A prospective, observational study of frailty, quality of life and dialysis in older people with advanced chronic kidney disease.

BACKGROUND: Frailty is prevalent in older people with chronic kidney disease (CKD) and robust evidence supporting the benefit of dialysis in this setting is lacking. We aimed to measure frailty and quality of life (QOL) longitudinally in older people with advanced CKD and assess the impact of dialysis initiation on frailty, QOL and mortality. METHODS: Outpatients aged ≥65 with an eGFR ≤ 20ml/minute/1.73m2 were enrolled in a prospective observational study and followed up four years later. Frailty status was measured using a Frailty Index (FI), and QOL was evaluated using the EuroQol 5D-5L instrument. Mortality and dialysis status were determined through inspection of electronic records. RESULTS: Ninety-eight participants were enrolled. Between enrolment and follow-up, 36% of participants commenced dialysis and 59% died. Frailty prevalence increased from 47% at baseline to 86% at follow-up (change in median FI = 0.22, p < 0.001). Initiating dialysis was not significantly associated with change in FI. QOL declined from baseline to follow-up (mean EQ-5D-5L visual analogue score of 70 vs 63, p = 0.034), though commencing dialysis was associated with less decline in QOL. Each 0.1 increment in baseline FI was associated with 59% increased mortality hazard (HR = 1.59, 95%CI = 1.20 to 2.12, p = 0.001), and commencing dialysis was associated with 59% reduction in mortality hazard (HR = 0.41, 95%CI = 0.20 to 0.87, p = 0.020) irrespective of baseline FI. CONCLUSIONS: Frailty increased substantially over four years, and higher baseline frailty was associated with greater mortality. Commencing dialysis did not affect the trajectory of FI but positively influenced the trajectory of QOL from baseline to follow-up. Within the limitations of small sample size, our data suggests that frail participants received similar survival benefit from dialysis as non-frail participants.

Psychosocial interventions for survivors of rape and sexual assault experienced during adulthood.

BACKGROUND: Exposure to rape, sexual assault and sexual abuse has lifelong impacts for mental health and well-being. Prolonged Exposure (PE), Cognitive Processing Therapy (CPT) and Eye Movement Desensitisation and Reprocessing (EMDR) are among the most common interventions offered to survivors to alleviate post-traumatic stress disorder (PTSD) and other psychological impacts. Beyond such trauma-focused cognitive and behavioural approaches, there is a range of low-intensity interventions along with new and emerging non-exposure based approaches (trauma-sensitive yoga, Reconsolidation of Traumatic Memories and Lifespan Integration). This review presents a timely assessment of international evidence on any type of psychosocial intervention offered to individuals who experienced rape, sexual assault or sexual abuse as adults. OBJECTIVES: To assess the effects of psychosocial interventions on mental health and well-being for survivors of rape, sexual assault or sexual abuse experienced during adulthood. SEARCH METHODS: In January 2022, we searched CENTRAL, MEDLINE, Embase, 12 other databases and three trials registers. We also checked reference lists of included studies, contacted authors and experts, and ran forward citation searches. SELECTION CRITERIA: Any study that allocated individuals or clusters of individuals by a random or quasi-random method to a psychosocial intervention that promoted recovery and healing following exposure to rape, sexual assault or sexual abuse in those aged 18 years and above compared with no or minimal intervention, usual care, wait-list, pharmacological only or active comparison(s). We classified psychosocial interventions according to Cochrane Common Mental Disorders Group's psychological therapies list. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 36 studies (1991 to 2021) with 3992 participants randomly assigned to 60 experimental groups (3014; 76%) and 23 inactive comparator conditions (978, 24%). The experimental groups consisted of: 32 Cognitive Behavioural Therapy (CBT); 10 behavioural interventions; three integrative therapies; three humanist; five other psychologically oriented interventions; and seven other psychosocial interventions. Delivery involved 1 to 20 (median 11) sessions of traditional face-to-face (41) or other individual formats (four); groups (nine); or involved computer-only interaction (six). Most studies were conducted in the USA (n = 26); two were from South Africa; two from the Democratic Republic of the Congo; with single studies from Australia, Canada, the Netherlands, Spain, Sweden and the UK. Five studies did not disclose a funding source, and all disclosed sources were public funding. Participants were invited from a range of settings: from the community, through the media, from universities and in places where people might seek help for their mental health (e.g. war veterans), in the aftermath of sexual trauma (sexual assault centres and emergency departments) or for problems that accompany the experience of sexual violence (e.g. sexual health/primary care clinics). Participants randomised were 99% women (3965 participants) with just 27 men. Half were Black, African or African-American (1889 participants); 40% White/Caucasian (1530 participants); and 10% represented a range of other ethnic backgrounds (396 participants). The weighted mean age was 35.9 years (standard deviation (SD) 9.6). Eighty-two per cent had experienced rape or sexual assault in adulthood (3260/3992). Twenty-two studies (61%) required fulfilling a measured PTSD diagnostic threshold for inclusion; however, 94% of participants (2239/2370) were reported as having clinically relevant PTSD symptoms at entry. The comparison of psychosocial interventions with inactive controls detected that there may be a beneficial effect at post-treatment favouring psychosocial interventions in reducing PTSD (standardised mean difference (SMD) -0.83, 95% confidence interval (CI) -1.22 to -0.44; 16 studies, 1130 participants; low-certainty evidence; large effect size based on Cohen's D); and depression (SMD -0.82, 95% CI -1.17 to -0.48; 12 studies, 901 participants; low-certainty evidence; large effect size). Psychosocial interventions, however, may not increase the risk of dropout from treatment compared to controls, with a risk ratio of 0.85 (95% CI 0.51 to 1.44; 5 studies, 242 participants; low-certainty evidence). Seven of the 23 studies (with 801 participants) comparing a psychosocial intervention to an inactive control reported on adverse events, with 21 events indicated. Psychosocial interventions may not increase the risk of adverse events compared to controls, with a risk ratio of 1.92 (95% CI 0.30 to 12.41; 6 studies; 622 participants; very low-certainty evidence). We conducted an assessment of risk of bias using the RoB 2 tool on a total of 49 reported results. A high risk of bias affected 43% of PTSD results; 59% for depression symptoms; 40% for treatment dropout; and one-third for adverse events. The greatest sources of bias were problems with randomisation and missing outcome data. Heterogeneity was also high, ranging from I2 = 30% (adverse events) to I2 = 87% (PTSD). AUTHORS' CONCLUSIONS: Our review suggests that survivors of rape, sexual violence and sexual abuse during adulthood may experience a large reduction in post-treatment PTSD symptoms and depressive symptoms after experiencing a psychosocial intervention, relative to comparison groups. Psychosocial interventions do not seem to increase dropout from treatment or adverse events/effects compared to controls. However, the number of dropouts and study attrition were generally high, potentially missing harms of exposure to interventions and/or research participation. Also, the differential effects of specific intervention types needs further investigation. We conclude that a range of behavioural and CBT-based interventions may improve the mental health of survivors of rape, sexual assault and sexual abuse in the short term. Therefore, the needs and preferences of individuals must be considered in selecting suitable approaches to therapy and support. The primary outcome in this review focused on the post-treatment period and the question about whether benefits are sustained over time persists. However, attaining such evidence from studies that lack an active comparison may be impractical and even unethical. Thus, we suggest that studies undertake head-to-head comparisons of different intervention types; in particular, of novel, emerging therapies, with one-year plus follow-up periods. Additionally, researchers should focus on the therapeutic benefits and costs for subpopulations such as male survivors and those living with complex PTSD.

Population Pharmacokinetic Model of Intravenous Busulfan in Hematopoietic Cell Transplantation: Systematic Review and Comparative Simulations.

BACKGROUND: Busulfan is commonly used in the chemotherapy prior to hematopoietic cell transplantation (HCT). Busulfan has a narrow therapeutic window and a well-established exposure-response relationship with important clinical outcomes. Model-informed precision dosing (MIPD) based on population pharmacokinetic (popPK) models has been implemented in the clinical settings. We aimed to systematically review existing literature on popPK models of intravenous busulfan. METHODS: We systematically searched Ovid MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science databases from inception to December 2022 to identify original popPK models (nonlinear mixed-effect modeling) of intravenous busulfan in HCT population. Model-predicted busulfan clearance (CL) was compared using US population data. RESULTS: Of the 44 eligible popPK studies published since 2002, 68% were developed predominantly in children, 20% in adults, and 11% in both children and adults. The majority of the models were described using first-order elimination or time-varying CL (69% and 26%, respectively). All but three included a body-size descriptor (e.g., body weight, body surface area). Other commonly included covariates were age (30%) and GSTA1 variant (15%). Median between-subject and between-occasion variabilities of CL were 20% and 11%, respectively. Between-model variabilities in predicted median CL were < 20% in all of the weight tiers (10-110 kg) in the simulation based on US population data. CONCLUSION: Busulfan PK is commonly described using a first-order elimination or time-varying CL. A simple model with limited covariates were generally sufficient to attain relatively small unexplained variabilities. However, therapeutic drug monitoring may still be necessary to attain a narrow target exposure.

Neurocognitive and mental health impact of adrenoleukodystrophy across the lifespan: Insights for the era of newborn screening.

X-linked adrenoleukodystrophy (ALD) is a rare inherited neurological disorder that poses considerable challenges for clinical management throughout the lifespan. Although males are generally more severely affected than females, the time course and presentation of clinical symptoms are otherwise difficult to predict. Opportunities to improve outcomes for individuals with ALD are rapidly expanding due to the introduction of newborn screening programs for this condition and an evolving treatment landscape. The aim of this comprehensive review is to synthesize current knowledge regarding the neurocognitive and mental health effects of ALD. This review provides investigators and clinicians with context to improve case conceptualization, inform prognostic counseling, and optimize neuropsychological and mental health care for patients and their families. Results highlight key predictive factors and brain-behavior relationships associated with the diverse manifestations of ALD. The review also discusses considerations for endpoints within clinical trials and identifies gaps to address in future research.

Survivor, family and professional experiences of psychosocial interventions for sexual abuse and violence: a qualitative evidence synthesis.

BACKGROUND: It is well-established that experiencing sexual abuse and violence can have a range of detrimental impacts; a wide variety of interventions exist to support survivors in the aftermath. Understanding the experiences and perspectives of survivors receiving such interventions, along with those of their family members, and the professionals who deliver them is important for informing decision making as to what to offer survivors, for developing new interventions, and enhancing their acceptability. OBJECTIVES: This review sought to: 1. identify, appraise and synthesise qualitative studies exploring the experiences of child and adult survivors of sexual abuse and violence, and their caregivers, regarding psychosocial interventions aimed at supporting survivors and preventing negative health outcomes in terms of benefits, risks/harms and barriers; 2. identify, appraise and synthesise qualitative studies exploring the experiences of professionals who deliver psychosocial interventions for sexual abuse and violence in terms of perceived benefits, risks/harms and barriers for survivors and their families/caregivers; 3. develop a conceptual understanding of how different factors influence uptake, dropout or completion, and outcomes from psychosocial interventions for sexual abuse and violence; 4. develop a conceptual understanding of how features and types of interventions responded to the needs of different user/survivor groups (e.g. age groups; types of abuse exposure; migrant populations) and contexts (healthcare/therapeutic settings; low- and middle-income countries (LMICs)); 5. explore how the findings of this review can enhance our understanding of the findings from the linked and related reviews assessing the effectiveness of interventions aimed at supporting survivors and preventing negative health outcomes. SEARCH METHODS: In August 2021 we searched MEDLINE, Embase, PsycINFO and nine other databases. We also searched for unpublished reports and qualitative reports of quantitative studies in a linked systematic review, together with reference checking, citation searches and contacting authors and other researchers to identify relevant studies. SELECTION CRITERIA: We included qualitative and mixed-methods studies (with an identifiable qualitative component) that were linked to a psychosocial intervention aimed at supporting survivors of sexual abuse and violence. Eligible studies focused on at least one of three participant groups: survivors of any age, gender, sexuality, ethnicity or [dis]ability who had received a psychosocial intervention; their carers, family members or partners; and professionals delivering such interventions. We placed no restrictions in respect of settings, locations, intervention delivery formats or durations. DATA COLLECTION AND ANALYSIS: Six review authors independently assessed the titles, abstracts and full texts identified. We extracted data using a form designed for this synthesis, then used this information and an appraisal of data richness and quality in order to stratify the studies using a maximum variation approach. We assessed the methodological limitations using the Critical Skills Appraisal Programme (CASP) tool. We coded directly onto the sampled papers using NVivo and synthesised data using a thematic synthesis methodology and used the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach to assess our confidence in each finding. We used a narrative synthesis and matrix model to integrate our qualitative evidence synthesis (QES) findings with those of intervention review findings. MAIN RESULTS: We identified 97 eligible studies and sampled 37 of them for our analysis. Most sampled studies were from high-income countries, with four from middle-income and two from low-income countries. In 27 sampled studies, the participants were survivors, in three they were intervention facilitators. Two included all three of our stakeholder groups, and five included two of our groups. The studies explored a wide range of psychosocial interventions, with only one type of intervention explored in more than one study. The review indicates that features associated with the context in which interventions were delivered had an impact on how individuals accessed and experienced interventions. This included organisational features, such as staff turnover, that could influence survivors' engagement with interventions; the setting or location in which interventions were delivered; and the characteristics associated with who delivered the interventions. Studies that assess the effectiveness of interventions typically assess their impact on mental health; however, as well as finding benefits to mental health, our QES found that study participants felt interventions also had positive impacts on their physical health, mood, understanding of trauma, interpersonal relationships and enabled them to re-engage with a wide range of areas in their lives. Participants explained that features of interventions and their contexts that best enabled them to benefit from interventions were also often things that could be a barrier to benefiting from interventions. For example, the relationship with the therapist, when open and warm was a benefit, but if such a relationship could not be achieved, it was a barrier. Survivors' levels of readiness and preparedness to both start and end interventions could have positive (if they were ready) or negative (if they were not) impacts. Study participants identified the potential risks and harms associated with completing interventions but felt that it was important to face and process trauma. Some elements of interventions were specific to the intervention type (e.g. faith-based interventions), or related to an experience of an intervention that held particular relevance to subgroups of survivors (e.g. minority groups); these issues could impact how individuals experienced delivering or receiving interventions. AUTHORS' CONCLUSIONS: We had high or moderate confidence in all but one of our review findings. Further research in low- and middle-income settings, with male survivors of sexual abuse and violence and those from minority groups could strengthen the evidence for low and moderate confidence findings. We found that few interventions had published quantitative and qualitative evaluations. Since this QES has highlighted important aspects that could enable interventions to be more suitable for survivors, using a range of methodologies would provide valuable information that could enhance intervention uptake, completion and effectiveness. This study has shown that although survivors often found interventions difficult, they also appreciated that they needed to work through trauma, which they said resulted in a wide range of benefits. Therefore, listening to survivors and providing appropriate interventions, at the right time for them, can make a significant difference to their health and well-being.

Interhospital transfer (IHT) in emergency general surgery patients (EGS): A scoping review.

Background/Aims of study: Interhospital transfer of emergency general surgery patients continues to rise, and no system for transfer of emergency general surgery patients exists. This has major implications for cost of care and patient experience. We performed a scoping review to understand outcomes related to transfer and the associated factors and to identify any opportunities for improvement. Methods: Studies involving emergency general surgery patients with interhospital transfer were identified by searching OVID MEDLINE, EMBASE, Cochrane Library, and Scopus. There were 1,785 records identified. After duplicates were removed, there were 1,303 articles screened in the initial phase. Fifty-eight articles were included in the second phase. Eventually, 21 articles were included in the review. Thirty-seven articles were removed during the full-text screening phase due to the following: wrong publication type (2), wrong population (8), abstract (11), outside the United States (3), and wrong study design (6). Results: Transferred patients had a higher mortality rate, were older, were more likely to be male and to undergo reoperation, and had higher resource utilization compared to patients who were not transferred. All emergency general surgery patients had a high burden of chronic disease. Unnecessary transfer, typically defined by lack of intervention and discharge within 72 hours, was reported to be 8.8% to 19%. Conclusion: Emergency general surgery patients have a high rate of comorbidities. Limited physiologic status information prior to patient transfer limits understanding of the necessity for transfer. Areas for improvement include assigning a physiologic status for all patients and utilizing telehealth. More detailed information needs to be captured to determine the appropriateness of transfer.

A contemporary case file analysis of child sexual abuse in institutional settings in England and Wales.

BACKGROUND: Despite increased institutional safeguards and regularly updated statutory guidance that stresses safeguarding is 'everybody's responsibility', children continue to be sexually abused in institutional contexts in England and Wales. There also remains a lack of contemporary knowledge about institutions' responses to concerns about [risk of] CSA. OBJECTIVE: Reviewing Disclosure and Barring Service (DBS) discretionary-decision case files, as a detailed source of information about CSA in institutions occurring in the last 5 years, the aim of this paper was to understand what institutions knew about CSA and inappropriate behaviours that indicated children could be at risk of harm prior to formal disclosures to the DBS and how institutions did, or did not, respond to this knowledge. PARTICIPANTS AND SETTING: Cases involved 32 male and 11 female barred persons and 19 male and 51 female sexually abused children. METHOD: Thematic analysis was applied to 43 files where decisions were made by the DBS to add individuals to the Children's Barred list (which prevents them by law from working with children) between 2017 and 2020. RESULTS: In 79% of cases there was some level of awareness of concerns relating to inappropriate behaviour or CSA, through rumours and gossip, concerns about professionalism, and observed changes in the behaviour of subsequently barred individuals or victims. There was wide variation in the degree to which institutions responded. In a small number of cases action was taken promptly; however, this was not typical. CONCLUSIONS: Institutions and professionals failed in their duty of care by not taking any action at all, or responding slowly in ways that did not prevent CSA.

Comparison of 3-factor versus 4-factor prothrombin complex concentrate for emergent warfarin reversal: a systematic review and meta-analysis.

BACKGROUND: Patients requiring emergent warfarin reversal (EWR) have been prescribed three-factor prothrombin complex concentrate (PCC3) and four-factor prothrombin complex concentrate (PCC4) to reverse the anticoagulant effects of warfarin. There is no existing systematic review and meta-analysis of studies directly comparing PCC3 and PCC4. METHODS: The primary objective of this systematic review and meta-analysis was to determine the effectiveness of achieving study defined target INR goal after PCC3 or PCC4 administration. Secondary objectives were to determine the difference in safety endpoints, thromboembolic events (TE), and survival during the patients' hospital stay. Random-effects meta-analysis models were used to estimate the odds ratios (OR), and heterogeneity associated with the outcomes. The Newcastle-Ottawa Scale was used to assess study quality, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: Ten full-text manuscripts and five abstracts provided data for the primary and secondary outcomes. Patients requiring EWR had more than three times the odds of reversal to goal INR when they were given PCC4 compared to PCC3 (OR = 3.61, 95% CI: 1.97-6.60, p < 0.001). There was no meaningful clinical association or statistically significant result between PCC4 and PCC3 groups in TE (OR = 1.56, 95% CI: 0.83-2.91, p = 0.17), or survival during hospital stay (OR = 1.34, 95% CI: 0.81-2.23, p = 0.25). CONCLUSION: PCC4 is more effective than PCC3 in meeting specific predefined INR goals and has similar safety profiles in patients requiring emergent reversal of the anticoagulant effects of warfarin.

Older Individuals Convicted of Sexual Offenses: A Literature Review.

The population of older individuals convicted of sexual offenses (OSOs) is rapidly increasing. However, we have little understanding of their characteristics (e.g., demographic, psychological, individual, offense, and risk) and needs. To identify any similarities or differences that are unique to older individuals convicted of sexual offending, it is important to compare such characteristics across the adult lifespan. Therefore, the aim of this systematic review was to specify and synthesize the current knowledge of characteristics across the adult lifespan of the population of individuals convicted of sexual offenses. Five databases were searched and 10,680 results were screened, resulting in 100 studies included in the final review. The findings were grouped into four emergent themes: age of onset and prevalence; offender and offense characteristics; age and the risk of reoffending; and treatment. Implications of the findings from this review are discussed in relation to future research and clinical practice.

PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons.

Recent evidence suggests neurogenesis is on-going throughout life but the relevance of these findings for neurodegenerative disorders such as Parkinson's disease (PD) is poorly understood. Biallelic PINK1 mutations cause early onset, Mendelian inherited PD. We studied the effect of PINK1 deficiency on adult neurogenesis of dopaminergic (DA) neurons in two complementary model systems. Zebrafish are a widely-used model to study neurogenesis in development and through adulthood. Using EdU analyses and lineage-tracing studies, we first demonstrate that a subset of ascending DA neurons and adjacent local-projecting DA neurons are each generated into adulthood in wild type zebrafish at a rate that decreases with age. Pink1-deficiency impedes DA neurogenesis in these populations, most significantly in early adult life. Pink1 already exerts an early effect on Th1+ progenitor cells rather than on differentiated DA neurons only. In addition, we investigate the effect of PINK1 deficiency in a human isogenic organoid model. Global neuronal differentiation in PINK1-deficient organoids and isogenic controls is similar, but PINK1-deficient organoids display impeded DA neurogenesis. The observation of impaired adult dopaminergic neurogenesis in Pink1 deficiency in two complementing model systems may have significant consequences for future therapeutic approaches in human PD patients with biallelic PINK1 mutations.

Pain is Associated with Physical Activity and Health-Related Quality of Life in Overweight and Obese Children.

This study examined associations between pain, physical activity, physical fitness, and health-related quality of life (HRQOL) in overweight and obese children. Participants were 270 overweight and obese children 8-12 years of age and their parents. Children were separated into No Pain Frequency, Low Pain Frequency, and High Pain Frequency groups. Children in the Low Pain Frequency group spent less time in moderately intense physical activities compared to the No Pain Frequency group. Children in the High Pain Frequency group reported significantly lower HRQOL in most domains of functioning compared to children in the No Pain and Low Pain Frequency groups. Pain in overweight and obese children may negatively impact physical activity and HRQOL and should be assessed and treated in research and clinical work.

Do readers obtain preview benefit from word N + 2? A test of serial attention shift versus distributed lexical processing models of eye movement control in reading.

Two experiments tested predictions derived from serial lexical processing and parallel distributed models of eye movement control in reading. The boundary paradigm (K. Rayner, 1975) was used, and the boundary location was set either at the end of word n - 1 (the word just to the left of the target word) or at the end of word n - 2. Serial lexical processing models predict that there should be preview benefit only when the boundary is set at word n - 1 (when the target word will be the next word fixated) and no preview benefit when the boundary is set at word n - 2. Parallel lexical models, on the other hand, predict that there should be some preview benefit in both situations. Consistent with the predictions of the serial lexical processing models, there was no preview benefit for a target word when the boundary was set at the end of word n - 2. Furthermore, there was no evidence of parafoveal-on-foveal effects.

The experiences of lecturer practitioners in clinical practice.

AIM: The aim of the study was to describe and understand the lived experiences of teaching for lecturer practitioners in the clinical workplace. BACKGROUND: Lecturer practitioners appear to have been introduced into practice to bridge the gap between academic and clinical learning although there appears to be little empirical evidence of how they work in clinical practice. METHODS: A qualitative approach was used in interpreting the transcribed interviews of five lecturer practitioners from different practice backgrounds working from the same university in the south of England. FINDING: Two synthesised interpretations of the lecturer practitioner experiences of teaching were described. One was of looking and seeing practice differently and challenging practitioners to do the same. The second was of working in the middle of the practice theory gap rather than trying to reduce it. CONCLUSIONS: Although the findings are not generalisable to other lecturer practitioners the participants appeared to work in partnership with practitioners to bring a change in the clinical environment where learning was supported and encouraged. The partnership appeared to place the onus on the practitioner to develop their practice and the lecturer practitioners appeared to work as an educational enabler.