RNA-Mediated Feedback Control of Transcriptional Condensates.

Regulation of biological processes typically incorporates mechanisms that initiate and terminate the process and, where understood, these mechanisms often involve feedback control. Regulation of transcription is a fundamental cellular process where the mechanisms involved in initiation have been studied extensively, but those involved in arresting the process are poorly understood. Modeling of the potential roles of RNA in transcriptional control suggested a non-equilibrium feedback control mechanism where low levels of RNA promote condensates formed by electrostatic interactions whereas relatively high levels promote dissolution of these condensates. Evidence from in vitro and in vivo experiments support a model where RNAs produced during early steps in transcription initiation stimulate condensate formation, whereas the burst of RNAs produced during elongation stimulate condensate dissolution. We propose that transcriptional regulation incorporates a feedback mechanism whereby transcribed RNAs initially stimulate but then ultimately arrest the process.

A systematic literature review on the global epidemiology of Dravet syndrome and Lennox-Gastaut syndrome: Prevalence, incidence, diagnosis, and mortality.

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies associated with seizure and nonseizure symptoms. A comprehensive understanding of how many individuals are affected globally, the diagnostic journey they face, and the extent of mortality associated with these conditions is lacking. Here, we summarize and evaluate published data on the epidemiology of DS and LGS in terms of prevalence, incidence, diagnosis, genetic mutations, and mortality and sudden unexpected death in epilepsy (SUDEP) rates. The full study protocol is registered on PROSPERO (CRD42022316930). After screening 2172 deduplicated records, 91 unique records were included; 67 provided data on DS only, 17 provided data on LGS only, and seven provided data on both. Case definitions varied considerably across studies, particularly for LGS. Incidence and prevalence estimates per 100 000 individuals were generally higher for LGS than for DS (LGS: incidence proportion = 14.5-28, prevalence = 5.8-60.8; DS: incidence proportion = 2.2-6.5, prevalence = 1.2-6.5). Diagnostic delay was frequently reported for LGS, with a wider age range at diagnosis reported than for DS (DS, 1.6-9.2 years; LGS, 2-15 years). Genetic screening data were reported by 63 studies; all screened for SCN1A variants, and only one study specifically focused on individuals with LGS. Individuals with DS had a higher mortality estimate per 1000 person-years than individuals with LGS (DS, 15.84; LGS, 6.12) and a lower median age at death. SUDEP was the most frequently reported cause of death for individuals with DS. Only four studies reported mortality information for LGS, none of which included SUDEP. This systematic review highlights the paucity of epidemiological data available for DS and especially LGS, demonstrating the need for further research and adoption of standardized diagnostic criteria.

A comprehensive systematic literature review of the burden of illness of Lennox-Gastaut syndrome on patients, caregivers, and society.

Fully elucidating the burden that Lennox-Gastaut syndrome (LGS) places on individuals with the disease and their caregivers is critical to improving outcomes and quality of life (QoL). This systematic literature review evaluated the global burden of illness of LGS, including clinical symptom burden, care requirements, QoL, comorbidities, caregiver burden, economic burden, and treatment burden (PROSPERO ID: CRD42022317413). MEDLINE, Embase, and the Cochrane Library were searched for articles that met predetermined criteria. After screening 1442 deduplicated articles and supplementary manual searches, 113 articles were included for review. A high clinical symptom burden of LGS was identified, with high seizure frequency and nonseizure symptoms (including developmental delay and intellectual disability) leading to low QoL and substantial care requirements for individuals with LGS, with the latter including daily function assistance for mobility, eating, and toileting. Multiple comorbidities were identified, with intellectual disorders having the highest prevalence. Although based on few studies, a high caregiver burden was also identified, which was associated with physical problems (including fatigue and sleep disturbances), social isolation, poor mental health, and financial difficulties. Most economic analyses focused on the high direct costs of LGS, which arose predominantly from medically treated seizure events, inpatient costs, and medication requirements. Pharmacoresistance was common, and many individuals required polytherapy and treatment changes over time. Few studies focused on the humanistic burden. Quality concerns were noted for sample representativeness, disease and outcome measures, and reporting clarity. In summary, a high burden of LGS on individuals, caregivers, and health care systems was identified, which may be alleviated by reducing the clinical symptom burden. These findings highlight the need for a greater understanding of and better definitions for the broad spectrum of LGS symptoms and development of treatments to alleviate nonseizure symptoms.

The IFNγ-PDL1 Pathway Enhances CD8T-DCT Interaction to Promote Hypertension.

BACKGROUND: Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal convoluted tubule cells (DCTs) to increase NCC (sodium chloride co-transporter) expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated. METHODS: We used mouse models of DOCA+salt (DOCA) treatment and adoptive transfer of CD8+ T cells (CD8T) from hypertensive animals to normotensive animals in in vivo studies. Co-culture of mouse DCTs and CD8Ts was used as in vitro model to test the effect of CD8T activation in promoting NCC-mediated sodium retention and to identify critical molecular players contributing to the CD8T-DCT interaction. Interferon (IFNγ)-KO mice and mice receiving renal tubule-specific knockdown of PDL1 were used to verify in vitro findings. Blood pressure was continuously monitored via radio-biotelemetry, and kidney samples were saved at experimental end points for analysis. RESULTS: We identified critical molecular players and demonstrated their roles in augmenting the CD8T-DCT interaction leading to salt-sensitive hypertension. We found that activated CD8Ts exhibit enhanced interaction with DCTs via IFN-γ-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of NCC in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFN-γ or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in 2 different mouse models. CONCLUSIONS: Our results identified the role of activated CD8Ts in contributing to increased sodium retention in DCTS through the IFNγ-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.

Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup.

The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine (e.g., oncology), and is becoming a unifying concept common to all neurodegenerative diseases, not just AD. The present document is consistent with this principle. Our intent is to present objective criteria for diagnosis and staging AD, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care. These criteria are not intended to provide step-by-step clinical practice guidelines for clinical workflow or specific treatment protocols, but rather serve as general principles to inform diagnosis and staging of AD that reflect current science. HIGHLIGHTS: We define Alzheimer's disease (AD) to be a biological process that begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms. Early-changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers [especially phosphorylated tau 217]) map onto either the amyloid beta or AD tauopathy pathway; however, these reflect the presence of ADNPC more generally (i.e., both neuritic plaques and tangles). An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. Later-changing Core 2 biomarkers (biofluid and tau PET) can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms. An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages.

Expectations and clinical meaningfulness of randomized controlled trials.

Alzheimer's disease (AD) clinical trials are designed and powered to detect the impact of a therapeutic intervention, and there has been considerable discussion on what constitutes a clinically meaningful change in those receiving treatment versus placebo. The pathology of AD is complex, beginning many years before clinical symptoms are detectable, with multiple potential opportunities for therapeutic engagement. Introducing treatment strategies early in the disease and assessing meaningful change over the course of an 18-month clinical trial are critical to understanding the value to an effective intervention. With new clinical trial data expected soon on emerging therapeutics from several AD studies, the Alzheimer's Association convened a work group of experts to discuss key considerations for interpreting data from cognitive and functional measures and what is considered a clinically meaningful benefit or meaningful slowing of this fatal disease. Our expectations of outcomes from therapeutic interventions in AD may need to be modified.

Weight and BMI Patterns in a Biologicals-Treated IBD Cohort.

BACKGROUND: Biologic therapies are effective at inducing and maintaining remission in people with inflammatory bowel disease (IBD). Previous studies have associated TNF-a inhibitors with weight gain, however, it is unclear if this is a class-specific effect or a manifestation of good disease control. To clarify this issue, a retrospective study was undertaken to examine weight changes over time during therapy with different biologic agents. METHODS: Adult patients with IBD who received any biological therapy for at least 12 months, between 2008 and 2020, were identified at two specialised IBD services. Demographic, disease, and therapy-related data were examined. Weight change and patterns thereof were examined for each specific therapy and relationships amongst weight outcomes and various predictive factors explored. RESULTS: Of 294 patients (156 females), 165 received Infliximab (IFX), 68 Adalimumab (ADA), 36 Vedolizumab (VDZ) and 25 Ustekinumab (UST). There was a statistically significant weight gain over time in the IFX and VDZ groups and more weight gain in the IFX vs ADA and VDZ vs ADA at most time points. Three weight trajectories were identified: around 95% of patients had small weight loss or a modest weight gain but 5% of patients, most of whom were on IFX had marked weight gain (24.3 kg). Having a baseline high BMI, being female, having an initiation CRP ≤ 5 or albumin > 35 reduced the odds of major weight gain. CONCLUSION: Weight gain in biologic treated IBD patients appears to be associated with clinical factors (male gender, high CRP, low albumin) and therapy-specific factors.

Making remote measurement technology work in multiple sclerosis, epilepsy and depression: survey of healthcare professionals.

BACKGROUND: Epilepsy, multiple sclerosis (MS) and depression are long term, central nervous system disorders which have a significant impact on everyday life. Evaluating symptoms of these conditions is problematic and typically involves repeated visits to a clinic. Remote measurement technology (RMT), consisting of smartphone apps and wearables, may offer a way to improve upon existing methods of managing these conditions. The present study aimed to establish the practical requirements that would enable clinical integration of data from patients' RMT, according to healthcare professionals. METHODS: This paper reports findings from an online survey of 1006 healthcare professionals currently working in the care of people with epilepsy, MS or depression. The survey included questions on types of data considered useful, how often data should be collected, the value of RMT data, preferred methods of accessing the data, benefits and challenges to RMT implementation, impact of RMT data on clinical practice, and requirement for technical support. The survey was presented on the JISC online surveys platform. RESULTS: Among this sample of 1006 healthcare professionals, respondents were positive about the benefits of RMT, with 73.2% indicating their service would be likely or highly likely to benefit from the implementation of RMT in patient care plans. The data from patients' RMT devices should be made available to all nursing and medical team members and could be reviewed between consultations where flagged by the system. However, results suggest it is also likely that RMT data would be reviewed in preparation for and during a consultation with a patient. Time to review information is likely to be one of the greatest barriers to successful implementation of RMT in clinical practice. CONCLUSIONS: While further work would be required to quantify the benefits of RMT in clinical practice, the findings from this survey suggest that a wide array of clinical team members treating epilepsy, MS and depression would find benefit from RMT data in the care of their patients. Findings presented could inform the implementation of RMT and other digital interventions in the clinical management of a range of neurological and mental health conditions.

Measurement of CP Violation in the Decay B

A measurement of CP violation in the decay B^{+}→K^{+}π^{0} is reported using data corresponding to an integrated luminosity of 5.4 fb^{-1} collected with the LHCb experiment at a center-of-mass energy of sqrt[s]=13 TeV. The CP asymmetry is measured to be 0.025±0.015±0.006±0.003, where the uncertainties are statistical, systematic, and due to an external input. This is the most precise measurement of this quantity. It confirms and significantly enhances the observed anomalous difference between the direct CP asymmetries of the B^{0}→K^{+}π^{-} and B^{+}→K^{+}π^{0} decays, known as the Kπ puzzle.

Formation of Supported Lipid Bilayers (SLBs) from Buffers Containing Low Concentrations of Group I Chloride Salts.

Supported lipid bilayers (SLBs) are a useful tool for studying the interactions between lipids and other biomolecules that make up a cell membrane. SLBs are typically formed by the adsorption and rupture of vesicles from solution. Although it is known that many experimental factors can affect whether SLB formation is successful, there is no comprehensive understanding of the mechanism. In this work, we have used a quartz crystal microbalance (QCM) to investigate the role of the salt in the buffer on the formation of phosphatidylcholine SLBs on a silicon dioxide (SiO2) surface. We varied the concentration of sodium chloride in the buffer, from 5 to 150 mM, to find the minimum concentration of NaCl that was required for the successful formation of an SLB. We then repeated the experiments with other group I chloride salts (LiCl, KCl, and CsCl) and found that at higher salt concentrations (150 mM) SLB formation was successful for all of the salts used, and the degree of deformation of the adsorbed vesicles at the critical vesicle coverage was cation-dependent. The results showed that at an intermediate salt concentration (50 mM) the critical vesicle coverage was cation-dependent and at low salt concentrations (12.5 mM) the cation used determined whether SLB formation was successful. We found that the successful formation of SLBs could occur at lower electrolyte concentrations for KCl and CsCl than it did for NaCl. To understand these results, we calculated the magnitude of the vesicle-surface interaction energy using the Derjaguin-Landau-Verwey-Overbeek (DLVO) and extended-DLVO theory. We managed to explain the results obtained at higher salt concentrations by including cation-dependent surface potentials in the calculations and at lower salt concentrations by the addition of a cation-dependent hydration force. These results showed that the way that different cations in solution affect the 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)-SiO2 surface interaction energy depends on the ionic strength of the solution.

Habitual dietary fibre and prebiotic intake is inadequate in patients with inflammatory bowel disease: findings from a multicentre cross-sectional study.

BACKGROUND: Recommendations for dietary fibre intake in patients with inflammatory bowel disease are highly variable. Despite the potential benefits of prebiotic fibres on the gut microbiome, many patients with inflammatory bowel disease follow a low fibre diet. The present study comprehensively evaluated intakes of total and prebiotic fibres in patients with inflammatory bowel disease, aiming to determine the adequacy of fibre intake and factors that may influence intake. METHODS: Outpatients with a formal diagnosis of inflammatory bowel disease were recruited to this multicentre cross-sectional study. Habitual dietary fibre intake including prebiotic fibre types was measured using a validated comprehensive nutrition assessment questionnaire. Adequacy of total fibre intake was compared with Australian Nutrient Reference Values. Multiple linear regressions were performed to determine factors influencing fibre intake. RESULTS: Of 92 participants, 52% had Crohn's disease, 51% were male and the mean age was 40 years. Overall, only 38% of the cohort consumed adequate total fibre (median 24 g day-1 , interquartile range 18.5-32.9 g day-1 ). Adequate fibre consumption was significantly less common in males than females (21.3% versus 55.6%, P = 0.002). Resistant starch intake (median 2.9 g day-1 , interquartile range 2.1-4.8 g day-1 ) was significantly less than the proposed recommendations (20 g day-1 ). Disease-related factors such as phenotype and disease activity were not found to influence fibre intake. CONCLUSIONS: Patients with inflammatory bowel disease habitually consume inadequate fibre, particularly prebiotic fibre resistant starch. The potential deleterious effects of low prebiotic intake on the gut microbiome and disease-related outcomes in inflammatory bowel disease are unknown and warrant further research.

The impact of data from remote measurement technology on the clinical practice of healthcare professionals in depression, epilepsy and multiple sclerosis: survey.

BACKGROUND: A variety of smartphone apps and wearables are available both to help patients monitor their health and to support health care professionals (HCPs) in providing clinical care. As part of the RADAR-CNS consortium, we have conducted research into the application of wearables and smartphone apps in the care of people with multiple sclerosis, epilepsy, or depression. METHODS: We conducted a large online survey study to explore the experiences of HCPs working with patients who have one or more of these conditions. The survey covered smartphone apps and wearables used by clinicians and their patients, and how data from these technologies impacted on the respondents' clinical practice. The survey was conducted between February 2019 and March 2020 via a web-based platform. Detailed statistical analysis was performed on the answers. RESULTS: Of 1009 survey responses from HCPs, 1006 were included in the analysis after data cleaning. Smartphone apps are used by more than half of responding HCPs and more than three quarters of their patients use smartphone apps or wearable devices for health-related purposes. HCPs widely believe the data that patients collect using these devices impacts their clinical practice. Subgroup analyses show that views on the impact of this data on different aspects of clinical work varies according to whether respondents use apps themselves, and, to a lesser extent, according to their clinical setting and job role. CONCLUSIONS: Use of smartphone apps is widespread among HCPs participating in this large European survey and caring for people with epilepsy, multiple sclerosis and depression. The majority of respondents indicate that they treat patients who use wearables and other devices for health-related purposes and that data from these devices has an impact on clinical practice.

Gold Standard Cholera Diagnostics Are Tarnished by Lytic Bacteriophage and Antibiotics.

A fundamental, clinical, and scientific concern is how lytic bacteriophage, as well as antibiotics, impact diagnostic positivity. Cholera was chosen as a model disease to investigate this important question, because cholera outbreaks enable large enrollment, field methods are well established, and the predatory relationship between lytic bacteriophage and the etiologic agent Vibrio cholerae share commonalities across bacterial taxa. Patients with diarrheal disease were enrolled at two remote hospitals in Bangladesh. Diagnostic performance was assessed as a function of lytic bacteriophage detection and exposure to the first-line antibiotic azithromycin, detected in stool samples by mass spectrometry. Among diarrheal samples positive by nanoliter quantitative PCR (qPCR) for V. cholerae (n = 78/849), the odds that a rapid diagnostic test (RDT) or qPCR was positive was reduced by 89% (odds ratio [OR], 0.108; 95% confidence interval [CI], 0.002 to 0.872) and 87% (OR, 0.130; 95% CI, 0.022 to 0.649), respectively, when lytic bacteriophage were detected. The odds that an RDT or qPCR was positive was reduced by more than 99% (OR, 0.00; 95% CI, 0.00 to 0.28) and 89% (OR, 0.11; 95% CI, 0.03 to 0.44), respectively, when azithromycin was detected. Analysis of additional samples from South Sudan found similar phage effects on RDTs; antibiotics were not assayed. Cholera burden estimates may improve by accommodating for the negative effects of lytic bacteriophage and antibiotic exposure on diagnostic positivity. One accommodation is using bacteriophage detection as a proxy for pathogen detection. These findings have relevance for other diagnostic settings where bacterial pathogens are vulnerable to lytic bacteriophage predation.

Measurement of f_{s}/f_{u} Variation with Proton-Proton Collision Energy and B-Meson Kinematics.

The ratio of the B_{s}^{0} and B^{+} fragmentation fractions f_{s} and f_{u} is studied with B_{s}^{0}→J/ψϕ and B^{+}→J/ψK^{+} decays using data collected by the LHCb experiment in proton-proton collisions at 7, 8, and 13 TeV center-of-mass energies. The analysis is performed in bins of B-meson momentum, longitudinal momentum, transverse momentum, pseudorapidity, and rapidity. The fragmentation-fraction ratio f_{s}/f_{u} is observed to depend on the B-meson transverse momentum with a significance of 6.0σ. This dependency is driven by the 13 TeV sample (8.7σ), while the results for the other collision energies are not significant when considered separately. Furthermore, the results show a 4.8σ evidence for an increase of f_{s}/f_{u} as a function of collision energy.

Observation of Several Sources of CP Violation in B

Observations are reported of different sources of CP violation from an amplitude analysis of B^{+}→π^{+}π^{+}π^{-} decays, based on a data sample corresponding to an integrated luminosity of 3 fb^{-1} of pp collisions recorded with the LHCb detector. A large CP asymmetry is observed in the decay amplitude involving the tensor f_{2}(1270) resonance, and in addition significant CP violation is found in the π^{+}π^{-}S wave at low invariant mass. The presence of CP violation related to interference between the π^{+}π^{-}S wave and the P wave B^{+}→ρ(770)^{0}π^{+} amplitude is also established; this causes large local asymmetries but cancels when integrated over the phase space of the decay. The results provide both qualitative and quantitative new insights into CP -violation effects in hadronic B decays.

Treatment Outcomes in Patients Treated With Galcanezumab vs Placebo: Post Hoc Analyses From a Phase 3 Randomized Study in Patients With Episodic Cluster Headache.

BACKGROUND: Cluster headache (CH) is a highly disabling primary headache disorder. To date, characterization of outcomes in the preventive treatment of episodic CH, including precise definitions of clinically meaningful attack frequency reduction and impact on acute treatment management, is lacking. METHODS: This was a Phase 3, randomized, double-blind, placebo-controlled study in patients (men or women aged 18-65 years) diagnosed with episodic CH as defined by the International Classification of Headache Disorders-3 beta criteria. In this post hoc analysis, we evaluated the median time-to-first occurrence of ≥50, ≥75, or 100% reduction from baseline in CH attack frequency, and impact on acute medication use. An anchor-based assessment of clinically relevant attack frequency reduction using the Patient Global Impression of Improvement (PGI-I) scores at Week 4 was also assessed. RESULTS: The median time-to-first occurrence of ≥50, ≥75, or 100% reduction from baseline in CH attacks was consistently shorter (9-10 days sooner) with galcanezumab vs placebo (median [95% confidence interval, 95% CI]: ≥50%, 5 days [4.0 to 7.0] vs 14 days [6.0 to 19.0]; ≥75%, 11 days [7.0 to 16.0] vs 21 days [13.0 to 26.0]; 100%, 22 days [16.0 to 37.0] vs 32 days [23.0 to 34.0]). Mean reduction from baseline in the overall frequency of weekly pooled acute medication use across Weeks 1-3 was significantly greater with galcanezumab vs placebo (11.0 vs 5.5; odds ratio, OR [95% CI]: 5.52 [1.02, 10.01]; P value = .017). Patients reporting "much better" on the PGI-I experienced a median weekly CH attack reduction of approximately 43% from baseline across Weeks 1-3. The overall odds of achieving an attack reduction threshold of 43% across Weeks 1-3 was significantly higher with galcanezumab vs placebo (Weeks 1-3: OR [95% CI], 2.60 [1.3 to 5.3]). CONCLUSIONS: Faster median time-to-first occurrence of response rates, lower frequency of pooled acute medications use, and a greater proportion of patients achieving a response anchored by patient-reported improvement were observed for galcanezumab vs placebo.

Factors associated with long-term impact on informal caregivers during Alzheimer's disease dementia progression: 36-month results from GERAS.

OBJECTIVE: To identify, in caregivers of patients with Alzheimer's disease (AD) dementia, factors associated with subjective (personal, physical, emotional, and social) and objective (informal caregiver time and costs) caregiver burden. DESIGN: Prospective longitudinal European observational study: post-hoc analysis. SETTING: Clinic. PARTICIPANTS: Community-dwelling patients in France and Germany aged ≥ 55 years (n = 969) with probable AD and their informal caregivers. MEASUREMENTS: Mini-Mental State Examination (MMSE), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), 12-item Neuropsychiatric Inventory (NPI-12), Zarit Burden Interview (ZBI), informal caregiver basic and instrumental ADL hours (Resource Utilization in Dementia instrument), and informal caregiver costs. Mixed-effect models of repeated measures (MMRM) were run, including baseline and time-dependent covariates (change from baseline [CFB] to 18 months in MMSE, ADCS-ADL, and NPI-12 scores) associated with CFB in ZBI score/informal caregiver time over 36 months (analyzed using linear regression models) and informal caregiver costs over 36 months (analyzed using generalized linear models). RESULTS: Greater decline in patient function (ADCS-ADL) over 18 months was associated with increased subjective caregiver burden (ZBI), hours, and costs over 36 months. Increased behavioral problems (NPI-12) over 18 months also negatively impacted ZBI. Cognitive decline (MMSE) over 18 months did not affect change in caregiver burden. CONCLUSIONS: Long-term informal caregiver burden was driven by worsening functional abilities and behavioral symptoms but not cognitive decline, over 18 months in community-dwelling patients with AD dementia. Identifying the drivers of caregiver burden could highlight areas in which interventions may benefit both caregivers and patients.

Impact of galcanezumab on total pain burden: findings from phase 3 randomized, double-blind, placebo-controlled studies in patients with episodic or chronic migraine (EVOLVE-1, EVOLVE-2, and REGAIN trials).

BACKGROUND: Focus on the frequency of migraine pain may undervalue the total burden of migraine as pain duration and severity may present unique, additive burden. A composite measure of total pain burden (TPB; frequency, severity, and duration) may provide a more comprehensive characterization of pain burden and treatment response in patients with episodic migraine (EM) or chronic migraine (CM). The impact of galcanezumab versus placebo on TPB among patients with EM or CM was analyzed. METHODS: Patients from randomized, double-blind, placebo-controlled episodic (two 6-month studies pooled) and chronic migraine (3-month) studies received once-monthly subcutaneous injection of galcanezumab 120 mg or placebo. A post hoc analysis of TPB for a given month was calculated as severity-weighted duration by multiplying duration (hours) and maximum pain severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) of migraine for each day and summing these over the days in a month. Least square mean change from baseline in monthly TPB across Months 1-6 (EM, N = 444 galcanezumab, N = 894 placebo) and Months 1-3 (CM, N = 278 galcanezumab, N = 558 placebo) were compared using a mixed-model repeated measures model. Correlation of the Migraine Specific Quality of Life Questionnaire (MSQ) and Migraine Disability Assessment Scale (MIDAS) to TPB at baseline was assessed. RESULTS: At baseline, the duration of migraine on a given migraine headache day accounted for the greatest unique proportion of variability (EM, 57.4% and CM, 61.1%) to TPB after adjusting for frequency of migraine headache days and maximum pain severity. The decrease from baseline in monthly TPB was greater with galcanezumab than placebo for patients with EM (68.6 versus 36.2) and CM (102.6 versus 44.4). The average percent reduction of TPB from baseline was significantly greater with galcanezumab compared with placebo in patients with EM (50.8% versus 17.2%) and CM (29.7% versus 11.0%). In patients with EM and CM, TPB correlated with MSQ total score (r = - 0.35 and r = - 0.37) and MIDAS (r = 0.34 and r = 0.32). CONCLUSIONS: Greater reduction in TPB was seen in patients with EM and CM treated with galcanezumab 120 mg once-monthly injection relative to placebo. Discussing TPB supports patient-centric conversations regarding treatment expectations when clinicians are evaluating options for migraine prevention. TRIAL REGISTRATION: ClinicalTrials.gov : # NCT02614183 (I5Q-MC-CGAG; EVOLVE-1), # NCT02614196 (I5Q-MC-CGAH; EVOLVE-2), and # NCT02614261 (I5Q-MC-CGAI; REGAIN) - all 3 trials were registered on 23 November 2015.

Observation of B_{(s)}

The first observation of the decays B_{(s)}^{0}→J/ψpp[over ¯] is reported, using proton-proton collision data corresponding to an integrated luminosity of 5.2 fb^{-1}, collected with the LHCb detector. These decays are suppressed due to limited available phase space, as well as due to Okubo-Zweig-Iizuka or Cabibbo suppression. The measured branching fractions are B(B^{0}→J/ψpp[over ¯])=[4.51±0.40(stat)±0.44(syst)]×10^{-7}, B(B_{s}^{0}→J/ψpp[over ¯])=[3.58±0.19(stat)±0.39(syst)]×10^{-6}. For the B_{s}^{0} meson, the result is much higher than the expected value of O(10^{-9}). The small available phase space in these decays also allows for the most precise single measurement of both the B^{0} mass as 5279.74±0.30(stat)±0.10(syst) MeV and the B_{s}^{0} mass as 5366.85±0.19(stat)±0.13(syst) MeV.

Search for Lepton-Flavor Violating Decays B

A search for the lepton-flavor violating decays B^{+}→K^{+}µ^{±}e^{∓} is performed using a sample of proton-proton collision data, collected with the LHCb experiment at center-of-mass energies of 7 and 8 TeV and corresponding to an integrated luminosity of 3 fb^{-1}. No significant signal is observed, and upper limits on the branching fractions are set as B(B^{+}→K^{+}µ^{-}e^{+})<7.0(9.5)×10^{-9} and B(B^{+}→K^{+}µ^{+}e^{-})<6.4(8.8)×10^{-9} at 90% (95)% confidence level. The results improve the current best limits on these decays by more than one order of magnitude.