Full Period Research Articles

A Randomized Trial Comparing Standard of Care to Bayesian Warfarin Dose Individualization.

The quality of warfarin treatment may be improved if management is guided by the use of models based upon pharmacokinetic-pharmacodynamic theory. A prospective, two-armed, single-blind, randomized controlled trial compared management aided by a web-based dose calculator (NextDose) with standard clinical care. Participants were 240 adults receiving warfarin therapy following cardiac surgery, followed up until the first outpatient appointment at least 3 months after warfarin initiation. We compared the percentage of time spent in the international normalized ratio acceptable range (%TIR) during the first 28 days following warfarin initiation, and %TIR and count of bleeding events over the entire follow-up period. Two hundred thirty-four participants were followed up to day 28 (NextDose: 116 and standard of care: 118), and 228 participants (114 per arm) were followed up to the final study visit. Median %TIR tended to be higher for participants receiving NextDose guided warfarin management during the first 28 days (63 vs. 56%, P = 0.13) and over the entire follow-up period (74 vs. 71%, P = 0.04). The hazard of clinically relevant minor bleeding events was lower for participants in the NextDose arm (hazard ratio: 0.21, P = 0.041). In NextDose, there were 89.3% of proposed doses accepted by prescribers. NextDose guided dose management in cardiac surgery patients requiring warfarin was associated with an increase in %TIR across the full follow-up period and fewer hemorrhagic events. A theory-based, pharmacologically guided approach facilitates higher quality warfarin anticoagulation. An important practical benefit is a reduced requirement for clinical experience of warfarin management.

Active stabilization of an open-access optical microcavity for low-noise operation in a standard closed-cycle cryostat

Open-access optical microcavities are Fabry–Perot type cavities consisting of two micrometer-size mirrors, separated by an air (or vacuum) gap typically of a few micrometers. Compared to integrated microcavities, this configuration is more flexible as the relative position of the two mirrors can be tuned, allowing for easy changes in parameters such as cavity length and mode volume and the selection of specific transverse cavity modes. These advantages come at the expense of the mechanical stability of the cavity itself, which is particularly relevant in noisy closed-cycle cryostats. Here, we show an open-access optical microcavity based on scanning-probe microscope design principles. When operated at 4 K in a tabletop optical closed-cycle cryostat without any dedicated mechanical low-pass filter, we obtain stabilities of 5.7 and 10.6 pm rms in the quiet and full periods of the cryocooler cycle, respectively. Our device has free-space optical access, essential, for instance, for full polarization control.

Temporal transcriptomic dynamics in developing macaque neocortex

Despite intense research on mice, the transcriptional regulation of neocortical neurogenesis remains limited in humans and non-human primates. Cortical development in rhesus macaque is known to recapitulate multiple facets of cortical development in humans, including the complex composition of neural stem cells and the thicker supragranular layer. To characterize temporal shifts in transcriptomic programming responsible for differentiation from stem cells to neurons, we sampled parietal lobes of rhesus macaque at E40, E50, E70, E80, and E90, spanning the full period of prenatal neurogenesis. Single-cell RNA sequencing produced a transcriptomic atlas of developing parietal lobe in rhesus macaque neocortex. Identification of distinct cell types and neural stem cells emerging in different developmental stages revealed a terminally bifurcating trajectory from stem cells to neurons. Notably, deep-layer neurons appear in the early stages of neurogenesis, while upper-layer neurons appear later. While these different lineages show overlap in their differentiation program, cell fates are determined post-mitotically. Trajectories analysis from ventricular radial glia (vRGs) to outer radial glia (oRGs) revealed dynamic gene expression profiles and identified differential activation of BMP, FGF, and WNT signaling pathways between vRGs and oRGs. These results provide a comprehensive overview of the temporal patterns of gene expression leading to different fates of radial glial progenitors during neocortex layer formation.

Second-order linear recurrences with identically distributed residues modulo p^e

Let $p$ be an odd prime and let $u(a,-1)$ and $u(a',-1)$ be two Lucas sequences whose discriminants have the same nonzero quadratic character modulo $p$ and whose periods modulo $p$ are equal. We prove that there is then an integer $c$ such that for all $d\in\mathbb Z_p$, the frequency with which $d$ appears in a full period of $u(a,-1)\pmod p$ is the same frequency as $cd$ appears in $u(a',-1)\pmod p$. Here $u(a,b)$ satisfies the recursion relation $u_{n+2}=au_{n+1}+bu_n$ with initial terms $u_0=0$ and $u_1=1$. Similar results are obtained for the companion Lucas sequences $v(a,-1)$ and $v(a',-1)$. This paper extends analogous statements for Lucas sequences of the form $u(a,1)\pmod p$ given in a previous article. We further generalize our results by showing for a certain class of primes $p$ that if $e>1$, $b=\pm 1$, and $u(a,b)$ and $u(a',b)$ are Lucas sequences with the same period modulo $p$, then there exists an integer $c$ such that for all residues $d\pmod{p^e}$, the frequency with which $d$ appears in $u(a,b)\pmod{p^e}$ is the same frequency as $cd$ appears in $u(a',b)\pmod{p^e}$.

The day-to-day relationship between posttraumatic stress symptoms and social support after sexual assault

ABSTRACT Background: Experiencing sexual assault is associated with a significant increase in risk for developing posttraumatic stress disorder and related concerns (e.g. alcohol misuse). Cross-sectional and longitudinal evidence suggests that social support may be both broadly protective against and eroded by posttraumatic stress symptoms. However, little is known about how different aspects of social support and posttraumatic stress symptoms influence each other in the weeks and months immediately following sexual assault, when posttraumatic stress (PTS) symptoms first emerge. Objective: The present study assessed the day-to-day relationship between social support and PTS in a sample of distressed, alcohol-using, recently-assaulted female survivors participating in a clinical trial of an app-based intervention (N = 41). Method: Participants completed 3 weeks of daily diaries starting within 10 weeks of sexual assault. Mixed-effects models were used to examine prior-day and same-day relationships between PTS and four social support constructs (social contact, emotional support, pleasantness of social interactions, and talking about sexual assault). Results: Results indicate that higher quantity and pleasantness of social interactions over the full sampling period was associated with lower PTS symptoms on any given day. Experiencing better-than-typical social interactions on one day was associated with lower than typical PTS symptoms on that day and the next day. On days when participants discussed their sexual assault with others, they tended to be having higher than usual PTS symptoms. Conclusions: Findings suggest that increasing the quantity and pleasantness of social interactions soon after sexual assault might protect against worsening posttraumatic stress symptoms. Trial registration: ClinicalTrials.gov identifier: NCT03703258.

Evaluation of Muscle Long Non-Coding RNA Profile during Rearing and Finishing Phase of Bulls Subjected to Different Prenatal Nutritional Strategies.

Maternal nutrition has the ability of influence critical processes in fetal life, including muscle development. Also, in this period, epigenetic sensitivity to external stimuli is higher and produces long-lasting effects. Thus, the aim of this study was to investigate epigenetic mechanisms, including the identification and characterization of long non-coding RNA (lncRNA) from animals that had undergone different strategies of prenatal supplementation. A group of Nellore cows (n = 126) were separated into three nutritional plans: NP (control)-Not Programmed, without protein-energy supplementation; PP-Partially Programmed, protein-energy supplementation in the final third of pregnancy; and CP-Complete Programming, protein-energy supplementation during the full period of gestation. A total of 63 male offspring were used in this study, of which 15 (5 per treatment) had Longissimus thoracis muscle at 15 (biopsy) and 22 months (slaughter). Biopsy samples were subjected to RNA extraction and sequencing. Differential expression (DE) of remodeling factors and chromatin-modifying enzyme genes were performed. For the identification and characterization of lncRNA, a series of size filters and protein coding potential tests were performed. The lncRNAs identified had their differential expression and regulatory potential tested. Regarding DE of epigenetic mechanisms, no differentially expressed gene was found (p > 0.1). Identification of potential lncRNA was successful, identifying 1823 transcripts at 15 months and 1533 at 22 months. Among these, four were considered differentially expressed between treatments at 15 months and 6 were differentially expressed at 22 months. Yet, when testing regulatory potential, 13 lncRNAs were considered key regulators in the PP group, and 17 in the CP group. PP group lncRNAs possibly regulate fat-cell differentiation, in utero embryonic development, and transforming growth factor beta receptor, whereas lncRNA in the CP group regulates in utero embryonic development, fat-cell differentiation and vasculogenesis. Maternal nutrition had no effect on differential expression of epigenetic mechanisms; however, it seems to impair lncRNA regulation of epigenetics.

Three Strategies for Supporting Elementary Writers through the Practice of Sharing

AbstractAlthough orally sharing and discussing written compositions has been shown to benefit elementary students, it can be challenging to entwine this additional pedagogy with an already full literacy instructional period. This article acknowledges these challenges and outlines three evidence‐based instructional modifications to encourage active sharing in literacy classrooms to support developing writers. The three strategies are (1) The “Single Share,” (2) “The Sticky and the Sticker,” and (3) “The Borrow.” The benefits of each strategy are discussed within the elementary literacy context, and insight into the successful implementation of each pedagogical approach is provided for educators.

Substandard housing and the risk of COVID-19 infection and disease severity: A retrospective cohort study

In this study we examine associations between substandard housing and the risk of COVID-19 infection and severity during the first year of the pandemic by linking individual-level housing and clinical datasets. Residents of Chelsea, Massachusetts who were tested for COVID-19 at any Mass General Brigham testing site and who lived at a property that had received a city housing inspection were included (N = 2873). Chelsea is a densely populated city with a high prevalence of substandard housing. Inspected properties with housing code violations were considered substandard; inspected properties without violations were considered adequate. COVID-19 infection was defined as any positive PCR test, and severe disease defined as hospitalization with COVID-19. We used a propensity score design to match individuals on variables including age, race, sex, and income. In the severity model, we also matched on ten comorbidities. We estimated the risk of COVID-19 infection and severity associated with substandard housing using Cox Proportional Hazards models for lockdown, the first phase of reopening, and the full study period. In our sample, 32% (919/2873) of individuals tested positive for COVID-19 and 5.9% (135/2297) had severe disease. During lockdown, substandard housing was associated with a 48% increased risk of COVID-19 infection (95%CI 1.1–2.0, p = 0.006). Through Phase 1 reopening, substandard housing was associated with a 39% increased infection risk (95%CI 1.1–1.8, p = 0.020). The difference in risk attenuated over the full study period. There was no difference in severe disease risk between the two groups. The increased risk, observed only during lockdown and early reopening – when residents were most exposed to their housing – strengthens claims that substandard housing conveys higher infection risk. The results demonstrate the value of combining cross-sector datasets. Existing city housing data can be leveraged 1) to identify and prioritize high-risk areas for future pandemic response, and 2) for longer-term housing solutions.

Assessment and characteristics of S-NPP VIIRS Deep Blue and Dark Target aerosol properties under clean, polluted and fire scenarios over the Amazon

The present study carries out the systematic performance evaluation of aerosol optical depth (AOD) products retrieved using Visible Infrared Imaging Radiometer Suite (VIIRS) Deep Blue (DB) and Dark Target (DT) onboard Suomi National Polar-orbiting Partnership (S-NPP) satellite over the Amazon Basin. Characteristics and uncertainty were evaluated under distinct air pollution scenarios such as a clean background in the wet season, polluted conditions in the dry season with biomass burning emissions and peak burning season with higher fire activity. VIIRS retrievals were also analyzed under aerosol loading, particle size and surface vegetation coverage against the Aerosol Robotic Network (AERONET) measurements at 9 sites in 2012–2022. VIIRS DB showed good accuracy, with 78% of AOD matchups falling within the expected error, 84% in the wet season, and 71% in the dry and burning seasons. In contrast, VIIRS DT indicated poor accuracy (64%) and trends overestimate the AOD in all air pollution scenarios. Both algorithms were sensitive to AERONET sites with high elevation and dark vegetated coverage characteristics. VIIRS DB and DT systematically overestimated AERONET AOD as increased aerosol loading. DB trends underestimate aerosol under background conditions and overestimate with coarse and fine particle predominance. Additionally, both algorithms indicated poor accuracy under forest type with a large positive bias. VIIRS DB demonstrated the highest accuracy in the presence of aerosol loading in sites characterized by mixed land cover type. This was observed in both coarse and fine mode scenarios for grassland. VIIRS DT demonstrated satisfactory accuracy under background conditions and dominance of coarse particles within grassland land cover type. For mixed land cover, satisfactory accuracy was found under intermediate aerosol loading conditions. DB algorithm showed greater uncertainty associated with the coarse particle aerosol for the full period and all polluted scenarios. Overall, VIIRS DT accuracy was more sensitive to varying air pollution scenarios.

Retrieval of cherry flowering phenology on Flickr and YouTube: a case study along the Tarumi railway, Gifu, Japan

To further develop the accuracy of monitoring cherry flowering dates, we require phenological records from multiple points in multiple years at the catchment scale, as well as conventional in situ phenological observations, phenological data published on the Internet, and analysis using statistics of Internet search engines. We tried to detect the dates of cherry flowering phenology along the Tarumi railway, Gifu Prefecture, Japan, by using Flickr, an image hosting service, and YouTube, an online video sharing and social media platform. We detected full bloom of Cerasus ×yedoensis and Cerasus jamasakura mainly at cherry blossom viewing spots (around some train stations) on Flickr and at both viewing spots and multiple points in the landscape along the railway on YouTube. Despite local climatological differences along the railway, the detected full blooming dates corresponded not only with each other, but also with the full bloom period of Neodani Usuzumi-zakura (Cerasus itosakura), a famous tree with long-term detailed records. We could not detect the date and location in many photographs on Flickr or in any videos on YouTube. However, the usefulness of both platforms is supported by the facts that we can evaluate the year-to-year variability of full bloom dates, especially at cherry blossom viewing spots, and detect flowering phenology even in a non-photogenic landscape. By applying our method to other railways, we expect to collect multi-year records of plant phenology dates at multiple points that cannot be collected by older methods.

Report on a novel approach to foundation year 1 doctor workforce planning

In early 2020, North Manchester General Hospital took steps to increase the number of doctors providing out-of-hours cover in response to the COVID-19 pandemic. This included introducing higher intensity rota patterns. Following positive feedback, it was decided that maintaining an increased level of staffing at foundation year 1 level across the site was beneficial for both patient safety and junior doctor working conditions. A new workplan was designed to maintain this higher level of out-of-hours cover by foundation year 1 doctors without an unmanageable financial impact on the trust, while complying with workforce regulations. In this model, foundation year 1 doctors work across multiple areas when providing out-of-hours cover, across medicine, surgery, urology and trauma and orthopaedics, rather than staying in their own current parent department. This whole-site model spanned the full 52-week period of the foundation year. In addition to increasing staffing numbers, this structure was also designed to provide foundation year 1 doctors with more stability in their rota pattern and monthly income, while improving their ability to prospectively plan their personal lives. The new model led to 20% additional cover during weekday evenings, 50% additional cover during nights and 60% additional cover on weekend daytimes, at an additional cost of £61 383 per year to the trust, excluding additional employer costs associated with a salary (‘on costs’). Foundation year 1 doctors reported that this model gave them educational opportunities and allowed them to take more breaks. This article describes this model, its implementation, key considerations and the potential to expand it across other NHS trusts.

Quantitative Determination of Four Lignans in Phyllanthus niruri L. by HPLC

A simple analytical method using high performance liquid chromatography (HPLC) with ultraviolet (UV) detection was developed for the simultaneous determination of four main lignans (niranthin, nirtetralin B, hypophyllanthin, and phyltetralin) in Phyllanthus niruri L. plant samples from Guangxi province, China. The aim was to validate the accumulation rule in the growth periodicity of the active lignans for anti-hepatitis B virus (HBV). The results indicated that the active lignans niranthin and nirtetralin B were mainly distributed in the leaves of Phyllantthus niruri L., and the highest total content was found in the end of July to August (full fruiting period). Therefore, the Phyllanthus niruri L. of Guangxi province (China) should be collected for antihepatitis B treatment on the full fruiting period (the end of July to August), and its leaves might be the main part for collection. The results of the study provided a strong support for the use of Phyllanthus niruri L. from Guangxi province, China.

How far back do we need to look to capture diagnoses in electronic health records? A retrospective observational study of hospital electronic health record data

ObjectivesAnalysis of routinely collected electronic health data is a key tool for long-term condition research and practice for hospitalised patients. This requires accurate and complete ascertainment of a broad range...

Get Back, a person-centred digital programme targeting physical activity for patients undergoing spinal stenosis surgery—a study protocol of a randomized feasibility study

BackgroundSpinal stenosis is the most common reason for elective spine surgery, and the cardinal symptom is leg pain and discomfort when walking. Patients with spinal stenosis have a decreased level of physical activity and thereby an increased risk of poor health. Get Back is a person-centred digital programme that strives to support patients being physically active after surgery. The aim is to explore if Get Back, in its present format (referred to as Get Backfeasibility), is feasible and contributes to detectable change in variables related to intervention content.MethodsThirty patients planned for decompression surgery due to central lumbar spinal stenosis who present with low physical activity, pain catastrophizing or fear of movement, will be included in a randomized feasibility study. All patients will be randomly allocated to either Get Backfeasibility or usual physical therapy. Get Backfeasibility aims to increase the patient’s physical activity level by combining a person-centred and cognitive behavioural approach. It comprises 10 video and telephone sessions led by a physical therapist over 12 weeks (pre/postoperatively). Outcomes are treatment fidelity (treatment dose, adherence, and content), process feasibility (recruitment, intervention use, and acceptability of measurements and intervention), and variables related to the intervention content (steps per day, physical activity level, pain catastrophizing, fear of movement, and general self-efficacy). Treatment fidelity and feasibility data will be assessed during the full study period (12 weeks). Physical activity, physical capacity, and patient-reported outcomes will be assessed digitally at baseline (2 weeks preoperatively) and 11–12 weeks postoperatively. Variables related to the intervention content will be monitored weekly through a digital application. Feasibility data will be analysed descriptively and inferentially using a nonparametric approach, data from repeated measures will be displayed graphically and data from telephone interviews will be analysed using content analysis with a descriptive manifest approach.DiscussionThe results will provide information on whether Get Back in its present format is feasible and can be evaluated for effectiveness in a larger randomized controlled trial, for patients with a low physical activity level and a high fear of movement who are undergoing decompression surgery.Trial registrationRegistered at ClinicalTrails.gov 04/08/2023, registration no. NCT05806593.

P509 Upadacitinib improves symptomatic responses in patients with moderately to severely active Crohn’s disease

Abstract Background Upadacitinib (UPA), an oral Janus kinase inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD), has demonstrated the ability to provide rapid symptom relief within the first week of induction treatment in patients with CD.1 As symptomatic remission is critical for patients, this phase 3 post hoc analysis evaluated the impact of UPA on patient-reported outcomes (PROs) of abdominal pain score (APS) and stool frequency (SF) over the full induction and maintenance time periods. Methods Data were pooled from the U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) induction studies evaluating patients with moderately to severely active CD with an average daily APS ≥ 2 and/or SF ≥ 4 and received UPA 45 mg (UPA45) once daily (QD) or PBO for 12 weeks. Patients who achieved clinical response to 12 weeks of UPA45 induction were re-randomised in a maintenance study (U-ENDURE, NCT03345823) to receive UPA 15 mg (UPA15) QD, UPA 30 mg (UPA30) QD, or PBO for 52 weeks. APS and SF were recorded in a daily diary and evaluated over time. Results The average daily APS (mean: PBO 1.9, UPA45 1.9) and SF (mean: PBO 5.6, UPA45 5.4), were similar between the treatment groups at induction baseline (BL). Of patients reporting BL APS ≥ 1 (PBO 91.6%, UPA45 92.4%) or BL SF ≥ 2.8 (PBO 85.6%, UPA45 85.2%), higher proportions of patients receiving UPA vs PBO achieved APS = 0 or SF ≤ 1, or complete resolution of symptoms (APS = 0 and SF ≤ 1) at week 12 of induction, as well as at week 52 of maintenance (all P ≤ .001; Figure 1A). During induction, the mean change from BL in APS and SF was improved with UPA45 vs PBO starting at week 2 through to week 12 (all P < .001; Figure 1B-C). Throughout the 52-week maintenance period, a higher proportion of patients receiving UPA15 or UPA30 achieved APS ≤ 1 or SF ≤2.8 vs PBO (Figure 1B-C). Patients treated with UPA30 demonstrated a numerically higher rate of symptomatic response vs UPA15. In patients who met the Crohn's Disease Activity Index (CDAI) criteria per US labeling (CDAI ≥ 220 at induction BL; clinical response [CR-100] at week 12 with UPA45),2 comparable symptom improvements were observed over time compared to the overall study population. Conclusion Patients with moderately to severely active CD demonstrated improvements in APS and SF as early as 2 weeks after UPA induction treatment. A greater proportion of patients achieved PRO-defined remission within 12 weeks of UPA induction treatment compared with PBO, which were sustained through week 52 of UPA maintenance treatment.

Recreational and Medical Cannabis Legalization and Opioid Prescriptions and Mortality

While some have argued that cannabis legalization has helped to reduce opioid-related morbidity and mortality in the US, evidence has been mixed. Moreover, existing studies did not account for biases that could arise when policy effects vary over time or across states or when multiple policies are assessed at the same time, as in the case of recreational and medical cannabis legalization. To quantify changes in opioid prescriptions and opioid overdose deaths associated with recreational and medical cannabis legalization in the US. This quasiexperimental, generalized difference-in-differences analysis used annual state-level data between January 2006 and December 2020 to compare states that legalized recreational or medical cannabis vs those that did not. Recreational and medical cannabis law implementation (proxied by recreational and medical cannabis dispensary openings) between 2006 and 2020 across US states. Opioid prescription rates per 100 persons and opioid overdose deaths per 100 000 population based on data from the US Centers for Disease Control and Prevention. Between 2006 and 2020, 13 states legalized recreational cannabis and 23 states legalized medical cannabis. There was no statistically significant association of recreational or medical cannabis laws with opioid prescriptions or overall opioid overdose mortality across the 15-year study period, although the results also suggested a potential reduction in synthetic opioid deaths associated with recreational cannabis laws (4.9 fewer deaths per 100 000 population; 95% CI, -9.49 to -0.30; P = .04). Sensitivity analyses excluding state economic indicators, accounting for additional opioid laws and using alternative ways to code treatment dates yielded substantively similar results, suggesting the absence of statistically significant associations between cannabis laws and the outcomes of interest during the full study period. The results of this study suggest that, after accounting for biases due to possible heterogeneous effects and simultaneous assessment of recreational and medical cannabis legalization, the implementation of recreational or medical cannabis laws was not associated with opioid prescriptions or opioid mortality, with the exception of a possible reduction in synthetic opioid deaths associated with recreational cannabis law implementation.

Aerial parts of Angelica sinensis supplementation for improved broiler growth and intestinal health

This research examined the impact of incorporating Angelica sinensis's aerial components (APA), commonly referred to as "female ginseng", into broilers' diet. Two hundred eighty-eight 1-day-old Cobb 500 broilers were randomly assigned to the 4 experimental groups with 6 replications and 12 birds/replicate. The 4 groups were fed the diets included 4 concentrations of APA (0 %, 1 %, 2 %, and 3%, respectively). The study spanned 42 days, categorized as the starter phase (1-21 days) and the finisher phase (22-42 days). Notably, broilers fed with 3% APA demonstrated a pronounced surge in feed consumption and weight gain during the 22-42 days and over the full 42-day period (P<0.05). Furthermore, when examining the broilers' intestinal structure, there was a notable increase in the villus height and villi ratio across the duodenum, jejunum, and ileum, with a decrease in crypt depth upon 3% APA inclusion (P<0.05). On a molecular note, certain genes connected to the intestinal mechanical barrier, such as Zona Occludens 1 and Claudin-2, saw significant elevation in the jejunum (P<0.05). The jejunum also displayed heightened levels of antimicrobial peptides like lysozyme, mucin 2, sIgA, IgG, and IgM, showcasing an enhanced chemical and immune barrier(P<0.05). Delving into the 16SrDNA sequencing of intestinal content, a higher microbial diversity was evident with a surge in beneficial bacteria, particularly Firmicutes, advocating a resilient and balanced microecosystem. The findings imply that a 3% APA dietary addition bolsters growth metrics and fortifies the intestinal barrier's structural and functional integrity in broilers.

Assessing the importance of primary care diagnoses in the UK Biobank

The UK Biobank has made general practitioner (GP) data (censoring date 2016–2017) available for approximately 45% of the cohort, whilst hospital inpatient and death registry (referred to as “HES/Death”) data are available cohort-wide through 2018–2022 depending on whether the data comes from England, Wales or Scotland. We assessed the importance of case ascertainment via different data sources in UKB for three diseases that are usually first diagnosed in primary care: Parkinson’s disease (PD), type 2 diabetes (T2D), and all-cause dementia. Including GP data at least doubled the number of incident cases in the subset of the cohort with primary care data (e.g. from 619 to 1390 for dementia). Among the 786 dementia cases that were only captured in the GP data before the GP censoring date, only 421 (54%) were subsequently recorded in HES. Therefore, estimates of the absolute incidence or risk-stratified incidence are misleadingly low when based only on the HES/Death data. For incident cases present in both HES/Death and GP data during the full follow-up period (i.e. until the HES censoring date), the median time difference between an incident diagnosis of dementia being recorded in GP and HES/Death was 2.25 years (i.e. recorded 2.25 years earlier in the GP records). Similar lag periods were also observed for PD (median 2.31 years earlier) and T2D (median 2.82 years earlier). For participants with an incident GP diagnosis, only 65.6% of dementia cases, 69.0% of PD cases, and 58.5% of T2D cases had their diagnosis recorded in HES/Death within 7 years since GP diagnosis. The effect estimates (hazard ratios, HR) of established risk factors for the three health outcomes mostly remain in the same direction and with a similar strength of association when cases are ascertained either using HES only or further adding GP data. The confidence intervals of the HR became narrower when adding GP data, due to the increased statistical power from the additional cases. In conclusion, it is desirable to extend both the coverage and follow-up period of GP data to allow researchers to maximise case ascertainment of chronic health conditions in the UK.

Long-term patient-reported outcomes from monarchE: Abemaciclib plus endocrine therapy as adjuvant therapy for HR+, HER2-, node-positive, high-risk, early breast cancer

BackgroundIn monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up. MethodsPatients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized. ResultsAt baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69–78 %) reported being bothered “a little bit” or “not at all” by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline. ConclusionPRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer.

Modeling the Volatility of Daily Listed Real Estate Returns during Economic Crises: Evidence from Generalized Autoregressive Conditional Heteroscedasticity Models

In this paper, we focus on the dynamic volatility behavior of the daily Swedish Real Estate Sector Index and analyze the existence and degree of a long-range dependence or asymmetric news effect since 2003. More specifically, we give extra attention to the 2007–2008 financial crisis, the 2009–2012 European debt crisis, and the first two years of the global COVID-19 pandemic era (2020–2021). We examine changes in volatility during these extreme events. We apply standard GARCH models, asymmetric GARCH models, and long-memory GARCH models with various error distributions to identify the most accurate volatility models of the daily returns of the Swedish Real Estate Sector Index for the full sample period, January 2003 to June 2021. Our results show that the volatility of the Swedish Real Estate Sector Index is time-varying and highly volatile. The impacts of the global financial crisis, European debt crisis, and COVID-19 pandemic are noticeable. Moreover, the volatility pattern during COVID-19 displays significant time-varying long-range dependence and an asymmetrical news impact, which lead to market inefficiency. Finally, the volatility pattern shows a tendency towards increasing leverage effects and less persistent behavior, indicating that the market stakeholders are highly sensitive to negative returns and becoming quicker to respond to market changes.