Protocol Version Research Articles

Comparison of the ability of resection versus nonresection surgery to prevent the recurrence of sigmoid volvulus: A protocol of a meta-analysis and systematic review.

Based on clinical research guidelines and clinical practice, patients with sigmoid volvulus (SV) who receive conservative treatment have a greater recurrence rate than patients who do not receive conservative treatment, which is almost without any controversy. Surgical treatment is usually the final treatment for patients with SV. However, there are multiple surgical methods for the treatment of SV, which can be roughly divided into resection and nonresection methods. The available evidence on the effectiveness of surgery for preventing postoperative recurrence is still inadequate. Therefore, we drafted this systematic review protocol with meta-analysis aimed to compare the effects of these two major types of surgery on preventing the recurrence of SV. We comprehensively and systematically reviewed the PubMed, EMBASE, MEDLINE and Cochrane Library databases of articles on SV from inception to November 16, 2023. Two independent authors will screen and analyze the detected literature, and disputes will be resolved through communication with a third experienced person. After evaluating the quality of the literature and estimating the risk of bias, we calculate the pooled effect size and 95% confidence interval. Heterogeneity is analyzed by subgroup analysis, and sensitivity analysis can be carried out to assure the reliability of the results. Finally, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) will be used to evaluate the strength of the evidence. The results of each analysis will be recorded in detail. The whole process was carried out in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines (PRISMA-P). Protocol registration: The study protocol has been registered at the International Prospective Register of Systematic Reviews platform (PROSPERO) (CRD42024508350). Protocol version 1.0, 13 Feb 2024.

A randomized phase II trial on the addition of dutasteride to combined androgen blockade therapy versus combined androgen blockade therapy alone in patients with advanced or metastatic salivary duct carcinoma – the DUCT study protocol

BackgroundSalivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer, frequently associated with incurable recurrences and distant metastases (R/M). Proliferation of SDC relies on androgen receptor (AR) signalling, prompting the use of combined androgen blockade (CAB, i.e., luteinizing hormone-releasing hormone agonist and/or AR antagonists) to R/M SDC patients. However, only a subset of patients benefits from such treatments. We have shown that response to CAB is associated with steroid 5α-reductase 1 (SRD5A1) mRNA expression. SRD5A1 catalyses the intracellular conversion of testosterone into the more potent AR-agonist dihydrotestosterone. This conversion can be inhibited by dutasteride, a potent SRD5A1-inhibitor, which is currently prescribed for benign prostatic hyperplasia. We hypothesize that repurposing dutasteride to target AR signalling in SDC could enhance therapeutic response and clinical outcome in SDC patients.MethodsThis prospective, open-label, randomized controlled phase II clinical trial, is designed to investigate whether dutasteride as an adjunct drug to CAB improves response rate and clinical outcome in patients with AR-positive R/M SDC. Patients are divided in two cohorts based on their prior systemic treatments. In cohort A, CAB-naïve patients (n = 74) will be randomly assigned to either a control arm (Arm 1) receiving CAB (goserelin 10.8 mg/3m and bicalutamide 50 mg/OD) or an experimental arm (Arm 2) where dutasteride (0.5 mg/OD) is added to the CAB regimen. In cohort B, patients with disease progression after adjuvant or first-line palliative CAB therapy (max. n = 24) will receive goserelin, bicalutamide, and dutasteride to assess whether the addition of dutasteride can overcome therapy resistance. The primary endpoints are the objective response rate and duration of response. Secondary endpoints are progression-free survival, overall survival, clinical benefit rate, quality of life, and safety. Translational research will be performed to explore molecular target expression differences and their correlation with clinical outcome.DiscussionThe DUCT study addresses an unmet medical need by investigating the repurposing of dutasteride to enhance treatment response and improve clinical outcome for patients with R/M SDC, especially those with limited alternative treatment options, such as HER2-negative cases. By repurposing a registered low-cost drug, this trial’s findings could be readily applied into clinical practice.Trial registrationClinicaltrials.gov Identifier: NCT05513365. Date of registration: August 24, 2022.Protocol versionCurrent protocol version 4.0, February 21, 2024.

Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK

IntroductionThere remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the...

A cluster randomized controlled trial to assess the impact of the ‘Caring for Providers to Improve Patient Experience’ (CPIPE) intervention in Kenya and Ghana: study protocol

BackgroundPoor person-centered maternal care (PCMC) contributes to high maternal mortality and morbidity, directly and indirectly, through lack of, delayed, inadequate, unnecessary, or harmful care. While evidence on poor PCMC prevalence, as well as inequities, expanded in the last decade, there is still a significant gap in evidence-based interventions to address PCMC. We describe the protocol for a trial to test the effectiveness of the “Caring for Providers to Improve Patient Experience” (CPIPE) intervention, which includes five strategies, targeting provider stress and bias as intermediate factors to improve PCMC and address inequities.MethodsThe trial will assess the effect of CPIPE on PCMC, as well as on intermediate and distal outcomes, using a two-arm cluster randomized controlled trial in 40 health facilities in Migori and Homa Bay Counties in Kenya and Upper East and Northeast Regions in Ghana. Twenty facilities in each country will be randomized to 10 intervention and 10 control sites. The primary intervention targets are all healthcare workers who provide maternal health services. The intervention impact will be assessed among healthcare workers in the study health facilities and among women who give birth in the study health facilities. The primary outcome is PCMC measured with the PCMC scale, via multiple cross-sectional surveys of mothers who gave birth in the preceding 12 weeks in study facilities at baseline (prior to the intervention), midline (6 months after intervention start), and endline (12 months post-baseline) (N = 2000 across both countries at each time point). Additionally, 400 providers in the study facilities across both countries will be followed longitudinally at baseline, midline, and endline, to assess intermediate outcomes. The trial incorporates a mixed-methods design; survey data alongside in-depth interviews (IDIs) with healthcare facility leaders, providers, and mothers to qualitatively explore factors influencing the outcomes. Finally, we will collect process and cost data to assess intervention fidelity and cost-effectiveness.DiscussionThis trial will be the first to rigorously assess an intervention to improve PCMC that addresses both provider stress and bias and will advance the evidence base for interventions to improve PCMC and contribute to equity in maternal and neonatal health.Trial registrationClinicalTrials.gov: NCT06085105. Protocol version and date: v2-11-07-23

Prehospital neurological emergencies– a survey on the state of prehospital neurological assessment by emergency medical professionals

BackgroundNeurological emergencies are one of the major diagnosis groups in the Emergency Medical Services (EMS) with the highest rate of misdiagnosis. Despite the knowledge of time sensitivity and the importance of prehospital factors, prehospital delay is common. Although several stroke triage scales have been developed, a gold standard in the prehospital setting is lacking.ObjectivesOur aim was to evaluate the perception of neurological emergencies by EMS personnel and to identify current problems, difficulties and opportunities for improvement in the prehospital management of stroke, seizure, non-specific neurological symptoms, and paediatric neurological emergencies.MethodsThe study was conducted as an online survey through SoSci Survey and was made available from March 1st to June 30th 2023 to all personnel working in emergency medical services. The access link was distributed through snowballing, social media, and through a QR code on a promotional poster. The survey was completed anonymously. The final survey consisted of 30 questions in German on the topics of neurological emergencies, general neurological assessment, specific neurological examination including paediatric assessment, stroke, and seizures, and finally suggestions for improvement.ResultsThe largest group of participants were paramedics, who estimated to encounter neurological emergencies at a general rate of 20–60%. When unease was felt, the main reasons were ambiguity of symptoms and insufficient admission capacity of hospitals. The biggest challenges were highly varied. Almost 80% of participants assumed that the neurological assessment would be omitted in difficult patient groups such as demented, intoxicated or children. 75% felt uncomfortable making a paediatric assessment, 50% were unfamiliar with the Paediatric Glasgow Coma Scale.ConclusionsSupport through more standardized practical training and defined, uniform guidelines is needed. There was also a clear need for peer collaboration, feedback and case sharing. Digitalization, the usage of telemedicine and updated versions of the documentation protocols including paediatric adaptations to current guidelines could further improve current neurological assessment in the prehospital setting.

Abstract P315: Using Home Blood Pressure Monitors in the Office Setting as an Alternative to Automated Office Blood Pressure: A Quality Improvement Project

Background: Accurate blood pressure (BP) measurement is key to the diagnosis and effective treatment of hypertension (HTN). The U.S. HTN guideline recommends having patients rest for 5 minutes before measuring BP and obtaining at least two measurements 1-2 minutes apart. This is difficult to achieve in a busy primary care practice, and while automated office BP (AOBP) has been advanced as a solution, the required device may be cost-prohibitive. As home BP monitors are much less expensive, a protocol employing them in the office setting could prove to be an attractive alternative to AOBP. Objective: To promote the recording of multiple BP readings in primary care visits by using home BP monitors for measurement. Methods: Our primary care practice hosts 110 internal medicine residents and completes more than 35,000 patient visits annually. Prior to the intervention, medical assistants (MAs) obtained vital signs (VS) at every visit using a VS cart. In the first version of the new protocol, MAs measured all VS except BP using the VS cart, then measured BP once using an Omron 5 series BP monitor and recorded that reading in the chart. MAs left the cuff on the patient’s arm and instructed him/her to rest quietly for 5 minutes before taking a second BP reading him/herself while waiting for the provider after the MA exited the room. The patient took a third reading 1-2 minutes after the second. The provider recorded the second and third readings in the chart. Results: We implemented the new protocol in November 2023. In February 2024, we met with MAs to solicit feedback. They found the protocol easy to follow overall but had two concerns: (1) It was cumbersome to use two different devices to obtain a full set of VS; and (2) since many patients had normal BP, it did not seem worthwhile to obtain multiple BP measurements for all patients. After this meeting, we began measuring heart rate and oxygen saturation with a portable pulse oximeter instead of the VS cart, which is now only used in special circumstances. We also modified the protocol so that patients with systolic BP < 120 mm Hg and diastolic BP < 80 mm Hg are not required to obtain any repeat BP measurements. Conclusions: A new BP measurement protocol using home BP monitors to obtain multiple readings at each visit was feasible in our large academic primary care practice. We plan to investigate its effect on frequency of repeat BP measurement and likelihood of intensifying therapy for uncontrolled HTN.

Analysis of data from the Russian AURA registry (real-world data registry on AlbUminuRia detection rate among patients with previously undiAgnosed chronic kidney disease)

Aim. To present data from the AURA Registry (real-world data registry on AlbUminuRia detection rate among patients with previously undiAgnosed chronic kidney disease). It is important to perform population studies both to study the occurrence of markers (albuminuria (AU), decreased glomerular filtration rate (GFR)) and the prevalence of chronic kidney disease (CKD), which will provide information on the actual detection rate of CKD and the related markers in territories included in the registry of research centers.Material and methods. The article presents the first data from the AURA registry. Recruitment was carried out from March 6, 2023 to January 23, 2024. Thirty-four research centers in various federal districts of the Russian Federation and 104 doctors took part in the recruitment. We included 4580 subjects over the age of 40 years who had no previously established diagnosis of CKD and did not have type 1 or type 2 diabetes. During recruitment, the researchers were guided by the AURA study protocol (Version 1.7/12-26-2022).Results. AU more than 20 mg/g was detected in 64,9% of cases. At the same time, AU is more common at GFR values that may correspond to stage 3A of CKD. The rarer occurrence of AU in those examined with GFR >60 ml/min/1,73 m2 may be explained by less severe renal damage at this CKD stage. The incidence of AU was significantly higher in men, older people, smokers, people with metabolic syndrome, hypertension (HTN), prediabetes and overweight. The occurrence of AU also increased as HTN grade increased. AU detection rate was associated with hypertriglyceridemia, a high blood level of C-reactive protein, which is an integrative marker of inflammation that negatively affects cardiovascular risk.Conclusion. The presented first data from the AURA registry demonstrated the high AU prevalence in people over 40 years of age. A high incidence of AU was typical for patients with HTN, coronary artery disease, atrial fibrillation, heart failure, and prediabetes. An association has been demonstrated between the high incidence of AU and male sex, age, overweight, hyperuricemia, dyslipidemia, and a number of other cardiovascular risk factors.

Meeting Increasing Demands for Upstream Scope 3 Reporting: A Framework for the Drilling Industry

Summary This paper details the scope and framework applied for quantifying upstream Scope 3 greenhouse gas (GHG) emissions of offshore drilling operations. A step-by-step methodological approach is presented, comprising environmental impact modeling of drilling and rig operational activities through the application of the life cycle assessment (LCA) methodology. The study aims to break down upstream Scope 3 emissions to a process level, demonstrating how upstream Scope 3 emissions can be quantified and evaluated to a greater detail level compared with what current Scope 3 reporting levels offer today. A North Sea drilling case study conducted in collaboration with a major drilling contractor is used for showcasing the impact burden levels, challenges, and prosperity of accounting, reporting, and tracking upstream Scope 3 emissions as a drilling contractor. A total of 141 drilling and rig operational activities were identified and prioritized for impact calculation, presenting a detailed breakdown of upstream Scope 3 emissions results for offshore well drilling. Impacts are quantified in tonnes of carbon dioxide equivalent (CO2eq.) emitted per day in operation. The study does not include downstream Scope 3 and reports limited to direct (Scope 1) emissions. Results show a total upstream Scope 3 emissions burden of 412 tCO2eq./d in operation. Of the eight assessed upstream Scope 3 categories, purchased goods account for the largest contribution of 32%. Activities related to the operation and maintenance of drilling equipment account for the largest impact contribution of 351 tCO2eq./d, corresponding to 86% of total upstream Scope 3 emissions. The reported outputs may serve as a benchmark for future Scope 3 accounting and reporting within the drilling industry, as well as for LCA inventories for oil and gas production. A set of system boundaries for assessing upstream Scope 3 emissions is suggested, along with recommended emission calculation methods. The presented framework may serve as an alternate supplement to the International Petroleum Industry Environmental Conservation Association (IPIECA) adapted version of the GHG Protocol’s Scope 3 Standard in terms of Scope 3 inventory boundary setting and data prioritization with relevance to drilling contractors, and finally to the International Association of Drilling Contractors (IADC) industry guideline for environmental, social, and governance (ESG) reporting.

Move-PCD—a multi-center longitudinal randomized controlled superiority trial on the effect of a 6-month individualized supported physical activity (PA) program on quality of life (QoL) in children, adolescents, and adults with primary ciliary dyskinesia

BackgroundPrimary ciliary dyskinesia (PCD) is a rare genetical disease with malfunction of the motile cilia leading to impaired muco-ciliary clearance in the respiratory tract. There is no cure for PCD, only supportive therapy aimed at minimizing the progression of the disease and improving the patient’s quality of life (QoL). Physical activity (PA) is one of these recommended supportive therapies for people with PCD (pwPCD). However, there is no scientific evidence to support this recommendation. In addition, regular medical advice to increase PA remains largely ineffective in pwPCD.MethodsTo test the main hypothesis, that an individualized and supported PA program leads to a better QoL 6 months after randomization (QoL-PCD questionnaire) compared to usual recommendation in pwPCD, 158 pwPCD aged 7 to 55 years are to be included in this multi-center randomized controlled trial (RCT). After the screening visit, a 1:1 randomization stratified by age group and FEV1 will be performed. A QoL-PCD questionnaire, motor test, and lung function will be carried out at regular intervals in both groups. PA is recorded in both groups using activity trackers during the study period. The main aim of the trial is to estimate the difference in the change of QoL between the groups after 6 months. Therefore, our full analysis set consists of all randomized patients and analysis is performed using the intention-to-treat principle. Statistical software R (http://www.r-project.org) is used. Ethical approvement without any reservations: RUB Bochum Ethics Committee (No. 23–7938; December 4, 2023). Recruitment start: March 2024.DiscussionLimitations result from the rarity of PCD with its broad disease spectrum and the large age range. These are reduced by stratified randomization and the measurement of the individual change in QoL as primary endpoint. In our view, only a PA program tailored to individual needs with close contact to trainers offers the chance to meet personal needs of pwPCD and to establish PA as a pillar of therapy in the long term. The study protocol explains all procedures and methods of recruitment, implementation of the study visits and intervention, measures for patient and data safety, and for minimizing risks and bias.Trial registrationGerman Clinical Trials Register (DRKS) 00033030. Registered on December 7, 2023. Update 10 July 2024.Study protocol version 10Version 1.2; 12 June 2024

Hospital referrals, exclusions from hospital care, and deaths among long-term care residents in the Community of Madrid during the March–April 2020 COVID-19 epidemic period: a multivariate time series analysis

BackgroundFrom March 7 to April 7, 2020, the Community of Madrid (CoM), Spain, issued interventions in response to the COVID-19 epidemic, including hospital referral triage protocols for long-term care facility (LTCF) residents (March 18–25). Those with moderate to severe physical disability and cognitive impairment were excluded from hospital referral. This research assesses changes in the association between daily hospital referrals and the deaths of LTCF residents attributable to the triage protocols.MethodsDaily hospital referrals and all-cause mortality from January to June 2020 among LTCF residents and the CoM population aged 65 + were obtained. Significant changes in LTCF resident daily hospital referrals time series, and in-LTCF and in-hospital daily deaths, were examined with tests for breaks and regimes in time series. Multivariate time series analyses were conducted to test changes in the associations between LTCF resident hospital referrals with daily deaths in-hospital and in-LTCF, and in the CoM population aged 65 + when the triage protocols were implemented.ResultsAmong LTCF residents, hospital referrals declined sharply from March 6 to March 23, 2020. Increases in LTCF residents' daily deaths occurred from March 7 to April 1, followed by a decrease reaching pre-epidemic levels after April 28. The daily ratio of in-hospital deaths to in-LTCF deaths reached its lowest values from March 9 to April 19, 2020. The four versions of the triage protocol, published from March 18 to March 25 had no impact on further changes in the association of hospital referrals with daily deaths of LTCF residents in-hospital or in-LTCF.ConclusionsWhile LTCF residents’ deaths increased, hospital referrals of LTCF residents decreased with the introduction of the CoM governmental interventions on March 7. They were implemented before the enactment of the triage protocols, protecting hospitals from collapse while overlooking the need for standards of care within LTCFs. The CoM triage protocols sanctioned the existing restrictions on hospital referrals of LTCF residents.

Insomnia prehabilitation in newly diagnosed breast cancer patients: Protocol for a pilot, multicentre, randomised controlled trial comparing nurse delivered sleep restriction therapy to sleep hygiene education (INVEST trial).

Insomnia is a prevalent sleep disorder that negatively impacts daytime functioning and quality of life. Breast cancer patients report higher rates of insomnia and more circadian disruption than other cancer groups. Approximately 50% of patients experience acute insomnia following breast cancer diagnosis, which often persists during cancer treatment and rehabilitation. Sleep Restriction Therapy (SRT) is a clinically effective and tolerable treatment for persistent insomnia in breast cancer survivors. However, SRT has never been tested on patients with early signs of sleep disturbance who are undergoing cancer treatment. The aim of this pilot randomised controlled trial is to explore the feasibility and preliminary effectiveness of nurse delivered SRT for newly diagnosed breast cancer patients with acute insomnia. The trial has been registered on ClinicalTrials.gov (identifier: NCT06294041). The INVEST (INvestigating the Value of Early Sleep Therapy) trial will recruit 50 newly diagnosed breast cancer patients who meet criteria for acute insomnia. Patients will be recruited from breast cancer results clinics within two Scottish health boards (NHS Grampian and NHS Greater Glasgow and Clyde) and will be block randomised (1:1) to receive nurse delivered SRT or Sleep Hygiene Education (SHE). SRT will be delivered over 4 weekly sessions comprising two face-to-face meetings (either in person or online) and two telephone calls, whereas SHE will be administered in booklet form. Outcomes will be collected at baseline, 6 weeks, and 12 weeks post-randomisation. Primary outcomes in this trial relate to the feasibility of SRT for newly diagnosed breast cancer patients with acute insomnia. Specifically, we will explore (i) rates of patient recruitment and retention, (ii) intervention fidelity, (iii) data collection procedures and outcome measure completion, (iv) intervention acceptability. Secondary outcomes will focus on preliminary evaluation of patient responses to SRT, including insomnia severity, rest-activity rhythms, and mental health. Our dissemination plan comprises publishing trial outcomes in high-impact, peer-reviewed journals and on breast cancer charity websites and other patient resources. The outcomes from this pilot trial will also inform the development of a full-scale, multicentre RCT of SRT for acute insomnia in newly diagnosed breast cancer patients. University of Strathclyde is the sponsor (reference: UEC23/52). Protocol version v1.2 4 October 2023. This trial is the first to explore the value of sleep prehabilitation for newly diagnosed breast cancer patients.This will be the first trial to assess the feasibility of delivering SRT during breast cancer treatment, providing valuable insight into its tolerability and preliminary effectiveness.An embedded process evaluation will assess the acceptability of SRT, providing insight into potential optimisation of the intervention and recommendations for enhancing its future scalability and translation within cancer care.Due to the nature of the SRT intervention, nurse therapists and patients cannot be blinded to treatment allocation, increasing the risk of bias.

Hybridizing flower pollination algorithm with particle swarm optimization for enhancing the performance of IPv6 intrusion detection system

Internet Protocol version 6 (IPv6) is the most recent iteration of IP, designed to accommodate hundreds of thousands of devices with unique IP addresses. IPv6 introduces new features, such as the Neighbor Discovery Protocol (NDP) and Address Auto-configuration Scheme. For its effective operation, IPv6 relies on several protocols, including ICMPv6, which carries significant responsibilities. Similar to IPv4, IPv6 is susceptible to various attacks, including newer types like DDoS attacks executed via ICMPv6 messages, posing serious security and financial threats. Consequently, an Intrusion Detection System (IDS) is essential to safeguard against these attacks. IDS continuously evolve to incorporate features that can accurately detect such threats. However, feature selection strategies, particularly bio-inspired algorithms, often yield incorrect subsets of features. During machine learning processes, these inaccuracies impede the detection accuracy of DDoS attacks using ICMPv6. Many Optimization Search Algorithms become trapped in local minima and fail to consider multi-objective approaches, resulting in suboptimal feature selection. To address this, optimizing a bio-inspired algorithm within an IPv6 network has been proposed. Specifically, hybridizing the MFPA algorithm with the PSO algorithm is suggested to enhance detection accuracy. The selected features are used to train the dataset with a Support Vector Machine (SVM) classifier. The proposed approach is evaluated using the ICMPv6 dataset on various attacks, demonstrating superior classification accuracy of 97.99 %. It also reduced the number of features from 19 to 8, showcasing its efficiency.

Academy of Breastfeeding Medicine Clinical Protocol #19: Breastfeeding Promotion in the Prenatal Period (Revised 2024).

Background: The Academy of Breastfeeding Medicine revised the 2015 version of this clinical protocol to review the evidence and provide recommendations related to breastfeeding promotion in the prenatal period. Key Information: Promoting and normalizing breastfeeding in the prenatal period can improve breastfeeding outcomes including initiation and duration of breastfeeding. Ideally, prenatal interventions should be a part of a comprehensive longitudinal breastfeeding support program. Recommendations: Clinicians or other health workers should discuss breastfeeding at each prenatal visit. Counseling topics should include the health benefits of breastfeeding versus not breastfeeding, the basics of breastfeeding (e.g., physiology, positioning), what to expect of hospital-based and immediate postpartum breastfeeding support (i.e., Baby-Friendly Ten Steps), and the risks of unnecessary supplementation. Medical, anatomical, and other risk factors for breastfeeding challenges should be identified, and targeted anticipatory guidance should be given. Prenatal counseling should include distribution of structured breastfeeding education at low literacy levels and in the parent's preferred language. Counseling should be culturally sensitive and patient-centered, including family members when appropriate. Prenatal support may integrate various health workers (e.g., medical doctors, midwives, community health workers, lactation consultants, among others) and include various modalities including telecommunication. Enhancing breastfeeding education for prenatal care providers is also imperative. Additional themes related to implementation of recommendations for specific populations are also reviewed.

Radiofrequency ablation via catheter and transpapillary access in patients with cholangiocarcinoma (ACTICCA-2 trial) – a multicenter, randomized, controlled, open-label investigator-initiated trial

BackgroundDespite the recent advances in cancer treatment, the therapeutic options for patients with biliary tract cancer are still very limited and the prognosis very poor. More than 50% of newly diagnosed patients with biliary tract cancer are not amenable to curative surgical treatment and thus treated with palliative systemic treatment. Malignant bile duct obstructions in patients with perihilar and/or ductal cholangiocarcinoma (CCA) represents one of the most important challenges in the management of these patients, owning to the risk represented by developing life-threatening cholangitis which, in turn, limits the use of systemic treatment. For this reason, endoscopic stenting and/or bile duct decompression is the mainstay of treatment of these patients. Data on efficacy and safety of adding radiofrequency ablation (RFA) to biliary stenting is not conclusive. The aim of this multicenter, randomized trial is to evaluate the effect of intraductal RFA prior to bile duct stenting in patients with unresectable perihilar or ductal CCA undergoing palliative systemic therapy.Methods/DesignACTICCA-2 is a multicenter, randomized, controlled, open-label, investigator-initiated trial. 120 patients with perihilar or ductal CCA with indication for biliary stenting and systemic therapy will be randomized 1:1 to receive either RFA plus bile duct stenting (interventional arm) or bile duct stenting alone (control arm). Patients will be stratified by trial site and tumor location (perihilar vs. ductal). Both arms receive palliative systemic treatment according to the local standard of care determined by a multidisciplinary tumorboard. The primary endpoint is time to first biliary event, which is determined by an increase of bilirubin to > 5 mg/dl and/or the occurrence of cholangitis leading to premature stent replacement and/or disruption of chemotherapy. Secondary endpoints include overall survival, safety according to NCI CTCAE v5, quality of life assessed by questionnaires (EORTC QLQ-C30 and QLQ-BIL21), clinical event rate at 6 months after RFA and total days of over-night stays in hospital. Follow-up for the primary endpoint will be 6 months, while survival assessment will be continued until end of study (maximum follow-up 30 month). All patients who are randomized and who underwent endoscopic stenting will be used for the primary endpoint analysis which will be conducted using a cause-specific Cox proportional hazards model with a frailty for trial site and fixed effects for the treatment group, tumor location, and stent material.DiscussionACTICCA-2 is a multicenter, randomized, controlled trial to assess efficacy and safety of adding biliary RFA to bile duct stenting in patients with CCA receiving palliative systemic treatment.Trial registrationThe study is registered with ClinicalTrials.gov (NCT06175845) and approved by the local ethics committee in Hamburg, Germany (2024-101232-BO-ff). This manuscript reflects protocol version 1 as of January 9th, 2024.Graphical

Radiation therapy and IRreversible electroporation for intermediate risk prostate cancer (RTIRE)

IntroductionRadiation Therapy and IRreversible Electroporation for Intermediate Risk Prostate Cancer (RTIRE) is a phase II clinical trial testing combination of radiation therapy and irreversible electroporation for intermediate risk prostate cancerBackgroundPCa is the most common non-cutaneous cancer in men and the second leading cause of cancer death in men. PCa treatment is associated with long term side effects including urinary, sexual, and bowel dysfunction. Management of PCa is based on risk stratification to prevent its overtreatment and associated treatment-related toxicity. There is increasing interest in novel treatment strategies, such as focal therapy, to minimize treatment associated morbidity. Focal therapy alone has yet to be included in mainstream guidelines, given ongoing concerns with potentially higher risk of recurrence. We hypothesize combining focal therapy with whole gland, reduced dose radiotherapy will provide acceptable oncologic efficacy with minimal treatment associated morbidity. RTIRE is a phase II single institution, investigator-initiated study combining a local ablative technique though local irreversible electroporation (IRE) with MR guided RT (MRgRT) to treat the entire prostate. The goal is to provide excellent oncologic outcomes and minimize treatment related side effects through leveraging benefits of locally ablative therapy with established radiation treatment techniques.MethodsA total of 42 men with intermediate risk PCa per NCCN guidelines and focal grade group (GG) 2 or 3, Gleason Score (GS) 3 + 4 or GS 4 + 3, cancer in an MRI target will be enrolled. Patients with MRI visible foci of GG2/GG3 will undergo focal therapy with IRE of this lesion. Following successful focal therapy, patients will then undergo a course of reduced dose, whole gland MRgRT with either 32.5 Gy in 5 Fractions or 22 Gy in 2 fractions. The primary objective of the study is to determine safety. Secondary outcomes include evaluation of oncologic efficacy (as measured by the proportion of patients free of clinically significant cancer as defined as > Grade Group 1 at 1-year follow-up biopsy), imaging characteristics of patients pre and post RTIRE, impact on quality of life (QoL), and PSA kinetics.DiscussionCombining IRE with a reduced dose radiotherapy may offer a new treatment paradigm for PCa by both reducing treatment effects of full dose radiotherapy and minimizing the risk of recurrence observed with focal therapy.Trial RegistrationClinicaltrials.gov identifier: NCT05345444. Date of registration: April 25, 2022. Protocol Version: 6.0, July 7, 2023.

ESTARK: extending STARKs with arguments

STARK is a widely used transparent proof system that uses low-degree tests for proving the correctness of a computer program. STARK consumes an intermediate representation known as AIR that is more appropriate for programs with a relatively short and structured description. However, an AIR is not able to succinctly express non-equality constraints, leading to the incorporation of unwanted polynomials. We present the eSTARK protocol, a new probabilistic proof that generalizes the STARK family through the introduction of a more generic intermediate representation called eAIR. We describe eSTARK in the polynomial IOP model, which combines the optimized version of the STARK protocol with the incorporation of three arguments into the protocol. We also explain various techniques that enhance the vanilla STARK complexity, including optimizations applied to polynomial computations, and analyze the tradeoffs between controlling the constraint degree either at the representation of the AIR or inside the eSTARK itself.

Translated and culturally adapted internet-delivered cognitive therapy for social anxiety disorder in Japanese clinical settings: study protocol for a randomised controlled trial

BackgroundCognitive therapy for social anxiety disorder (CT-SAD) has extensive empirical support and is recommended in several national guidelines. However, ensuring access to evidence-based psychological therapies such as CT-SAD remains a global challenge. An internet-delivered version of this treatment protocol (iCT-SAD) has recently been developed in the UK as a way to overcome this challenge, demonstrating comparable outcomes to face-to-face CT-SAD whilst requiring less therapist time per client. Initial findings also suggest its cross-cultural transferability, but the previous studies in other cultural settings used the English language programme and only included English-fluent participants as a second language. It is not yet known what outcomes can be achieved once the programme has been translated and adapted for a different cultural context. Therefore, this trial aims to evaluate the clinical efficacy of Japanese iCT-SAD when combined with treatment as usual (TAU) in clients with SAD.MethodsThis two-arm, parallel-group, superiority randomised controlled trial will recruit 60 Japanese participants with SAD, randomly assigning them to either Japanese iCT-SAD + TAU or TAU alone at a ratio of 1:1. The primary outcome measure is the self-report Liebowitz Social Anxiety Scale, and secondary.outcomes include other measures of social anxiety symptoms and processes, general mood and functioning, and response to treatment. We will also assess treatment acceptability and gather participant feedback. Assessments will take place at baseline (week 0), mid-treatment (week 8), and post-treatment (week 15), with a further 3-month follow-up (week 27) for the iCT-SAD + TAU arm. The primary analyses will be conducted on an intent-to-treat basis, comparing the primary and secondary outcome measures between groups using linear mixed-effect models, along with additional mediation analysis.DiscussionInvestigating the efficacy of translated and culturally adapted iCT-SAD in different cultural contexts is an important step in evaluating the global reach of internet interventions. This trial will provide valuable insights into the effects of iCT-SAD combined with usual care, and how this treatment could be delivered in routine clinical settings in Japan.Trial registrationInternational Standard Randomized Controlled Trials (ISRCTN), ISRCTN82859645, registered on January 19, 2024. UMIN Clinical Trials Registry (UMIN-CTR), UMIN000052702, registered on November 6, 2023.

A feasibility randomized controlled trial of culturally adapted Getting Better Bite-by-Bite (Ca-GBBB) intervention for individuals with eating disorders in Pakistan

BackgroundEating disorders (EDs) are serious mental health conditions that affect a person physically and psychologically. In the past, EDs were only recognized as a cultural phenomenon/societal by-product of the West. However, research evidence marks its presence in non-western countries also, including South Asia. This study aims to evaluate the feasibility and acceptability of a manualized psychological intervention called Getting Better Bite by Bite (GBBB) in individuals who screened positive on measures of EDs in Pakistan.MethodsThe proposed study is a feasibility randomized controlled trial (fRCT). The study will be conducted at five sites across Pakistan: Karachi, Hyderabad, Lahore, Rawalpindi, and Multan to recruit a total of 80 participants. Eligible participants will be randomized to either (1) the intervention group; in which they will receive one-to-one sessions of GBBB along with routine care or (2) the routine care group; in which they will only have access to the routine care. We have received ethics approval by the National Bioethics Committee. The study is registered at clinicaltrials.gov (NCT05724394). The study team has received permission from recruitment centers: hospitals (i.e. the psychiatry department of public and private hospitals based in these cities), fitness centers (i.e., gyms), educational institutes (i.e., colleges and universities), and community settings (i.e. community health clinics). Self-referrals from General Practitioners and community settings will be accepted. The intervention manual has been translated into Urdu and a multidisciplinary team including service users has culturally adapted the content of intervention for local context.DiscussionThis study will provide evidence on feasibility and acceptability of a culturally adapted intervention for individuals who screen positive on measures of EDs. The findings of this study will inform a fully powered Randomized Controlled Trial of the proposed intervention.Trial Registration. The study is registered on clinicaltrials.gov (NCT05724394). Protocol version (1.0. 1st June 2022).

Gendered perspective on water security, rights and conflicts in sub-Saharan Africa: a systematic review

The 2017 Global Risk Report ranked water crisis third among the top six global risks that greatly impact society. While the water crisis is disproportionately distributed worldwide, sub-Saharan Africa (SSA) has more people (most of whom are women) who face water problems compared to other regions worldwide. Through the application of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol version 2020, a systematic review examining the connection between gender and water security, rights, and water conflicts in SSA was done. A total of 24 out of 229 articles made it into the final analysis. Previous research studies on gender politics in the water sector have done so in a fragmented way, focusing on specific water security parameters. The emerging findings show that 14 years after the adoption of an enforceable human right to water and about 6 years prior to the cut-off date for the 2030 Agenda for Sustainable Development, matters of gender and water in SSA are far from being addressed. Rural people, especially women, still face multiple water-related challenges and conflicts, including discriminatory practices upholding male hegemony in water governance. It is recommended that actors in the water sector precede the implementation of water projects by understanding contextual settings that influence gendered water security. Furthermore, the implementation of the water Sustainable Development Goal (SGD 6) should be done in the context of SDG 5 (Gender Equity) and the prioritization of procedural water justice and governance, access to technical skills, and water conveyance technologies.Systematic review registrationhttps://www.prisma-statement.org/.

Adapting COVID-19 research infrastructure to capture influenza and respiratory syncytial virus alongside SARS-CoV-2 in UK healthcare workers winter 2022/23 and beyond: protocol for a pragmatic sub-study

Introduction During the COVID-19 pandemic, extensive research was conducted on SARS-CoV-2; however, important questions about other respiratory pathogens remain unanswered. A severe influenza season in 2022–2023 with simultaneous circulation of SARS-CoV2 and respiratory syncytial virus is anticipated. This sub-study aims to determine the incidence and impact of these respiratory viruses on healthcare workers, the symptoms they experienced, the effectiveness of both COVID-19 and influenza vaccination and the burden of these infections on the National Health Service (NHS) workforce. Methods and analysis This is a longitudinal prospective cohort sub-study, utilising the population and infrastructure of the SARS-CoV-2 Immunity & Reinfection Evaluation (SIREN) study, which focuses on hospital staff in the UK. Participants undergo fortnightly nucleic acid amplification testing on a multiplex assay including SARS-CoV-2, influenza A and B and RSV, regardless of symptoms. Questionnaires are completed every two weeks, capturing symptoms, sick days, exposures, and vaccination records. Serum samples are collected monthly or quarterly from participants associated with a SIREN site. This sub-study commenced on 28/11/22 to align with the predicted influenza season and participants’ influenza vaccine status. The SIREN Participant Involvement Panel shaped the aims and methods for the study, highlighting its acceptability. UK devolved administrations were supported to develop local protocols. Analysis plans include incidence of asymptomatic and symptomatic infection, comparisons of vaccination coverage, assessment of sick day burden, and effectiveness of seasonal influenza against infection and time off work. Data are also integrated into UKHSA nosocomial modelling. Ethics and dissemination The protocol was approved by the Berkshire Research Ethics Committee (IRAS ID 284460, REC Reference 20SC0230) on 14/11/2022. Participants were informed in advance. As the frequency and method of sampling remained the same, implied consent processes were approved by the committee. Participants returning to the study give informed consent. Regular reports to advisory groups and peer-reviewed publications are planned to disseminate findings and inform decision making. Clinical trial registration number: ISRCTN11041050; registration date: 12 January 2021. Sub study included in protocol version: v8.0, and amended in v9.0