Awareness of Current Surgical Practice for Congenital Scoliosis and Optimal Timing of Treatment Among Physicians and Patients' Families in Saudi Arabia.

BACKGROUND: Congenital scoliosis (CS) is a developmental spinal deformity characterized by an abnormal curvature of the spine, affecting one in 1,000 births. The mainstay of treatment involves either observation or surgery in significant curve progression. The optimal timing of surgical intervention is debated, with early intervention preferred. Therefore, understanding physicians' and patients' families' perspectives is crucial for optimizing surgical outcomes in CS. OBJECTIVE: To assess the awareness and knowledge of physicians and patients' families regarding current, as well as new surgical practices and the optimal timing of treatment for CS. METHODS: A cross-sectional study was conducted in Saudi Arabia using an online self-administered questionnaire distributed through social media platforms and neurosurgery clinics. Levels of awareness were assessed by a knowledge-scoring system. RESULTS: The study involved 403 participants, primarily patients' families (85.1%, N = 343) and physicians (14.9%, N = 60). The results show that physicians had a significantly higher correct response than patients' families regarding the ideal age for surgical correction of CS, the timing of surgical intervention whether before or after maturity, and the role of conservative management, as evident from statistically significant p-values of <0.001, 0.031, and <0.001, respectively. On the contrary, patients' families excelled in understanding interventions irrespective of symptomatic status if Cobb's angle is 40 degrees or above, with a statistically significant p-value of 0.031. Both groups exhibited a good level of overall knowledge, as evidenced by mean awareness scores of 12.18 and 11.64, respectively. Additionally, physicians had a statistically significant higher level of awareness compared to patients' families, with a p-value of (0.014). However, both groups demonstrated poor knowledge of the latest techniques, including distraction-based magnetically controlled growing rods (MCGRs), growth-guided modern Luque trolleys, and posterior dynamic deformity correction (ApiFix). CONCLUSION: The mean awareness score of both physicians and patients' families indicates a good level of knowledge. However, both groups exhibited poor knowledge in relation to the optimal timing of treatment and new surgical techniques.

Venous thromboembolism prophylaxis in operative traumatic brain injury.

Background: Venous thromboembolism (VTE) is a significant complication in patients with traumatic brain injury (TBI), but the optimal timing of pharmacological prophylaxis in operative cases remains controversial. Methods: This retrospective study aimed to describe the timing of pharmacological prophylaxis initiation in operative TBI cases, stratified by surgery type, and to report the frequency of worsening postoperative intracranial pathology. Results: Data from 90 surgical TBI patients were analyzed, revealing that 87.8% received VTE pharmacological prophylaxis at a mean of 85 hours postsurgery. The timing of initiation varied by procedure, with burr holes having the earliest start at a mean of 66 h. Craniotomy and decompressive craniectomy had the longest delay, with means of 116 and 109 h, respectively. Worsening intracranial pathology occurred in 5.6% of patients, with only one case occurring after VTE pharmacological prophylaxis initiation. The overall VTE rate was 3.3%. Conclusion: These findings suggest that initiating VTE pharmacological prophylaxis between 3 and 5 days postsurgery may be safe in operative TBI patients, with the timing dependent on the procedure's invasiveness. The low frequencies of worsening intracranial pathology and VTE support the safety of these proposed timeframes. However, the study's limitations, including its single-center retrospective nature and lack of a standardized protocol, necessitate further research to confirm these findings and establish evidence-based guidelines for VTE pharmacological prophylaxis in operative TBI patients.

Mice monitor their timing errors.

Animals often engage in representationally guided goal-directed behaviors. These behaviors are thus also subjected to representational uncertainty (e.g. timing uncertainty during waiting), which has been previously shown to adaptively guide behaviors normatively. These observations raise the question of whether non-human animals can track the direction and magnitude of their timing errors (i.e. temporal error monitoring). Only a few studies have investigated this question without addressing the key components of temporal error monitoring (e.g. due to differential reinforcement of metacognitive judgments and primary task representation). We conducted the critical test of temporal error monitoring in mice by developing a novel behavioral task that involved temporal production that exponentially favored temporal accuracy and minimized the contribution of sensorimotor noise. The response rate for an upcoming probabilistic reward following the timing performance was used as a proxy for confidence. We found that mice exhibited high reward expectancy after accurate and low reward expectancy after inaccurate timing performance. The reward expectancy decreased as a function of deviations from the target interval for the short and long reproductions; pointing to the symmetrical sensitivity of metacognition to shorter/longer than target responses. These findings suggest a complete temporal error monitoring ability for mice with human-like metacognitive features.

The Impact of Hormone Replacement Therapy on the Risk of Heart Failure in Postmenopausal Women: A Meta-Analysis of Clinical and Observational Studies.

PURPOSE: The relationship between heart failure (HF) and hormone replacement therapy (HRT) in postmenopausal women remains unclear. This paper aimed to elucidate the association between HRT and HF outcomes in postmenopausal women by scrutinizing evidence from clinical trials and observational studies. METHODS: The meta-analysis was systematically executed following the PRISMA guidelines to include studies identified from the electronic databases, including PubMed, EMBASE, EBSCO, ICTRP, and NIH clinical trials. The primary endpoint of the effect comprised risk ratios (RR) for HF incidence and mortality, attended by 95% confidence intervals (CIs). The risk of bias was assessed employing the Cochrane Risk of Bias 2 (RoB2) tool for clinical trials and the Newcastle-Ottawa Scale (NOS) for observational studies. RESULTS: The search yielded a total of eight reports, originating from six individual studies, for inclusion in the current study, and 25 047 participants were included. The meta-analysis demonstrated no remarkable association between HRT and the incidence of HF in postmenopausal women (RR: 1.07, 95% CI: 0.91-1.25, p = 0.37). However, a significant reduction in all-cause mortality was observed among post-menopausal HF patients who received HRT (RR: 0.65, 95% CI: 0.49-0.87, p = 0.003). In age-related subgroup analyses, no significant change in the risk of HF was noticed among participants on HRT. CONCLUSIONS: The findings of this paper demonstrate that HRT use is not associated with a significant increase in the risk of incident HF. This meta-analysis also suggests a benefit in all-cause mortality when HRT is administered to postmenopausal women with HF.

Age-dependent prevalence of malocclusions requiring treatment according to the KIG classification : A multipart cross-sectional study over a 10-year period from the district of Viersen/North Rhine.

BACKGROUND AND AIM: Patients with statutory health insurance (SHI) in Germany must undergo an assessment of orthodontic treatment need using the "Kieferorthopädische Indikationsgruppen" (KIG; orthodontic indication groups) classification system since 2002. A treatment need only exists if anomalies of a certain degree of severity are present. The aim of this study was to evaluate the age-dependent prevalence and percentage distribution of KIG grades requiring treatment in patients with SHI before the age of 18 over a 10-year period. PATIENTS AND METHODS: Between 2012 and 2021, treatment indication existed for 1951 (1025 female, 926 male) out of 2288 patients with SHI in the cohort of this study before the age of 18 according to current SHI guidelines. The KIG classification was based on the highest existing KIG grade. There were no multiple classifications. The patient cohort was divided into three patient groups (PG) according to chronological age for analysis: PG 1 < 10 years of age (early treatment), PG 2 10 to < 13 years of age (main treatment) and PG 3 13 to < 18 years of age (late treatment). RESULTS: In PG 1 (454 patients), the KIG classifications D (26.5%), K (25.5%), M (19.4%), and P (18.0%) dominated. In PG 2 (998 patients), classifications D (33.2%), predominated, whereas K (7.5%) and M (5.9%) rarely occurred. The classifications E (12.6%) and P (13.3%) appeared quite frequently. Transverse deviations occurred only about half as often in PG 2 as in PG 1 and PG 3. In PG 3 (499 patients), the classification E (17.6%) was particularly common, while P (2.6%) was rare. The proportion of KIG grades 5 decreased depending on age: 19% in PG 1, 13.5% in PG 2, 10.4% in PG 3. The prevalence of sagittal classifications was highest in all age groups (45.9% in PG 1, 39.1% in PG 2, 31.5% in PG 3). CONCLUSIONS: The distribution of KIG classifications requiring treatment was not homogeneous, but age dependent. The differences were particularly evident in the early treatment group and may be due to the limited applicability of the KIG classification system in patients before late mixed dentition. With increasing age at initial examination, the prevalence of sagittal classifications decreased, while that of vertical classifications increased. Still, the sagittal classifications D and M occurred most frequently in all age groups. The KIG classification D was always the most common in all patients until the age of 18.

Examining Health Behaviors as Mechanisms Linking Earlier Pubertal Timing with Accelerated Epigenetic Aging in Late Adolescence.

Earlier pubertal timing is associated with accelerated epigenetic aging, but the underlying mechanisms are not well understood. This three-wave longitudinal study examined negative health behaviors, specifically substance use, short sleep duration, and poor diet quality in middle adolescence, as mediators of links between earlier phenotypic and perceived pubertal timing measured in early adolescence and epigenetic aging on three epigenetic clocks in late adolescence (GrimAge, DunedinPACE, and PhenoAge). Phenotypic pubertal timing measured physical pubertal maturation relative to chronological age, whereas perceived pubertal timing was based on adolescents' subjective interpretation of their pubertal timing relative to their peers. Participants included 1213 youth (51% female, 49% male; 62% Black, 34% White) who participated during early adolescence (mean age = 13.10 years), middle adolescence (mean age = 16.1 years) and late adolescence (mean age = 19.7 years). Results from a mediation model revealed a mediation effect of earlier phenotypic pubertal timing on accelerated GrimAge in late adolescence through higher substance use during middle adolescence. There was also a direct effect of earlier phenotypic pubertal timing on accelerated DunedinPACE in males. Sleep duration and diet quality did not emerge as mediators but shorter sleep duration predicted accelerated GrimAge in females. These findings suggest that higher substance use presents a mechanism through which earlier maturing youth experience faster epigenetic aging that puts them at risk for poorer health across the lifespan.

The Impact of Different Timing of Mouth Opening Exercises on Trismus in Postoperative Radiotherapy Patients with Oral Cancer.

OBJECTIVE: To compare the effects of starting mouth opening exercises at two different times on trismus in postoperative radiotherapy patients with oral cancer. METHODS: Through a prospective randomized controlled trial, purposive sampling was used to select 76 patients undergoing postoperative radiotherapy for oral cancer from March 2023 to January 2024 at the Department of Oral and Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Patients were randomly divided into an experimental group (n=38) and a control group (n=38) using a random number table at a ratio of 1:1. The experimental group began mouth opening exercises in the second week after surgery (before radiotherapy), while the control group began in the fourth week after surgery (at the start of radiotherapy). The primary outcome measure was maximum interincisal opening (MIO). Secondary outcome measures included pain visual analog scale (VAS) scores and quality of life scores (UW-QOL), assessed at baseline, the second week post-surgery (before radiotherapy), the fourth week post-surgery (at the start of radiotherapy), the ninth week post-surgery (end of radiotherapy), and the twelfth week post-surgery (three weeks after the end of radiotherapy). RESULTS: A total of 72 patients completed all assessments, with 36 in each group, resulting in an overall sample attrition rate of 5.26% (less than 15%). There were no statistically significant differences in general demographic and clinical characteristics between the two groups. Repeated measures ANOVA showed significant differences in MIO, VAS, and UW-QOL scores between groups, over time, and in group-time interactions (P<0.001). From the fourth week post-surgery (at the start of radiotherapy), the experimental group had significantly higher MIO (P<0.001), significantly lower VAS scores (P<0.001), and significantly higher UW-QOL scores (P<0.001) compared to the control group. These differences persisted at subsequent assessment points. CONCLUSION: Initiating mouth opening exercises in the second week post-surgery (before radiotherapy) can significantly improve mouth opening, reduce pain, and enhance the quality of life in postoperative radiotherapy patients with oral cancer. This provides important evidence for clinical practice, although further research is needed to verify the long-term effects.

Long-term monitoring of a population of greater horseshoe bat emphasises the importance of a pest beetle prey on demographic trends.

The global decline in insect biomass has far-reaching implications for terrestrial and freshwater food webs, impacting species reliant on insects as a crucial component of their diet. This issue extends to species traditionally considered agricultural pests, such as the common cockchafer Melolontha melolontha. In the race to combat cockchafers through collection, insecticide use, and other control methods, the repercussions of their numerical fluctuations on predators, including species of high conservation importance like bats, have been largely overlooked. Drawing on 31-years of monitoring data for a greater horseshoe bat Rhinolophus ferrumequinum population in the Aosta Valley (Western Italian Alps), we investigated whether annual fluctuations in bat counts are influenced by cockchafer availability and weather conditions. Despite an overall positive trend in bat abundance, we observed pronounced annual fluctuations, mostly driven by cockchafer availability rather than variations in temperature and precipitation. Furthermore, we found a significant association between cockchafer availability and the median date of birth and birth rate of bats. Births occurred approximately 5 days earlier in cockchafer flight years, with earlier births also linked to warmer spring temperatures and higher numbers of warm days in April. Moreover, the ratio pups/older bats was 0.56 in cockchafer flight years, compared to 0.47 in other years. Our results underscore the importance of considering predator-prey dynamics when examining the long-term population trends of species of conservation concern. We recommend implementing restrictions on the use of chemicals and other potentially harmful practices that may diminish prey abundance or quality, including that of species considered as agricultural pests. In designing conservation strategies, a delicate balance should be struck between the current interests of farmers and the overarching goal of preserving biodiversity against potential future threats.

Timing of onset of intraoperative transfusion anaphylaxis: a literature review.

Clinical diagnosis of intraoperative transfusion anaphylaxis using clinical symptoms is challenging and should be made carefully, as an incorrect clinical diagnosis can exacerbate surgical bleeding secondary to stopping a clinically indicated blood transfusion. The timing of onset of anaphylaxis to start of transfusion may be the key to correctly diagnosing intraoperative transfusion anaphylaxis clinically. However, the reliability of this measure remains unknown. A literature search was conducted using MEDLINE, Embase, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials up to June 29, 2021. No language restriction was applied. Two pairs of review authors independently reviewed intraoperative transfusion anaphylaxis cases and extracted data on the timing of onset of anaphylaxis to start of transfusion. A total of 8,918 articles were reviewed, the full texts of 186 articles were assessed, and 20 intraoperative transfusion anaphylaxis cases were included in this study. The 20 intraoperative transfusion anaphylaxis cases included a precise timing of onset. With nine cases, cardiovascular surgery was the most prevalent, and one case was fatal. Fifteen cases had a timing of onset in minutes, and of those, 14 reported timeframes within 30 minutes of initiation of transfusion (median: 15.5, 5-30 minutes). Almost all cases of intraoperative transfusion anaphylaxis occurred within 30 minutes of the transfusion initiation. This timeframe may be helpful in the clinical diagnosis of intraoperative transfusion anaphylaxis.

Effect of surgical fixation timing on in-hospital mortality and morbidity of distal femur fractures.

INTRODUCTION: The literature lacks a large-scale study investigating the effect of surgical fixation timing on early mortality and morbidity outcomes in distal femur fractures. The aims of this study were to determine the effect of fixation timing on in-hospital mortality and morbidity outcomes for operatively treated distal femur fractures retrospectively using large database data. METHODS: This study is a retrospective analysis using data from the National Trauma Data Bank. Patients were stratified into a fragility cohort (age ≥ 60, ISS < 16) and polytrauma cohort (age < 60, ISS ≥16), with both cohorts analyzed separately. Within each cohort, patients were split into three fixation timing groups: within 24 h, between 24 and 48 h, and greater than 48 h from presentation to the hospital. Fixation-timing groups were compared based on the primary outcome of in-hospital mortality rate. Secondary outcomes included hospital length of stay (LOS), ICU length of stay (ICU LOS), days on a ventilator, and complications. RESULTS: The fragility and polytrauma cohorts included 22,045 and 5,905 patients, respectively. The in-hospital mortality rate was 1.23 % in the fragility cohort and 2.56 % in the polytrauma cohort. Multivariate analysis of the fragility cohort showed that fixation greater than 48 h from time of presentation was associated with increased mortality compared to fixation within 24 h (OR 1.89, CI: 1.26-2.83, p=0.002) and between 24 and 48 h (OR 1.63, CI: 1.23-2.15, p<0.001). In the polytrauma cohort, multivariate analysis showed no significant mortality differences between fixation timing groups. Multivariate analysis of morbidity outcomes in both cohorts showed that fixation greater than 48 h was associated with increased LOS, ICU LOS, ventilator days, and complications compared to fixation within 24 h. In the polytrauma cohort, fixation between 24 and 48 h was associated with decreased LOS, ICU LOS, and complications compared to the other two timing groups. CONCLUSIONS: Fixation of distal femur fractures before 48 h from presentation may lead to improved mortality and morbidity in older, lower injury severity patients. No significant mortality benefit was observed in younger, polytrauma fractures. Further prospective work is needed to validate these findings.

Anthropogenic noise and light pollution decrease the repeatability of activity patterns and dampen expression of chronotypes in a free-living songbird.

Anthropogenic environmental change is introducing a suite of novel disturbance factors, which can have wide-ranging effects on mean behavior and behavioral repeatability. For example, exposure to sensory pollutants, such as anthropogenic noise and artificial light at night (ALAN), may affect consistent and repeatable individual-level timing of daily activity, which is referred to as chronotypes. Although chronotypes have been increasingly documented in wild animal populations and may affect fitness, evidence for long-term stability across life-history stages and seasons is notably lacking. Furthermore, how multiple anthropogenic stressors may interact to erode or magnify the expression of chronotypes remains unclear. We tested for existence of chronotypes across life-history stages and seasons in suburban female great tits (Parus major), using emergence time from nest boxes in the morning as a proxy for activity onset. We then examined joint effects of noise pollution and ALAN on expression of chronotypes, and tested for effects of noise, ALAN, and weather conditions on mean emergence time. We found repeatability of daily activity patterns (emergence times) across life-history stages and seasons, providing evidence of chronotypes, as well as interactive effects of anthropogenic disturbance factors and weather conditions on population mean behavior. Furthermore, across-season repeatability of emergence times was approximately double in magnitude in low light and low noise conditions, relative to in conditions with higher light and/or noise pollution. Thus, joint exposure to these sensory pollutants tends to erode expression of chronotypes. This effect was driven by higher among-individual variance in the relatively undisturbed environment and collapse of this variance in the more disturbed environments. Decreased repeatability in environments with high disturbance levels may reduce potential for behavioral traits, such as chronotype, to be the target of selection and limit adaptability.

Timing of intravenous immunoglobulin treatment and outcome in Guillain-Barré syndrome: Is time nerve?

INTRODUCTION/AIMS: Despite treatment, a considerable proportion of patients with Guillain-Barré syndrome (GBS) experience poor recovery, highlighting a therapeutic need. There is a lack of evidence that treatment timing affects recovery. This study aims to investigate the effects of intravenous immunoglobulin (IVIg) timing on disability and speed of recovery in GBS. METHODS: We performed a retrospective study of 136 IVIg-treated GBS patients admitted to two Korean centers between 2010 and 2021. We analyzed the effect of time to IVIg on the GBS disability scale (GBS-DS) and the degree of improvement from nadir (∆GBS-DS) at 1, 3, 6, and 12 months, as well as the time to regain the ability to walk or run unaided. Time to IVIg was treated either as a continuous variable or categorized into 1-week intervals to explore critical time windows. Known prognostic factors, the modified Erasmus GBS Outcome Scores on admission and pre-treatment serum albumin levels were adjusted as covariates. RESULTS: Shorter time to IVIg was independently associated with better GBS-DS, greater ∆GBS-DS, and shorter time to walk or run unaided at all time points. The therapeutic effect of IVIg was notably diminished when administered beyond the first 2 weeks of onset. DISCUSSION: Our study highlights the timing of IVIg as a modifiable prognostic factor in GBS. The earlier IVIg is initiated, the better the outcomes, with the ideal time window being within the first 2 weeks. These findings underscore the importance of prompt diagnosis and early intervention to optimize recovery in GBS patients.

Individual timing consistency across long-distance songbird migrations.

Migration timing in long-distance migratory birds plays an essential role in individual survival and fitness and is thought to be driven by circannual routines cued by photoperiod with some plasticity to environmental conditions. We examined the individual order of migration timing in purple martins (Progne subis), a neotropical migratory songbird that travels between breeding sites throughout eastern North America and nonbreeding sites in Brazil. Migration timing data were collected for 295 different individual purple martins over 9 years using light-level geolocators deployed at breeding sites across the range. We used linear mixed-effect models to examine the influence of the rank order of individual departure dates in one season on the rank order of four subsequent migration events while controlling for the effects of breeding latitude, sex, and age. Overall, we found evidence for consistent individual timing that can extend across 8 months and 12,000-24,000 km of migration. Individual rank order of migration timing in purple martins was generally conserved across migrations with consistent timings between fall departure dates from, and spring arrival dates to the breeding site the following year (0.28 ± 0.03, 95% CI 0.22-0.34), as well as at a finer scale across fall migration (0.33 ± 0.05, 95% CI 0.23-0.43), over the stationary nonbreeding period (0.39 ± 0.04, 95% CI 0.31-0.47), and across spring migration (0.03 ± 0.001, 95% CI 0.028-0.032). These results demonstrate that purple martins exhibit consistency in individual migration timing throughout the annual cycle that is likely driven by inherent individual circannual schedules. We additionally found that migration distance played a significant role, as the consistency of individual timing lessened over longer distances. Understanding how individual birds time migrations and if individuals are consistent between events can provide insight into how birds respond to shifts in their environment with climate change.

Next day sentinel node biopsy for melanoma after lymphoscintigraphy using 99mTc-labelled nanocolloid does not adversely affect long-term outcomes.

OBJECTIVE: Sentinel Lymph Node Biopsy (SLNB) is an important management tool for early-stage melanoma. Different radiopharmaceuticals are used internationally to localise the sentinel node using lymphoscintigraphy (LSG) before surgery. Recent reports have suggested that a delayed interval between LSG and SLNB using 99mTc-labelled nanocolloid tracer has an adverse survival impact, but not with 99mTc-labelled antimony sulphide colloid. This study aims to analyse survival outcome in a prospective cohort of melanoma patients undergoing same day or next day SLNB after LSG using 99mTc-labelled nanocolloid. METHODS: Outcome data were reviewed for patients undergoing SLNB, stratified by time interval between LSG and SLNB at a single UK academic centre. Kaplan-Meier survival analysis was used to assess overall survival (OS), melanoma-specific survival (MSS) and progression-free survival (PFS). Cox multivariable regression analysis identified independent risk factors. RESULTS: 925 patients had LSG using the 99mTc-nanocolloid tracer between 2009 and 2019, with a median follow-up of 6.36 years. No difference was seen on univariate analysis in OS, MSS, PFS, or nodal recurrence between patients undergoing same day or next day SLNB (Log-rank P = 0.437, 0.293, 0.587, 0.342 respectively). In addition, nodal recurrence as first site or anytime site of recurrence in SLNB negative patients was similar between the groups (Log-rank P = 0.093 and 0.457 respectively). Stratified analysis of time did not demonstrate an outcome difference (MSS Log-rank P = 0.938). Cox multivariable regression did not show time interval to independently influence OS, MSS or PFS. CONCLUSIONS: We do not find a significant effect on long-term outcomes when SLNB is performed the day after LSG with 99mTc-labelled nanocolloid tracer. We infer that tracer migration is not clinically significant within 24 h of injection based on long term clinical outcome data.

Design of an Electronic Interface for Single-Photon Avalanche Diodes.

Single-photon avalanche diodes (SPADs) belong to a family of avalanche photodiodes (APDs) with single-photon detection capability that operate above the breakdown voltage (i.e., Geiger mode). Design and technology constraints, such as dark current, photon detection probability, and power dissipation, impose inherent device limitations on avalanche photodiodes. Moreover, after the detection of a photon, SPADs require dead time for avalanche quenching and recharge before they can detect another photon. The reduction in dead time results in higher efficiency for photon detection in high-frequency applications. In this work, an electronic interface, based on the pole-zero compensation technique for reducing dead time, was investigated. A nanosecond pulse generator was designed and fabricated to generate pulses of comparable voltage to an avalanche transistor. The quenching time constant (τq) is not affected by the compensation capacitance variation, while an increase of about 30% in the τq is related to the properties of the specific op-amp used in the design. Conversely, the recovery time was observed to be strongly influenced by the compensation capacitance. Reductions in the recovery time, from 927.3 ns down to 57.6 ns and 9.8 ns, were observed when varying the compensation capacitance in the range of 5-0.1 pF. The experimental results from an SPAD combined with an electronic interface based on an avalanche transistor are in strong accordance, providing similar output pulses to those of an illuminated SPAD.

Multifaceted role of the DNA replication protein MCM10 in maintaining genome stability and its implication in human diseases.

MCM10 plays a vital role in genome duplication and is crucial for DNA replication initiation, elongation, and termination. It coordinates several proteins to assemble at the fork, form a functional replisome, trigger origin unwinding, and stabilize the replication bubble. MCM10 overexpression is associated with increased aggressiveness in breast, cervical, and several other cancers. Disruption of MCM10 leads to altered replication timing associated with initiation site gains and losses accompanied by genome instability. Knockdown of MCM10 affects the proliferation and migration of cancer cells, manifested by DNA damage and replication fork arrest, and has recently been shown to be associated with clinical conditions like CNKD and RCM. Loss of MCM10 function is associated with impaired telomerase activity, leading to the accumulation of abnormal replication forks and compromised telomere length. MCM10 interacts with histones, aids in nucleosome assembly, binds BRCA2 to maintain genome integrity during DNA damage, prevents lesion skipping, and inhibits PRIMPOL-mediated repriming. It also interacts with the fork reversal enzyme SMARCAL1 and inhibits fork regression. Additionally, MCM10 undergoes several post-translational modifications and contributes to transcriptional silencing by interacting with the SIR proteins. This review explores the mechanism associated with MCM10's multifaceted role in DNA replication initiation, chromatin organization, transcriptional silencing, replication stress, fork stability, telomere length maintenance, and DNA damage response. Finally, we discuss the role of MCM10 in the early detection of cancer, its prognostic significance, and its potential use in therapeutics for cancer treatment.

Antecedents of and experiences with voluntary early exit from working life before the expected retirement age in Sweden.

BACKGROUND: In most Western countries, senior workers have increased their participation in the workforce. However, at the same time, early retirement also increases. The reasons behind this early exit from the workforce are still unclear. OBJECTIVE: This qualitative study aims to explore the antecedents of and experiences with a voluntary exit from working life before the expected retirement age of 65 in Sweden. METHODS: Data consist of semi-structured interviews with 18 participants who exited working life between the ages of 61-63. In Sweden, these ages are considered as an early exit from working life since, for many years, the expected retirement age has been 65. Qualitative content analysis with an abductive approach was utilized. RESULTS: The analysis revealed four sub-themes: 1) Health benefits with an early exit from working life (with the categories: own health status, the possibility for recovery time, and avoidance of strain); 2) Having economic conditions that enable an early exit from working life (with the categories: offers from the employer and financial compromises); 3) Social benefits with an early exit from working life (with the categories: enabling more time with my social network and avoidance of unsatisfying social work environment); 4) Self-fulfillment activities during the senior years (with the categories: enabling time for activities beyond work and avoidance of decreased job satisfaction. CONCLUSION: This variety of antecedents of and experiences with a voluntary early exit from working life before the expected retirement age highlights that the ongoing increased statutory retirement age also increases the risk for extended inequalities among the aging population.

Treatment of juvenile myasthenia gravis with tacrolimus: A cohort study.

BACKGROUND: We investigated the proper timing, efficacy and safety of tacrolimus for juvenile myasthenia gravis (JMG). METHODS: We conducted a retrospective cohort study for JMG patients treated with tacrolimus at Xiangya Hospital, Central South University, Changsha, China from 2010 to 2023. The clinical information of patients with a follow-up of more than 1 year was collected. Comparisons of clinical features between groups of patients who achieved therapeutic goal and those who did not achieve therapeutic goal as well as between groups of patients treated with tacrolimus within or after 1 year from JMG onset was carried out. RESULTS: Forty-three patients were enrolled, of whom 28 achieved therapeutic goal. Tacrolimus reduced glucocorticoids (GC) dosages for the 28 cases and 15 cases discontinued GC completely. Generalized myasthenia gravis (GMG) subtype had an association with a group of patients who achieved therapeutic goal (p = 0.001). Median duration from JMG onset to tacrolimus use was 10.50 months for those who achieved therapeutic goal and 36.00 months for those who did not achieve therapeutic goal (p = 0.010). The median Myasthenia Gravis Activities of Daily Living (MG-ADL) score improved significantly (p = 0.003). The initiation of tacrolimus within 1 year of JMG onset showed an association with achievement of therapeutic goal (p = 0.026). GMG subtype showed an association with a group of patients who received tacrolimus within 1 year (p = <0.001). Tacrolimus side effects were tolerable. CONCLUSION: The provision of tacrolimus within 1 year of JMG onset is effective and safe.

Anticoagulant Therapy in Patients Undergoing Acute Pulmonary Embolism Interventions.

Catheter-based interventions and surgical embolectomy represent alternatives to systemic fibrinolysis for patients with high-risk pulmonary embolism (PE) or those with intermediate-high-risk PE who deteriorate hemodynamically. They are indicated when systemic fibrinolysis is contraindicated or ineffective, or if obstructive shock is imminent. Extracorporeal membrane oxygenation can be added to reperfusion therapies or used alone for severe right ventricular dysfunction and cardiogenic shock. These advanced therapies complement but do not replace anticoagulation, which remains the cornerstone in PE management. This review summarizes the evidence and shares practical recommendations for the use of anticoagulant therapy before, during, and after acute PE interventions.