Consideration of sex and gender in Alzheimer's disease and related disorders from a global perspective.

Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable risk factors for intervention. However, few epidemiological or clinical ADRD studies examine sex differences; even fewer evaluate gender in the context of ADRD risk. The goals of this perspective are to: (1) provide definitions of gender, biologic sex, and sexual orientation. and the limitations of examining these as binary variables; (2) provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD; and (3) discuss these sex and gender differences from a global, worldwide perspective. Identifying drivers of sex and gender differences in ADRD throughout the world is a first step in developing interventions unique to each geographical and sociocultural area to reduce these inequities and to ultimately reduce global ADRD risk. HIGHLIGHTS: The burden of dementia is unevenly distributed geographically and by sex and gender. Scientific advances in genetics and biomarkers challenge beliefs that sex is binary. Discrimination against women and sex and gender minority (SGM) populations contributes to cognitive decline. Sociocultural factors lead to gender inequities in Alzheimer's disease and related dementias (ADRD) worldwide.

Kids With Altitude: Acute Mountain Sickness and Changes in Body Mass and Total Body Water in Children Travelling to 3800 m.

INTRODUCTION: We explored the incidence of acute mountain sickness (AMS) and extravascular lung water (ELW) in children in relation to changes in body composition and peripheral blood oxygenation (SpO2) during 1 week of acclimatization to 3800 m. METHODS: In a prospective cohort study, 10 children (7 female, ages 7-14 y) and 10 sex-matched adults (ages 23-44 y) traveled via automobile from sea level to 3000 m for 2 nights, followed by 4 nights at 3800 m. Each morning, body mass and body water (bioelectrical impedance), SpO2 (pulse oximetry), AMS (Lake Louise Questionnaire), and ELW (transthoracic echocardiography) were measured. RESULTS: No differences were found between children and adults in SpO2 or ELW. At 3800 m 7 of 10 children were AMS+ vs 4 of 10 adults. Among those AMS+ at 3800 m, the severity was greater in children compared to adults (5±1 vs 3 ± 0; P=0.005). Loss of body mass occurred more quickly in children (day 5 vs day 7) and to a greater extent (-7±3% vs -2±2%; P<0.001); these changes were mediated via a larger relative loss in total body water in children than in adults (-6±5% vs -2±2%; P=0.027). CONCLUSIONS: Children demonstrated a higher incidence of AMS than adults, with greater severity among those AMS+. The loss of body water and body mass at high altitude was also greater in children, albeit unrelated to AMS severity. In addition to awareness of AMS, strategies to maintain body weight and hydration in children traveling to high altitudes should be considered.

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease.

BACKGROUND: Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. METHODS: We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months. RESULTS: CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma. CONCLUSIONS: CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, "secondary prevention" based on prodromal pathology may prove challenging; instead, "primary prevention" trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.

Clinical Trials and Tribulations in the COVID-19 Era.

Advances in treating and preventing Alzheimer disease and other neurocognitive disorders of aging arise from rigorous preclinical and clinical research, with randomized controlled treatment trials as the last and definitive test. The COVID-19 pandemic has greatly disrupted ongoing interventional studies and researchers are scrambling to find ways to safely continue this critical work amidst rapidly shifting guidelines from sponsors, institutions, and state and federal guidelines. Here the authors describe novel approaches and work-flow adaptations to study visits, drug delivery and interim and endpoint safety and outcomes assessments to avoid sacrificing years of preparation and substantial financial investments, to work in the best interest of participants and their caregivers, and to continue on the path toward discovering disease-modifying treatments for the millions of individuals impacted by major neurocognitive disorders.

Intracranial Vascular Responses to High-Intensity Interval Exercise and Moderate-Intensity Steady-State Exercise in Children.

PURPOSE: To understand the extent different types of acute exercise influence cerebral blood flow during and following exercise in children. METHODS: Eight children (7-11 y; 4 girls) completed 2 conditions: high-intensity interval exercise (HIIE; 6 × 1-min sprints at 90% watt maximum) and moderate-intensity steady-state exercise (MISS; 15 min at 44% watt maximum). Blood velocity in the middle cerebral artery (MCAV) and heart rate were assessed continuously. The partial pressure of end-tidal carbon dioxide and mean arterial pressure were assessed at baseline and following exercise. RESULTS: Percentage of maximum heart rate during HIIE was 82% (4%), compared with 69% (4%) during MISS. MCAV was increased above baseline in MISS after 75 seconds (5.8% [3.9%], P × .004) but was unchanged during HIIE. MCAV was reduced below baseline (-10.7% [4.1%], P × .004) during the sixth sprint of HIIE. In both conditions, MCAV remained below baseline postexercise, but returned to baseline values 30-minute postexercise (P < .001). A postexercise increase in mean arterial pressure was apparent following HIIE and MISS, and persisted 30-minute postexercise. Partial pressure of end-tidal carbon dioxide declined post HIIE (-3.4 mm Hg, P < .05), but not following MISS. CONCLUSION: These preliminary findings show HIIE and MISS elicit differing intracranial vascular responses; however, research is needed to elucidate the implications and underlying regulatory mechanisms of these responses.

A Comparison of the Efficacy and Safety of Intravenous Followed by Oral Delafloxacin With Vancomycin Plus Aztreonam for the Treatment of Acute Bacterial Skin and Skin Structure Infections: A Phase 3, Multinational, Double-Blind, Randomized Study.

Background: Delafloxacin is an intravenous (IV)/oral anionic fluoroquinolone with activity against gram-positive (including methicillin-resistant Staphylococcus aureus [MRSA]), gram-negative, atypical, and anaerobic organisms. It is approved in the United States for acute bacterial skin and skin structure infections (ABSSSIs) caused by designated susceptible gram-positive and gram-negative organisms, and is in development for the treatment of community-acquired bacterial pneumonia. Methods: A multicenter, randomized, double-blind trial of 850 adults with ABSSSI compared delafloxacin 300 mg IV every 12 hours for 3 days with a switch to 450 mg oral delafloxacin, to vancomycin 15 mg/kg IV with aztreonam for 5-14 days. The primary endpoint was objective response at 48-72 hours. Investigator-assessed response based on resolution of signs and symptoms at follow-up (day 14 ± 1), and late follow-up (day 21-28) were secondary endpoints. Results: In the intent-to-treat analysis set, the objective response was 83.7% in the delafloxacin arm and 80.6% in the comparator arm. Investigator-assessed success was similar at follow-up (87.2% vs 84.4%) and late follow-up (83.5% vs 82.2%). Delafloxacin was comparable to vancomycin + aztreonam in eradication of MRSA at 96.0% vs 97.0% at follow-up. Frequency of treatment-emergent adverse events between the groups was similar. Treatment-emergent adverse events leading to study drug discontinuation was higher in the vancomycin + aztreonam group (1.2% vs 2.4%). Conclusions: In ABSSSI patients, IV/oral delafloxacin monotherapy was noninferior to IV vancomycin + aztreonam combination therapy for both the objective response and the investigator-assessed response at follow-up and late follow-up. Delafloxacin was well tolerated as monotherapy in treatment of ABSSSIs. Clinical Trials Registration: NCT01984684.

A Phase 3, Randomized, Double-Blind, Multicenter Study To Evaluate the Safety and Efficacy of Intravenous Iclaprim versus Vancomycin for Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed To Be Due to Gram-Positive Pathogens (REVIVE-2 Study).

Iclaprim is a novel diaminopyrimidine antibiotic that may be an effective and safe treatment for serious skin infections. The safety and effectiveness of iclaprim were assessed in a global phase 3, double-blind, randomized, active-controlled trial. Six hundred thirteen adults with acute bacterial skin and skin structure infections (ABSSSIs) suspected or confirmed to be due to Gram-positive pathogens were randomized to iclaprim (80 mg) or vancomycin (15 mg/kg of body weight), both of which were administered intravenously every 12 h for 5 to 14 days. The primary endpoint was a ≥20% reduction in lesion size compared with that at the baseline at 48 to 72 h after the start of administration of study drug in the intent-to-treat population. Among patients randomized to iclaprim, 78.3% (231 of 295) met this primary endpoint, whereas 76.7% (234 of 305) of those receiving vancomycin met this primary endpoint (difference, 1.58%; 95% confidence interval, -5.10% to 8.26%). This met the prespecified 10% noninferiority margin. Iclaprim was well tolerated, with most adverse events being categorized as mild. In conclusion, iclaprim was noninferior to vancomycin in this phase 3 clinical trial for the treatment of acute bacterial skin and skin structure infections. On the basis of these results, iclaprim may be an efficacious and safe treatment for skin infections suspected or confirmed to be due to Gram-positive pathogens. (This trial has been registered at ClinicalTrials.gov under identifier NCT02607618.).

Mediating effects of body composition between physical activity and body esteem in Hong Kong adolescents: a structural equation modeling approach.

This study investigated the mediating role of body mass index (BMI) in the relationship between physical activity and body esteem in adolescents. Nine hundred and five Hong Kong Chinese students aged 12-18 years participated in a cross-sectional study in 2007. Students' BMI was computed as an indicator of their body composition. Their physical activity level and body esteem were examined using the Physical Activity Rating for Children and Youth (PARCY) and Body Esteem Scale (BES), respectively. Structural equation modelling was used to investigate the mediating effects of BMI and physical activity in predicting body esteem, with stratification by sex. The overall fit of the hypothesized models was satisfactory in boys (NFI = 0.94; NNFI = 0.88; CFI = 0.95; RMSEA = 0.07) and girls (NFI = 0.89; NNFI = 0.77; CFI = 0.91; RMSEA = 0.11). When BMI was considered as a mediator, higher physical activity had a significant negative total effect on body esteem in boys, but not in girls. The indirect effect of higher physical activity on body esteem via BMI was positive in boys, but negative in girls. CONCLUSIONS: Regular physical activity may help overweight adolescents, especially boys, improve their body esteem. Kinesiologists and health professionals could explore the use of physical activity prescriptions for weight management, aiming at body esteem improvement in community health programs for adolescents. WHAT IS KNOWN: Among Western adolescents, negative body esteem is more pervasive in girls than in boys. There are consistent findings of the association between higher body mass index and lower body esteem in adolescents, but the association between physical activity and body esteem are equivocal. WHAT IS NEW: A negative association between body mass index and body esteem was found in both Hong Kong adolescent boys and girls. The indirect effect of physical activity on body esteem via body mass index was positive in Hong Kong adolescent boys, but negative in girls.

Energies and structures in biradical chemistry from the parametric two-electron reduced-density matrix method: applications to the benzene and cyclobutadiene biradicals.

The treatment of biradical chemistry presents a challenge for electronic structure theory, especially single-reference methods, as it requires the description of varying degrees and kinds of electron correlation. In this work we assess the ability of the parametric two-electron reduced-density matrix (p2-RDM) method to describe biradical chemistry through application to the benzene and cyclobutadiene biradicals. The relative energy of o- and m-benzynes predicted by the p2-RDM method is consistent with Wenthold et al.'s experimental determinations, while the more difficult relative energy prediction of the more multi-referenced p-benzyne is within 1.4 kcal mol(-1) of the experimental value [P. G. Wenthold et al., J. Am. Chem. Soc., 1998, 120, 5279], which is significantly better than traditional single-reference methods. We observe that the degree of multireference correlation in the biradicals depends upon the distance between their radical centers, with the largest radical separation displaying the largest degree of multireference correlation. In addition to relative and absolute electronic energies, we report molecular geometries, natural orbitals, and natural-orbital occupations for the benzene and cyclobutadiene biradicals.

Body size dissatisfaction among young Chinese children in Hong Kong: a cross-sectional study.

OBJECTIVE: To determine the potential predictors of body size dissatisfaction in Chinese children. DESIGN: The Child's Body Image Scale was used to assess body size perception and dissatisfaction. BMI was calculated from objectively measured height and weight. Predictors of body size dissatisfaction were examined by logistic regression analysis. SETTING: Hong Kong, China. SUBJECTS: Six hundred and twenty children (53 % boys, aged 6·1-12·9 years) from a state-run primary school. RESULTS: Female sex (adjusted OR (AOR)=1·91; 95 % CI 1·32, 2·76), age (AOR=2·62; 95 % CI 1·65, 4·16 for 8-10 years; AOR=2·16; 95 % CI 1·38, 3·38 for >10 years), overweight (AOR=6·23; 95 % CI 3·66, 10·60) and obesity (AOR=19·04; 95 % CI 5·64, 64·32) were positively associated with desire to be thinner. Size misperception was a strong predictor of body size dissatisfaction, irrespective of actual weight status (AOR=1·90; 95 % CI 1·02, 3·54 for overestimation; AOR=0·43; 95 % CI 0·27, 0·67 for underestimation). CONCLUSIONS: Body size dissatisfaction is prevalent among Chinese children as young as 6 years. Female sex, age, overweight, obesity and overestimation of size were associated with increased desire to be thinner. These findings emphasise the importance of preventing body image issues from an early age.

Muscle metabolism changes with age and maturation: How do they relate to youth sport performance?

AIM: To provide an evidence-based review of muscle metabolism changes with sex-, age- and maturation with reference to the development of youth sport performance. METHODS: A narrative review of data from both invasive and non-invasive studies, from 1970 to 2015, founded on personal databases supported with computer searches of PubMed and Google Scholar. RESULTS: Youth sport performance is underpinned by sex-, age- and maturation-related changes in muscle metabolism. Investigations of muscle size, structure and metabolism; substrate utilisation; pulmonary oxygen uptake kinetics; muscle phosphocreatine kinetics; peak anaerobic and aerobic performance; and fatigue resistance; determined using a range of conventional and emerging techniques present a consistent picture. Age-related changes have been consistently documented but specific and independent maturation-related effects on muscle metabolism during exercise have proved elusive to establish. Children are better equipped for exercise supported primarily by oxidative metabolism than by anaerobic metabolism. Sexual dimorphism is apparent in several physiological variables underpinning youth sport performance. As young people mature there is a progressive but asynchronous transition into an adult metabolic profile. CONCLUSIONS: The application of recent developments in technology to the laboratory study of the exercising child and adolescent has both supplemented existing knowledge and provided novel insights into developmental exercise physiology. A sound foundation of laboratory-based knowledge has been established but the lack of rigorously designed child-specific and sport-specific testing environments has clouded the interpretation of the data in real life situations. The primary challenge remains the translation of laboratory research into the optimisation of youth sports participation and performance.

Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion.

OBJECTIVES: To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion. METHODS: This single-center longitudinal cohort study has followed known carriers of PRNP pathogenic variants at risk for prion disease, individuals with a close relative who died of genetic prion disease but who have not undergone predictive genetic testing, and controls. All participants were asymptomatic at first visit and returned roughly annually. We determined PRNP genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and beta-synuclein in CSF. RESULTS: Among 41 carriers and 21 controls enrolled, 28 (68%) and 15 (71%) were female, and mean ages were 47.5 and 46.1. At baseline, all individuals were asymptomatic. We observed RT-QuIC seeding activity in the CSF of 3 asymptomatic E200K carriers who subsequently converted to symptomatic and died of prion disease. 1 P102L carrier remained RT-QuIC negative through symptom conversion. No other individuals developed symptoms. The prodromal window from detection of RT-QuIC positivity to disease onset was 1 year long in an E200K individual homozygous (V/V) at PRNP codon 129 and 2.5 and 3.1 years in 2 codon 129 heterozygotes (M/V). Changes in neurodegenerative and neuroinflammatory markers were variably observed prior to onset, with increases observed for plasma NfL in 4/4 converters, and plasma GFAP, CSF NfL, CSF T-tau, and CSF beta-synuclein each in 2/4 converters, although values relative to age and fold changes relative to individual baseline were not remarkable for any of these markers. CSF PrP was longitudinally stable with mean coefficient of variation 9.0% across all individuals over up to 6 years, including data from converting individuals at RT-QuIC-positive timepoints. DISCUSSION: CSF prion seeding activity may represent the earliest detectable prodromal sign in E200K carriers. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT05124392 posted 2017-12-01, updated 2023-01-27.

The mechanism of carbon dioxide adsorption in an alkylamine-functionalized metal-organic framework.

The mechanism of CO2 adsorption in the amine-functionalized metal-organic framework mmen-Mg2(dobpdc) (dobpdc(4-) = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate; mmen = N,N'-dimethylethylenediamine) was characterized by quantum-chemical calculations. The material was calculated to demonstrate 2:2 amine:CO2 stoichiometry with a higher capacity and weaker CO2 binding energy than for the 2:1 stoichiometry observed in most amine-functionalized adsorbents. We explain this behavior in the form of a hydrogen-bonded complex involving two carbamic acid moieties resulting from the adsorption of CO2 onto the secondary amines.

Orlistat improves endothelial function in obese adolescents: a randomised trial.

AIM: To investigate the effect of orlistat on endothelial function in obese adolescents. METHODS: Single-blind 10-week controlled trial of 67 normolipidaemic obese adolescents randomised into three groups. Group 1 (diet alone), Group 2 (diet and orlistat), Group 3 (diet, orlistat and exercise). Endothelial function measured by flow-mediated dilatation (FMD) of the brachial artery, anthropometric parameters, blood pressure, fasting blood lipids, insulin and glucose levels were recorded at baseline and at 10 weeks. RESULTS: Sixty four subjects completed the study. Groups were comparable at baseline. FMD increased significantly with orlistat (Groups 2 and 3) but not in Group 1. Orlistat treatment resulted in significantly reduced bodyweight, body mass index (BMI), waist circumference, total and low-density lipoprotein (LDL) cholesterol levels. High-density lipoprotein cholesterol levels were unchanged. Triglyceride and insulin levels were significantly reduced in all three groups. The reduction in cholesterols did not correlate with reductions in weight and BMI. A slight reduction of body fat, both with and without orlistat treatment, correlated with reduction in BMI after adjustment for baseline values. Blood pressure was unaltered by orlistat. Calorie intake was reduced with orlistat, and the decrease noted in % fat and increase in % carbohydrate was significant only in those taking orlistat. The addition of exercise (Group 3 compared with Group 2) altered no parameter. CONCLUSIONS: Orlistat improves endothelial function and reduces bodyweight, BMI, fasting total and LDL-cholesterol in obese adolescents when combined with dietary control. Improvement in endothelial function if maintained could reflect long-term cardiovascular benefit.

Validity of self-estimated adiposity assessment against general and central adiposity in Hong Kong adolescents.

BACKGROUND AND AIM: The relationships between self-estimated adiposity using Stunkard's body silhouette scale with general and central adiposity in adolescents are unclear. This study examines the criterion validity of Stunkard's body silhouette scale as a self-estimated rating of adiposity against anthropometric measures of adiposity and percentage body fat in Hong Kong adolescents. SUBJECTS AND METHODS: The body composition of 903 adolescents (55.7% boys) was assessed by measured waist circumference (WC), waist-to-stature ratio (WSR), body mass index (BMI) and percentage body fat (%BF). Self-estimated adiposity was subjectively assessed using Stunkard's body silhouette scale. The association between self-estimated adiposity and body composition was examined by Spearman correlation coefficients and hierarchical multiple regression analyses. RESULTS: Self-estimated adiposity correlated significantly and positively with BMI (boys: r = 0.65; girls: r = 0.59), WC (boys: r = 0.62; girls: r = 0.51), WSR (boys: r = 0.55; girls: r = 0.42) and %BF (boys: r = 0.47; girls: r = 0.55). CONCLUSION: Self-estimated adiposity using the Stunkard's body silhouette scale was positively associated with actual measures of adiposity; however, the association was modest at best. It is unlikely that the Stunkard's body silhouette scale provides a suitably accurate substitute for actual body composition measures in Chinese adolescents.

Percentage body fat and anthropometric measures in Hong Kong adolescents.

This study investigates the associations between percentage body fat (%BF) and anthropometric parameters in adolescents of mixed weight status. Anthropometric parameters including height, weight, and waist circumference (WC), and %BF were assessed in 903 Hong Kong Chinese students (mean age 14.7 years). The calculated body mass index (BMI) and waist-to-stature ratio (WSR) were used to classify students into different weight status groups and central obesity groups, respectively. The %BF/BMI and %BF/WC relationships were examined by partial correlation coefficients and linear regression models. The %BF correlated significantly with BMI, except in underweight boys. BMI predicted %BF better (adjusted R (2): 0.40 in boys; 0.85 in girls) than WC (adjusted R (2): 0.34 in boys; 0.63 in girls) or WSR (adjusted R (2): 0.33 in boys; 0.60 in girls). In general, BMI predicts %BF better than WC or WSR in Hong Kong adolescents, but these relationships are sex and weight status specific.

Biomarker changes preceding symptom onset in genetic prion disease.

Importance: Genetic prion disease is a universally fatal and rapidly progressive neurodegenerative disease for which genetically targeted therapies are currently under development. Preclinical proofs of concept indicate that treatment before symptoms will offer outsize benefit. Though early treatment paradigms will be informed by the longitudinal biomarker trajectory of mutation carriers, to date limited cases have been molecularly tracked from the presymptomatic phase through symptomatic onset. Objective: To longitudinally characterize disease-relevant cerebrospinal fluid (CSF) and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion, alongside non-converters and healthy controls. Design setting and participants: This single-center longitudinal cohort study has followed 41 PRNP mutation carriers and 21 controls for up to 6 years. Participants spanned a range of known pathogenic PRNP variants; all subjects were asymptomatic at first visit and returned roughly annually. Four at-risk individuals experienced prion disease onset during the study. Main outcomes and measures: RT-QuIC prion seeding activity, prion protein (PrP), neurofilament light chain (NfL) total tau (t-tau), and beta synuclein were measured in CSF. Glial fibrillary acidic protein (GFAP) and NfL were measured in plasma. Results: We observed RT-QuIC seeding activity in the CSF of three E200K carriers prior to symptom onset and death, while the CSF of one P102L carrier remained RT-QuIC negative through symptom conversion. The prodromal window of RT-QuIC positivity was one year long in an E200K individual homozygous (V/V) at PRNP codon 129 and was longer than two years in two codon 129 heterozygotes (M/V). Other neurodegenerative and neuroinflammatory markers gave less consistent signal prior to symptom onset, whether analyzed relative to age or individual baseline. CSF PrP was longitudinally stable (mean CV 10%) across all individuals over up to 6 years, including at RT-QuIC positive timepoints. Conclusion and relevance: In this study, we demonstrate that at least for the E200K mutation, CSF prion seeding activity may represent the earliest detectable prodromal sign, and that its prognostic value may be modified by codon 129 genotype. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity.

Follow up of aerobic capacity in children affected by severe acute respiratory syndrome.

BACKGROUND AND OBJECTIVE: The aim of this study was to investigate the aerobic capacity of children 3 years after they were diagnosed with severe acute respiratory syndrome (SARS). METHODS: Twenty-seven patients who completed both pulmonary function and maximal aerobic capacity tests at 6 and 15 months after the acute illness were invited to return for reassessment. RESULTS: Twenty-one patients (median age 18.2 years, interquartile range (IQR) 16.5-19.7) completed all investigations at 36 months. Pulmonary function was normal in all patients. Maximal aerobic capacity, peak oxygen pulse (peak VO(2) ) and ventilatory anaerobic threshold showed significant improvements compared with values measured at 6 months in both boys and girls. In girls, ventilatory efficiency (ventilatory equivalents for oxygen and carbon dioxide) and perfusion of the lungs (end-tidal partial carbon dioxide pressure) had not increased further compared with the values measured at 15 months. Although peak VO(2) improved further at 36 months in patients with or without persistent radiological abnormalities, the values were 68% (IQR 50-84) and 74% (IQR 60-99), respectively, of those for normal control subjects. CONCLUSIONS: There were improvements in aerobic capacity at 36 months in children affected by SARS; however, the measured values remained suboptimal.

Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS.

Prion protein (PrP) concentration controls the kinetics of prion replication and is a genetically and pharmacologically validated therapeutic target for prion disease. In order to evaluate PrP concentration as a pharmacodynamic biomarker and assess its contribution to known prion disease risk factors, we developed and validated a plate-based immunoassay reactive for PrP across 6 species of interest and applicable to brain and cerebrospinal fluid (CSF). PrP concentration varied dramatically across different brain regions in mice, cynomolgus macaques, and humans. PrP expression did not appear to contribute to the known risk factors of age, sex, or common PRNP genetic variants. CSF PrP was lowered in the presence of rare pathogenic PRNP variants, with heterozygous carriers of P102L displaying 55%, and D178N just 31%, of the CSF PrP concentration of mutation-negative controls. In rodents, pharmacologic reduction of brain Prnp RNA was reflected in brain parenchyma PrP and, in turn in CSF PrP, validating CSF as a sampling compartment for the effect of PrP-lowering therapy. Our findings support the use of CSF PrP as a pharmacodynamic biomarker for PrP-lowering drugs and suggest that relative reduction from individual baseline CSF PrP concentration may be an appropriate marker for target engagement.

Prevalence of exercise and non-exercise physical activity in Chinese adolescents.

Non-exercise physical activity (NEPA) is an important part of energy expenditure. This study aimed to investigate the prevalence of exercise and NEPA among adolescents. In the HKSOS project 2006-2007, the proportions of Hong Kong Chinese adolescents (N=32,005) achieving 60-minute exercise and 60-minute NEPA per day were analyzed. Exercise was defined as structured and planned physical activities, and NEPA was defined as unstructured and unplanned physical activities including walking for transportation and climbing stairs. The prevalence of exercise was higher in boys than girls (after school: 63.8% vs 39.6%; holidays: 78.7% vs 60.0%), but the prevalence of NEPA in boys was similar to that in girls (after school: 72.2% vs 68.0%; holidays: 80.3% vs 79.4%). In general, the prevalence of both exercise and NEPA decreased with age in boys and girls, but was more marked for exercise than NEPA. In conclusion, the prevalence of exercise was lower in adolescent girls than boys, and decreased more rapidly with age than NEPA. NEPA seems to be easier to accumulate than exercise among adolescents regardless of sex and age.