Successful transcatheter coil embolization of a coronary cameral fistula in a young male with a structurally normal heart: A case report.

INTRODUCTION AND IMPORTANCE: Coronary-cameral fistulas (CCFs) are the anomalous connection between a coronary artery (CA) and a great vessel or cardiac chamber. About 90 % of CA fistulas are congenital and are related to persistent sinusoids during the embryonic period. Most fistulas originate from the right and left anterior descending CAs. The circumflex CA is rarely involved. CASE PRESENTATION: A 20-year-old male was referred to a tertiary children's heart hospital center due to retrosternal chest pain (CP) and dyspnea on exertion (functional class Ш). The transthoracic echocardiography (TTE) was done, and it demonstrated a dilated left coronary artery (LCA) (size:5 mm) with a large aneurysm (2 cm) and a small orifice to the right ventricle (RV) body. Then, cardiac angiography was done, and dilated LCA and CCF were demonstrated in the RV. Subsequently, the aneurysm was occluded by eight coils. CLINICAL DISCUSSION: CCAs can be treated by transcatheter approach or surgical repair. In the presented case, we planned to treat this condition through Cardiac Angiography. Cardiac Angiography was done, and eight coils occluded the aneurysm. The day after the angiography, the symptoms were completely resolved, and the patient didn't complain of CP and dyspnea. CONCLUSION: CCFs represent an uncommon cardiac anomaly with diverse anatomical variations and clinical manifestations. Coronary angiography (CAG) is the most accurate diagnostic test to determine fistula anatomy and possible therapeutic options. Small symptomatic and large fistulas, regardless of symptoms, necessitate intervention through either a transcatheter approach or surgical repair.

Promising clinical effect of arthroscopic autologous iliac bone grafting with suture anchor binding fixation for recurrent anterior shoulder instability.

Background: To evaluate the clinical efficacy of arthroscopic autologous iliac bone grafting with suture anchor binding fixation combined with a Bankart repair for recurrent anterior shoulder dislocation with a significant anterior glenoid defect. Methods: Patients with recurrent anterior shoulder dislocation with an anterior glenoid defect area greater than 20% admitted to our department from March 2019 to March 2022 were prospectively enrolled. Arthroscopic autologous iliac bone grafting with suture anchor binding fixation combined with a Bankart repair was performed. Computed tomography (CT) images were captured preoperatively, immediately after surgery, and at 3, 6, and 12 months postoperatively to evaluate the glenoid defect area, graft area, and graft healing. Shoulder function was assessed using the Instability Severity Index, Oxford Shoulder Instability, and Rowe scores recorded preoperatively and at the final follow-up. The shoulder range of motion, shoulder stability test, surgery-related complications, subluxation/dislocation, and revision surgery were also evaluated. Results: A total of 32 patients were included in the study, with an average follow-up time of 18.3 ± 6.3 months, when the graft healing rate was shown to be 100%. The area ratio of the graft to the glenoid was 37.6% ± 10.5% (range, 23.5%-44.1%) determined by an enface-view three-dimensional CT performed immediately after surgery, and 29.2 ± 8.2% (range, 19.6%-38.7%) at 12 months postoperatively. At the final follow-up, the glenoid defect had improved from 28.7 ± 6.4% (range, 20.5%-40.6%) before surgery to -10.2 ± 4.7% (range, -13.8% to 6.1%). The preoperative Rowe and Oxford scores were 56.4 ± 8.5 and 34.7 ± 7.1 respectively, which improved to 94.3 ± 6.7 and 15.3 ± 3.2 at the final follow-up (p < .001). All patients had no limited shoulder joint activity, no re-dislocation or revision surgery, and no neurovascular injury. Conclusions: For recurrent anterior shoulder dislocation with an anterior glenoid defect area greater than 20%, arthroscopic autologous iliac bone grafting with suture anchor fixation combined with a Bankart repair produced a promising clinical effect. A significant shoulder function score was achieved, as was a 100% bone healing rate and ideal glenoid reconstruction without major complications. Thus, this technique may be considered an alternative to the classic Latarjet approach to treat recurrent anterior shoulder dislocation with an anterior glenoid defect area greater than 20%. Level of Evidence: IV.

Stepped-Care Web-Based Parent Support Following Congenital Heart Disease: Protocol for a Randomized Controlled Trial.

BACKGROUND: Early neurodevelopmental risks, compounded with traumatic medical experiences, contribute to emotional and behavioral challenges in as many as 1 in 2 children with congenital heart disease (CHD). Parents report a strong need for supports; yet, there remains a lack of accessible, evidence-based behavioral interventions available for children with CHD and their families. I-InTERACT-North is a web-based stepped-care mental health program designed to support family well-being and reduce behavioral concerns through positive parenting for children with early medical complexity. In previous pilot studies, the program was effective in increasing positive parenting skills and decreasing child behavior problems, with high parent-reported acceptability. This paper presents the protocol for the first randomized study of stepped-care parent support for families of children with CHD. OBJECTIVE: This study will involve a single-site, 2-arm, single-blind randomized controlled trial to evaluate (1) the feasibility and acceptability of a web-based stepped-care parent support program (I-InTERACT-North) and (2) the effectiveness of the program in enhancing positive parenting skills and reducing behavioral concerns among families of children with CHD. METHODS: Families will be randomized (1:1) to either receive treatment or continue with care as usual for 12 months. Randomization will be stratified by child's sex assigned at birth and baseline parent-reported child behavior intensity. Primary outcomes include positive parenting skills and child behavior at baseline, 3 months, 6 months, and 12 months. Secondary outcomes include parental mental health, quality of life, service usage, and feasibility including program reach and adherence. A sample size of 244 families will provide >95% power to detect an effect size of d=0.64. Based on attrition data from pilot studies, a target of 382 families will be enrolled. Parent reports of acceptability, adoption, and suggested adaptability of the program will be examined using cross-case thematic analyses. Primary efficacy analysis will be conducted using an intent-to-treat approach. Generalized estimating equations will be used to examine changes in positive parenting. Child behavior, quality of life, and parent mental health will be tested with repeated-measures analyses. Additional sensitivity and replication analyses will also be carried out. RESULTS: Recruitment began in February 2024, and recruitment and follow-up will continue until January 2029. We anticipate results in late 2029. CONCLUSIONS: This study aims to test the effectiveness of I-InTERACT-North web-based stepped-care parent support in improving positive parenting skills and reducing child behavior problems in families of children with CHD compared with a care as usual control group. Results will inform future clinical implementation and expansion of this program among families of children with early medical conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT06075251; https://clinicaltrials.gov/study/NCT06075251. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/64216.

Embers of autoregression show how large language models are shaped by the problem they are trained to solve.

The widespread adoption of large language models (LLMs) makes it important to recognize their strengths and limitations. We argue that to develop a holistic understanding of these systems, we must consider the problem that they were trained to solve: next-word prediction over Internet text. By recognizing the pressures that this task exerts, we can make predictions about the strategies that LLMs will adopt, allowing us to reason about when they will succeed or fail. Using this approach-which we call the teleological approach-we identify three factors that we hypothesize will influence LLM accuracy: the probability of the task to be performed, the probability of the target output, and the probability of the provided input. To test our predictions, we evaluate five LLMs (GPT-3.5, GPT-4, Claude 3, Llama 3, and Gemini 1.0) on 11 tasks, and we find robust evidence that LLMs are influenced by probability in the hypothesized ways. Many of the experiments reveal surprising failure modes. For instance, GPT-4's accuracy at decoding a simple cipher is 51% when the output is a high-probability sentence but only 13% when it is low-probability, even though this task is a deterministic one for which probability should not matter. These results show that AI practitioners should be careful about using LLMs in low-probability situations. More broadly, we conclude that we should not evaluate LLMs as if they are humans but should instead treat them as a distinct type of system-one that has been shaped by its own particular set of pressures.

Development of synergistic antifungal in situ gel of miconazole nitrate loaded microemulsion as a novel approach to treat vaginal candidiasis.

Limited solubility is the main cause of the low local availability of anti-candidiasis drug, miconazole nitrate (MN). The study's objective was to develop and characterize microemulsion (ME) based temperature-triggered in situ gel of MN for intravaginal administration to enhance local availability and antifungal activity. The solubility of MN was initially studied in different oils, surfactants, and co-surfactants. Then, pseudo-ternary phase diagrams were constructed to select the best ratio of various components. The ME formulations were characterized by thermodynamic study, droplet size, polydispersity index (PDI), viscosity, and in-vitro antifungal mean inhibition zone (MIZ). Selected MEs were incorporated into different in situ gel bases using a combination of two thermosensitive polymers (poloxamer (PLX) 407 and 188), with 0.6% of hydroxypropyl methylcellulose (HPMC K4M) and gellan gum (GG) as mucoadhesive polymer. ME-based gels (MG) were investigated for gelation temperature, gelation time, viscosity, spreadability, mucoadhesive strength, in vitro release profile, and MIZ test. Furthermore, the optimum MG was assessed for in vivo animal irritation test and FESEM investigation. Tea tree oil, lavender oil, tween 80, and propylene glycol (PG) were chosen for ME preparation for the optimal formulation; formulation ME7 and ME10 were chosen. After incorporation of the selected formulation into a mixture of P407 and P188 (18:2% w/w) with 0.6% mucoadhesive polymer, the resultant MG formulation (MG1) revealed optimum gelation temperature (33 ± 0.01℃) and appropriate viscosity with enhanced sustained release (98%) and retention through sheep vaginal mucosa, MG1 exhibited a better MIZ compared to the 2% MN gel formulation and the marketed MN product, and no rabbit vagina irritation. In conclusion, the miconazole nitrate-loaded MG-based formula sustained the duration of action and better antifungal activity than the marketed miconazole nitrate formulation.

Spatial distribution and characteristics of women reporting cervical cancer screening in Malawi: An analysis of the 2020 to 2021 Malawi Population-based HIV Impact Assessment survey data.

BACKGROUND: Malawi has one of the highest incidence and mortality rates of cervical cancer in the world. Despite a national strategic plan and the roll-out of VIA and screen-and-treat services, cervical cancer screening coverage in Malawi remains far below the national target.Using a nationally representative sample of women enumerated in the Malawi Population-based Impact Assessment (MPHIA) survey we estimated the prevalence and spatial distribution of self-reported cervical cancer screening as a proxy for uptake in Malawi. METHODS: MPHIA was a nationally representative household survey in Malawi, targeting adults aged 15 and above, that employed a cross-sectional, two-stage, cluster design. The primary aim of MPHIA was to assess the regional prevalence of viral load suppression and the progress towards achieving the UNAIDS 95-95-95 goals among adults aged 15 and above. The survey was carried out between January 2020 and April 2021. Prevalence of self-reported cervical cancer screening by different characteristics was estimated accounting for the survey design using the Taylor series approach. We used univariable and multivariable logistic regression approaches to examine associations between the prevalence of cervical cancer screening and demographic characteristics. FINDINGS: A total of 13,067 adult (15 years and older) female individuals were surveyed during the MPHIA 2020 to 2021 survey, corresponding to a weighted total of 5,604,578. The prevalence of self-reported cervical cancer screening was 16.5% (95% CI 15.5-18.0%), with women living with HIV having a higher prevalence of 37.8% (95% CI 34.8-40.9) compared to 14.0% (95% CI 13.0-15.0) in HIV negative women. The highest prevalence of screening was reported in the Southwest zone (SWZ) (24.1%, 95% CI 21.3-26.9) and in major cities of Blantyre (25.9%, 95% CI 22.9-29.0), and Lilongwe (19.6%, 95% CI 18.0-21.3). Higher self-reported screening was observed in women who resided in urban regions ((22.7%; 95% CI 21.4-24.0) versus women who resided in rural areas (15.2%; 95% CI 14.0-16.8). Cervical cancer screening was strongly associated with being HIV positive (aOR 2.83; 95% CI 2.29-3.50), ever having been pregnant (aOR 1.93; 95% CI 1.19-3.14), attaining higher education level than secondary education (aOR 2.74; 95% CI 1.67-4.52) and being in the highest wealth quintile (aOR 2.86; 95% CI 2.01-4.08). INTERPRETATION: The coverage of cervical cancer screening in Malawi remains low and unequal by region and wealth/education class. Current screening efforts are largely being focussed on women accessing HIV services. There is need for deliberate interventions to upscale cervical cancer screening in both HIV negative women and women living with HIV.

"Someone who hates themself doesn't come for their drugs": Experiences of mental health along the HIV care continuum in South-Central, Uganda.

INTRODUCTION: Poor mental health occurs more frequently among people living with HIV. Understanding what mental health problems occur and at what point during the continuum of HIV care is critical to ensure these problems are identified and appropriately addressed. We explored how mental health is experienced along the HIV care continuum in Rakai, Uganda. METHODS: We conducted qualitative semi-structured in-depth interviews with 20 adults living with HIV and 10 health workers from March to December 2020. Interviews followed a timeline approach. Responses were analyzed using content analysis. RESULTS: At the time of HIV diagnosis, nearly all participants described a range of strong emotions, including shock, fear and intense worry. Most participants described continued fear and intense worry leading up to, and at the time of, ART initiation. However, they said these emotions often subside after ART is initiated and viral suppression is achieved. Across interviews and at multiple points of the continuum, participants discussed how fear and worry led individuals to be "thinking too much" or be in "deep thoughts" and experience self-hatred. Individuals who stopped taking ART were thought to have more severe mental health problems ("madness", psychosis, suicidality). Participants were divided about the mental health of persons who returned to care after disengagement. CONCLUSION: In this setting, mental health problems experienced by people living with HIV are dynamic across the care continuum. With expanded HIV testing campaigns and Universal Test and Treat policies, targeted interventions for psychosocial support at the time of testing and ART initiation remain critical.

Factors influencing the acceptability of the test, treat and refer practice for malaria among caregivers of under 5 children at community pharmacies and drug shops in Nigeria.

BACKGROUND: Malaria affects children under the age of five and pregnant women, leading to high morbidity and mortality rates. In sub-Saharan Africa, Patent and Proprietary Medicine Vendors (PPMVs) have been identified as key players in the provision of malaria treatment due to their accessibility and availability in communities, but PPMVs are not usually tested before fever cases are treated as malaria or refer clients. The aim of this study was to explore the factors influencing caregivers' acceptance of the test, treatment and referral practices for malaria management provided by CPs and PPMVs in Kaduna and Lagos states, Nigeria. METHODS: A cross-sectional quantitative telephone survey was conducted among 150 caregivers of children under five years old who received malaria services from trained CPs and PPMVs between May and July 2022. Descriptive and bivariate analyses were performed to identify factors significantly associated with the acceptability of malaria management services. All statistically significant factors from the bivariate analysis were explored using logistic regression models, and odds ratios (ORs) with confidence intervals (CIs) were calculated to predict acceptability. The 95% level was used to define statistically significant associations (p ≤ 0.05). RESULTS: All caregivers were asked questions that aided in obtaining a diagnosis of malaria. More than two-thirds of the caregivers (68%) reported that the child was tested by a CP/PPMV. Among those treated (148), 89% reported that the child was administered artemisinin combination therapy (ACT) irrespective of whether the child tested positive or negative for malaria. At the bivariate level, acceptability was greater among caregivers of children aged 13 months and older than among caregivers of children aged 0-12 months (93% vs. 76%, p = 0.004). Caregivers of children who prescribed ACT had greater acceptance than did those not prescribing ACT (92% vs. 69%, p = 0.010). Multivariate analysis revealed that these relationships held. CONCLUSIONS: The adoption of the test, treat, and refer practice as a standard approach by CPs and PPMVs could replace the widespread practice of prescribing medications without conducting tests. This shift has the potential to improve the quality of malaria management services and enhance patient outcomes.

A Case Study Based on a Complementary and Alternative Medicine Approach on an Oligoasthenoteratozoospermic Patient and its Effect on Assisted Reproductive Technology Outcome.

A couple visited the IVF clinic to seek treatment for primary infertility. A 45-year-old quadragenarian female and her 49-year-old male partner were recommended infertility treatment after 2 years of unsuccessful attempts to conceive. The woman had a recent history of dengue and chickenpox. The male partner was advised to do a semen analysis. The report showed asthenoteratozoospermia and the semen sample viscous. On the other hand, the female was diagnosed with hypothyroidism. The male patient was given a 3-month medication treatment that included probiotic supplements and cranberry juice to treat bacterial infections and urinary tract infections. The male partner also advised medication, and regular semen analysis was performed after every 3 months. The treatment plan included intrauterine insemination (IUI), which increased the possibility of pregnancy. Fourteen days following the IUI and pregnancy test, the outcomes were positive. The case illustrates the difficulties in treating primary infertility by combining reproductive procedures, medication, and lifestyle modifications. Regularly monitoring semen quality and hormonal levels is crucial in assessing treatment success. The positive outcome of IUI suggests the effectiveness of the fertility treatment plan.

New Instruments for the Management of Cochlear Implantation in an Individual with a Fracture of the Temporal Bone and Cochlear Ossification.

Cochlear implant surgery can be highly complex in cases where ossification of the internal ear has taken place. In this case report, we report the use of new technological instruments to optimise the surgical process of implantation. These were the combined use of a surgical approach extended by a subtotal petrosectomy, a pre-operative radiological study with the OTOPLAN software for choosing the most suitable electrode array, and a residual functionality test of the auditory nerve using the ANTS test electrode array prior to inserting the cochlear implant electrode array. These were used to successfully treat a case of total deafness caused by a fracture in the temporal bone complicated with ossification of the basal turn of the cochlea. These instruments ensured that the operation was performed with excellent results, reducing the risk of failure to a minimum in this complex case.

Effect of non-steroidal anti-inflammatory drugs on the management of postoperative pain after cardiac surgery: a multicenter, randomized, controlled, double-blind trial (KETOPAIN Study).

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended for the management of acute postoperative pain as part of a multimodal strategy to reduce opioid use, relieve pain, and reduce chronic pain in non-cardiac surgery. However, significant concerns arise in cardiac surgery due to the potential adverse effects of NSAID including increased bleeding and acute kidney injury (AKI). We hypothesized that NSAIDs are effective against pain and safe in the early postoperative period following cardiac surgery, taking contraindications into account. METHODS: The KETOPAIN trial is a prospective, double blind, 1:1 ratio, versus placebo multicentric trial, randomizing 238 patients scheduled for cardiac surgery. Written consent will be obtained for all participants. The inclusion criterion is patients more than 18 years old undergoing for elective cardiac surgery under cardiopulmonary bypass (CPB). Patients will be allocated to the intervention (ketoprofen) group (n = 119) or the control (placebo) group (n = 119). In the intervention group, in addition to the standard treatment, patients will receive NSAIDs (ketoprofen) at a dose of 100 mg each 12 h 48 h after. The control group, in addition to the standard treatment, will receive a placebo of NSAIDs every 12 h for 48 h after surgery. An intention-to-treat analysis will be performed. The primary endpoint will be the intensity of acute postoperative pain at rest at 24 h from the end of surgery. Pain will be assessed using the numerous rating scale. The secondary endpoints will be postoperative pain on coughing during chest physiotherapy, postoperative pain until day 7, the pain trajectory between day 3 and day 7, cumulative opioid consumption within 48 h after surgery, nausea and vomiting, the occurrence of postoperative pulmonary complications within the first 7 days after surgery, neuropathic pain at 3 months, and quality of life at 3 months. DISCUSSION: NSAIDs function as non-selective, reversible inhibitors of the cyclooxygenase enzyme and play a role in a multimodal pain management approach. While there are recommendations supporting the use of NSAIDs in major non-cardiac surgery, recent guidelines do not favor their use in cardiac surgery. However, this is based on low-quality evidence. Major concerns regarding NSAID use in cardiac surgery patients are potential increase in postoperative bleeding or AKI. However, few studies support the possible use of NSAIDs without the risk of bleeding and/or AKI. Also, in a recent French survey, many anesthesiologists reported using NSAIDs in cardiac surgery. To date, no large randomized study has been conducted to evaluate the efficacy of NSAIDs in the management of postoperative pain in cardiac surgery. The expected outcome of this study is an improvement in the management of acute postoperative pain in cardiac surgery with a multimodal strategy including the use of NSAIDs. TRIAL REGISTRATION: ClinicalTrials.gov NCT06381063. Registered on April 24, 2024.

Prescription Digital Therapeutics for Substance Use Disorder in Primary Care: Mixed Methods Evaluation of a Pilot Implementation Study.

BACKGROUND: Delivering prescription digital therapeutics (ie, evidence-based interventions designed to treat, manage, or prevent disorders via websites or smartphone apps) in primary care could increase patient access to substance use disorder (SUD) treatments. However, the optimal approach to implementing prescription digital therapeutics in primary care remains unknown. OBJECTIVE: This pilot study is a precursor to a larger trial designed to test whether implementation strategies (practice facilitation [PF] and health coaching [HC]) improve the delivery of prescription digital therapeutics for SUDs in primary care. This mixed methods study describes outcomes among patients in the 2 pilot clinics and presents qualitative findings on implementation. METHODS: From February 10 to August 6, 2021, a total of 3 mental health specialists embedded in 2 primary care practices of the same integrated health system were tasked with offering app-based prescription digital therapeutics to patients with SUD. In the first half of the pilot, implementation activities included training and supportive tools. PF (at 1 clinic) and HC (at 2 clinics) were added in the second half. All study analyses relied on secondary data, including electronic health records and digital therapeutic vendor data. Primary outcomes were the proportion of patients reached by the prescription digital therapeutics and fidelity related to ideal use. We used qualitative methods to assess the adherence to planned activities and the barriers and facilitators to implementing prescription digital therapeutics. RESULTS: Of all 18 patients prescribed the apps, 10 (56%) downloaded the app and activated their prescription, and 8 (44%) completed at least 1 module of content. Patients who activated the app completed 1 module per week on average. Ideal use (fidelity) was defined as completing 4 modules per week and having a monthly SUD-related visit; 1 (6%) patient met these criteria for 10 weeks (of the 12-week prescription period). A total of 5 (28%) patients had prescriptions while HC was available, 2 (11%) were successfully contacted, and both declined coaching. Clinicians reported competing clinical priorities, technical challenges, and logistically complex workflows in part because the apps required a prescription. Some pilot activities were impacted by staff turnover that coincided with the COVID-19 pandemic. The facilitators to implementation were high engagement and the perception that the apps could meet patient needs. CONCLUSIONS: The pilot study encountered the barriers to implementing prescription digital therapeutics in a real-world primary care setting, especially staffing shortages, turnover, and competing priorities for clinic teams. The larger randomized trial will clarify the extent to which PF and HC improve the implementation of digital therapeutics. TRIAL REGISTRATION: ClinicalTrials.gov NCT04907045; https://clinicaltrials.gov/study/NCT04907045.

Epidemiology of epilepsy in Wulu County, an onchocerciasis-endemic area in South Sudan.

Background: We sought to investigate the epidemiology of epilepsy in Wulu County (Lakes State, South Sudan), and document the onchocerciasis transmission status in the study villages. Methods: In February 2024, a community-based epilepsy study was conducted Wulu County and participants were surveyed via a door-to-door approach in five villages, namely: Kombi, Makundi Center, Tonjo, War-Pac, and Woko. All village residents were asked about ivermectin intake during the 2023 round of community-directed treatment with ivermectin (CDTI). In addition, children aged 3-9 years were tested for Ov16 antibodies using a rapid diagnostic test. Epilepsy diagnosis in screened individuals was confirmed by a physician. Results: We surveyed 1355 persons in the five study sites. The overall CDTI coverage in 2023 was 67.4 %. Fifty-five persons with epilepsy (PWE) were identified (prevalence 4.1 %) and a history of nodding seizures was noted in 11/55 (20 %) PWE. The mean age of PWE was 21.5 ± 9.6 years, with 32 (58.2 %) being males. Epilepsy onset frequently occurred under 5 years of age (38.6 % of cases). In two PWE, seizure onset occurred during the past 12 months (annual incidence: 147.6 per 100,000 persons). Twenty-nine PWE (52.7 %) were taking anti-seizure medicines, but only five were taking them daily. Overall, Ov16 seroprevalence in children aged 3-9 years (n = 119) was 15.1 % and differed across villages, peaking at 30.9 % in Woko village where epilepsy prevalence was also highest (7.1 %). Of the 35 recorded deaths during the past two years, 9 (25.7 %) occurred in PWE. Annual estimates for epilepsy mortality and fatality rates were 323.7 per 100,000 persons and 7031.3 per 100,000 PWE, respectively. Conclusion: High epilepsy prevalence was found in Wulu, particularly in villages with persistent onchocerciasis transmission. Frequent epilepsy onset among under-fives suggests that perinatal/early childhood etiologies are common. Appropriate measures should be instituted to prevent and treat epilepsy in Wulu villages.

3D Slicer reconstruction combined with neuroendoscopic keyhole approach for the treatment of cerebrospinal fluid rhinorrhea：2 cases report and literature review.

Background and importance: Explore the techniques, advantages and disadvantages of 3D Slicer reconstruction combined with transcranial neuroendoscopy in cerebrospinal fluid rhinorrhea surgery. Clinical presentation: We collected complete clinical data of two patients with cerebrospinal fluid rhinorrhea who underwent minimally invasive surgery using 3D Slicer reconstruction combined with transcranial neuroendoscopy through the supraorbital eyebrow arch keyhole approach in our hospital from June 2022 to May 2023. The patients were one male and one female, aged 50 and 63 years old. At the same time, a retrospective summary of relevant literature at home and abroad in recent years was conducted. 1 case had spontaneous cerebrospinal fluid rhinorrhea with secondary cribriform plate lesion, and the other 1 case had traumatic cerebrospinal fluid rhinorrhea. Both 2 patients were ineffective after long-term conservative treatment, and ultimately recovered after detailed preoperative evaluation and preparation and surgical treatment. Conclusion: Cerebrospinal fluid rhinorrhea is a challenging disease in neurosurgery, and improper management can lead to serious complications such as meningitis. Our team used 3D Slicer reconstruction combined with transcranial endoscopic minimally invasive keyhole surgery to treat cerebrospinal fluid rhinorrhea, achieving good results, proving that this combined technology has certain advantages and is a new surgical technique worth promoting. However, the widespread application and promotion of this technology in anterior skull base surgery still require comprehensive and reliable prospective clinical studies to test.

A discrete time-to-event model for the meta-analysis of full ROC curves.

The development of new statistical models for the meta-analysis of diagnostic test accuracy studies is still an ongoing field of research, especially with respect to summary receiver operating characteristic (ROC) curves. In the recently published updated version of the "Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy", the authors point to the challenges of this kind of meta-analysis and propose two approaches. However, both of them come with some disadvantages, such as the nonstraightforward choice of priors in Bayesian models or the requirement of a two-step approach where parameters are estimated for the individual studies, followed by summarizing the results. As an alternative, we propose a novel model by applying methods from time-to-event analysis. To this task we use the discrete proportional hazard approach to treat the different diagnostic thresholds, that provide means to estimate sensitivity and specificity and are reported by the single studies, as categorical variables in a generalized linear mixed model, using both the logit- and the asymmetric cloglog-link. This leads to a model specification with threshold-specific discrete hazards, avoiding a linear dependency between thresholds, discrete hazard, and sensitivity/specificity and thus increasing model flexibility. We compare the resulting models to approaches from the literature in a simulation study. While the estimated area under the summary ROC curve is estimated comparably well in most approaches, the results depict substantial differences in the estimated sensitivities and specificities. We also show the practical applicability of the models to data from a meta-analysis for the screening of type 2 diabetes.

Angiotensin-(1-7) infusion in COVID-19 patients admitted to the ICU: a seamless phase 1-2 randomized clinical trial.

BACKGROUND: The coronavirus-related disease (COVID-19) is mainly characterized by a respiratory involvement. The renin-angiotensin system (RAS) has a relevant role in the pathogenesis of COVID-19, as the virus enters host's cells via the angiotensin-converting enzyme 2 (ACE2). METHODS: This investigator-initiated, seamless phase 1-2 randomized clinical trial was conceived to test the safety and efficacy of continuous short-term (up to 7 days) intravenous administration of Angiotensin-(1-7) in COVID-19 patients admitted to two intensive care units (ICU). In addition to standard of care, intravenous administration of Angiotensin-(1-7) was started at 5 mcg/Kg day and increased to 10 mcg/Kg day after 24 h (Phase 1; open label trial) or given at 10 mcg/Kg day and continued for a maximum of 7 days or until ICU discharge (Phase 2; double-blind randomized controlled trial). The rate of serious adverse events (SAEs) served as the primary outcome of the study for Phase 1, and the number of oxygen free days (OFDs) by day 28 for Phase 2. RESULTS: Between August 2020 and July 2021, when the study was prematurely stopped due to low recruitment rate, 28 patients were included in Phase 1 and 79 patients in Phase 2. Of those, 78 were included in the intention to treat analysis, and the primary outcome was available for 77 patients. During Phase 1, one SAE (i.e., bradycardia) was considered possibly related to the infusion, justifying its discontinuation. In Phase 2, OFDs did not differ between groups (median 19 [0-21] vs. 14 [0-18] days; p = 0.15). When patients from both phases were analyzed in a pooled intention to treat approach (Phase 1-2 trial), OFDs were significantly higher in treated patients, when compared to controls (19 [0-21] vs. 14 [0-18] days; absolute difference -5 days, 95% CI [0-7] p = 0.04). CONCLUSIONS: The main findings of our study indicate that continuous intravenous infusion of Angiotensin-(1-7) at 10 mcg/Kg day in COVID-19 patients admitted to the ICU with severe pneumonia is safe. In Phase II intention to treat analysis, there was no significant difference in OFD between groups. Trial Registration ClinicalTrials.gov Identifier: NCT04633772-Registro Brasileiro de Ensaios Clínicos, UTN number: U1111-1255-7167.

Dimethyl Fumarate-Loaded Gellan Gum Hydrogels Can Reduce In Vitro Chemokine Expression in Oral Cells.

Dimethyl fumarate (DMF), originally proposed to treat multiple sclerosis, is considered to have a spectrum of anti-inflammatory effects that effectively control periodontitis, mainly when applied with a hydrogel delivery system. Chemokine expression by gingival fibroblasts is a significant driver of periodontitis; thus, hydrogel-based strategies to deliver DMF, which in turn dampen chemokine expression, are of potential clinical relevance. To test this approach, we have established a bioassay where chemokine expression is induced by exposing gingival fibroblast to IL1ß and TNFα, or with saliva. We show herein that DMF effectively reduced the expression of CXCL8, CXCL1, CXCL2, and CCL2-and lowered the phosphorylation of ERK and JNK-without affecting cell viability. This observation was confirmed by immunoassays with CXCL8. Consistently, the forced chemokine expression in HSC2 oral squamous epithelial cells was greatly diminished by DMF. To implement our hydrogel-based delivery system, gingival fibroblasts were cocultured with gellan gum hydrogels enriched for DMF. In support of our strategy, DMF-enriched gellan gum hydrogels significantly reduced the forced chemokine expression in gingival fibroblasts. Our data suggest that DMF exerts its anti-inflammatory activity in periodontal cells when released from gellan gum hydrogels, suggesting a potential clinical relevance to control overshooting chemokine expression under chronic inflammatory conditions.

Antibacterial Activity and Multi-Targeted Mechanism of Action of Suberanilic Acid Isolated from Pestalotiopsis trachycarpicola DCL44: An Endophytic Fungi from Ageratina adenophora.

Methicillin-resistant Staphylococcus aureus (MRSA) is a highly threatening foodborne pathogen capable of causing severe organ and life-threatening diseases. Over the past years, various commercial antibiotics have been used to treat MRSA infections. However, these commercial antibiotics have not yielded efficient results and also cause other side effects; therefore, there is a need for the development of effective alternatives to replace these commercial antibiotics. Suberanilic acid, an amide alkaloid obtained from the endophytic fungus Pestalotiopsis trachycarpicola DCL44, has been identified as a significant antimicrobial agent. However, its antibiotic properties on multi-drug-resistant bacteria such as MRSA have not been fully explored. Therefore, to investigate the potential antimicrobial mechanism of suberanilic acid against MRSA, a quantitative proteomics approach using tandem mass tagging (TMT) was used. The results obtained in the study revealed that suberanilic acid targets multiple pathways in MRSA, including disruption of ribosome synthesis, inhibition of membrane translocation for nutrient uptake (ABC transporter system), and causing dysregulation of carbohydrate and amino acid energy metabolism. These results provide new insights into the mechanism of action of suberanilic acid against MRSA and offer technical support and a theoretical basis for the development of novel food antimicrobial agents derived from endophytic fungal origin.

Impact of L-PRF on pain and healing outcomes in lower third molar surgery: a randomized split-mouth trial.

This study explored the effects of L-PRF on pain, soft tissue healing, periodontal condition, and post-extraction bone repair of mandibular third molars (3Ms). A randomized, prospective, triple-blind, split-mouth clinical trial was conducted with 34 volunteers. Eligible patients were randomly allocated into two treatments: G1 (without L-PRF), G2 (alveoli filled with L-PRF), in which the removal of bilateral 3Ms was performed at the same surgical time. Outcomes were assessed according to a visual analogue scale (pain), soft tissue scoring system (wound healing), periodontal probing of mandibular second molar. Bone repair was determined by volumetric analysis (ITK-SNAP software) and fractal analysis (ImageJ software). An intention-to-treat approach to Statistical analysis was used. L-PRF reduced pain in the 7-day postoperative follow-up (p = 0.019) and not only improved soft tissue healing after 1 month of follow-up (p = 0.021), but also probing depth (distal face) in 3 months postoperatively (p = 0.011). Significant alveolar reduction occurred in 3 months after surgery in both treatments (p < 0.05), however, this was more significant in G1 (p = 0.016). The fractal dimension showed no statistical differences. L-PRF improved postoperative clinical parameters of pain, soft tissue healing, and periodontal condition, suggesting that it has a beneficial effect on preserving the alveolar ridge and accelerating the initial repair process.

Exercise-based cardiac rehabilitation for adults with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, disrupts the heart's rhythm through numerous small re-entry circuits in the atrial tissue, leading to irregular atrial contractions. The condition poses significant health risks, including increased stroke risk, heart failure, and reduced quality of life. Given the complexity of AF and its growing incidence globally, exercise-based cardiac rehabilitation (ExCR) may provide additional benefits for people with AF or those undergoing routine treatment for the condition. OBJECTIVES: To assess the benefits and harms of ExCR compared with non-exercise controls for people who currently have AF or who have been treated for AF. SEARCH METHODS: We searched the following electronic databases: CENTRAL in the Cochrane Library, MEDLINE Ovid, Embase Ovid, PsycINFO Ovid, Web of Science Core Collection Thomson Reuters, CINAHL EBSCO, LILACS BIREME, and two clinical trial registers on 24 March 2024. We imposed no language restrictions. SELECTION CRITERIA: We included randomised clinical trials (RCTs) that investigated ExCR interventions compared with any type of non-exercise control. We included adults 18 years of age or older with any subtype of AF or those who had received treatment for AF. DATA COLLECTION AND ANALYSIS: Five review authors independently screened and extracted data in duplicate. We assessed risk of bias using Cochrane's RoB 1 tool as outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We assessed clinical and statistical heterogeneity by visual inspection of the forest plots and by using standard Chi² and I² statistics. We performed meta-analyses using random-effects models for continuous and dichotomised outcomes. We calculated standardised mean differences where different scales were used for the same outcome. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 20 RCTs involving a total of 2039 participants with AF. All trials were conducted between 2006 and 2024, with a follow-up period ranging from eight weeks to five years. We assessed the certainty of evidence as moderate to very low. Five trials assessed comprehensive ExCR programmes, which included educational or psychological interventions, or both; the remaining 15 trials compared exercise-only cardiac rehabilitation with controls. The overall risk of bias in the included studies was mixed. Details on random sequence generation, allocation concealment, and use of intention-to-treat analysis were typically poorly reported. Evidence from nine trials (n = 1173) suggested little to no difference in mortality between ExCR and non-exercise controls (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.76 to 1.49; I² = 0%; 101 deaths; low-certainty evidence). Based on evidence from 10 trials (n = 825), ExCR may have little to no effect on SAEs (RR 1.30, 95% CI 0.63 to 2.67; I² = 0%; 28 events; low-certainty evidence). Evidence from four trials (n = 378) showed that ExCR likely reduced AF recurrence (measured via Holter monitoring) compared to controls (RR 0.70, 95% CI 0.56 to 0.88; I² = 2%; moderate-certainty evidence). ExCR may reduce AF symptom severity (mean difference (MD) -1.59, 95% CI -2.98 to -0.20; I² = 61%; n = 600; low-certainty evidence); likely reduces AF symptom burden (MD -1.61, 95% CI -2.76 to -0.45; I² = 0%; n = 317; moderate-certainty evidence); may reduce AF episode frequency (MD -1.29, 95% CI -2.50 to -0.07; I² = 75%; n = 368; low-certainty evidence); and likely reduces AF episode duration (MD -0.58, 95% CI -1.14 to -0.03; I² = 0%; n = 317; moderate-certainty evidence), measured via the AF Severity Scale (AFSS) questionnaire. Moderate-certainty evidence from six trials (n = 504) showed that ExCR likely improved the mental component summary measure in health-related quality of life (HRQoL) of the 36-item Short Form Health Survey (SF-36) (MD 2.66, 95% CI 1.22 to 4.11; I² = 2%), but the effect of ExCR on the physical component summary measure was very uncertain (MD 1.75, 95% CI -0.31 to 3.81; I² = 52%; very low-certainty evidence). ExCR also may improve individual components of HRQoL (general health, vitality, emotional role functioning, and mental health) and exercise capacity (peak oxygen uptake (VO2peak) and 6-minute walk test) following ExCR. The effects of ExCR on serious adverse events and exercise capacity were consistent across different models of ExCR delivery: centre compared to home-based, exercise dose, exercise only compared to comprehensive programmes, and aerobic training alone compared to aerobic plus resistance programmes. Using univariate meta-regression, there was evidence of significant association between location of trial and length of longest follow-up on exercise capacity. AUTHORS' CONCLUSIONS: Due to few randomised participants and typically short-term follow-up, the impact of ExCR on all-cause mortality or serious adverse events for people with AF is uncertain. ExCR likely improves AF-specific measures including reduced AF recurrence, symptom burden, and episode duration, as well as the mental components of HRQoL. ExCR may improve AF symptom severity, episode frequency, and VO2peak. Future high-quality RCTs are needed to assess the benefits of ExCR for people with AF on patient-relevant outcomes including AF symptom severity and burden, AF recurrence, AF-specific quality of life, and clinical events such as mortality, readmissions, and serious adverse events. High-quality trials are needed to investigate how AF subtype and clinical setting (i.e. primary and secondary care) may influence ExCR effectiveness.