At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. DESIGN: Phase 2, open-label, single arm study. SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-ß antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Reversed Holocene temperature-moisture relationship in the Horn of Africa.

Anthropogenic climate change is predicted to severely impact the global hydrological cycle1, particularly in tropical regions where agriculture-based economies depend on monsoon rainfall2. In the Horn of Africa, more frequent drought conditions in recent decades3,4 contrast with climate models projecting precipitation to increase with rising temperature5. Here we use organic geochemical climate-proxy data from the sediment record of Lake Chala (Kenya and Tanzania) to probe the stability of the link between hydroclimate and temperature over approximately the past 75,000 years, hence encompassing a sufficiently wide range of temperatures to test the 'dry gets drier, wet gets wetter' paradigm6 of anthropogenic climate change in the time domain. We show that the positive relationship between effective moisture and temperature in easternmost Africa during the cooler last glacial period shifted to negative around the onset of the Holocene 11,700 years ago, when the atmospheric carbon dioxide concentration exceeded 250 parts per million and mean annual temperature approached modern-day values. Thus, at that time, the budget between monsoonal precipitation and continental evaporation7 crossed a tipping point such that the positive influence of temperature on evaporation became greater than its positive influence on precipitation. Our results imply that under continued anthropogenic warming, the Horn of Africa will probably experience further drying, and they highlight the need for improved simulation of both dynamic and thermodynamic processes in the tropical hydrological cycle.

Final Measurement of the

This Letter reports one of the most precise measurements to date of the antineutrino spectrum from a purely ^{235}U-fueled reactor, made with the final dataset from the PROSPECT-I detector at the High Flux Isotope Reactor. By extracting information from previously unused detector segments, this analysis effectively doubles the statistics of the previous PROSPECT measurement. The reconstructed energy spectrum is unfolded into antineutrino energy and compared with both the Huber-Mueller model and a spectrum from a commercial reactor burning multiple fuel isotopes. A local excess over the model is observed in the 5-7 MeV energy region. Comparison of the PROSPECT results with those from commercial reactors provides new constraints on the origin of this excess, disfavoring at 2.0 and 3.7 standard deviations the hypotheses that antineutrinos from ^{235}U are solely responsible and noncontributors to the excess observed at commercial reactors, respectively.

Development of an improved standard reference material for folate vitamers in human serum.

The US National Institute of Standards and Technology (NIST) developed a Standard Reference Material® (SRM®) 3949 Folate Vitamers in Frozen Human Serum to replace SRM 1955 Homocysteine and Folate in Human Serum. The presence of increased endogenous levels of folic acid and 5-methyltetrahydrofolate (5mTHF) in SRM 3949, enhanced folate stability via addition of ascorbic acid, and inclusion of values for additional minor folates are improvements over SRM 1955 that should better serve the clinical folate measurement community. The new SRM contains folates at three levels. To produce SRM 3949, pilot sera were collected from 15 individual donors, 5 of whom were given a 400-µg folic acid supplement 1 h prior to blood draw to increase serum levels of 5mTHF and folic acid for the high-level material. To stabilize the folates, 0.5% (mass concentration) ascorbic acid was added as soon as possible after preparation of serum. These pilot sera were screened for five folates plus the pyrazino-s-triazine derivative of 4-α-hydroxy-5-methyltetrahydrofolate (MeFox) at the US Centers for Disease Control and Prevention (CDC) by isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS). Based on these results, a blending protocol was specified to obtain the three desired folate concentrations for SRM 3949. ID-LC-MS/MS analysis at the CDC and NIST was utilized to assign values for folic acid and 5mTHF, as well as several minor folates.

Joint Measurement of the

The PROSPECT and STEREO collaborations present a combined measurement of the pure ^{235}U antineutrino spectrum, without site specific corrections or detector-dependent effects. The spectral measurements of the two highest precision experiments at research reactors are found to be compatible with χ^{2}/ndf=24.1/21, allowing a joint unfolding of the prompt energy measurements into antineutrino energy. This ν[over ¯]_{e} energy spectrum is provided to the community, and an excess of events relative to the Huber model is found in the 5-6 MeV region. When a Gaussian bump is fitted to the excess, the data-model χ^{2} value is improved, corresponding to a 2.4σ significance.

Overnight consolidation of speech sounds predicts decoding ability in skilled adult readers.

PURPOSE: Phonological representations are important for reading. In the current work, we examine the relationship between speech-perceptual memory encoding and consolidation to reading ability in skilled adult readers. METHOD: Seventy-three young adults (age 18-24) were first tested in their word and nonword reading ability, and then trained in the late evening to identify an unfamiliar speech sound contrast (Hindi retroflex-dental). Participants were assessed in their ability to perceive the target contrast immediately before training, after training, and 12 hours later. RESULTS: While perceptual performance on the target at any time point was unassociated with reading ability, overnight changes to the post-training perceptual ability over the 12-hour delay was significantly associated with nonword reading (i.e. decoding) ability, but not real-word reading. CONCLUSION: These results provide preliminary support for the hypothesis that individual differences in memory processes that update phonological representations following acoustic-phonetic exposure relate to decoding performance, including in adulthood.

Separations by Shape: Molecular Shape Recognition in Liquid Chromatography.

Molecular shape can provide a basis for chromatographic separations that is distinct from other interaction mechanisms often considered in liquid chromatography. Molecular shape recognition, or shape selectivity, is most evident for the separation of isomeric compounds that have constrained molecular structures, such as polycyclic aromatic hydrocarbons. A central feature of shape-selective columns is conformational order within the stationary phase; this aspect of stationary phase morphology is revealed through spectroscopic studies and molecular dynamics simulations, and is correlated with chromatographic performance.

Physical activity thresholds for predicting longitudinal gait decline in adults with knee osteoarthritis.

OBJECTIVE: To investigate the longitudinal relationship between physical performance (via real-life accelerometry) and physical capacity (laboratory measurement of gait speed) in patients with knee osteoarthritis (KOA), and to derive accelerometry measured thresholds associated with gait speed decline in KOA that may provide targets for disease-specific physical activity guidelines. DESIGN: Longitudinal data from the Osteoarthritis Initiative (OAI) accelerometer sub-study was extracted from 1,229 participants assessed 2 years apart. Extracted data include functional capacity, demographic and anthropometric characteristics, patient-reported outcome measures, and accelerometry-based physical activity measures. A "poor capacity" group was defined based on the gait speed quintile decline between baseline and the 2-yr follow-up. A Random Forest classifier was trained to classify individuals' capacity status, and the impact of each extracted factor on the prediction outcome was analyzed using a novel machine learning interpretation algorithm. RESULTS: The most impactful predicting feature for gait decline is low minutes in the performance of moderate-vigorous activity (count per min 2,500+). Slower sit-to-stand performance, higher age and self-reported knee pain, and lower minutes in performance light activities (count per min 350-2499) also contributed to the model prediction. The overall classification accuracy is 76.3% (75.4% sensitivity, 76.5% specificity). CONCLUSIONS: We investigated the impact magnitude and direction of each predicting feature on the longitudinal capacity status among KOA patients. Using novel data interpretation method, we established feature thresholds that may increase the probability of gait decline. These identified thresholds may provide meaningful information for establishing specific physical activity guidelines for KOA.

Nonfuel Antineutrino Contributions in the High Flux Isotope Reactor.

Reactor neutrino experiments have seen major improvements in precision in recent years. With the experimental uncertainties becoming lower than those from theory, carefully considering all sources of ν ¯ e is important when making theoretical predictions. One source of ν ¯ e that is often neglected arises from the irradiation of the nonfuel materials in reactors. The ν ¯ e rates and energies from these sources vary widely based on the reactor type, configuration, and sampling stage during the reactor cycle and have to be carefully considered for each experiment independently. In this article, we present a formalism for selecting the possible ν ¯ e sources arising from the neutron captures on reactor and target materials. We apply this formalism to the High Flux Isotope Reactor (HFIR) at Oak Ridge National Laboratory, the ν ¯ e source for the the Precision Reactor Oscillation and Spectrum Measurement (PROSPECT) experiment. Overall, we observe that the nonfuel ν ¯ e contributions from HFIR to PROSPECT amount to 1% above the inverse beta decay threshold with a maximum contribution of 9% in the 1.8-2.0 MeV range. Nonfuel contributions can be particularly high for research reactors like HFIR because of the choice of structural and reflector material in addition to the intentional irradiation of target material for isotope production. We show that typical commercial pressurized water reactors fueled with low-enriched uranium will have significantly smaller nonfuel ν ¯ e contribution.

Imaging indications and findings in evaluation of lung transplant graft dysfunction and rejection.

Lung transplantation is a treatment option in end-stage lung disease. Complications can develop along a continuum in the immediate or longer post-transplant period, including surgical and technical complications, primary graft dysfunction, rejection, infections, post-transplant lymphoproliferative disorder, and recurrence of the primary disease. These complications have overlapping clinical and imaging features and often co-exist. Time of onset after transplant is helpful in narrowing the differential diagnosis. In the early post transplantation period, imaging findings are non-specific and need to be interpreted in the context of the clinical picture and other investigations. In contrast, imaging plays a key role in diagnosing and monitoring patients with chronic lung allograft dysfunction. The goal of this article is to review primary graft dysfunction, acute rejection, and chronic rejection with emphasis on the role of imaging, pathology findings, and differential diagnosis.

Electronic and magnetic properties of stoichiometric CeAuBi2.

We report the electronic and magnetic properties of stoichiometric CeAuBi2 single crystals. At ambient pressure, CeAuBi2 orders antiferromagnetically below a Néel temperature (TN ) of 19 K. Neutron diffraction experiments revealed an antiferromagnetic propagation vector τ ^ = [ 0 , 0 , 1 ∕ 2 ] , which doubles the paramagnetic unit cell along the c axis. At low temperatures several metamagnetic transitions are induced by the application of fields parallel to the c axis, suggesting that the magnetic structure of CeAuBi2 changes as a function of field. At low temperatures, a linear positive magnetoresistance may indicate the presence of band crossings near the Fermi level. Finally, the application of external pressure favors the antiferromagnetic state, indicating that the 4f electrons become more localized.

A Case of Transcranial Direct-Current Stimulation for Childhood Stroke Hemiparesis: A Brief Report.

Purpose: Survivors of childhood stroke incur lifelong physical disability. Treatment options are limited, however, models of motor reorganization after stroke are revealing cortical targets for neuromodulation. Transcranial direct-current stimulation (tDCS) enhances motor learning and may improve motor recovery in adult stroke, but remains uninvestigated in childhood-onset stroke. Here we documented the feasibility and safety of tDCS in an adolescent with chronic stroke-induced hemiparesis.Materials and methods: Over 10 days, the participant underwent occupational therapy paired with contralesional, primary motor cortex-targeting, cathodal tDCS. Clinical motor outcomes, and safety and tolerability measures were completed.Results: tDCS was well-tolerated with no adverse events. Motor outcomes did not regress post-intervention, with clinically significant changes still evident at 6 months.Conclusions: Application of controlled trials of non-invasive neuromodulation are safe and tolerability in childhood-onset stroke.

A Novel Diagnostic Algorithm for Heparin-Induced Thrombocytopenia in a Retrospective Cohort of Lung Transplant Recipients.

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is characterized by thrombocytopenia and potential for thromboembolism. Lung transplant recipients are at risk of developing HIT due to heparin exposure peritransplant. We describe the incidence and impact of HIT in lung transplant recipient index hospital length of stay and survival. DESIGN: A retrospective cohort was obtained from electronic medical records which were queried for all recipients treated with bivalirudin (institutional treatment of choice for HIT) between January 1, 2005, and February 16, 2017 (N = 1171). Patients who developed HIT >30 days after transplant or after their index transplant admission were excluded. A diagnostic algorithm was used retrospectively to determine clinical HIT with an intermediate or high pretest clinical suspicion ("4T" score ≥4) and either (1) positive anti-heparin-platelet-factor 4 (HPF4) assay and a positive functional platelet assay or (2) a positive HPF4 assay only, in patients who did not undergo cardiopulmonary bypass. RESULTS: Among all lung transplant recipients, 2.1% were found to develop HIT in the peritransplant period (N = 25, mean = 88%) with a mean lung allocation score of 50.8 and an incidence of venous thromboembolism of 72%, most upper extremity in location. When matched with historical controls, patients with HIT had a longer overall index hospital length of stay of 43 days (P = .008). There was no difference in short- or long-term survival posttransplant. CONCLUSION: Vigilance for the development of HIT in lung transplant recipients is necessary to prevent further morbidity from thromboembolic events. In our cohort, HIT increased hospital length of stay but did not appear to affect recipient survival.

Characterization of triacontyl (C-30) liquid chromatographic columns.

Differences in the characteristics of seventeen commercial C-30 liquid chromatographic columns were studied for the separation of carotenoid isomers. A mixture consisting of nine xanthophyll and hydrocarbon carotenoids were separated under conditions carefully chosen to reveal changes in selectivity. The influence of the mobile phase composition, column temperature, and mobile phase flow rate were evaluated. Shape selectivity was characterized with Standard Reference Material (SRM) 869b Column Selectivity Test Mixture, for correlation with carotenoid retention behavior. Regular changes were observed across a broad spectrum of shape selectivity characteristics as indicated by SRM 869b. Better separations of carotenoid isomers were achieved with C-30 columns than were possible with C-18 columns, even after optimization of separation conditions.

A single bout of resistance exercise improves postprandial lipid metabolism in overweight/obese men with prediabetes.

AIMS/HYPOTHESIS: Prediabetes is associated with postprandial hypertriacylglycerolaemia. Resistance exercise acutely lowers postprandial plasma triacylglycerol (TG); however, the changes in lipid metabolism that mediate this reduction are poorly understood. The aim of this study was to identify the constitutive metabolic mechanisms underlying the changes in postprandial lipid metabolism after resistance exercise in obese men with prediabetes. METHODS: We evaluated the effect of a single bout of whole-body resistance exercise (seven exercises, three sets, 10-12 repetitions at 80% of one-repetition maximum) on postprandial lipid metabolism in ten middle-aged (50 ± 9 years), overweight/obese (BMI: 33 ± 3 kg/m2), sedentary men with prediabetes (HbA1c >38 but <48 mmol/mol [>5.7% but <6.5%]), or fasting plasma glucose >5.6 mmol/l but <7.0 mmol/l or 2 h OGTT glucose >7.8 mmol/l but <11.1 mmol/l). We used a randomised, crossover design with a triple-tracer mixed meal test (ingested [(13C4)3]tripalmitin, i.v. [U-13C16]palmitate and [2H5]glycerol) to evaluate chylomicron-TG and total triacylglycerol-rich lipoprotein (TRL)-TG kinetics. We used adipose tissue and skeletal muscle biopsies to evaluate the expression of genes regulating lipolysis and lipid oxidation, skeletal muscle respirometry to evaluate oxidative capacity, and indirect calorimetry to assess whole-body lipid oxidation. RESULTS: The single bout of resistance exercise reduced the lipaemic response to a mixed meal in obese men with prediabetes without changing chylomicron-TG or TRL-TG fractional clearance rates. However, resistance exercise reduced endogenous and meal-derived fatty acid incorporation into chylomicron-TG and TRL-TG. Resistance exercise also increased whole-body lipid oxidation, skeletal muscle mitochondrial respiration, oxidative gene expression in skeletal muscle, and the expression of key lipolysis genes in adipose tissue. CONCLUSIONS/INTERPRETATION: A single bout of resistance exercise improves postprandial lipid metabolism in obese men with prediabetes, which may mitigate the risk for cardiovascular disease and type 2 diabetes.

Spectroscopic Evidence for Electron-Boson Coupling in Electron-Doped Sr_{2}IrO_{4}.

The pseudogap, d-wave superconductivity and electron-boson coupling are three intertwined key ingredients in the phase diagram of the cuprates. Sr_{2}IrO_{4} is a 5d-electron counterpart of the cuprates in which both the pseudogap and a d-wave instability have been observed. Here, we report spectroscopic evidence for the presence of the third key player in electron-doped Sr_{2}IrO_{4}: electron-boson coupling. A kink in nodal dispersion is observed with an energy scale of ∼50 meV. The strength of the kink changes with doping, but the energy scale remains the same. These results provide the first noncuprate platform for exploring the relationship between the pseudogap, d-wave instability, and electron-boson coupling in doped Mott insulators.

Adipose tissue NAD+ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice.

Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD+ metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD+ biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of ß-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD+-SIRT1-caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD+ synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD+ biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.

Measurement of the Antineutrino Spectrum from

This Letter reports the first measurement of the ^{235}U ν[over ¯]_{e} energy spectrum by PROSPECT, the Precision Reactor Oscillation and Spectrum experiment, operating 7.9 m from the 85 MW_{th} highly enriched uranium (HEU) High Flux Isotope Reactor. With a surface-based, segmented detector, PROSPECT has observed 31678±304(stat) ν[over ¯]_{e}-induced inverse beta decays, the largest sample from HEU fission to date, 99% of which are attributed to ^{235}U. Despite broad agreement, comparison of the Huber ^{235}U model to the measured spectrum produces a χ^{2}/ndf=51.4/31, driven primarily by deviations in two localized energy regions. The measured ^{235}U spectrum shape is consistent with a deviation relative to prediction equal in size to that observed at low-enriched uranium power reactors in the ν[over ¯]_{e} energy region of 5-7 MeV.

Longitudinal analysis of Voice Handicap Index in early glottic cancer patients treated with transoral laser microsurgery: age, gender, stage and time dependence.

OBJECTIVES: Transoral laser microsurgery is an increasingly common treatment modality for glottic carcinoma. This study aimed to determine the effect of age, gender, stage and time on voice-related quality of life using the Voice Handicap Index-10. METHODS: Primary early glottic carcinoma patients treated with transoral laser microsurgery were included in the study. Self-reported Voice Handicap Index testing was completed pre-operatively, three months post-operatively, and yearly at follow-up appointments. RESULTS: Voice Handicap Index improvement was found to be dependent on age and tumour stage, while no significant differences were found in Voice Handicap Index for gender. Voice Handicap Index score was significantly improved at 12 months and 24 months. Time versus Voice Handicap Index modelling revealed a preference for non-linear over linear regression. CONCLUSION: Age and stage are important factors, as younger patients with more advanced tumours show greater voice improvement post-operatively. Patient's Voice Handicap Index is predicted to have 95 per cent of maximal improvement by 5.5 months post-operatively.