Early Withdrawal Research Articles

Significant Long-Term Prevention of High Sensitization After Kidney Allograft Failure by Maintaining Calcineurin Inhibitor-Based Immunosuppression.

Broad national or international programs contribute to mitigating the expected longer waiting list (WL) time for sensitized patients but with minor benefits for highly sensitized subjects. Therefore, strategies to prevent high sensitization are urgently required. In this study, we investigated the risk of developing highly sensitized patients with different immunosuppressive (IS) handling after kidney allograft failure (KAF). Data from 185 patients with KAF, retransplanted/relisted from 2010 to 2020 in two regions of Italy that share the same regional WL, were analyzed. Patients were categorized according to IS management at 12 months after KAF as follows: patients maintaining IS with calcineurin inhibitors (CNI) (late withdrawal group [LWG], n = 58) and those who withdrew all IS therapy or were on steroids only (early withdrawal group [EWG], n = 127). Patients in the LWG showed lower panel reactive antibodies (PRA) at 12 (29.0%vs. 85.5%, p < 0.001) and 24 months (61.0%vs. 91.0%, p = 0.001), reduced risk of high sensitization (PRA ≥90%) at 12 (9.4%vs. 40.7%, p < 0.001, OR = 0.15) and 24 months (25.6%vs. 57.3%, p = 0.001, OR = 0.26) and almost no very high sensitization (PRA ≥ 98%) at 12 months (1.9%vs. 18.6%, p=0.003, OR=0.08) after KAF. In the LWG subgroup analysis, patients who maintained IS for up to 24 months after KAF did not show very high sensitization. The LWG showed shorter active WL times (406vs. 813 days, p = 0.001) without an increased risk of complications. CNI maintenance for at least 12 months after KAF could be a useful approach to prevent high sensitization and reduce WL times in patients who are offered retransplantation, without a higher burden of complications.

RAZLOGI ZA PREKINITEV ŠPORTNE POTI ODRASLIH ARMENSKIH ORODNIH TELOVADCEV

Abstract The information about the reasons for sports career (SC) termination among athletes is of significant importance, as it provides a theoretical foundation to prevent early withdrawal. A sociological survey was conducted among 76 former male artistic gymnasts who have ended their careers to determine the causes of SC termination. As a result, 11 different reasons for SC termination were identified. The most frequent reasons include sports injuries (35.52%), mandatory military service (31.57%), and employment (25.0%). The least mentioned reasons are coach-related issues (5.26%), health problems (2.63%), and age (2.63%). The survey offers a broader understanding of why Armenian athletes terminate their sports careers. This insight will enable the governing bodies of Armenian gymnastics and sports to provide targeted assistance to adult artistic gymnasts, helping to prevent early withdrawal in the future.

Innovative development of water transport enterprises as a branch of high-tech industry

The article is devoted to the innovative development of enterprises of high-tech products on the example of water transport. Water transport refers to high-tech products and in this regard, its production has a rather complex production logistics (intellectual, supply, organizational, financial, information, personnel, innovation, etc.) [2-3]. In this regard, the search for promising directions in the development of high-tech products becomes particularly relevant and important: a real opportunity to implement research and innovation and investment projects, the implementation of which will bring enterprises of the high-tech industry for the production of water transport to leading positions not only in the national economy, but also in the world [4-6]. This determines the importance of monitoring research projects as a vector for the development of innovative production at two levels: product (high-tech products) and technological (innovative technologies) [7]. The innovative vector of development of enterprises of high-tech products allows the actual efficiency of high-tech production to be brought closer to full potential efficiency, other things being equal, production factors in a short time of the stage of research and scientific and technical development of the life cycle of products of shipbuilding products, which is given the main attention in the article [6-7]. At the same time, an innovative approach, introducing products into industrial circulation, naturally provides conditions for further scientific and technical (innovative) development of both the products themselves and technologies (in other words, early introduction of products ensures its early withdrawal: the speed of the wheel of economic efficiency of production activities). When the actual efficiency of the limit of the potential efficiency of technological production is reached, in accordance with the laws of synergy, there is a leap, an innovative transition to a new (next, subsequent) level of potential efficiency of production of high-tech products, which naturally puts forward new requirements of an innovative nature to production. Otherwise, production due to the (law) moral aging of industrial products is doomed to bankruptcy due to the so-called factor of technological flexibility of production (TG). Which (TG), if organizationally taken into account in the economic activities of enterprises as forecasting, planning and management (design and innovation management), forms (economically ensures) the sustainable functioning and development of enterprises of high-tech products in modern conditions (the wheel of economic efficiency of production activities is the human factor): in the market model of the state transformation of a product (product) into a commodity and contracting.

LGG-09. REBOUND GROWTH AFTER MAPKI WITHDRAWAL INVOLVES RAPID MAPK REACTIVATION AND CYTOKINE-MEDIATED MICROGLIA RECRUITMENT IN PEDIATRIC LOW-GRADE GLIOMA MODEL

Abstract Patients with pediatric low-grade gliomas (pLGG), the most common primary brain tumor in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge. Four patient-derived pLGG models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset of the rebound model encompassing different MAPKi withdrawal timepoints was generated using RNA sequencing and LC-MS/MS based phospho-/proteomics to investigate possible driving mechanisms of rebound growth. Following in vitro validation, putative rebound driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model. Of the tested models, BT-40 (BRAFV600E, CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal, characterized by faster cell regrowth after MAPKi withdrawal compared to standard-of-care chemotherapy. Using this model, we observed MAPK pathway reactivation within hours after withdrawal, associated with a transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels. Additionally, we observed increased expression and secretion of cytokines (in particular CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal (at least until 24 h). While increased cytokine expression did not affect response to MAPKi or rebound growth upon withdrawal in an autocrine manner, increased attraction of microglia cells mediated by these cytokines was observed. MAPK pathway reactivation during rebound growth and increased expression of CX3CL1 and CXCL10 induced by MAPKi treatment could further be confirmed in vivo. Taken together, these data indicate a rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound driving mechanism. Furthermore, increased microglia recruitment during MAPKi treatment and withdrawal, mediated by cytokines, may play a role in response to MAPKi treatment and rebound growth upon withdrawal, warranting further evaluation.

Housing and mental health inequalities during COVID-19: the role of income and housing support measures

The COVID-19 pandemic negatively impacted people’s mental health and wellbeing. Using a national dataset of >11,000 Australians collected before and during the first two years of the pandemic, this study examines housing and mental health effects of COVID-19, and the extent to which access to government income support (social security measures, crisis payments and wage subsidy), early superannuation withdrawal, mortgage and rent relief, and tenant eviction moratoriums offered protection. Results show that the mental health gap between private rental and more secure housing tenures and between good- and poor-quality housing widened during the pandemic. Government income support provided a social safety net and was important in buffering housing instability especially when strong eviction moratoriums were lacking. Mortgage relief measures were associated significantly lower risks of housing affordability stress. Strong eviction moratoriums were effective in reducing risks of residential instability and forced moves. The pandemic exposed health vulnerabilities generated from people’s housing circumstances, reinforcing the need for public policies to address these social inequities to improve health and wellbeing. Findings emphasise the importance of tenure security, housing quality and enforcement of rental market interventions during disasters and identify the benefits of policies providing income support and strong eviction protection.

Final overall survival results from phase 3 SPOTLIGHT study evaluating zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin 18 isoform 2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.

4036 Background: The phase 3 SPOTLIGHT study showed statistically significant improvements in progression-free survival (PFS) and overall survival (OS) with 1L zolbetuximab + modified folinic acid, 5-FU, and oxaliplatin regimen (mFOLFOX6) vs placebo (PBO) + mFOLFOX6 in pts with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma at prespecified interim and later updated analyses. We present the prespecified final OS analysis. Methods: Pts were randomly assigned 1:1 to zolbetuximab IV 800 mg/m2 (cycle 1, day [D] 1) followed by 600 mg/m2 (every 3 weeks) + mFOLFOX6 IV (D1, D15, D29) for four 42-day cycles or to PBO + mFOLFOX6; pts without PD continued with zolbetuximab or PBO, + folinic acid and 5-FU at investigator’s discretion, until PD or discontinuation criteria were met. The primary endpoint was PFS per RECIST v1.1 by IRC. OS was a key secondary endpoint; additional secondary endpoints were objective response rate (ORR) and safety. Ad hoc analyses examined PFS and OS in per-protocol set population (PPS; pts adherent to protocol) and time to progression (TTP) by best overall response (BOR). Results: At data cutoff (September 8, 2023), 565 pts were assigned to zolbetuximab arm (n = 283) or PBO arm (n = 282). In zolbetuximab vs PBO arms, median follow-up was 18.04 vs 17.91 mo for PFS and 33.28 vs 31.38 mo for OS, respectively. Efficacy results are summarized in Table. Median PFS and OS were significantly longer in zolbetuximab vs PBO arms. Separation of PFS and OS curves occurred earlier in the PPS population analysis (excluded majority of early withdrawals) compared with the ITT population. ORR was similar between treatment arms in ITT and pts with measurable lesions – despite this, TTP for patients with BOR of CR/PR was numerically longer in zolbetuximab vs PBO arms. Safety and tolerability were maintained with no new findings. Conclusions: Zolbetuximab + mFOLFOX6 continued to demonstrate statistically significant and clinically meaningful improvement in PFS and OS vs PBO + mFOLFOX6, with no new safety signals—supporting zolbetuximab + mFOLFOX6 as a new standard of care option for 1L treatment of pts with CLDN18.2+, HER2–, LA unresectable or mG/GEJ adenocarcinoma. Clinical trial information: NCT03504397 . [Table: see text]

Predictors of adherence to follow-up and treatment success in childhood obesity

IntroductionManagement of childhood obesity, based upon behavioural, physical activity and dietary guidance, usually achieves limited success and is hindered by a high attrition rate. The identification of potential predictors of either weight loss or early weight management attrition could help develop personalised management plans in order to improve patient outcomes. Patients and methodsWe conducted a retrospective study in a cohort of 1300 patients with obesity managed in speciality clinics for up to 5 years with outpatient conservative treatment. We studied the family background and personal characteristics (demographic, behavioural, psychosocial, anthropometric and metabolic) of patients who dropped out before completing the first year of the programme and patients who achieved significant weight loss, with a separate analysis of patients who achieved substantial reductions in weight compared to the rest of the cohort. ResultsThe mean age of the patients in the cohort was 10.46 years (SD, 3.48) the mean BMI z-score 4.01 (SD, 1.49); 52.8% of the patients were male, 53.3% were prepubertal, 75.8% were Caucasian and 19% Latin. We found a higher proportion of Latinla ethnicity and compulsive eating in the group of patients with early attrition from the weight management follow-up. In the group of patients with substantial weight loss, a greater proportion were male, there was a higher frequency of dietary intake control at home and obesity was more severe, and the latter factor was consistently observed in patients who achieved substantial weight loss at any point of the follow-up. ConclusionsSome family and personal characteristics in childhood obesity are associated with an increased risk of early withdrawal from follow-up or a greater probability of successful outcomes; however, the predictive value of these variables is limited.

국민참여재판 활성화를 위한 실무적 제안

The current public participation trial system is facing a crisis due to poor performance. If looking at detailed indicators, the situation is serious. This is because the number of applications for public participation trials themselves is being maintained, but the number of enforcement cases is decreasing due to an increase in courts’ exclusion decisions and defendants’ early withdrawals. This can be seen as proof that public participation trials are not easily accepted within the criminal justice process. Since public participation trials are alien to our criminal justice system, we are bound to face many difficulties until this system is fully established. Various methods have been proposed so far to overcome these and activate public participation trials. These include abolition of the defendant application principle, introduction of the mandatory public participation trial principle, restriction on prosecutorial appeals against unanimous acquittal verdicts, and granting of binding forces to jury verdicts. In this paper, the above suggestions, which have already been studied a lot, are not mentioned again. Rather, very microscopic and technical methods are proposed. Above all, constant communication and explanation are needed to relieve the defendant's vague anxiety about the participatory trial. Legally, it is possible to consider continuing the participatory trial even after the defendant withdraws the application. When an application for a participatory trial is filed, the court should not exclude it based on vague provisions. When making an inevitable decision to exclude, it should specify as detailed reasons as possible. In addition, it is considered necessary to proceed with the trial as quickly as possible to reduce the fatigue and burden of courts and jurors performing participatory trials. Therefore, the jury selection method should be unified in a way that allows quick jury selection. Most important of all, it is to efficiently conduct a written investigation by the prosecutor, which takes a very long time in a participatory trial. It is necessary to prepare active alternatives, such as issuing records to the jury in the form of electronic records. This can be said to be a kind of emergency prescription, not a fundamental solution. Nevertheless, the reason for making some suggestions in this paper is because I think an immediate response to recent public participation trials is required. If the current downturn continues, it is difficult to rule out the risk that the public participation trial will go to the process of factual abolition. I hope that the public participation trial will soon be activated above a certain level, and that it will be reborn as a more advanced system beyond normalization.

The Impact of the Online Learning Readiness Self-Check Survey with Australian Tertiary Enabling Students

This study reports on two key aspects relating to the use of the Online Learning Readiness Self-Check (OLRSC) survey, which has been proposed as identifying non-traditional students’ readiness for online learning, and their strengths and weaknesses in six key areas. The first aspect validates the use of the instrument based on data from 199 students engaged in an online tertiary enabling course at a regional university in Australia. Factor analysis verified the scale structure of the instrument; however, two items were removed prior to the final analysis due to low communality and/or high cross loading with other items. This is followed by an examination of whether the instrument might be useful for the early identification of students who are at risk of disengagement from the enabling program. While it was hypothesised that the instrument, which measured factors such as the quality of interaction with peers and instructors, their capacity to manage technology and how well they managed learning, should have been a useful tool to identify early disengagement, the hypothesis was not supported. No significant associations were identified between any of the instrument’s scales and early withdrawal from the course or completion of the first unit of study. Future recommendations for educators are made with a view to improving student engagement.

Outcome Trajectories after Intracerebral Hemorrhage.

Spontaneous intracerebral hemorrhage (ICH) is the most morbid of all stroke types with a high early mortality and significant early disability burden. Traditionally, outcome assessments after ICH have mirrored those of acute ischemic stroke, with 3 months post-ICH being considered a standard time point in most clinical trials, observational studies, and clinical practice. At this time point, the majority of ICH survivors remain with moderate to severe functional disability. However, emerging data suggest that recovery after ICH occurs over a more protracted course and requires longer periods of follow-up, with more than 40% of ICH survivors with initial severe disability improving to partial or complete functional independence over 1 year. Multiple other domains of recovery impact ICH survivors including cognition, mood, and health-related quality of life, all of which remain under studied in ICH. To further complicate the picture, the most important driver of mortality after ICH is early withdrawal of life-sustaining therapies, before initiation of treatment and evaluating effects of prolonged supportive care, influenced by early pessimistic prognostication based on baseline severity factors and prognostication biases. Thus, our understanding of the true natural history of ICH recovery remains limited. This review summarizes the existing literature on outcome trajectories in functional and nonfunctional domains, describes limitations in current prognostication practices, and highlights areas of uncertainty that warrant further research.

#2205 Varying practice patterns in prevention, screening and treatment of diabetes early after kidney transplantation: a European survey

Abstract Background and Aims Although post-transplant diabetes mellitus (PTDM) is a common complication after kidney transplantation, there is no consensus on preventive measures, nor on the optimal screening and treatment strategy. Method The European Renal Association—DESCARTES working group—distributed a web-based survey to transplant centers across Europe to gather information on the risk assessment, screening procedures and management practices for the prevention and treatment of PTDM in kidney-transplant recipients. Results Answers were obtained from 121 transplant centers across 15 European countries. Screening practices for pre-existing diabetes during the transplant work-up varied considerably, with only 13% of centers using the recommended oral glucose tolerance test (OGTT), while 14% did not screen at all. At transplantation, 19% (n = 23) of centers tailored the immunosuppressive regimen based on perceived PTDM risk, employing strategies like cyclosporin use (12/23), or early steroid withdrawal (2/23). Fifty-two percent adopted strict glycemic control with long-acting insulin in the first days post-transplant. Sixty-eight percent had defined screening protocols for early PTDM (45 days—six months), mostly based on fasting glycemia and/or HbA1c, while only 8/82 incorporated an OGTT. Changes in immunosuppression were considered by 41% in cases of early hyperglycemia (&amp;lt;45 days) and by 58% in established PTDM (&amp;gt;45 days). Besides insulin therapy, dipeptidyl peptidase-4 (DPP4) inhibitors and metformin were most frequently used to manage early hyperglycemia (&amp;lt;45 days) and PTDM (&amp;gt;45 days). Conclusion This European survey underscores significant variation in PTDM prevention, screening, and treatment practices, emphasizing the imperative for clearer guidance in approaching this complication.

#1347 Development and validation of a nomogram for predicting complete kidney function recovery after drug-induced acute interstitial nephritis

Abstract Background and Aims Drug-induced acute interstitial nephritis (DI-AIN) represents a common cause of acute kidney injury. Early withdrawal of the culprit drug along with corticosteroid therapy (CS) remains the mainstay of treatment. Despite this, up to 50% of patients may not fully recover kidney function after DI-AIN. The aims of this study were to develop and externally validate a predictive nomogram to assess the probability of complete recovery (CR) of kidney function at 6 months after treatment. Method Multicenter, retrospective, observational study in 13 nephrology departments belonging to the GLOSEN group. Patients with biopsy proven DI-AIN treated with CS between 1996-2023 were included. Other potential causes of AIN such as infections or systemic diseases were carefully ruled out. Dataset was randomly divided into training group (n = 164) and validation group (n = 60). The least absolute shrinkage and selection operator (LASSO) regression was used to screen the main predictors of CR (serum creatinine value &amp;lt;25% of the last value before DI-AIN), and used to build the nomogram. Accuracy of the nomogram was assessed by discrimination and risk calibration, in the training and validation sets. Results The study group comprised 224 patients with DI-AIN, of whom: 51 (31%) in the training group and 19 (32%) in the validation set, achieved CR at 6 months after treatment with CS. Median age was 70 (IQR 57–76), and 115 (51%) were males. The clinical characteristics were well balanced between the training and validation data sets. The selected variables by LASSO were age (under/above 65 years), gender, degree of interstitial fibrosis and time to CS initiation (under/above 7 days). Based on multivariable logistic regression model, a nomogram was developed for assessing the probability of CR (Fig. 1). The area under the curve (AUC) of the nomogram was 0.809 (95% CI 0.721–0.880) indicating a good discriminative power. Bootstrap self- sampling was performed 1000 times for validation of the nomogram model. The AUC was 0.837 (95 % CI: 0.705–0.931), indicating good predictive stability. Calibration plot revealed that the predicted outcomes aligned well with the observations. Decision curve analysis (DCA), and clinical impact curve analysis (CICA) suggested that the model had clinical benefit. Conclusion We constructed and validated a practical nomogram with good discrimination and calibration, to predict the probability of CR of kidney function at 6 months in DI-AIN treated with corticosteroids. This clinical tool can provide clinicians with an estimate of kidney prognosis and can potentially assist them in titrating the intensity and duration of corticosteroid therapy.

Early Feeding Strategy Mitigates Major Physiological Dynamics Altered by Heat Stress in Broilers.

Heat stress is one of the stressors that negatively affect broiler chickens, leading to a reduction in production efficiency and profitability. This reduction affects the economy in general, especially in hot and semi-hot countries. Therefore, improving heat tolerance of broiler chicks is a key to sustained peak performance, especially under adverse environmental heat stress conditions. The present study investigated three early feed withdrawal regimes (FWD) as a potential mitigation for thermal stress exposure. A total of 240 unsexed one-day-old Cobb-500 chicks were randomly recruited to one of four experimental groups using a completely randomized design (10 birds × 6 replicates). The experimental groups included the control group with no feed withdrawal (control), while the other three groups were subjected to early feed withdrawal for either 24 h on the 5th day of age (FWD-24), 12 h on the 3rd and 5th day of age (FWD-12), or 8 h on the 3rd, 4th, and 5th day of age (FWD-8), respectively. Production performance was monitored throughout the experiment. Meanwhile, blood and liver samples were taken at the end of the experimental period to evaluate major physiological dynamic changes. Our findings demonstrated that under chronic heat stress conditions, FWD treatments significantly improved broilers' production performance and enhanced several physiological parameters compared with the control. Serum levels of thyroid hormones were elevated, whereas leptin hormone was decreased in FWD groups compared with the control. Moreover, serum total protein, globulin, and hemoglobin levels were higher, while total cholesterol and uric acid were lower in the FWD groups. Furthermore, FWD groups showed significantly higher antioxidant marker activity with a significantly lower lipid peroxidation level. Immunoglobulin levels, lysozyme, complement factor C3, and liver heat shock protein 70 (HSP70) concentration were also elevated in FWD compared with the control. Also, serum interleukin-1β (IL-1β) and interferon-gamma (IFN-γ) significantly increased with FWD. Based on our findings, early feed withdrawal can be applied as a promising non-invasive nutritional strategy for broilers reared under chronic heat stress conditions. Such a strategy promotes the alleviation of the deleterious effects of heat stress on broiler performance, immunity, and redox status, owing to the onset of physiological adaptation and the development of thermotolerance ability.

The impact of early withdrawal on superannuation balance at retirement: Evidence from Australia

AbstractThis study examines the effect of the early tax‐free release of the superannuation (ERS), which was introduced as a financial stimulus to counter the economic havoc created by the COVID‐19 pandemic, on Australians' superannuation retirement balances. By considering 2800 scenarios based on individuals' working industries, age, withdrawal amounts, and asset allocation strategies, we find that individuals with non‐aggressive asset allocation strategies may struggle to reach the minimum required superannuation balance for a comfortable lifestyle in retirement if they opt‐in for the ERS. This impact is more evident for individuals employed in certain industries such as accommodation and food, and retail trade.

Short-term functional outcomes of patients with acute intracerebral hemorrhage in the native and expatriate population.

Functional outcomes in patients with intracerebral hemorrhage (ICH) have not been well characterized in the Middle East and North Africa Region. We report the 30 and 90-day clinical outcomes in the native and expatriate of Qatar with ICH. We evaluated the Glasgow Coma Scale (GCS), NIHSS, and imaging in the Qatar Stroke Registry (2013-22). The outcome measures were a modified Rankin Scale (mRS) at 90 days and mortality at 30 and 90 days. Unfavorable outcome was defined as mRS of 4-6. We performed non-parametric ROC analyses to measure the concordance index (C-index) to assess the goodness-of-fit of ICH score for predicting 30 day and 90-day mortality and functional outcome. 1,660 patients (median age of 49 (41.5-58) years; male 83.1%, expatriates 77.5%) with ICH, including supratentorial deep in 65.2%, cortical in 16.2%, infratentorial 16% and primary intraventricular in 2.5% were studied. The median baseline ICH volume was 7.5 (3.2-15.8) ml. An unfavorable outcome was seen in 673 (40.5%) patients at 90 days. The unfavorable 90-day outcome (mRS 4-6) was 49.2% in the native population vs. 44.4% in Africans, 39.0% in South Asian, 35.3% in Far Eastern, and 7.7% in Caucasians, p < 0.001. Mortality at 30 days and 90 days was 10.4 and 15.1%. Increasing age [OR (95% CI), 1.02 (1.00-1.03)], lower GCS [0.77 (0.73-0.80)], prior use of antiplatelet medications [1.82 (1.19-2.08)], higher ICH volume [1.03 (1.02-1.04)], and presence of any intraventricular hemorrhage [1.57(1.19-2.08)], were associated with unfavorable outcome. In this relatively younger ICH cohort more than 75% were expatriates. The ICH volume, 90-day unfavorable outcome and mortality was lower in the expatriates compared to the local Arab population, likely related to the younger age and smaller size of the hemorrhages. Prognostic scoring systems may have to be modified in this population to avoid early withdrawal of care.

Dysphoric milk ejection reflex - call for future trials.

Dysphoric milk ejection reflex is a condition that causes an abrupt emotional downturn during the initial moments of milk ejection in a breastfeeding mother. Depression, anxiety, hopelessness, anger, irritability, homesickness, and stomach hollowness are all possible symptoms. The exact cause of D-MER remains unknown. However, it is proposed that it is caused by an alteration in oxytocin signaling response where secretion of oxytocin upregulates the stress response instead of its downregulation. Activation of the defensive response of the mother by oxytocin during breastfeeding, disruption in dopamine levels, and activation of vasopressin-regulated pathways are other probable causes. Due to a lack of awareness, this phenomenon is easily misdiagnosed as postpartum depression and aversion by many healthcare professionals. Its prevalence in various populations of the world remains unknown due to the lack of research studies conducted in these populations. While no medically approved therapeutic strategy is available, supportive techniques such as maintaining a healthy diet, mental distraction, relaxation methods, and increasing skin-to-skin contact can help alleviate dysphoria during breastfeeding. However, due to a lack of D-MER research, specific challenges exist regarding early withdrawal from breastfeeding and women's help-seeking attitude toward perinatal mental health.

Clinical features of drug reaction with eosinophilia and systemic symptoms: A retrospective study in a reference centre of dermatology in Madagascar

AbstractBackgroundDrug reaction with eosinophilia and systemic symptoms (DRESS) is drug‐induced hypersensitivity reaction that can have fatal complications. Three sets of diagnostic criteria have been proposed, however, consensus is lacking.ObjectivesThis study aimed to describe the causative agents, severity, and the clinical course of patients with DRESS in Antananarivo, Madagascar.MethodsA cross‐sectional study was conducted in patients seen for DRESS, in the department of dermatology at the University Hospital Antananarivo, Madagascar from 2014 to 2022. European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) criteria was used for the diagnosis. Demographic data, latency periods, clinical and laboratory findings, culprit drugs, and outcomes were assessed.ResultsA total of 24 patients were included. Fifteen patients were female. The three most common culprit drugs were carbamazepine (17 patients), phenobarbital (2 patients), and ampicilline (2 patients). Median onset time (interquartile range) was 20 days (range: 7–62 days). Skin rash was present in all patients, and fever in 18 patients. A total of 12 patients showed two or more internal organs involved. Liver and kidney injuries were the most common visceral manifestation. All patients had eosinophilia. Fifteen patients received systemic corticosteroids. Two mortality cases were reported due to DRESS‐related fulminant liver failure and to nosocomial respiratory infection. Mortality was associated with higher eosinophilia (p = 0.03), higher creatininemia (p = 0.04), and shorter time of latency (p = 0.04).ConclusionsOur study show that DRESS is associated with severe morbidity. Early detection and withdrawal of the culprit dru gis crucial to save life and reduce morbidity.

Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines

IntroductionPatients with pediatric low-grade gliomas (pLGGs), the most common primary brain tumors in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge.MethodsFour patient-derived pediatric glioma models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset (RNA sequencing and LC-MS/MS based phospho-/proteomics) was generated to investigate possible rebound-driving mechanisms. Following in vitro validation, putative rebound-driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model.ResultsOf the tested models, only a BRAFV600E-driven model (BT-40, with additional CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal. Using this model, we identified a rapid reactivation of the MAPK pathway upon MAPKi withdrawal in vitro, also confirmed in vivo. Furthermore, transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels, was observed in vitro. Additionally, we detected increased expression and secretion of cytokines (CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal. While increased cytokine expression did not have tumor cell intrinsic effects, presence of these cytokines in conditioned media led to increased attraction of microglia cells in vitro.ConclusionTaken together, these data indicate rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound-driving mechanism. Furthermore, increased secretion of microglia-recruiting cytokines may play a role in treatment response and rebound growth upon withdrawal, warranting further evaluation.

Continuous immunosuppression is required for suppressing immune responses to xenografts in non-human primate brains.

Continuous immunosuppression has been widely used in xenografts into non-human primate brains. However, how immune responses change after transplantation in host brains under continuous immunosuppressive administration and whether immunosuppression can be withdrawn to mitigate side effects remain unclear. Human induced neural stem/progenitor cells (iNPCs) have shown long-term survival and efficient neuronal differentiation in primate brains. Here, we evaluate the immune responses in primate brains triggered by human grafts. The results show that the immune responses, including the evident activation of microglia and the strong infiltration of lymphocytes (both T- and B-cells), are caused by xenografts at 4months post transplantation (p.t.), but significantly reduced at 8months p.t. under continuous administration of immunosuppressant Cyclosporin A. However, early immunosuppressant withdrawal at 5months p.t. results in severe immune responses at 10months p.t. These results suggest that continuous long-term immunosuppression is required for suppressing immune responses to xenografts in primate brains.

РЕЦИДИВ ПРЕСТУПЛЕНИЙ КАК УГОЛОВНО-ПРАВОВОЕ ПОСЛЕДСТВИЕ СУДИМОСТИ: ПРОТИВОРЕЧИЯ РОССИЙСКОГО УГОЛОВНОГО ЗАКОНОДАТЕЛЬСТВА

Criminal liability continues to have an impact on the convicted person even after serving a criminal sentence until the repayment of the criminal record or its early withdrawal. As a criminal consequence, a criminal record is one of the main factors contributing to the formation of recidivism, recidivism. The question arises about the correctness of the content of the specified criminal law consequence, its contradiction to some principles of criminal law. The article analyzes the problems associated with the existence of criminal law norms that dictate the further application of criminal law to citizens who are in the status of convicts. The question is raised that these norms do not fully correspond to the principles of justice and equality of citizens before the law. The author has studied the recurrence of crimes, penitentiary relapse as one of the criminal consequences of a criminal record, and analyzed the growth of recidivism. The data of judicial statistics and statistics of the Ministry of Internal Affairs of Russia are analyzed. The analysis concluded that Article 86 of the Criminal Code of the Russian Federation has many contradictions that affect the number of repeat offenses. The author’s solution to the problem of setting the repayment dates of a criminal record is proposed.