Clinical Research Protocols Research Articles

Tips from an expert panel on the development of a clinical research protocol

A research protocol is a document that outlines the proposed research idea and is submitted to funding agencies, institutions, or journals for approval. Writing a research protocol represents a challenge, particularly for early-career researchers. In this guide, we aim to provide detailed guidance with the key components and offer practical tips for crafting a research protocol in line with the various study designs. Specifically, the structure of a research protocol should contain the following items: (1) a title that is specific, catchy, and impressive within the word limitation; (2) an abstract that briefs the critical points of the study; (3) an introduction highlighting the study context from broad to narrow and defining the knowledge gap; (4) a justification underlining the significance of the proposed study; (5) Specific, Measurable, Attainable, Relevant, and Time-bound (SMART) objective(s) and aim(s); (6) a methodology covering seven sub-items, including [i] study design and settings, [ii] study subjects, [iii] sample size calculation and sampling, [iv] participants recruitment and follow-up, [v] questionnaire development, [vi] potential variables and outcomes, and [vii] data analysis plan; (7) dissemination of the results; (8) ethics and conflict of interests; (9) budgets analysis/ funding disclosure; and (10) references. This guide will give an overview of these steps and provide clear and concise tips on how to successfully draft a scientific protocol. With careful planning and appropriate guidance, it is possible to develop a well-structured and compelling protocol to obtain approval for the conduction of the study or funding from agencies, institutions, or organizations.

GMP-Compliant Automated Radiolabeling and Quality Controls of [68Ga]Ga-FAPI-46 for Fibroblast Activation Protein-Targeted PET Imaging in Clinical Settings.

In nuclear medicine, molecular imaging of the tumor microenvironment using radiopharmaceuticals (RPs) targeting cancer-associated fibroblasts is gaining significant interest. Among these RPs, [68Ga]Ga-FAPI-46 for positron emission tomography (PET) imaging is frequently used in clinical research protocols. To ensure that the production of this RP complies with good manufacturing practices, process automation is widely adopted. In this context, an automated method for preparing [68Ga]Ga-FAPI-46 was designed using a GAIA® synthesizer. Additionally, a HPLC method was developed and validated to determine the radiochemical purity (RCP) of [68Ga]Ga-FAPI-46 and ensure product quality. The validated HPLC method showed excellent repeatability, with coefficients of variation (%CV) for RCP and retention time (tR) below 0.03 and 0.16%, respectively, across 10 measurements. The radiochemical identification of [68Ga]Ga-FAPI-46 showed comparable tr values to [natGa]Ga-FAPI-46 (6.65 and 6.59 min, respectively). The limits of detection (LOD) and quantification (LOQ) were 79 and 42 kBq/mL, respectively, with a linear detector response between 62.9 and 0.08 MBq/mL (R2 = 0.9999). The method proved robust, tolerating minor variations in mobile phase flow rate and composition. This validated radio-HPLC method can be used routinely for the quality control of [68Ga]Ga-FAPI-46. Finally, three RP validation batches were produced using the automated method described and subjected to multiple quality controls. All three synthesis products met the expected specifications, notably regarding appearance, chemical and isotope identification, pH, sterility, stability, and radionuclidic and radiochemical purity.

Influence of Bladder Filling on Parameters of Body Composition by Bioimpedance Electrical Analysis: Observational Study.

Bioelectrical impedance analysis (BIA) is a widely used method for estimating body composition, and its accuracy may be influenced by various factors, including bladder filling. This study aims to investigate the impact of bladder filling on the accuracy of BIA measurements. An experimental crossover study was conducted with sedentary young adults. The influence of bladder filling on total body water (TBW), fat mass (FM), fat-free mass (FFM), and basal metabolic rate (BMR) was assessed. Participant in underwear followed an overnight fast. They were instructed to abstain from vigorous physical activity and alcohol for at least 24 h prior to the session. The results obtained from single-frequency and multi-frequency BIA devices were compared. The findings suggest that bladder filling does not affect measured impedance; however, changes in weight following bladder voiding influenced derived BIA results. Specifically, TBW, FM, and BMR values significantly reduced after voiding (p < 0.05). Furthermore, the study found poor agreement between single-frequency and multi-frequency BIA devices, indicating that they are not interchangeable. Bladder filling does affect BIA measurements, not clinically meaningful. Further research is needed to explore the implications of these findings for clinical practice and research protocols.

Achieving Inter-Rater Agreement and Inter-Rater Reliability to Assess Fidelity of an Occupation-Based Coaching (OBC) Clinical Trial Intervention

Introduction: Establishing inter-rater agreement and reliability ascertains that multiple raters consistently evaluate observed interventions to ensure that clinical research protocols are delivered as intended by the trial protocol. Purpose: Using the Guidelines for Reporting Reliability and Agreement Studies, we (a) exemplified the steps to establish inter-rater reliability and inter-rater agreement on the occupation-based coaching Video Evaluation Tool and (b) evaluated best practices that promoted high inter-rater reliability and inter-rater agreement between blinded raters prior to starting a pilot randomized controlled trial. The randomized controlled trial examined the preliminary effectiveness of occupation-based coaching via telehealth for rural families with children living with type 1 diabetes to improve family quality of life, participation, self-efficacy, and child health outcomes. Method: We created a library of 13 occupation-based coaching videos portraying a range of evaluations, scores, and ratings. The inter-rater agreement and reliability on the occupation-based coaching Video Evaluation Tool were established through the iterations of (a) blinded rater training, (b) data collection using the tool, and (c) statistical analysis using Cohen’s kappa and Cronbach’s alpha. Findings: Occurrence and Non-Occurrence Checklist (κ = 0.881, p &lt; 0.001); “Caregiver Talk” and “Interventionist Talk Analysis” (ICC = 0.991–0.999, p &lt; 0.001); Evidence of Independent Capacity Rating (ICC = 0.867 p = 0.006). Conclusion: Strong inter-rater reliability and inter-rater agreement was established by engaging two blinded raters through multifaceted training, integrating real-life clients and contexts into the instrumentation and training, and precisely defined rubric criteria. By employing such practices, high inter-rater reliability and agreement can be achieved in clinical research involving interventions and instruments that are highly subjective and individualized. To ascertain greater scientific confidence in the intervention effect, developing a multidomain fidelity framework and establishing high inter-rater agreement and reliability in the instruments a priori to implementation of clinical trials are necessary.

Blue-button: A tool for institution-agnostic, EHR-integrated regional clinical trial matching.

65 Background: Research indicates that most people with cancer are willing to enroll in clinical trials when offered the chance, but only 7% actually participate in cancer treatment trials. Barriers to screening and enrollment include time and effort for providers to screen patients for trials, and lack of awareness of available regional trials. Stakeholders recommended creation of free, automated screening tools and processes integrated into provider workflows, directly interfacing with site electronic health records (EHRs), that would search for regional trial eligibility. The need for such tools was independently identified in a large national survey of oncology providers. Methods: The Blue-button tool was developed to automatically identify relevant, regional clinical trials. A collaboration between ACS CAN and MITRE, a not-for-profit organization working in the public interest, created the tool’s functionality. Clinical workflow and research protocol were developed in collaboration with University of Texas Southwestern Simmons Comprehensive Cancer Center. This SMART-on-FHIR application works within existing EHR systems by automatically extracting and sending limited, deidentified patient data elements to third-party trial matching services via the FHIR mCODE standard, a core set of non-proprietary, open-source structured data elements that establishes minimum standards for the structure and content of oncology data in health records. Potential trial matches within a specified radius of the practice are returned in a standard format using the FHIR Research Study resource. Results: Blue-button extracts limited patient data from EHR and provides it in an interface allowing users to update data before sending to trial matching services. Only non-identifiable information is sent to the external clinical trial matching services, which then return prescreen trial matches for manual review to confirm patient eligibility. Thus, with a few clicks in a medical record, the tool quickly identifies comprehensive trial availability within a specified distance of the patient’s location. When used by providers, Blue-button reduces the manual burden that often prevents consideration of clinical trials and identifies regional opportunities beyond the treating institution. Conclusions: Successful feasibility testing demonstrated the effectiveness of automated regional trial screening as a model. We have launched a clinical trial at two sites to assess the effectiveness of the Blue-button tool with patients in healthcare settings. We expect patient enrollment to continue through part or all of 2025. This trial of the Blue-button tool will provide additional information on provider accessibility and uptake and will demonstrate whether EHR-integrated regional trial screening leads to increased opportunities and enrollment in cancer clinical trials. Clinical trial information: NCT05885880 .

Neurologic Care for Transgender and Gender-Diverse People: A Review of Current Evidence and Clinical Implications.

To summarize the literature on neurologic care for transgender and gender-diverse (TGD) people and provide implications for clinical practice. There are limited data on the frequency and management of neurologic conditions among TGD people. TGD people have a higher prevalence of various neurologic conditions compared with cisgender or general population cohorts, including migraine, subjective cognitive decline, sleep disturbances, functional disorders, and cerebrovascular disease. Gender-affirming hormone therapy interacts with commonly prescribed neurologic medications and increases stroke risk among transfeminine people. Sex hormones and sex chromosomes may play a role in neurodegeneration and disability progression in neuroimmunologic diseases. Clitoral reduction surgeries on intersex children can cause neurologic disability and sexual dysfunction in adulthood. Socioeconomic disparities among TGD people contribute to health care barriers. Neurologists should consider the unique experiences and health care needs of TGD people in their clinical practice and research protocols.

Does exposure matter? Association between exposure to clinical trial conduct during training and intent to participate in clinical trials post-training among oncology fellows: An ASCO State of Cancer Care in America study.

69 Background: Clinical trials are part of standard cancer care. Yet, a quarter of oncology fellows in a 2023 survey reported feeling underprepared to conduct research after training and nearly half did not identify research as important to their practice. In a 2024 survey, we explore the impact of exposure to research activities in fellowship on intentions to conduct research post-training. Methods: Fellows who took the 2024 ASCO Medical Oncology In-Training Exam (ITE) were invited to an optional IRB-exempted post-exam survey to measure (1) research exposure during training and (2) anticipated research participation once in practice. Responses of moderate and great amount are combined as frequent (vs. never, rarely, occasionally as not frequent). Rates of frequent research engagement in future practice are compared by frequent/not frequent research exposure during fellowship, expected practice setting, and program year using chi-squared analysis. Results: Of the 1884 US medical oncology fellows taking the ITE, 1491 (79%) participated in this study, 33% 1st year, 37% 2nd year, 39% 3rd year. 891 (60%) expect their first post-training role to be in academics, 527 (35%) in a non-academic practice, and 67 (5%) in other settings. Anticipated engagement in enrollment and management of participants on clinical trials post-training was associated with exposure to those activities in fellowship and with expected practice setting. Overall, 827 (63%) anticipate frequent participation in research once in practice. 531 (76%) of 701 with frequent exposure in training compared to 296 (37%) of 790 with not frequent exposure anticipate frequent participation in practice (p&lt;0.001). 610 (78%) of fellows expecting to practice in an academic setting vs. 192 (40%) in a non-academic setting anticipate frequent future participation in practice (p&lt;0.001). For research leadership activities (writing clinical research protocols, applying for clinical research grants, serving as principal investigator), 622 (49%) anticipate frequent participation once in practice. 390 (79%) of 519 with frequent vs. 229 (29%) of 855 with not frequent exposure to leadership activities during fellowship anticipate frequent future engagement (p&lt;0.001). 523 (67%) of fellows expecting to practice in an academic setting vs. 76 (16%) in a non-academic setting anticipate frequent leadership engagement after training (p&lt;0.001). Anticipated future participation did not vary by program year for either type of research activity. Conclusions: Findings show an urgent need to increase exposure to research during fellowship training to improve participation in clinical trials by practicing oncologists. This is a critical component of improving patient access to research.

Development of hepatic fibrosis in common variable immunodeficiency-related porto-sinusoidal vascular disorder.

Liver involvement is an increasingly recognised complication of common variable immunodeficiency (CVID). Nodular regenerative hyperplasia (NRH), a subgroup of porto-sinusoidal vascular disorder, and manifestations of portal hypertension (PH) unrelated to cirrhosis are the most common findings. Nonetheless, the evolution of liver disease over time remains unknown. Retrospective review of patients followed at the National Institutes of Health with CVID-related liver disease and liver biopsy from 1990 to 2020. Clinical, imaging and histological follow-up were recorded as part of clinical research protocols. Forty patients were included, with a median age of 37.5 years at initial biopsy, 73% presenting with clear evidence of NRH, and a median fibrosis stage of 1. At biopsy, median platelet count was 100 × 109/L, spleen size 19.5 cm, hepatic venous pressure gradient 9.5 mmHg and 37.5% of patients had signs of PH. Cumulative incidence of PH was 65% at 5 years. In a subgroup of 16 patients, a follow-up liver biopsy, performed at a median time of 3 years after the index biopsy, revealed an increase in fibrosis by ≥2 stages in 31% of cases and an increase to an overall stage of 2.2 (p = 0.001). No clinical or histological factors were associated with progression of fibrosis. In this CVID cohort, NRH is the most common initial histological finding; however, unexpectedly fibrosis progresses over time in a subgroup of patients. A better understanding of the underlying causal process of liver disease CVID might lead to improved outcomes.

Leptomeningeal metastases from solid tumors: A Society for Neuro-Oncology and American Society of Clinical Oncology consensus review on clinical management and future directions.

Leptomeningeal metastases (LM) are increasingly becoming recognized as a treatable, yet generally incurable, complication of advanced cancer. As modern cancer therapeutics have prolonged the lives of patients with metastatic cancer, specifically in patients with parenchymal brain metastases, treatment options, and clinical research protocols for patients with LM from solid tumors have similarly evolved to improve survival within specific populations. Recent expansions in clinical investigation, early diagnosis, and drug development have given rise to new unanswered questions. These include leptomeningeal metastasis biology and preferred animal modeling, epidemiology in the modern cancer population, ensuring validation and accessibility of newer leptomeningeal metastasis diagnostics, best clinical practices with multimodality treatment options, clinical trial design and standardization of response assessments, and avenues worthy of further research. An international group of multi-disciplinary experts in the research and management of LM, supported by the Society for Neuro-Oncology and American Society of Clinical Oncology, were assembled to reach a consensus opinion on these pressing topics and provide a roadmap for future directions. Our hope is that these recommendations will accelerate collaboration and progress in the field of LM and serve as a platform for further discussion and patient advocacy.

β3-adREnoceptor Analysis in CORD Blood of Neonates (β3 RECORD): Study Protocol of a Pilot Clinical Investigation.

Background and Objective: The embryo and the fetus develop in a physiologically hypoxic environment, where vascularization is sustained by HIF-1, VEGF, and the β-adrenergic system. In animals, β3-adrenoceptors (β3-ARs), up-regulated by hypoxia, favor global fetal wellness to such an extent that most diseases related to prematurity are hypothesized to be induced or aggravated by a precocious β3-AR down-regulation, due to premature exposure to a relatively hyperoxic environment. In animals, β3-AR pharmacological agonism is currently investigated as a possible new therapeutic opportunity to counteract oxygen-induced damages. Our goal is to translate the knowledge acquired in animals to humans. Recently, we have demonstrated that fetuses become progressively more hypoxemic from mid-gestation to near-term, but starting from the 33rd-34th week, oxygenation progressively increases until birth. The present paper aims to describe a clinical research protocol, evaluating whether the expression level of HIF-1, β3-ARs, and VEGF is modulated by oxygen during intrauterine and postnatal life, in a similar way to animals. Materials and Methods: In a prospective, non-profit, single-center observational study we will enroll 100 preterm (group A) and 100 full-term newborns (group B). We will collect cord blood samples (T0) and measure the RNA expression level of HIF-1, β3-ARs, and VEGF by digital PCR. In preterms, we will also measure gene expression at 48-72h (T1), 14 days (T2), and 30 days (T3) of life and at 40 ± 3 weeks of post-menstrual age (T4), regardless of the day of life. We will compare group A (T0) vs. group B (T0) and identify any correlations between the values obtained from serial samples in group A and the clinical data of the patients. Our protocol has been approved by the Pediatric Ethical Committee for Clinical Research of the Tuscany region (number 291/2022). Expected Results: The observation that in infants, the HIF-1/β3-ARs/VEGF axis shows similar modulation to that of animals could suggest that β3-ARs also promote fetal well-being in humans.

Neuropsychological Assessment for Early Detection and Diagnosis of Dementia: Current Knowledge and New Insights.

Dementia remains an underdiagnosed syndrome, and there is a need to improve the early detection of cognitive decline. This narrative review examines the role of neuropsychological assessment in the characterization of cognitive changes associated with dementia syndrome at different states. The first section describes the early indicators of cognitive decline and the major barriers to their identification. Further, the optimal cognitive screening conditions and the most widely accepted tests are described. The second section analyzes the main differences in cognitive performance between Alzheimer's disease and other subtypes of dementia. Finally, the current challenges of neuropsychological assessment in aging/dementia and future approaches are discussed. Essentially, we find that current research is beginning to uncover early cognitive changes that precede dementia, while continuing to improve and refine the differential diagnosis of neurodegenerative disorders that cause dementia. However, neuropsychology faces several barriers, including the cultural diversity of the populations, a limited implementation in public health systems, and the adaptation to technological advances. Nowadays, neuropsychological assessment plays a fundamental role in characterizing cognitive decline in the different stages of dementia, but more efforts are needed to develop harmonized procedures that facilitate its use in different clinical contexts and research protocols.

Understanding tightened muscle in knee osteoarthritis and the impacts of Fu's subcutaneous needling: A pilot trial with shear-wave elastography and near-infrared spectroscopy.

Given the scarce reports on the interplay between Fu's subcutaneous needling (FSN), tightened muscle, and therapeutic effects, we developed a clinical research protocol to synchronously collect data on clinical efficacy and muscle characteristics in patients with knee osteoarthritis, exploring the mechanism of FSN action. The primary aim was to assess the feasibility and safety of this protocol, guiding future trials and their sample size calculations. In this prospective, single-blind, self-controlled study, 19 patients with early to mid-stage unilateral knee osteoarthritis underwent FSN therapy on both knees over 1 week (4 sessions, every other day). We measured local elastic modulus, muscle thickness, blood flow volume, and oxygen consumption rate of bilateral vastus lateralis muscles using shear-wave elastography and near-infrared spectroscopy (NIRS) before and after the first and fourth treatments. Additionally, real-time NIRS indicators (oxygenated hemoglobin [O2Hb], deoxyhemoglobin [HHb], total hemoglobin [THb], and tissue saturation index [TSI]) were recorded during these treatments. Pain intensity (visual analogue scale [VAS]), functional status (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), and active range of motion were evaluated before these treatments. All 19 participants completed the trial without serious adverse events. After 3 FSN treatments, significant changes were observed in VAS and WOMAC scores (VAS: P < .001; WOMAC: P < .001), and knee flexion (P < .001) and external rotation (P = .02), except for internal rotation. No meaningful significant differences were observed in muscle characteristics at baseline or between pre- and post-treatment periods. NIRS results during treatments indicated significant increases in local O2Hb and THb post-FSN therapy (First treatment: O2Hb: P = .005; THb: P = .006. Fourth treatment: O2Hb: P = .002; THb: P = .004); however, no significant increases were observed for HHb (First treatment: P = .06; Fourth treatment: P = .28). No linear correlation was found between therapeutic effects and changes in tightened muscle indices. FSN reduces pain and improves joint function in knee osteoarthritis, while also enhancing blood flow and oxygenation in the vastus lateralis muscle of the affected side. Further revisions of this protocol are warranted based on our insights.

Isolated REM Sleep without Atonia Is Not Equivalent to REM Sleep Behavior Disorder in Early-Stage Parkinson's Disease.

In early-stage Parkinson's disease (PD), rapid eye movement (REM) sleep behavior disorder (RBD) predicts poor cognitive and motor outcome. However, the baseline significance and disease evolution associated with isolated REM sleep without atonia (iRWA, ie, enhanced muscle tone during 8.7% of REM sleep, but no violent behavior) are not well understood. The objective is to determine whether iRWA was a mild form of RBD and progressed similarly over time. Participants with early PD (<4 years from medical diagnosis) were included from 2014 to 2021 in a longitudinal study. They underwent interviews and examinations in the motor, cognitive, autonomous, psychiatric, sensory, and sleep domains every year for 4 years along with a video polysomnography and magnetic resonance imaging examination of the locus coeruleus/subcoeruleus complex (LC/LsC) at baseline. The clinical characteristics were compared between groups with normal REM sleep, with iRWA and with RBD, at baseline and for 4 years. Among 159 PD participants, 25% had RBD, 25% had iRWA, and 50% had normal REM sleep. At baseline, the non-motor symptoms were less prevalent and the LC/LsC signal intensity was more intense in participants with iRWA than with RBD. Over 4 years, participants with normal REM sleep and with iRWA had a similar cognitive and motor trajectory, whereas participants with RBD had greater cognitive and motor decline. We demonstrated that iRWA is frequent in early PD, but is not a milder form of RBD. Both groups have distinct baseline characteristics and clinical trajectories. They should be distinguished in clinical routine and research protocols. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Enhancing Dissemination and Understanding in Clinical Research Protocols: Optimizing Visual Communication in a Phantom Limb Pain Clinical Trial.

Enhancing Dissemination and Understanding in Clinical Research Protocols: Optimizing Visual Communication in a Phantom Limb Pain Clinical Trial.

Cerebral oxygen metabolism and brain electrical activity of healthy full-term neonates in high-altitude areas: a multicenter clinical research protocol

Further evidence is needed to explore the impact of high-altitude environments on the neurologic function of neonates. Non-invasive techniques such as cerebral near-infrared spectroscopy and amplitude-integrated electroencephalography can provide data on cerebral oxygenation and brain electrical activity. This study will conduct multiple cerebral near-infrared spectroscopy and amplitude-integrated electroencephalography monitoring sessions at various time points within the first 3 days postpartum for healthy full-term neonates at different altitudes. The obtained data on cerebral oxygenation and brain electrical activity will be compared between different altitudes, and corresponding reference ranges will be established. The study involves 6 participating centers in the Chinese High Altitude Neonatal Medicine Alliance, with altitude gradients divided into 4 categories: 800 m, 1 900 m, 2 400 m, and 3 500 m, with an anticipated sample size of 170 neonates per altitude gradient. This multicenter prospective cohort study aims to provide evidence supporting the impact of high-altitude environments on early brain function and metabolism in neonates.

Surgical treatment of degenerative stenotic lesions of the lumbar spine. Own experience of using minimally invasive techniques

Lumbar spinal stenosis is a multifactorial progressive condition mainly affecting older individuals, characterized by narrowing of the natural anatomical pathways passage of nerve structures, resulting in typical clinical symptoms. The disease affects about 103 million people in worldwide with an incidence of absolute lumbar spinal stenosis 19.4% among individuals aged 60-69 years. In the United States, about 600,000 surgical interventions for lumbar spinal stenosis are performed annually. This disease is one of the most common causes of lumbar pain and lower limbs in the elderly individuals, accompanied by claudication and ultimately leading to disability. The main cause of clinical symptoms of the lumbar spinal stenosis is the discrepancy between the sizes of nerve structures and their osteofibrous sheaths, resulting from gradually developing degenerative-dystrophic changes. Objective: To compare the outcomes of surgical treatment of patients with degenerative stenotic lesions of the lumbar spine using open and minimally invasive methods. Materials and methods. The results of surgical treatment of 97 patients with lumbar spinal stenosis aged from 28 to 81 years on the basis of the Department of Minimally Invasive and Laser Spinal Neurosurgery of the State Institution " A.P. Romodanov Neurosurgery Institute, Ukraine", " Neurosurgical Department №20 of Vinnytsia Regional Clinical Psychoneurological Hospital named after Acad. O.I. Yushchenko" of Vinnytsia Regional Council and "Spinex" Medical Center following all clinical research protocols. Patients were divided into four groups depending on the surgical intervention method. Results. The development of concepts regarding the mechanisms of occurrence and treatment methods of lumbar spinal stenosis are highlighted, as well as personal experience of using minimally invasive treatment techniques for this pathology in combination with the use of the ERAS (Enhanced Recovery After Surgery) protocol of perioperative patient management. It was found that the duration of hospital stay for patients with lumbar spinal stenosis statistically significantly desreased when using minimally invasive decompression (p≤0.05) and the ERAS rehabilitation protocol (p≤0.05). When comparing the average length of stay in the hospital of patients of the four groups, a statistically significant (p≤0.05) shorter length of stay in the hospital was observed for patients who underwent minimally invasive decompression using the ERAS rehabilitation protocol. The greatest reduction in pain intensity (according to the Numeric Pain Scale (NPS)) at 6 months post- intervention and rehabilitation was also noted in patients of this group. Conclusions. The use of minimally invasive techniques, the correct choice of surgical procedure volume (interbody fusion is desirable in surgery for degenerative spinal diseases) combined with Enhanced Recovery after Surgery protocol (ERAS) significantly improves postoperative well-being of patients, accelerates patient mobilization, and reduces the length of stay in the hospital.

Blood Pressure Variability in Acute Stroke: A Narrative Review.

The management of blood pressure variability (BPV) in acute stroke presents a complex challenge with profound implications for patient outcomes. This narrative review examines the role of BPV across various stages of acute stroke care, highlighting its impact on treatment strategies and prognostic considerations. In the prehospital setting, while guidelines lack specific recommendations for BP management, emerging evidence suggests a potential link between BPV and outcomes. Among ischaemic stroke patients who are ineligible for reperfusion therapies, BPV independently influences functional outcomes, emphasising the need for individualised approaches to BP control. During intravenous thrombolysis and endovascular therapy, the intricate interplay between BP levels, recanalisation status, and BPV is evident. Striking a balance between aggressive BP lowering and avoiding hypoperfusion-related complications is essential. Intracerebral haemorrhage management is further complicated by BPV, which emerges as a predictor of mortality and disability, necessitating nuanced BP management strategies. Finally, among patients with acute subarachnoid haemorrhage, increased BPV may be correlated with a rebleeding risk and worse outcomes, emphasizing the need for BPV monitoring in this population. Integration of BPV assessment into clinical practice and research protocols is crucial for refining treatment strategies that are tailored to individual patient needs. Future studies should explore novel interventions targeting BPV modulation to optimise stroke care outcomes.

Rethinking the clinical research protocol: Lessons learned from the COVID-19 pandemic and recommendations for reducing noncompliance.

Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, 103.4 million cases and 1.1 million deaths have occurred nationally as of November 2023. Despite the benefit of mitigating measures, the pandemic's effect on participant safety is rarely documented. This study assessed noncompliance occurring from July 2019 to August 2021 that were stratified by the date of noncompliance (before or after restrictions). Events were described by size, site, noncompliance type, primary category, subcategory, and cause. In addition, noncompliance associated with COVID-19 was analyzed to determine characteristics. In total, 323 noncompliance events occurred across 21,146 participants at risk in 35 protocols. The overall rate of noncompliance increased from 0.008 events per participant to 0.022 events per participant after the COVID-19 restrictions (p < 0.001). For onsite protocols, the median within protocol change in rates was 0.001 (interquartile range = 0.141) after the onset of COVID-19 restrictions (p = 0.54). For large-sized protocols (n ≥ 100), the median within protocol change in rates was also 0.001 (interquartile range = 0.017) after COVID-19 restrictions (p = 0.15). For events related to COVID-19 restrictions, 160/162 (99%) were minor deviations, 161/162 (99%) were procedural noncompliance, and 124/162 (77%) were an incomplete study visit. These noncompliance events have implications for clinical trial methodology because nonadherence to trial design can lead to participant safety concerns and loss of trial data validity. Protocols should be written to better facilitate the capture of all safety and efficacy data. This recommendation should be considered when changes occur to the protocol environment that are outside of the study team's control.

Randomized Controlled Trial of the Effect of an Exercise Rehabilitation Program on Symptom Burden in Maintenance Hemodialysis: A Clinical Research Protocol.

People receiving hemodialysis experience high symptom burden that contributes to low functional status and poor health-related quality of life. Management of symptoms is a priority for individuals receiving hemodialysis but limited effective treatments exist. There is emerging evidence that exercise programming can improve several common dialysis-related symptoms. The primary aim of this study is to evaluate the effect of an exercise rehabilitation program on symptom burden in individuals receiving maintenance hemodialysis. Multicenter, randomized controlled, 1:1 parallel, open label, prospective blinded end point trial. Three facility-based hemodialysis units in Winnipeg, Manitoba, Canada. Adults aged 18 years or older with end-stage kidney disease receiving facility-based maintenance hemodialysis for more than 3 months, with at least 1 dialysis-related symptom as indicated by the Dialysis Symptom Index (DSI) severity score >0 (n = 150). Supervised 26-week exercise rehabilitation program and 60 minutes of cycling during hemodialysis thrice weekly. Exercise intensity and duration were supervised and individualized by the kinesiologist as per participant baseline physical function with gradual progression over the course of the intervention. Usual hemodialysis care (no exercise program). Our primary outcome is change in symptom burden at 12 weeks as measured by the DSI severity score. Secondary outcomes include change in modified DSI severity score (includes 10 symptoms most plausible to improve with exercise), change in DSI severity score at 26 and 52 weeks; time to recover post-hemodialysis; health-related quality of life measured using EuroQol (EQ)-5D-5L; physical activity behavior measured by self-report (Godin-Shepherd questionnaire) and triaxial accelerometry; exercise capacity (shuttle walk test); frailty (Fried); self-efficacy for exercise; and 1-year hospitalization and mortality. Change in primary outcome will be compared between groups by independent 2-tailed t test or Mann-Whitney U test depending on data distribution and using generalized linear mixed models, with study time point as a random effect and adjusted for baseline DSI score. Similarly, change in secondary outcomes will be compared between groups over time using appropriate parametric and nonparametric statistical tests depending on data type and distribution. The COVID-19 pandemic restrictions on clinical research at our institution delayed completion of target recruitment and prevented collection of accelerometry and physical function outcome data for 15 months until restrictions were lifted. The application of an exercise rehabilitation program to improve symptom burden in individuals on hemodialysis may ameliorate common symptoms observed in individuals on hemodialysis and result in improved quality of life and reduced disability and morbidity over the long term. Importantly, this pragmatic study, with a standardized exercise intervention that is adaptable to baseline physical function, addresses an important gap in both clinical care of hemodialysis patients and our current knowledge.

High-Throughput Computing to Automate Population-Based Studies to Detect the 30-Day Risk of Adverse Outcomes After New Outpatient Medication Use in Older Adults with Chronic Kidney Disease: A Clinical Research Protocol.

Safety issues are detected in about one third of prescription drugs in the years following regulatory agency approval. Older adults, especially those with chronic kidney disease, are at particular risk of adverse reactions to prescription drugs. This protocol describes a new approach that may identify credible drug-safety signals more efficiently using administrative health care data. To use high-throughput computing and automation to conduct 700+ drug-safety cohort studies in older adults in Ontario, Canada. Each study will compare 74 acute (30-day) outcomes in patients who start a new prescription drug (new users) to a group of nonusers with similar baseline health characteristics. Risks will be assessed within strata of baseline kidney function. The studies will be population-based, new-user cohort studies conducted using linked administrative health care databases in Ontario, Canada (January 1, 2008, to March 1, 2020). The source population for these studies will be residents of Ontario aged 66 years or older who filled at least one outpatient prescription through the Ontario Drug Benefit (ODB) program during the study period (all residents have universal health care, and those aged 65+ have universal prescription drug coverage through the ODB). We identified 3.2 million older adults in the source population during the study period and built 700+ initial medication cohorts, each containing mutually exclusive groups of new users and nonusers. Nonusers were randomly assigned cohort entry dates that followed the same distribution of prescription start dates as new users. Eligibility criteria included a baseline estimated glomerular filtration rate (eGFR) measurement within 12 months before the cohort entry date (median time was 71 days before cohort entry in the new user group), no prior receipt of maintenance dialysis or a kidney transplant, and no prior prescriptions for drugs in the same subclass as the study drug. New users and nonusers will be balanced on ~400 baseline health characteristics using inverse probability of treatment weighting on propensity scores within 3 strata of baseline eGFR: ≥60, 45 to <60, <45 mL/min per 1.73 m2. We will compare new user and nonuser groups on 74 clinically relevant outcomes (17 composites and 57 individual outcomes) in the 30 days after cohort entry. We used a prespecified approach to identify these 74 outcomes. In each cohort, we will obtain eGFR-stratum-specific weighted risk ratios and risk differences using modified Poisson regression and binomial regression, respectively. Additive and multiplicative interaction by eGFR category will be examined. Drug-outcome associations that meet prespecified criteria (identified signals) will be further examined in additional analyses (including survival, negative-control exposure, and E-value analyses) and visualizations. The initial medication cohorts had a median of 6120 new users per cohort (interquartile range: 1469-38 839) and a median of 1 088 301 nonusers (interquartile range: 751 697-1 267 009). Medications with the largest number of new users were amoxicillin trihydrate (n = 1 000 032), cephalexin (n = 571 566), prescription acetaminophen (n = 571 563), and ciprofloxacin (n = 504,374); 19% to 29% of new users in these cohorts had an eGFR <60 mL/min per 1.73 m2. Despite our use of robust techniques to balance baseline indicators and to control for confounding by indication, residual confounding will remain a possibility. Only acute (30-day) outcomes will be examined. Our data sources do not include nonprescription (over-the-counter) drugs or drugs prescribed in hospitals and do not include outpatient prescription drug use in children or adults <65 years. This accelerated approach to conducting postmarket drug-safety studies has the potential to more efficiently detect drug-safety signals in a vulnerable population. The results of this protocol may ultimately help improve medication safety.