Shift work effects on incident neuropsychiatric disorders and shift work tolerance.

BACKGROUND: Shift work is associated with susceptibility to several neuropsychiatric disorders. This study aims to investigate the effect of shift work on the incidence of neuropsychiatric disorders, and highlighting how individual variability may influence the association. METHODS: UK Biobank participants with employment information were included. Cox survival was conducted in main and subgroup analyses. Correlation analyses explored the impact of shift work on brain structures, and mediation analyses were performed to elucidate the shared underlying mechanisms. Shift work tolerance was evaluated through survival analyses contrasting the risks associated with five neuropsychiatric disorders in shift versus non-shift workers across different demographic or occupational strata. RESULTS: The analysis encompassed 254,646 participants. Shift work was associated with higher risk of dementia (HR 1.29, 95 % CI 1.10-1.52), anxiety (1.08, 1.01-1.15), depression (1.29, 1.22-1.36), and sleep disorders (1.18, 1.09-1.28), but not stroke (p = 0.20). Shift work was correlated with decreasing volume of various brain regions, particularly in thalamus, lateral orbitofrontal, and middle temporal. Mediation analysis revealed that increased immune response and glucose levels are common pathways linking shift work to these disorders. We observed diversity in shift work tolerance across different individual characteristics, among which socioeconomic status and length of working hours were the most essential. LIMITATIONS: Self-reported employment information may cause misclassification and recall bias. And since we focused on the middle-aged population, the conclusions may not be representative of younger or older populations. CONCLUSIONS: Our findings indicated the need to monitor shift worker health and provide personalized management to help adapt to shift work.

Novel diagnostic and prognostic approach for rapidly progressive dementias: Indicators based on amyloid/tau/neurodegeneration (ATN) framework.

AIMS: Apply established cerebrospinal fluid (CSF) and serum biomarkers and novel combined indicators based on the amyloid/tau/neurodegeneration (ATN) framework to improve diagnostic and prognostic power in patients with rapidly progressive dementias (RPDs). METHODS: CSF and serum biomarkers of Alzheimer's disease (AD) common neuropathology including Aß42, Aß40, p-Tau, and t-Tau were measured in cognitively normal (CN) controls (n = 33) and three RPD groups with rapidly progressive AD (rpAD, n = 23), autoimmune encephalitis (AE, n = 25), and Creutzfeldt-Jakob disease (CJD, n = 28). Logistic regression and multiple linear regression were used for producing combined indicators and prognostic assessment, respectively, including A&T, A&N, T&N, A&T&N, etc. RESULTS: Combined diagnostic indicator with A&T&N had the potential for differentiating AE from other types of RPDs, identifying 62.51% and 75% of AE subjects based on CSF and serum samples, respectively, compared to 39.13% and 37.5% when using autoantibodies. CSF t-Tau was associated with survival in the CJD group (adjusted R-Square = 0.16, p = 0.02), and its prognosis value improved when using combined predictors based on the ATN framework (adjusted R-Square = 0.273, p = 0.014). CONCLUSION: Combined indicators based on the ATN framework provide a novel perspective for establishing biomarkers for early recognition of RPDs due to treatment-responsive causes.

Iron chelation therapy for children with transfusion-dependent ß-thalassemia: How young is too young?

In this review, we provide a summary of evidence on iron overload in young children with transfusion-dependent ß-thalassemia (TDT) and explore the ideal timing for intervention. Key data from clinical trials and observational studies of the three available iron chelators deferoxamine, deferiprone, and deferasirox are also evaluated for inclusion of subsets of young children, especially those less than 6 years of age. Evidence on the efficacy and safety of iron chelation therapy for children ≥2 years of age with transfusional iron overload is widely available. New data exploring the risks and benefits of early-start iron chelation in younger patients with minimal iron overload are also emerging.

Clinically meaningful improvements in patient-reported outcomes in mitapivat-treated patients with pyruvate kinase deficiency.

Clinically meaningful benefits in the signs, symptoms, and impacts of #PKDeficiency as assessed by disease-specific patient-reported outcome measures were observed in mitapivat-treated adult patients in two phase 3 clinical trials.

Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency.

ABSTRACT: Pyruvate kinase (PK) deficiency is a rare, hereditary disease characterized by chronic hemolytic anemia. Iron overload is a common complication regardless of age, genotype, or transfusion history. Mitapivat, an oral, allosteric PK activator, improves anemia and hemolysis in adult patients with PK deficiency. Mitapivat's impact on iron overload and ineffective erythropoiesis was evaluated in adults with PK deficiency who were not regularly transfused in the phase 3 ACTIVATE trial and long-term extension (LTE) (#NCT03548220/#NCT03853798). Patients in the LTE received mitapivat throughout ACTIVATE/LTE (baseline to week 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to week 24) to mitapivat (week 24 to week 96; placebo-to-mitapivat [P/M] arm). Changes from baseline in markers of iron overload and erythropoiesis were assessed to week 96. Improvements in hepcidin (mean, 4770.0 ng/L; 95% confidence interval [CI], -1532.3 to 11 072.3), erythroferrone (mean, -9834.9 ng/L; 95% CI, -14 328.4 to -5341.3), soluble transferrin receptor (mean, -56.0 nmol/L; 95% CI, -84.8 to -27.2), and erythropoietin (mean, -32.85 IU/L; 95% CI, -54.65 to -11.06) were observed in the M/M arm (n = 40) from baseline to week 24, sustained to week 96. No improvements were observed in the P/M arm (n = 40) to week 24; however, upon transitioning to mitapivat, improvements similar to those observed in the M/M arm were seen. Mean changes from baseline in liver iron concentration by magnetic resonance imaging at week 96 in the M/M arm and the P/M arm were -2.0 mg Fe/g dry weight (dw; 95% CI, -4.8 to -0.8) and -1.8 mg Fe/g dw (95% CI, -4.4 to 0.80), respectively. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency. This trial was registered at www.ClinicalTrials.gov as #NCT03548220 (ACTIVATE) and #NCT03853798 (LTE).

Diagnosis and management of pyruvate kinase deficiency: international expert guidelines.

Pyruvate kinase (PK) deficiency is the most common cause of chronic congenital non-spherocytic haemolytic anaemia worldwide, with an estimated prevalence of one in 100 000 to one in 300 000 people. PK deficiency results in chronic haemolytic anaemia, with wide ranging and serious consequences affecting health, quality of life, and mortality. The goal of the International Guidelines for the Diagnosis and Management of Pyruvate Kinase Deficiency was to develop evidence-based guidelines for the clinical care of patients with PK deficiency. These clinical guidelines were developed by use of GRADE methodology and the AGREE II framework. Experts were invited after consideration of area of expertise, scholarly contributions in PK deficiency, and country of practice for global representation. The expert panel included 29 expert physicians (including adult and paediatric haematologists and other subspecialists), geneticists, laboratory specialists, nurses, a guidelines methodologist, patients with PK deficiency, and caregivers from ten countries. Five key topic areas were identified, the panel prioritised key questions, and a systematic literature search was done to generate evidence summaries that were used in the development of draft recommendations. The expert panel then met in person to finalise and vote on recommendations according to a structured consensus procedure. Agreement of greater than or equal to 67% among the expert panel was required for inclusion of a recommendation in the final guideline. The expert panel agreed on 31 total recommendations across five key topics: diagnosis and genetics, monitoring and management of chronic complications, standard management of anaemia, targeted and advanced therapies, and special populations. These new guidelines should facilitate best practices and evidence-based PK deficiency care into clinical practice.

Association of grip strength and walking pace with the risk of incident Parkinson's disease: a prospective cohort study of 422,531 participants.

BACKGROUND: Muscle weakness is a prominent feature of Parkinson's disease, but whether the occurrence of this deficit in healthy adults is associated with subsequent PD diagnosis remains unclear. OBJECTIVE: This study sought to examine the relationship between muscle strength, represented by grip strength and walking pace, and the risk of incident PD. METHODS: A total of 422,531 participants from the UK biobank were included in this study. Longitudinal associations of grip strength and walking pace with the risk of incident PD were investigated by Cox proportional hazard models adjusting for several well-established risk factors. Subgroup and sensitivity analyses were also conducted for further validation. RESULTS: After a median follow-up of 9.23 years, 2,118 (0.5%) individuals developed incident PD. For per 5 kg increment of absolute grip strength, there was a significant 10.2% reduction in the risk of incident PD (HR = 0.898, 95% CI [0.872-0.924], P < 0.001). Similarly, per 0.05 kg/kg increment of relative grip strength was related to a 9.2% reduced risk of incident PD (HR = 0.908, 95% CI [0.887-0.929], P < 0.001). Notably, the associations remained consistent when grip strength was calculated as quintiles. Moreover, participants with a slower walking pace demonstrated an elevated risk of incident PD (HR = 1.231, 95%CI [1.075-1.409], P = 0.003). Subgroup and sensitivity analyses further validated the robustness of the observed associations. CONCLUSION: Our findings showed a negative association of grip strength and walking pace with the risk of incident PD independent of important confounding factors. These results hold potential implications for the early screening of people at high-risk of PD.

Αlpha-thalassemia: A practical overview.

α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and ß globin and thus varying degrees of ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and subsequent comorbidities. Clinical presentation varies depending on the genotype, ranging from a silent or mild carrier state to severe, transfusion-dependent or lethal disease. Management of patients with α-thalassemia is primarily supportive, addressing either symptoms (eg, RBC transfusions for anemia), complications of the disease, or its transfusion-dependence (eg, chelation therapy for iron overload). Several novel therapies are also in development, including curative gene manipulation techniques and disease modifying agents that target ineffective erythropoiesis and chronic hemolytic anemia. This review of α-thalassemia and its various manifestations provides practical information for clinicians who practice beyond those regions where it is found with high frequency.

The genetic architecture of the human hypothalamus and its involvement in neuropsychiatric behaviours and disorders.

Despite its crucial role in the regulation of vital metabolic and neurological functions, the genetic architecture of the hypothalamus remains unknown. Here we conducted multivariate genome-wide association studies (GWAS) using hypothalamic imaging data from 32,956 individuals to uncover the genetic underpinnings of the hypothalamus and its involvement in neuropsychiatric traits. There were 23 significant loci associated with the whole hypothalamus and its subunits, with functional enrichment for genes involved in intracellular trafficking systems and metabolic processes of steroid-related compounds. The hypothalamus exhibited substantial genetic associations with limbic system structures and neuropsychiatric traits including chronotype, risky behaviour, cognition, satiety and sympathetic-parasympathetic activity. The strongest signal in the primary GWAS, the ADAMTS8 locus, was replicated in three independent datasets (N = 1,685-4,321) and was strengthened after meta-analysis. Exome-wide association analyses added evidence to the association for ADAMTS8, and Mendelian randomization showed lower ADAMTS8 expression with larger hypothalamic volumes. The current study advances our understanding of complex structure-function relationships of the hypothalamus and provides insights into the molecular mechanisms that underlie hypothalamic formation.

THromboprophylaxis In Sickle Cell Disease with central venous catheters (THIS): an internal pilot randomised controlled trial protocol.

INTRODUCTION: Individuals with sickle cell disease (SCD) and central venous catheters (CVC) are at high risk for venous thromboembolism (VTE). Minimal data exist regarding the use of anticoagulation as thromboprophylaxis of VTE in this demographic, and as a result, clinical equipoise exists. Prophylactic dose rivaroxaban, a direct oral anticoagulant, is efficacious and safe as thromboprophylaxis in other demographics, and may be an optimal agent in SCD with CVC. Prior to conducting a full clinical trial to assess rivaroxaban as thromboprophylaxis in SCD with CVC, a pilot study is needed to gauge its feasibility. METHODS AND ANALYSIS: THromboprophylaxis In Sickle Cell Disease pilot trial is an investigator-initiated, multicentre, double-blinded, randomised controlled trial (RCT) assessing if it is feasible and safe to conduct an adequately powered RCT comparing rivaroxaban to matching placebo as thromboprophylaxis in those with SCD and CVC. Fifty adult patients with SCD and CVC will be randomised to receive either rivaroxaban 10 mg daily or matching placebo for the duration of the CVC in situ for up to 1 year. After randomisation, follow-up visits will occur every 3 months. The primary outcomes pertain to the feasibility of a full trial and include numbers of eligible and recruited participants. Exploratory outcomes include overall incidence of VTE and bleeding complications, as well as quality of life. If the full trial is feasible, blinding will be maintained and patients in the pilot study will be included in the full trial. ETHICS AND DISSEMINATION: The trial was initially approved by the University Health Network Research Ethics Board (REB) in Toronto, Canada. All sites will obtain approval from their respective REB prior to commencement of study activities. Study results will be disseminated through presentations at medical conferences and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05033314.

Pregnancy outcomes and iron status in ß-thalassemia major and intermedia: a systematic review and meta-analysis.

ABSTRACT: Advancements in orally bioavailable iron chelators and MRI methods have improved life expectancy and reproductive potential in thalassemia major (TM) and thalassemia intermedia (TI). Pregnancy is associated with adverse maternal and neonatal outcomes, frequency of which has not been well delineated. This systematic review aims to provide risk estimates of maternal and fetal outcomes in TM and TI and explore pregnancy's impact on iron homeostasis. Fifteen studies (429 participants, 684 pregnancies) were included. Meta-analysis revealed a higher thrombosis risk in TI (3.7%) compared to TM (0.92%), unchanged from prepregnancy. Heart failure risks in the earlier years appeared similar (TM 1.6% vs TI 1.1%), and maternal mortality in TM was 3.7%, but with current management, these risks are rare. Gestational diabetes and pre-eclampsia occurred in 3.9% and 11.3% of TM pregnancies, respectively. Caesarean section rates were 83.9% in TM and 67% in TI. No significant difference in stillbirth, small for gestational age neonates, or preterm birth incidence between TM and TI was observed. In TM pregnancies, red cell requirements significantly increased (from 102 to 139 ml/kg/year, P = 0.001), and 70% of TI pregnancies required blood transfusions. As expected, increased transfusion alongside chelation cessation led to a significant increase in serum ferritin during pregnancy (TM by 1005 ng/mL; TI by 332 ng/mL, P < 0.0001). Deterioration in iron status was further reflected by an increase in liver iron concentration (from 4.6 to 11.9 mg/g dry weight, P < 0.0001), and myocardial T2-star (T2∗) magnetic resonance imaging decreased (from 36.2 ± 2.5 ms to 31.1 ms) during pregnancy. These findings emphasize the elevated maternal risk of iron-related cardiomyopathy during pregnancy and labor, stressing the importance of cardiac monitoring and postpartum chelation therapy resumption.

Blood pressure thresholds for the diagnosis of hypertensive disorders of pregnancy in sickle cell disease.

In this retrospective cohort study of singleton pregnancies in people with sickle cell disease (SCD) delivered at two academic centres between 1990 and 2021, we collected demographic and SCD-related data, pregnancy outcomes, and the highest systolic and diastolic blood pressure (SBP and DBP) at seven time periods. We compared the characteristics of subjects with new or worsening proteinuria (NWP) during pregnancy to those without. We then constructed receiver operating characteristic (ROC) curves to determine the blood pressure (BP) that best identifies those with NWP. The SBP or DBP thresholds which maximized sensitivity and specificity were 120 mmHg SBP (sensitivity: 55.2%, specificity: 73.5%) and 70 mmHg DBP (sensitivity: 27.6%, specificity: 67.7%). The existing BP threshold of 140/90 mmHg lacked sensitivity in both genotype groups (HbSS/HbSß0 : SBP = 21% sensitive, DBP = 5.3% sensitive; HbSS/HbSß+ : SBP = 10% sensitive, DBP = 0% sensitive). Finally, percent change in SBP, DBP and MAP were all poor tests for identifying NWP. Existing BP thresholds used to diagnose hypertensive disorders of pregnancy (HDP) are not sensitive for pregnant people with SCD. For this population, lowering the BP threshold that defines HDP may improve identification of those who need increased observation, consideration of early delivery and eclampsia prophylaxis.

Natural history of blood pressure in sickle cell disease pregnancy.

In this retrospective cohort study of singleton pregnancies in people with sickle cell disease (SCD) delivered at two academic centres between 1990 and 2021, we collected demographic and SCD-related data, pregnancy outcomes, and the highest systolic and diastolic blood pressure (SBP and DBP) at seven time periods. We compared blood pressure values and trajectories in the composite cohort and in each genotype group to control values in a non-SCD pregnancy dataset. There were 290 pregnancies among 197 patients with SCD. Sixteen per cent (n = 47) of pregnancies had a hypertensive disorder of pregnancy (HDP); the rates did not differ by genotype. The mean SBP and DBP were lower in the HbSS/HbSß0 group than in the non-SCD control group at all timepoints. Mean SBP and DBP trajectories were similar between the HbSS/HbSß0 group and non-SCD controls, whereas the mean SBP and DBP in the HbSC/HbSß+ group decreased between the first and second trimesters and plateaued between the second and third trimesters. There were no differences in blood pressure trajectory by haemoglobin >/< 10 gm/dL or by chronic transfusion status. Overall, pregnant people with SCD have lower blood pressure than unaffected pregnant people, raising the possibility that HDP are underdiagnosed, particularly in people with HbSS/HbSß0 .

Genetic architectures of cerebral ventricles and their overlap with neuropsychiatric traits.

The cerebral ventricles are recognized as windows into brain development and disease, yet their genetic architectures, underlying neural mechanisms and utility in maintaining brain health remain elusive. Here we aggregated genetic and neuroimaging data from 61,974 participants (age range, 9 to 98 years) in five cohorts to elucidate the genetic basis of ventricular morphology and examined their overlap with neuropsychiatric traits. Genome-wide association analysis in a discovery sample of 31,880 individuals identified 62 unique loci and 785 candidate genes associated with ventricular morphology. We replicated over 80% of loci in a well-matched cohort of lateral ventricular volume. Gene set analysis revealed enrichment of ventricular-trait-associated genes in biological processes and disease pathogenesis during both early brain development and degeneration. We explored the age-dependent genetic associations in cohorts of different age groups to investigate the possible roles of ventricular-trait-associated loci in neurodevelopmental and neurodegenerative processes. We describe the genetic overlap between ventricular and neuropsychiatric traits through comprehensive integrative approaches under correlative and causal assumptions. We propose the volume of the inferior lateral ventricles as a heritable endophenotype to predict the risk of Alzheimer's disease, which might be a consequence of prodromal Alzheimer's disease. Our study provides an advance in understanding the genetics of the cerebral ventricles and demonstrates the potential utility of ventricular measurements in tracking brain disorders and maintaining brain health across the lifespan.

Spiritual Care in PICUs: A U.S. Survey of 245 Training Fellows 2020-2021.

OBJECTIVES: To understand the perspectives of pediatric fellows training in critical care subspecialties about providing spiritual care. DESIGN: Cross-sectional survey of United States National Residency Matching Program pediatric fellows training in critical care specialties. SETTING: Online survey open from April to May 2021. SUBJECTS: A total of 720 fellows (165 cardiology, 259 critical care, and 296 neonatology) were contacted, with a response rate of 245 of 720 (34%). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed fellows' survey responses about spiritual care in neonatal and pediatric critical care units. Categorical data were compared using chi-square test or Fisher exact tests. The Wilcoxon rank-sum test was used to compare the percentage correct on ten multiple-choice questions about world religions. Free-text responses were independently coded by two research investigators. A total of 203 of 245 (83%) responding fellows had never received training about spiritual care and 176 of 245 (72%) indicated that they would be likely to incorporate spiritual care into their practice if they received training. Prior training was associated with increased familiarity with a framework for taking a spiritual history (p < 0.001) and increased knowledge of spiritual practices that could influence medical care (p = 0.03). Prior training was also associated with increased self-reported frequency of taking a spiritual history (p < 0.001) and comfort in referring families to spiritual care resources (p = 0.02). Lack of time and training were the most reported barriers to providing spiritual care. CONCLUSIONS: Providing spiritual care for families is important in critical care settings. In 2020-2021, in the United States, 245 pediatric critical care fellows responded to a survey about spiritual care in their practice and reported that they lacked training in this subject. An opportunity exists to implement spiritual care curricula into pediatric fellowship training.

Pyruvate kinase activators: targeting red cell metabolism in thalassemia.

Thalassemia is an inherited red blood cell disorder whereby the qualitative and/or quantitative imbalance in α- to ß-globin ratio results in hemolysis and ineffective erythropoiesis. Oxidative stress, from the precipitated excess globin and free iron, is a major factor that drives hemolysis and ineffective erythropoiesis. Pyruvate kinase activity and adenosine triphosphate availability are reduced due to the overwhelmed cellular antioxidant system from the excessive oxidative stress. Mitapivat, a pyruvate kinase activator in development as a treatment for thalassemia, was shown to increase hemoglobin and reduce hemolysis in a small phase 2 single-arm trial of patients with α- and ß-thalassemia. The ongoing phase 3 studies with mitapivat and the phase 2 study with etavopivat will examine the role of pyruvate kinase activators as disease modifying agents in thalassemia.

Screening for cognitive impairment in adults with sickle cell disease: A systematic review and meta-analysis.

Neurovascular disease such as symptomatic stroke, silent brain infarcts and vascular cognitive impairment are common complications of sickle cell disease (SCD) that can have devastating consequences on quality of life, employment, and social functioning.  Early recognition of neurovascular disease is a prerequisite for the timely optimization of medical care and to connect patients to adaptive resources. While cognitive impairment has been well described in children, currently available data are limited in adults. As a result, guidance on the optimal cognitive screening strategies in adults is scarce. We conducted a systematic review to identify the different screening tools that have been evaluated in SCD. A meta-analysis was performed to estimate the prevalence of suspected cognitive impairment in this population. In this qualitative synthesis, we present 8 studies that evaluated 6 different screening tools. Patient characteristics that impacted on cognitive screening performance included age, education level, and a prior history of stroke. We report a pooled prevalence of 38% [14-62%] of suspected cognitive impairment. We discuss the relative benefits and limitations of the different screening tools to help clinicians select an adapted approach tailored to their specific patients' needs. Further studies are needed to establish and validate cognitive screening strategies in patients with diverse cultural and educational backgrounds.