30%), feeling nervous or afraid (25%), feeling lonely or isolated (20%), and relationship problems with your spouse/partner (11%). Finally, 32% reported insurance or money concerns. Conclusions: Respondents to our survey were most concerned with eating and nutrition, sleep problems, pain and/or physical discomfort, and worrying about the future. Informing patients and medical professionals of physical and psychosocial distress experienced by patients could create a unified approach to decreasing distress levels and increase patient overall health, even during a pandemic or when care is delayed. Patient-reported surveys via an online portal, like HealthTree, can help investigators assess the patient community and result in hypothesis-generating research questions to enhance patient outcomes. Citation Format: Nathan W. Sweeney, Jenny Ahlstrom. Cancer-related distress among multiple myeloma patients during the COVID-19 pandemic [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-009.

Impact of Obesity on Outcomes of Patients With Coronavirus Disease 2019 in the United States: A Multicenter Electronic Health Records Network Study

Impact of Obesity on Outcomes of Patients With Coronavirus Disease 2019 in the United States: A Multicenter Electronic Health Records Network Study

HealthTree Patient Portal mediated myeloma patient-reported vaccination and antibiotic use.

e20567 Background: Multiple myeloma (MM) is a cancer of the immune system. Infection is a major cause of morbidity and mortality in MM. Vaccines are the first line of prevention for infectious diseases. Anti-microbial prophylaxis may improve patient (pt) outcomes, but real-world use has not been well characterized. In order to engage the pt community regarding vaccination we utilized HealthTree (www.healthtree.org). Methods: An investigator-submitted online survey asking about infection prophylaxis and vaccinations was fielded to 4,944 pts from May 10, 2019, to January 9, 2020. The HealthTree platform queries pts about sharing data for research purposes. De-identified responses were aggregated and reviewed. The study was determined to be exempt by the Western Institutional Review Board. Results: 458 MM pts participated in the surveys and were able to select more than one option with the total response indicated below. Abbreviated questions and simplified responses are noted in Table including: 1. Have you ever been vaccinated in the last 5 years with a pneumococcal vaccine (PV)? 2. In the last 3 flu seasons, have you received the influenza vaccine (FV)? 3. After you began myeloma treatment, did you ever receive the anti-Varicella Zoster Virus (VZV, shingles) vaccine? 4. Were you (or are you currently) treated with anti-viral prophylaxis? 5. Were you (or are you currently) treated with antibiotic bactrim? 6. Were you (or are you currently) treated with levofloxacin prior to stem cell transplant or at the beginning of your MM therapy? Conclusions: Both FV and PV were fairly high in this self-selected cohort of volunteers compared with a large health system ( http://ow.ly/O8Dx30b9Wuc ) and a global registry ( http://ow.ly/Uofg30h6Qen ). Most did not receive an anti-VZV vaccine, but a few received a live vaccine. Anti-viral prophylaxis was common, but not universal. Anti-PJP and levofloxacin use were reported by a minority of participants. Pt reported interventions via an online portal can help investigators survey the pt community and result in hypothesis generating research questions including investigating vaccine: types, dosing, sequencing, and use of anti-infective interventions. [Table: see text]

HealthTree Patient Portal mediated myeloma patient reported diagnostic imaging and pathology testing.

e20565 Background: Multiple myeloma (MM) prognostic risk factors include cancer genetics as well as imaging characteristics. In order to engage the patient (pt) community regarding genetic testing and diagnostic imaging we utilized a patient-centered platform, HealthTree (www.healthtree.org), to evaluate the patient understanding of cancer genetic characteristics as well as evaluation of radiology methods used to evaluate their disease. Methods: An investigator-submitted online survey asking pts about myeloma genetic testing and imaging was fielded via HealthTree to 4,944 pts from May 10, 2019, to January 9, 2020. De-identified responses were aggregated and reviewed. The study was determined to be exempt by the Western Institutional Review Board. Results: 558 MM pts participated in the surveys. Pts who received more than one imaging or genetic test were able to indicate by selecting more than one option, this total response is indicated in the tables. Abbreviated questions and simplified responses are noted in the Table including: 1. At your diagnosis (or any time), did you receive any of the following tests to better understand the genetic profile of your disease? 2. At diagnosis (or any time), what imaging (radiology) tests were performed? Conclusions: Patient self-reported data registries are limited by patient perception or recall; however, these engaged and online MM pts may also be more biased toward knowing more about their medical history than the average pt. There are certainly real or perceived gaps in optimized genetic and imaging testing, which may reflect a communication or education gap. Pt reported interventions via an online portal can help investigators survey the pt community and result in hypothesis generating research questions including the actual use of testing, communication and education about testing and testing options, and MD trends in testing. [Table: see text][Table: see text]

Qualitative patient interviews on symptoms and impacts in metastatic synovial sarcoma (mSS).

e23576 Background: Synovial sarcoma (SS), a soft tissue sarcoma, is a rare and aggressive malignancy, with significant morbidity and mortality associated with mSS. There are currently no patient-reported outcome (PRO) instruments specific to mSS patients and little qualitative research to understand impacts on mSS patients’ health-related quality of life (QoL). The objective of this study was to characterize the symptoms and impacts experienced by mSS patients to inform the selection of content-valid PRO instruments for use in investigational trials in mSS patients. Methods: This was a non-interventional, qualitative interview study of adult participants in the United States (US) with physician-confirmed mSS. Participants were consented from a large private practice in the US. Six semistructured concept elicitation interviews (60–90m by telephone) were conducted by trained interviewers. Participants were asked to describe their mSS symptoms and their impact on functioning in an open-ended fashion with follow-up probes. Verbatim transcripts were analyzed using thematic analysis methods and Atlas.Ti software. Socio-demographics and clinical characteristics were collected by the site. The study received Institutional Review Board (IRB) approval from Western IRB. Results: Among the 6 participants, average age was 45y (range 21–61y) and 2 were female. All 6 participants had pulmonary metastasis, 1 participant had a liver metastasis, and 1 participant had a mediastinal mass. The most common symptoms participants spontaneously identified were pain (n = 6), fatigue (n = 6), coughing (n = 5, with 2 upon probing), shortness of breath (n = 4), phlegm/mucus in the lungs (n = 3), coughing up blood (n = 2), and gastrointestinal complications (n = 2). Nerve/shooting/burning pain (n = 5) was mentioned upon probing. Participants also reported impacts of their disease on sleep (quantity and quality) (n = 6), physical activity (n = 6), social life (n = 6), daily activities (n = 5), emotions (n = 5), loss of appetite (n = 3), and finances (n = 1). Although not spontaneously reported, global ratings of overall health and QoL were considered relevant by all participants. Conclusions: This is the first study to identify patient-relevant symptoms and impacts associated with mSS. Further interviews with additional participants are ongoing, and we will analyze these data to identify appropriate PRO instruments for use in investigational trials in mSS patients. Funding: GlaxoSmithKline (209386).

Evaluation of non-invasive continuous physiological monitoring devices for neonates in Nairobi, Kenya: a research protocol

IntroductionContinuous physiological monitoring devices are often not available for monitoring high-risk neonates in low-resource settings. Easy-to-use, non-invasive, multiparameter, continuous physiological monitoring devices could be instrumental in providing appropriate care and...

Orthobiologic Supplementation Improves Clinical Outcomes Following Lumbar Decompression Surgery.

BackgroundEndoscopic-assisted lumbar decompression is a minimally invasive spine surgery which has been touted to reduce collateral tissue damage, incisional pain, recovery time and complications. Residual back or leg pain and recurrent herniation are commonly reported post-operative outcomes. It has been suggested that injecting orthobiologics like cryopreserved amniotic-derived products (ADPs) and bone marrow aspiration (BMA) into the surgery site would have additional benefit on patient outcomes. This is a Western Institutional Review Board (WIRB)-approved level 1, randomized controlled trial of prospectively collected patient demographic and outcomes data for endoscopic-assisted lumbar decompression surgery. The primary goal of this study was to compare patient outcomes of orthobiologic supplementation during endoscopic-assisted lumbar decompression surgery.MethodsFollowing WIRB approval, 269 patients underwent lumbar endoscopic-assisted decompressive surgery between January 2011 and October 2017. Patients were randomized to receive ADP, BMA, both, or no supplementation (control group). Outcomes were measured by post-operative questionnaires (visual analog scale (VAS), Oswestry disability index (ODI), 36-item short-form health survey (SF-36)) over 12 months.ResultsMean VAS-leg for either BMA or ADP group displayed statistically significant improvements at 2 weeks (3.55 vs. 4.77, P = 0.002), 6 months (2.34 vs. 3.37, P = 0.026), and 9 months (2.18 vs. 3.57, P = 0.01) compared to no supplementation group (control group). Similarly, improvements in mean VAS-back were significant at 2 weeks (3.98 vs. 5.01, P = 0.011), 2 months (3.22 vs. 3.93, P = 0.04), 9 months (2.38 vs. 4.11, P = 0.004), and 12 months (2.23 vs. 3.58, P = 0.011) compared to no supplementation group (control group). There were statistically significant differences in the ODI (2 weeks, 42.19 vs. 31.11, P = 0.014) and SF-36 (4 months, 85 vs. 63, P = 0.043 for ADP only), but these differences did not subsist over time. Two patients (one control, one ADP) re-herniated at the same level.ConclusionsOrthobiologic BMA and ADP resulted in improved pain control during early post-operative periods.

Digital Care for Chronic Musculoskeletal Pain: A 10,000 User Longitudinal Study Demonstrating Efficacy and Scalability

Background: Chronic musculoskeletal pain has a vast global prevalence and economic burden. Conservative therapies are universally recommended but require patient engagement and self-management to be effective. In this study, we assessed engagement behaviors and subject-reported outcomes in subjects with chronic low back or knee pain who participated in a 12-week digital care pathway (DCP). Methods: Subjects participated in a 12-week multi-modal DCP administered via a mobile app incorporating education, sensor-guided exercise therapy, and behavioral health support with 1-on-1 remote health coaching. Primary outcome was VAS pain. Secondary measures included engagement levels, program completion, program satisfaction, condition-specific pain measures, depression, anxiety, and work productivity. Findings: Of 10,264 participants with chronic back or knee pain, 73% completed the DCP into the final month. 79% of these participants (70% of all participants) achieved minimally important change in pain. Mean improvement in VAS pain was 68% and the number of exercise therapy sessions and coaching interactions were both positively associated with improvement in pain, supporting that the amount of engagement influenced VAS pain outcomes. Secondary outcomes included 58% decrease in both depression and anxiety scores, and 62% improvement in work productivity. Lastly, three groups with distinct longitudinal pain response behaviors were identified and could be predicted from baseline measures with 76% accuracy. Interpretation: This is the first longitudinal digital health study to analyze musculoskeletal pain outcomes in a sample of this magnitude, supporting the efficacy and safety of using a digital care approach in a large, real-world population. Participants demonstrated high completion and engagement rates, and a significant positive relationship between engagement and pain reduction was identified, a finding not previously demonstrated in a DCP. Furthermore, the large sample size allowed for identification of distinct pain response subgroups which may prove beneficial in predicting recovery and tailoring future interventions. Funding Statement: Hinge Health, Inc. Declaration of Interests: Authors Bailey and Agarwal were academic collaborators on this study and were paid as consultants for their expertise for conducting this study. Bailey and Agarwal had unrestricted access to the data and lead the analysis and interpretation of the results. Author Krauss works at Hinge Health, Inc., and receives salary and equity compensation. Subsequent to paper completion, author Agarwal became employed at Hinge Health, Inc., and receives salary and equity compensation. Ethics Approval Statement: The trial was approved by the Western Institutional Review Board and complied with all ethical regulations.

Treatment of Selected Distal Radius Fractures with Nonbridging External Fixation.

A nonbridging external fixation (NBX) system with 1.6-mm diameter pins provided excellent stability for distal radius fractures in cadavers. For the present study, all patients with distal radius fractures were seen by the surgeon authors. Fractures that were displaced and unstable, including Orthopaedic Trauma Association (OTA) types 23-A2.3 to C3.3, were reduced and fixed with the NBX system. The Western Institutional Review Board granted approval (296864) for this retrospective study. Fractures numbered five OTA-A2, eight OTA-A3, two OTA-B3, one OTA-C1, two OTA-C2, and eight OTA-C3. In total, the study included 26 patients. At fixator removal, average dorsiflexion was 37.0° ± 17.8°; volar flexion, 39.4° ± 17.2°; pronation, 80.6° ± 16.1°; and supination, 48.1° ± 24.2°. Follow-up averaged 11.7 mo ± 19.2 mo. At final follow-up, average dorsiflexion was 52.9° ± 25.0°; volar flexion, 53.1° ± 23.7°; pronation, 80.8° ± 14.5°; and supination, 67.7° ± 30.3°. Average radial tilt at the time of injury was 11.6° ± 8.3°; post op to 23.9° ± 5.0°; and at last follow-up, 23.1° ± 5.0°. Average radial styloid length at the time of injury was 4.1 mm ± 3.7 mm; post op to 11.4 mm ± 3.0 mm; and at last follow-up, 10.5 mm ± 3.1 mm. Volar tilt at the time of injury averaged -19.6° ± 14.8°; reduced to 9.8° ± 6.3°; and at last follow-up, 7.5° ± 6.5°. This form of nonbridging fixation is safe and effective at maintaining reduced, extra- and intra-articular, distal radius fractures and allows functional range of motion with minimal complications.

Clinical Outcomes of Pneumonia and Other Comorbidities in Children Aged 2-59 Months in Lilongwe, Malawi: Protocol for the Prospective Observational Study "Innovative Treatments in Pneumonia".

BackgroundPneumonia is the leading infectious cause of death worldwide among children below 5 years of age. Clinical trials are conducted to determine optimal treatment; however, these trials often exclude children with comorbidities and severe illness.ConclusionsGiven the paucity of data from Africa, African-based research is necessary to establish optimal management of childhood pneumonia in malaria-endemic settings in the region. An expanded evidence base that includes children with pneumonia and other comorbidities, who are at high risk for mortality or have other complications and are therefore typically excluded from childhood pneumonia clinical trials, can contribute to future iterations of the World Health Organization Integrated Management of Childhood Illness guidelines.MethodsThe study enrolled 1000 children with pneumonia presenting to the outpatient departments of Kamuzu Central or Bwaila District Hospitals in Lilongwe, Malawi, who were excluded from concurrent randomized controlled clinical trials investigating fast breathing and chest indrawing pneumonia and who met the inclusion criteria for this prospective observational study. Each child received standard care for their illnesses per Malawian guidelines and hospital protocol and was prospectively followed up with scheduled study visits on days 1, 2 (if hospitalized), 6, 14 (in person), and 30 (by phone). Our primary objectives are to describe the clinical outcomes of children who meet the inclusion criteria for this study and to investigate whether the percentages of children cured at day 14 among those with either fast breathing or chest indrawing pneumonia and comorbidities such as severe malaria, anemia, severe acute malnutrition, or HIV are lower than those in children without these comorbidities in the standard care groups in concurrent clinical trials. This study was approved by the Western Institutional Review Board, Malawi College of Medicine Research and Ethics Committee, and the Malawi Pharmacy, Medicines and Poisons Board.ObjectiveThis prospective observational study aimed to assess the clinical outcomes of children aged 2-59 months with both pneumonia and other comorbidities in a malaria-endemic region of Malawi.ResultsThe Innovative Treatments in Pneumonia project was funded by the Bill and Melinda Gates Foundation (OPP1105080) in April 2014. Enrollment in this study began in 2016, and the primary results are expected in 2019.International Registered Report Identifier (IRRID)DERR1-10.2196/13377

Automated Voice Biomarkers for Depression Symptoms Using an Online Cross-Sectional Data Collection Initiative

Importance: Depression is an illness affecting a large percentage of the world's population throughout the lifetime. To date, there is no available biomarker for depression and detection and tracking of symptoms relies on patient self-report. Objective: To explore and validate features extracted from recorded voice samples of depressed subjects as digital biomarkers for suicidality, psychomotor retardation, and depression severity. Design: We conducted a cross-sectional study over the course of 12 months using a frequently visited web form version of the PHQ9 hosted by Mental Health America (MHA) to ask subjects for anonymous voice samples via a separate web form hosted by NeuroLex Laboratories. Subjects were asked to provide demographics, answers to the PHQ9, and two voice samples. Setting: Online only. Participants: Users of the MHA website. Main Outcomes and Measures: Performance of statistical models using extracted voice features to predict psychomotor retardation, suicidality, and depression severity as indicated by the PHQ9. Results: Voice features extracted from recorded audio of depressed subjects were able to predict PHQ9 question 9 and total scores with an area under the curve of 0.85 and a mean absolute error of 4.7, respectively. Psychomotor retardation prediction was less powerful with an area under the curve of 0.61. Conclusion and Relevance: Automated voice analysis using short recordings of patient speech may be used to augment depression screen and symptom management. Funding Statement: Funding for this study was provided by NeuroLex Laboratories, Inc. Funding supported study staff time only and there were no honoraria provided to participants. Our study partner, Mental Health America, provided depression survey and demographic data in addition to directing users to the voice survey. Declaration of Interests: The authors have no conflicts to disclose except for: Dr. Hosseini Ghomi is a stockholder of NeuroLex Laboratories, Inc. Ethics Approval Statement: Ethical oversight of the study was provided by the Western Institutional Review Board (WIRB #1174369). Subjects who participated were required to complete an online consent process.

User-centred clinical decision support to implement emergency department-initiated buprenorphine for opioid use disorder: protocol for the pragmatic group randomised EMBED trial

IntroductionThe goal of this trial is to determine whether implementation of a user-centred clinical decision support (CDS) system can increase adoption of initiation of buprenorphine (BUP) into the routine emergency...

The National Brain Injury Rescue and Rehabilitation Study - a multicenter observational study of hyperbaric oxygen for mild traumatic brain injury with post-concussive symptoms.

The National Brain Injury Rescue and Rehabilitation Project was established as a preliminary study to test the safety and practicality of multi-center hyperbaric oxygen administration for the post-concussive symptoms of chronic mild traumatic brain injury as a precursor to a pivotal, independent, multi-center, controlled clinical trial. This report presents the results for 32 subjects who completed a preliminary trial of hyperbaric oxygen several years before the passage of the 21st Century Cures Act. This study anticipated the Act and its reassessment of clinical research. Subjects received 40–82 one-hour treatments at 1.5 atmospheres absolute 100% oxygen. Outcome measures included repeated self-assessment measures and automated neurocognitive tests. The subjects demonstrated improvement in 21 of 25 neurocognitive test measures observed. The objective neurocognitive test components showed improvement in 13 of 17 measures. Earlier administration of hyperbaric oxygen post injury, younger age at the time of injury and hyperbaric oxygen administration, military status, and increased number of hyperbaric oxygen administrations were characteristics associated with improved outcomes. There were no adverse events. Hyperbaric oxygen was found to be safe, inexpensive and worthy of clinical application in the 21st Century model of facile data collection provided by recent research regulatory shifts in medicine. The study was approved by the ethics review committee of the Western Institutional Review Board (WIRB® Protocol #20090761).

Multicentre pilot study evaluation of lung ultrasound for the management of paediatric pneumonia in low-resource settings: a study protocol

IntroductionPneumonia is the leading infectious cause of death among children under 5 years of age worldwide. However, pneumonia is challenging to diagnose. Lung ultrasound (LUS) is a promising diagnostic technology....

Methods for conducting a double-blind randomized controlled clinical trial of three days versus five days of amoxicillin dispersible tablets for chest indrawing childhood pneumonia among children two to 59\xa0months of age in Lilongwe, Malawi: a study protocol

BackgroundPneumonia is the leading infectious cause of death in children under 5 years of age around the globe. In addition to preventing pneumonia, there is a critical need to provide greater access to appropriate and effective treatment. Studies in Asia have evaluated the effectiveness of 3 days of oral amoxicillin for the treatment of fast-breathing pneumonia; however, further evidence is needed to determine if 3 days of oral amoxicillin is also effective for the treatment of chest indrawing pneumonia.MethodsThis is a double-blind, randomized, non-inferiority trial with the objective to assess the effectiveness of shorter duration amoxicillin dispersible tablet (DT) treatment of chest indrawing childhood pneumonia in a malaria-endemic region of Malawi. The primary objective of this study is to determine whether 3 days of treatment with oral amoxicillin DT in HIV-uninfected Malawian children two to 59 months of age with chest indrawing pneumonia is as effective as 5 days of treatment. The study will enroll 2000 children presenting to Kamuzu Central or Bwaila District Hospitals in Lilongwe, Malawi. Each child will be randomized to either 3 days of amoxicillin DT followed by 2 days of placebo DT or 5 days of amoxicillin DT. Children in the study will be hospitalized for 48 h after enrollment and will have scheduled study visits at Days 2, 4, 6 and 14. Treatment failure by Day 6 is the primary outcome. We hypothesize that the rates of treatment failure will be similar in both arms and that 3 days of treatment will be non-inferior to 5 days of amoxicillin DT for chest indrawing pneumonia using a relative non-inferiority margin of 1.5. This trial was approved by the Western Institutional Review Board and Malawi College of Medicine Research and Ethics Committee.DiscussionGiven the paucity of data from Africa, African-based research is necessary to establish appropriate duration of treatment with amoxicillin DT for chest indrawing childhood pneumonia in malaria-endemic settings in the region. An expanded evidence base will contribute to future iterations of World Health Organization Integrated Management of Childhood Illness guidelines.Trial registrationNCT02678195: Pre-results. Date registered February 9, 2016.

The XN-30 Haematology Analyser for Rapid Sensitive Detection of Malaria: A Diagnostic Accuracy Study

Background: Accurate and timely diagnosis of malaria is essential for disease management and surveillance. Microscopy and malaria rapid diagnostic tests (RDTs) are standard malaria diagnostics, but both methods have significant limitations. The novel automated haematology analyser XN-30 provides standard complete blood counts (CBC) as well as quantification of malaria parasitaemia at the price of an RDT. This study assessed the accuracy of XN-30 for malaria detection in a Controlled Human Malaria Infection (CHMI) study and subsequently in a phase-3 diagnostic accuracy study in Burkina Faso. Methods: Sixteen healthy malaria-naive CHMI participants were challenged according to standardized protocols by exposure to five laboratory reared Plasmodium falciparum-infected mosquitoes and sampled daily for XN-30, blood smear microscopy, RDT and qPCR analyses (NCT02836002). The blinded diagnostic accuracy study included 908 patients aged >3 months, presenting with acute febrile illness (NCT02669823). XN-30, microscopy and RDTs (HRP-2/pLDH) were performed on site, qPCR was done in retrospect. Microscopy was used as reference standard, results were corrected for qPCR confirmed submicroscopic cases. RDT results were compared to XN-30 for both microscopic and qPCR confirmed cases. Findings: All CHMI participants became parasitaemic by qPCR and XN-30 with a strong correlation for parasite density (R2=0·91). In the field study, the sensitivity and specificity of XN-30 compared to microscopy were 98.7% and 99.4% respectively (PPV 98·7%, NPV 99·4%, AUC=0·99). Three microscopy confirmed cases were not detected by XN-30. However, XN-30 detected 24 of 119 (20.2%) qPCR confirmed submicroscopic cases. The sensitivity and specificity of XN-30 to diagnose microscopic cases were higher than that of HRP-2 and pLDH RDTs. Interpretation: XN-30 is a novel rapid automated malaria diagnostic outperforming standard microscopy and RDT's at a similar price. Since it simultaneously provides haemocytometric data and allows high-throughput testing, XN-30 is an attractive diagnostic tool for malaria management and control. Funding Statement: The CHMI study was funded by PATH MVI. Sysmex Corporation provided the analyzer and reagents. The diagnostic accuracy study was funded by Sysmex Corporation. The funding sources were involved in the study design, but not in data collection, analysis and interpretation, or the preparation of the report. Declaration of Interests: AvV and QdM have a non-restricted research grant from SYSMEX, which funded the current study. None of the other authors had any conflict of interest. Ethics Approval Statement: The studies were performed in accordance with the declaration of Helsinki and GCLP guidelines. The CHMI study was approved by the central committee for research involving human subjects (CCMO) of the Netherlands (NL56659.091.16), and the Western Institutional Review Board (WIRB) in the USA. The diagnostic study was approved by the national ethical committee of Burkina Faso (ref 2015-01-006), the internal review board of IRSS (ref A03-2016/CEIRES) the ethical committee of the university hospital of Antwerp (ref 15/47/492) and the institutional review board of the Institute of Tropical Medicine Antwerp (ref 1029/15).

Tulsa 1000: a naturalistic study protocol for multilevel assessment and outcome prediction in a large psychiatric sample

IntroductionAlthough neuroscience has made tremendous progress towards understanding the basic neural circuitry underlying important processes such as attention, memory and emotion, little progress has been made in applying these insights...

Further Studies of Unsuspected Emphysema in Nonsmoking Patients With Asthma With Persistent Expiratory Airflow Obstruction

Previously, we and other investigators have described reversible loss of lung elastic recoil in patients with acute and persistent, moderate-to-severe, chronic, treated asthma who never smoked, and its adverse effect on maximal expiratory airflow. In four consecutive autopsies, we reported the pathophysiologic mechanism(s) has been unsuspected mild, diffuse, middle and upper lobe centrilobular emphysema. We performed prospective studies (5 to 22 years) in 25 patients (12 female) with chronic asthma, age 55 ± 15 years, who never smoked, with persistent moderate-to-severe expiratory obstruction. Studies included measuring blood eosinophils, IgE, total exhaled nitric oxide (NO), central airway NO flux, peripheral airway/alveolar NO concentration, impulse oscillometry, heliox curves, lung elastic recoil, and high-resolution thin-section (1mm) lung CT imaging at full inspiration with voxel quantification. In 25 patients with stable asthma with varying type 2 phenotype, after 270 μg of aerosolized albuterol sulfate had been administered with a metered dose inhaler with space chamber, FVC was 3.1 ± 1.0L (83%± 13%predicted) (mean ± SD), FEV1 was 1.8 ± 0.6L (59%± 11%), the FEV1/FVC ratio was 59%± 10%, and the ratio of single-breath diffusing capacity of the lung for carbon monoxide to alveolar volume was 4.8 ± 1.1mL/min/mmHg/L (120%± 26%). All 25 patients with asthma had loss of static lung elastic recoil pressure, which contributed equally to decreased intrinsic airway conductance in limiting expiratory airflow. Lung CT scanning detected none or mild emphysema. In all four autopsied asthmatic lungs previously reported and one unreported explanted lung, microscopy revealed unsuspected mild, diffuse centrilobular emphysema in the upper and middle lung fields, and asthma-related remodeling in airways. In eight cases, during asthma remission, there were increases in measured static lung elastic recoil pressure-calculated intrinsic airway conductance, and measured maximal expiratory airflow at effort-independent lung volumes. As documented now in five cases, unsuspected microscopic mild centrilobular emphysema is the sentinel cause of loss of lung elastic recoil. This contributes significantly to expiratory airflow obstruction in never-smoking patients with asthma, with normal diffusing capacity and near-normal lung CT scan results. Protocol No. 20070934 and Study No. 1090472, Western Institutional Review Board, Olympia, WA; ClinicalTrials.gov; No. NCT00576069; URL: www.clinicaltrials.gov.