Compensation in Neonatal Clinical Trials: A Perspective.

Well conducted clinical trials are the mainstay for generating evidence on preferred treatments. In order to adequately protect the interests of the trial participants, the Central Licensing Authority of India has formulated guidelines to determine the quantum of compensation in cases of regulatory clinical trial related injury or death. However, these guidelines do not address the nuances of trials recruiting children aged under 16 years, within which, neonates are the most vulnerable population. Thus, there is a need for addressing this lacuna in the current guidelines. This article examines the challenges in determining the quantum of compensation in neonatal clinical trials using the current formula, which is a corollary to the challenges faced by the authors in procuring clinical trial insurance for the Probiotic supplementation for Prevention of Neonatal Sepsis (ProSPoNS) trial. Further, it suggests a template for a differential formula using birthweight of infants, which is one of the many important factors impacting neonatal mortality.

Project EPIC (Empowering People to Independence in COPD): Study protocol for a hybrid effectiveness-implementation pilot randomized controlled trial of telephonic, geriatrics-palliative care nurse-coaching in older adults with COPD and their family caregivers.

BACKGROUND: EPIC (Empowering People to Independence in COPD) is a geriatric-palliative care telephonic, nurse coach intervention informed by Baltes' Theory of Successful Aging and adapted from the ENABLE (Educate, Nurture, Advise, Before Life Ends) intervention. EPIC, focused on improving independence, mobility, well-being, and COPD symptoms, has undergone formative and summative evaluation for adults with COPD. METHODS: The primary study aim is to assess the refined EPIC intervention's feasibility and acceptability via a pilot hybrid effectiveness-implementation randomized control trial in community-dwelling older adults with moderate to severe COPD and their family caregivers. The secondary aim is to explore the impact of EPIC on patient and caregiver outcomes. Older adults with COPD and their family caregivers (target N = 60 dyads) will be randomized to EPIC (intervention) or usual COPD care (control). EPIC includes six patient and four family caregiver weekly, telephone-based nurse coach sessions using a manualized curriculum (Charting Your Course), plus three monthly follow-up calls. Feasibility will be measured as completion of EPIC intervention and trial components (e.g., recruitment, retention, data collection). Acceptability will be evaluated using satisfaction surveys and post-study feedback interviews. A blinded data collector will assess exploratory outcomes (e.g., Life-Space mobility, quality of life, caregiver burden, emotional symptoms, loneliness, cognitive impairment, functional status, healthcare utilization) at baseline, 12, and 24 weeks. DISCUSSION: This intervention fills a gap in addressing the geriatrics and palliative care needs and equity for adults with COPD and their family caregivers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05040386.

Prevalence, regional patterns and socio-demographic factors associated with poly-tobacco use in India: A secondary data analysis.

BACKGROUND: Tobacco use is associated with early, intermediate and long-term complications throughout the life course. With an influx of newer products containing nicotine, poly-tobacco use is slowly emerging as a public health concern, that is defined as existing tobacco users currently using two or more tobacco or nicotine products. While many studies have investigated single use tobacco, there is a paucity of research on regional patterns and socio-demographic factors associated with poly-tobacco use in India. OBJECTIVES: To assess prevalence of poly-tobacco use and determine the socio-demographic factors associated with poly-tobacco use in India. METHODS: Data from the Global Adult Tobacco Survey 2 (GATS, 2016-17) was analysed, which included information on tobacco use among people aged >15 years. The pattern of current tobacco status was described using descriptive statistics. Multiple logistic regression models were estimated to determine factors associated with poly-tobacco use. RESULTS: The prevalence of poly-tobacco use in India was found to be 9.8%. Among the current tobacco users, the prevalence was 33%. Significant socio-demographic factors associated with poly-tobacco use included younger age, male gender, religion and backward caste. North-eastern region reported highest prevalence of poly-tobacco use in the country, followed by the central region. CONCLUSION: The number of poly-tobacco users in India is considerably high and a matter of concern, more so in north east and central regions of the country. There is a need to create awareness about dangerous effects of all types of tobacco products and strengthen implementation of tobacco control policies with special focus on regions with high burden.

Clinical decision support to improve CBC and differential ordering.

OBJECTIVES: Complete blood count and differential (CBC diff) is a common laboratory test that may be overused or misordered, particularly in an inpatient setting. We assessed the ability of a clinical decision support (CDS) alert to decrease unnecessary orders for CBC diff and analyzed its impact in the laboratory. METHODS: We designed 3 CDS alerts to provide guidance to providers ordering CBC diff on inpatients at frequencies of daily, greater than once daily, or as needed. RESULTS: The 3 alerts were highly effective in reducing orders for CBC diff at the frequencies targeted by the alert. Overall, test volume for CBC diff decreased by 32% (mean of 5257 tests per month) after implementation of the alerts, with a corresponding decrease of 22% in manual differentials performed (mean of 898 per month). Turnaround time for manual differentials decreased by a mean of 41.5 minutes, with a mean decrease of up to 90 minutes during peak morning hours. CONCLUSIONS: The 3 CDS alerts successfully decreased inpatient orders for CBC diff and improved the quality of patient care by decreasing turnaround time for manual differentials.

Molecular analysis of the extracellular microenvironment: from form to function.

The extracellular matrix (ECM) proteome represents an important component of the tissue microenvironment that controls chemical flux and induces cell signaling through encoded structure. The analysis of the ECM represents an analytical challenge through high levels of post-translational modifications, protease-resistant structures, and crosslinked, insoluble proteins. This review provides a comprehensive overview of the analytical challenges involved in addressing the complexities of spatially profiling the extracellular matrix proteome. A synopsis of the process of synthesizing the ECM structure, detailing inherent chemical complexity, is included to present the scope of the analytical challenge. Current chromatographic and spatial techniques addressing these challenges are detailed. Capabilities for multimodal multiplexing with cellular populations are discussed with a perspective on developing a holistic view of disease processes that includes both the cellular and extracellular microenvironment.

Chronic Abdominal Discomfort Syndrome (CADS): Defining and Discussing a Novel Diagnosis.

In this article, we propose a new diagnostic paradigm known as Chronic Abdominal Discomfort Syndrome (CADS). Patient's presentation centers around chronic abdominal pain not explained by acute pathology with or without accompanying dyspepsia, bloating, nausea and vomiting among other symptoms. The pathophysiology is noted to be neurogenic, possibly stemming from visceral sympathetic nerves or abdominal wall afferent nerves. Diagnosis is supported by signs or symptoms traversing clinical, diagnostic and functional criteria. Included is a tool which can assist clinicians in diagnosing patients with CADS per those domains. We hope to facilitate primary care physicians' and gastroenterologists' utilization of our criteria to provide guidance for selecting which patients may benefit from further interventions or evaluation by a pain physician. The pain physician may then offer interventions to provide the patient with relief.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine response in adults with predominantly antibody deficiency.

Background: Patients with predominantly antibody deficiency (PAD) have lower anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibody levels after initial 2-dose SARS-CoV-2 vaccination than healthy controls do; however, the anti-spike antibody responses and neutralization function in patients with PAD following subsequent immunizations remain understudied. Objective: We sought to characterize anti-spike antibody responses in adults with PAD over the course of 5 SARS-CoV-2 vaccine doses and identify diagnostic and immunophenotypic risk factors for low antibody response. Methods: We evaluated anti-spike antibody levels in 117 adult patients with PAD and 192 adult healthy controls following a maximum of 5 SARS-CoV-2 immunizations. We assessed neutralization of the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant and analyzed infection outcomes. Results: The patients with PAD had significantly lower mean anti-spike antibody levels after 3 SARS-CoV-2 vaccine doses than the healthy controls did (1,439.1 vs 21,890.4 U/mL [P < .0001]). Adults with secondary PAD, severe primary PAD, and high-risk immunophenotypes had lower mean anti-spike antibody levels following vaccine doses 2, 3, and/or 4 but not following vaccine dose 5. Compared with patients with mild and moderate PAD, patients with severe PAD had a higher rate of increase in anti-spike antibody levels over 5 immunizations. A strong positive correlation was observed between anti-spike antibody levels and neutralization of both the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant. Most infections were managed on an outpatient basis. Conclusions: In all of the patients with PAD, anti-spike antibody levels increased with successive SARS-CoV-2 immunizations and were correlated with neutralization of both the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant. Secondary PAD, severe primary PAD, and high-risk immunophenotypes were correlated with lower mean anti-spike antibody levels following vaccine doses 2 through 4. Patients with severe PAD had the highest rate of increase in anti-spike antibody levels over 5 immunizations. These data suggest a clinical benefit to sequential SARS-CoV-2 immunizations, particularly among high-risk patients with PAD.

The Impact of Intracranial Pressure Telesensors: An Observational Propensity-Matched Control Analysis of Service Demand and Costs.

BACKGROUND AND OBJECTIVES: Implantable telemetric intracranial pressure (ICP) sensors (telesensors) enable routine, noninvasive ICP feedback, aiding clinical decision-making and attribution of pressure-related symptoms in patients with cerebrospinal fluid shunt systems. Here, we aim to explore the impact of these devices on service demand and costs in patients with adult hydrocephalus. METHODS: We performed an observational propensity-matched control study, comparing patients who had an MScio/Sensor Reservoir (Christoph Miethke, GmbH & Co) against those with a nontelemetric reservoir inserted between March 2016 and March 2018. Patients were matched on demographics, diagnosis, shunt-type, and revision status. Service usage was recorded with frequencies of neurosurgical admissions, outpatient clinics, scans, and further surgical procedures in the 2 years before and after shunt insertion. RESULTS: In total, 136 patients, 73 telesensors, and 63 controls were included in this study (48 matched pairs). Telesensor use led to a significant decrease in neurosurgical inpatient admissions, radiographic encounters, and procedures including ICP monitoring. After multivariate adjustment, the mean cumulative saving after 2 years was £5236 ($6338) in telesensor patients (£5498 on matched pair analysis). On break-even analysis, cost-savings were likely to be achieved within 8 months of clinical use, postimplantation. Telesensor patients also experienced a significant reduction in imaging-associated radiation (4 mSv) over 2 years. CONCLUSION: The findings of this exploratory study reveal that telesensor implantation is associated with reduced service demand and provides net financial savings from an institutional perspective. Moreover, telesensor patients required fewer appointments, invasive procedures, and had less radiation exposure, indicating an improvement in both their experience and safety.

Improving risk communication: a proof-of-concept randomised control trial assessing the impact of visual aids for neurosurgical consent.

Introduction: Informed consent is a fundamental component in the work-up for surgical procedures. Statistical risk information pertaining to a procedure is by nature probabilistic and challenging to communicate, especially to those with poor numerical literacy. Visual aids and audio/video tools have previously been shown to improve patients' understanding of statistical information. In this study, we aimed to explore the impact of different methods of risk communication in healthy participants randomized to either undergo the consent process with visual aids or the standard consent process for lumbar puncture. Material and methods: Healthy individuals above 18 years old were eligible. The exclusion criteria were prior experience of the procedure or relevant medical knowledge, lack of capacity to consent, underlying cognitive impairment and hospitalised individuals. After randomisation, both groups received identical medical information about the procedure of a lumbar puncture in a hypothetical clinical scenario via different means of consent. The control group underwent the standard consent process in current clinical practice (Consent Form 1 without any illustrative examples), whereas the intervention group received additional anatomy diagrams, the Paling Palette and the Paling perspective scale. Anonymised questionnaires were received to evaluate their perception of the procedure and its associated risks. Results: Fifty-two individuals were eligible without statistically significant differences in age, sex, professional status and the familiarity of the procedure. Visual aids were noted to improve the confidence of participants to describe the risks by themselves (p = 0.009) and participants in the intervention group felt significantly less overwhelmed with medical information (p = 0.028). The enhanced consent process was found to be significantly more acceptable by participants (p = 0.03). There was a trend towards greater appropriateness (p = 0.06) and it appeared to have "good" usability (median SUS = 76.4), although this also did not reach statistical significance (p = 0.06). Conclusion: Visual aids could be an appropriate alternative method for medical consent without being inferior regarding the understanding of the procedure, its risks and its benefits. Future studies could possibly compare or incorporate multiple interventions to determine the most effective tools in a larger scale of population including patients as well as healthy individuals.

Aids to improve understanding of statistical risk in patients consenting for surgery and interventional procedures: A systematic review.

BACKGROUND: Informed consent is an essential process in clinical decision-making, through which healthcare providers educate patients about benefits, risks, and alternatives of a procedure. Statistical risk information is difficult to communicate and the effectiveness of aids aimed at supporting this type of communication is uncertain. This systematic review aims to study the impact of risk communication adjuncts on patients' understanding of statistical risk in surgery and interventional procedures. METHODS: A systematic search was performed across Medline, Embase, PsycINFO, Scopus, and Web of Science until July 2021 with a repeated search in September 2022. RCTs and observational studies examining risk communication tools (e.g., information leaflets and audio-video) in adult (age >16) patients undergoing a surgical or interventional procedure were included. Primary outcomes included the objective assessment of statistical risk recall. Secondary outcomes included patient attitudes with respect to statistical information. Due to the study heterogeneity, a narrative synthesis was performed. RESULTS: A total of 4348 articles were identified, and following abstract and full-text screening 14 articles, including 9 RCTs, were included. The total number of adult patients was 1513. The most common risk communication tool used was written information (n = 7). Most RCTs (7/9, 77.8%) showed statistically significant improvements in patient understanding of statistical risk in the intervention group. Quality assessment found some concerns with all RCTs. CONCLUSION: Risk communication tools appear to improve recall of statistical risk. Additional prospective trials comparing various aids simultaneously are warranted to determine the most effective method of improving understanding.

Differential Protease Specificity by Collagenase as a Novel Approach to Serum Proteomics That Includes Identification of Extracellular Matrix Proteins without Enrichment.

Circulating extracellular matrix (ECM) proteins are serological biomarkers of interest due to their association with pathologies involving disease processes such as fibrosis and cancers. In this study, we investigate the potential for serum biomarker research using differential protease specificity (DPS), leveraging alternate protease specificity as a targeting mechanism to selectively digest circulating ECM protein serum proteins. A proof-of-concept study is presented using serum from patients with cirrhotic liver or hepatocellular carcinoma. The approach uses collagenase DPS for digestion of deglycosylated serum and liquid-chromatography-trapped ion mobility-tandem mass spectrometry (LC-TIMS-MS/MS) to enhance the detection of ECM proteins in serum. It requires no sample enrichment and minimizes the albumin average precursor intensity readout to less than 1.2%. We further demonstrate the capabilities for using the method as a high-throughput matrix-assisted laser/desorption ionization mass spectrometry (MALDI-MS) assay coupled with reference library searching. A goal is to improve the depth and breadth of biofluid proteomics for noninvasive assays.

Symptomatology and Quality of Life of Older People With HIV and Comorbid Chronic Obstructive Pulmonary Diseases From an HIV Clinic in Birmingham, Alabama.

ABSTRACT: Psychological symptomatology and quality of life (QoL) have been studied in older people with HIV (PWH) and those with chronic obstructive pulmonary disease (COPD), respectively, but there is a dearth of studies in older PWH with COPD. Our study compared depressive symptoms, anxiety, and QoL between older PWH with and without COPD using data from an HIV clinic in Birmingham, Alabama, from January 2018 to February 2020. Data on depressive symptoms (Patient Health Questionnaire-9), anxiety (Patient Health Questionnaire-5 Anxiety), and QoL (EuroQoL-5 Dimension) were analyzed. Among 690 PWH aged 50 years or older, 102 individuals (14.8%) had COPD. Significant differences were found between the two groups in depressive symptoms and components of QoL (e.g., mobility, self-care, usual activities, and pain/discomfort), but not in anxiety and general health. Experiencing COPD may worsen depressive symptomatology and QoL in older PWH, highlighting the need for tailored health care and research for this population.

SpaceANOVA: Spatial Co-occurrence Analysis of Cell Types in Multiplex Imaging Data Using Point Process and Functional ANOVA.

Multiplex imaging platforms have enabled the identification of the spatial organization of different types of cells in complex tissue or the tumor microenvironment. Exploring the potential variations in the spatial co-occurrence or colocalization of different cell types across distinct tissue or disease classes can provide significant pathological insights, paving the way for intervention strategies. However, the existing methods in this context either rely on stringent statistical assumptions or suffer from a lack of generalizability. We present a highly powerful method to study differential spatial co-occurrence of cell types across multiple tissue or disease groups, based on the theories of the Poisson point process and functional analysis of variance. Notably, the method accommodates multiple images per subject and addresses the problem of missing tissue regions, commonly encountered due to data-collection complexities. We demonstrate the superior statistical power and robustness of the method in comparison with existing approaches through realistic simulation studies. Furthermore, we apply the method to three real data sets on different diseases collected using different imaging platforms. In particular, one of these data sets reveals novel insights into the spatial characteristics of various types of colorectal adenoma.

Spatial Omics Reveals that Cancer-Associated Glycan Changes Occur Early in Liver Disease Development in a Western Diet Mouse Model of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disease and comprises different stages of liver damage; it is significantly associated with obese and overweight patients. Untreated MASLD can progress to life-threatening end-stage conditions, such as cirrhosis and liver cancer. N-Linked glycosylation is one of the most common post-translational modifications in the cell surface and secreted proteins. N-Linked glycan alterations have been established to be signatures of liver diseases. However, the N-linked glycan changes during the progression of MASLD to liver cancer are still unknown. Here, we induced different stages of MASLD in mice and liver-cancer-related phenotypes and elucidated the N-glycome profile during the progression of MASLD by quantitative and qualitative profiling in situ using matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS). Importantly, we identified specific N-glycan structures including fucosylated and highly branched N-linked glycans at very early stages of liver injury (steatosis), which in humans are associated with cancer development, establishing the importance of these modifications with disease progression. Finally, we report that N-linked glycan alterations can be observed in our models by MALDI-IMS before liver injury is identified by histological analysis. Overall, we propose these findings as promising biomarkers for the early diagnosis of liver injury in MASLD.

Post Hoc Analysis of Lung Function Improvement and Patient-Reported Outcomes With Revefenacin in Adults With Moderate-to-Very Severe COPD and Comorbid Anxiety or Depression.

Background: Revefenacin, a once-daily, nebulized, long-acting muscarinic antagonist approved in the United States for the maintenance of chronic obstructive pulmonary disease (COPD), significantly improves lung function and quality of life versus placebo in patients with moderate-to-very severe COPD. Comorbid anxiety and/or depression may alter patients' symptom perception and response to bronchodilators. The impact of revefenacin in patients with COPD with comorbid anxiety and/or depression has not been previously investigated. Methods: This post hoc subgroup analysis examined data from two 12-week, randomized, phase 3 trials in patients with moderate-to-very severe COPD with the following self-reported subgroups: anxiety only (A), depression only (D), anxiety and depression (+A/+D), and neither anxiety nor depression (-A/-D). We assessed change from baseline in trough forced expiratory volume in 1 second (FEV1) at Day 85 and health status by the St George's Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT). Results: Of 812 patients, 90 (11%), 110 (14%), 141 (17%), and 471 (58%) had A, D, +A/+D, and -A/-D respectively. In revefenacin versus placebo, trough FEV1 significantly improved from baseline at Day 85 across all subgroups as well as the SGRQ and CAT scores in patients with A, +A/+D, and -A/-D. Revefenacin was well tolerated regardless of A/D status, with a minimal incidence of treatment-emergent antimuscarinic adverse events across subgroups. Conclusion: In this analysis, revefenacin versus placebo significantly improved health outcomes in patients with moderate-to-very severe COPD with A, +A/+D, and -A/-D, but not in patients with D. The safety profile of revefenacin was not affected by comorbid anxiety/depression status.