Pioneering a Multi-Phase Framework to Harmonize Self-Reported Sleep Data Across Cohorts.

STUDY OBJECTIVES: Harmonizing and aggregating data across studies enable pooled analyses that support external validation and enhance replicability and generalizability. However, the multidimensional nature of sleep poses challenges for data harmonization and aggregation. Here we describe and implement our process for harmonizing self-reported sleep data. METHODS: We established a multi-phase framework to harmonize self-reported sleep data: (1) compile items; (2) group items into domains; (3) harmonize items; and (4) evaluate harmonizability. We applied this process to produce a pooled multi-cohort sample of five United States cohorts plus a separate yet fully harmonized sample from Rotterdam, Netherlands. Sleep and sociodemographic data are described and compared to demonstrate the utility of harmonization and aggregation. RESULTS: We collected 190 unique self-reported sleep items and grouped them into 15 conceptual domains. Using these domains as guiderails, we developed 14 harmonized items measuring aspects of Satisfaction, Alertness/Sleepiness, Timing, Efficiency, Duration, Insomnia, and Sleep Apnea. External raters determined that 13 of these 14 items had moderate-to-high harmonizability. Alertness/Sleepiness items had lower harmonizability, while continuous, quantitative items (e.g., timing, total sleep time, efficiency) had higher harmonizability. Descriptive statistics identified features that are more consistent (e.g., wake-up time, duration) and more heterogeneous (e.g., time in bed, bedtime) across samples. CONCLUSIONS: Our process can guide researchers and cohort stewards towards effective sleep harmonization and provides a foundation for further methodological development in this expanding field. Broader national and international initiatives promoting common data elements across cohorts are needed to enhance future harmonization and aggregation efforts.

rnaCrosslinkOO: an object-oriented R package for the analysis of RNA structural data generated by RNA crosslinking experiments.

SUMMARY: RNA (ribonucleic acid) molecules have secondary and tertiary structures in vivo which play a crucial role in cellular processes such as the regulation of gene expression, RNA processing and localization. The ability to investigate these structures will enhance our understanding of their function and contribute to the diagnosis and treatment of diseases caused by RNA dysregulation. However, there are no mature pipelines or packages for processing and analyzing complex in vivo RNA structural data. Here, we present rnaCrosslinkOO (RNA Crosslink Object-Oriented), a novel software package for the comprehensive analysis of data derived from the COMRADES (Crosslinking of Matched RNA and Deep Sequencing) method. rnaCrosslinkOO offers a comprehensive pipeline from raw sequencing reads to the identification and comparison of RNA structural features. It includes read processing and alignment, clustering of duplexes, data exploration, folding and comparisons of RNA structures. rnaCrosslinkOO also enables comparisons between conditions, the identification of inter-RNA interactions, and the incorporation of reactivity data to improve structure prediction. AVAILABILITY AND IMPLEMENTATION: rnaCrosslinkOO is freely available to noncommercial users and implemented in R, with the source code and documentation accessible at https://CRAN.R-project.org/package=rnaCrosslinkOO. The software is supported on Linux, macOS, and Windows platforms.

A Re-audit of the Management of Diabetic Ketoacidosis (DKA): The Importance of the Seven-Day Working Inpatient Diabetes Specialist Nurse Service.

Background Diabetic ketoacidosis (DKA) is a life-threatening metabolic emergency due to insulin deficiency in patients with diabetes mellitus. The United Kingdom national survey and local audits of the management of DKA have revealed several areas of suboptimal care, and room for improvement, necessitating the need for intensified education, updating local guidelines, and increased recruitment of seven-day working inpatient diabetes specialist nurses. Therefore, this project aimed to re-audit our adherence to the DKA treatment guidelines. Methodology A retrospective re-audit examining patient admissions with DKA between October 2022 and September 2023. A list of 18 standards/criteria, adopted from the Joint British Diabetes Society (JBDS) DKA treatment guidelines was used for this re-audit. Results were compared with that of the previous audit. Results We had 126 patients admitted with DKA between October 2022 and September 2023. There were 62 males and 64 females with an average (range) age of 46.5 (19-92) years. Eighty percent had type 1 diabetes, and common precipitating factors for admission included infection and poor adherence to insulin treatment. The median (IQR) length of hospital stay was 2.1 (1.0-5.1) days. Compared to the previous audit, improvements occurred in 11 of 18 standards/criteria. This included timely commencement of intravenous fluids and fixed-rate insulin, commencing glucose infusion to prevent hypoglycemia, potassium replacement, continuation of long-acting insulin during treatment, timely conversion to variable-rate insulin infusion, and conversion to the usual subcutaneous insulin regimen. Additionally, 124 patients (98.4%) were reviewed at least once by the inpatient diabetes specialist nurses (DSN) during their admission. Complications of treatment, namely, iatrogenic hypoglycemia and transient hypokalemia occurred in 13 (10.3%) and 40 (31.7%) patient admissions, respectively. Conclusions This re-audit demonstrated improved adherence to the guidelines during several steps in the management of DKA. It also demonstrated room for improvement regarding other aspects of care. The importance of continued education, accurate documentation, and the presence of seven-day working inpatient DSN cover cannot be overemphasized.

Patellar tilt, congruence angle, and tibial tubercle-trochlear groove distance are correlated with positive J-sign in adolescents.

PURPOSE: The J-sign is a clinical evaluation tool that assesses for patellar maltracking and is considered positive if lateral translation of the patella in extension, in the pattern of an inverted J is observed. This study aims to determine the association of clinical J-sign with imaging features noted on dynamic kinematic computed tomography (DKCT). METHODS: A retrospective review was conducted by reviewing the clinical records of all patients aged 18 years or younger who had a CT patellar tracking scan done between 1 January 2005 to 31 December 2016 in a single institution. Patients who had the presence or absence of a 'J-sign' evaluated clinically were included. Radiographic parameters evaluated using the axial cuts include the patellar tilt angle, congruence angle, Dejour's classification, femoral sulcus angle, trochlear groove depth, and Wiberg's classification. Patients were then divided into two groups based on the presence or absence of J-sign on clinical examination. The radiographic measurements were then analyzed for association with the presence or absence of J-sign on clinical examination. RESULTS: Patients with a positive J-sign had an increased patellar tilt of 23.3° ± 14.2° and an increased congruence angle of 47.1° ± 28.5° when measured in extension as compared to a patellar tilt of 18.3° ± 10.8° and a congruence angle of 32.1° ± 20.8° in patients with a negative J-sign (p = 0.024 and 0.004, respectively). Comparisons of the change in congruence angles with the knee in full extension and at 20° flexion also yielded significantly higher change of 28.0° ± 20.4° in patients with a positive J-sign as compared to 11.9° ± 17.5° in patients with a negative J-sign. Patients with a positive J-sign also had an increased TT-TG distance of 17.6 ± 5.6 mm as compared to a TT-TG distance of 14.7 ± 6.9 mm in patients with a negative J-sign (p = 0.01). CONCLUSION: Patients with a positive J-sign had an increased patellar tilt and an increased congruence angle when measured in extension. Increased TT-TG distance was also significantly associated with positive J-sign. Patients with a positive J-sign also had a greater change in their congruence angle when measured with the knee in full extension and at 20° of flexion.

Durable cross-protective neutralizing antibody responses elicited by lipid nanoparticle-formulated SARS-CoV-2 mRNA vaccines.

The advent of SARS-CoV-2 variants with defined mutations that augment pathogenicity and/or increase immune evasiveness continues to stimulate global efforts to improve vaccine formulation and efficacy. The extraordinary advantages of lipid nanoparticles (LNPs), including versatile design, scalability, and reproducibility, make them ideal candidates for developing next-generation mRNA vaccines against circulating SARS-CoV-2 variants. Here, we assess the efficacy of LNP-encapsulated mRNA booster vaccines encoding the spike protein of SARS-CoV-2 for variants of concern (Delta, Omicron) and using a predecessor (YN2016C isolated from bats) strain spike protein to elicit durable cross-protective neutralizing antibody responses. The mRNA-LNP vaccines have desirable physicochemical characteristics, such as small size (~78 nm), low polydispersity index (<0.13), and high encapsulation efficiency (>90%). We employ in vivo bioluminescence imaging to illustrate the capacity of our LNPs to induce robust mRNA expression in secondary lymphoid organs. In a BALB/c mouse model, a three-dose subcutaneous immunization of mRNA-LNPs vaccines achieved remarkably high levels of cross-neutralization against the Omicron B1.1.529 and BA.2 variants for extended periods of time (28 weeks) with good safety profiles for all constructs when used in a booster regime, including the YN2016C bat virus sequences. These findings have important implications for the design of mRNA-LNP vaccines that aim to trigger durable cross-protective immunity against the current and newly emerging variants.

Combination of tibial tubercle transfer, medial patellofemoral ligament reconstruction, trochleoplasty and lateral release for patellofemoral instability provides good middle- to long-term outcomes in adolescents.

PURPOSE: There are limited studies that have reported the middle- to long-term outcomes of combined procedures consisting of more than two procedures for patellofemoral instability. The current study aims to investigate and report the middle- to long-term outcomes of a combination procedure of tibial tubercle transfer, medial patellofemoral ligament reconstruction, trochleoplasty and lateral release for patellofemoral instability in patients aged 18 years and below. METHODS: In the cohort study, all patients aged 18 years old or younger who underwent a combination procedure of tibial tubercle transfer, medial patellofemoral ligament reconstruction, trochleoplasty and lateral release for recurrent patellofemoral instability were included. RESULTS: A total of 21 patients were included in the study. All patients had no further patellofemoral dislocation, pain and apprehension following the 4-in-1 surgery (p < 0.01). There was a significant improvement in the Kujala score from 36.1 (SD 12.9) pre-operatively to 93.1 (SD 3.6) post-operatively (p < 0.001). The patients also had a statistically significant improvement in their radiological factors, including the patellar tilt angle (p < 0.001), sulcus angle (p = 0.001), trochlear groove depth (p = 0.041), tibial tubercle-trochlear groove distance (p < 0.001) and Caton-Deschamps index (p = 0.001). CONCLUSION: A combination procedure of tibial tubercle transfer, medial patellofemoral ligament reconstruction, trochleoplasty and lateral release leads to good middle- to long-term subjective, functional and radiographic outcomes for patients with recurrent patellofemoral instability and underlying predisposing factors of increased TT-TG distance of more than 20 mm, Dejour B or D trochlear dysplasia and medial patellofemoral ligament rupture. LEVEL OF EVIDENCE: IV.

Health Care Professional Education on Cancer Screening of SGM Individuals: An Integrative Review.

Sexual and gender minority (SGM) individuals are disproportionately affected by cancer. Health care professional (HCP) and health sciences education rarely includes content on cancer screening in this population. This article aims to synthesize literature on educational programs for HCPs and health sciences students related to cancer screening for SGM individuals. An integrative review methodology guided a systematic search of five databases: CINAHL, PubMed, Embase, PsycInfo, and ERIC. Articles were included if they were empirically-based and described educational programs targeted at HCPs and health sciences students with content of cancer screening for SGM people. Eleven studies met the inclusion criteria. Of these, three were pilot studies and the majority of the articles (n = 9) used pre- and post-test designs. All of the interventions showed efficacy in increasing knowledge, attitudes, skills, and behavior. However, the vastly different programs and the fact that most of the cancer screening content was embedded in programs with broad SGM issues content limit the ability to make firm recommendations for any one particular program. In-person didactic content delivered multiple times incorporating modalities such as standardized patient encounters, case studies, and guest speakers increased knowledge, attitude, and skills of participants. Future studies should incorporate behavioral theories, develop more consistent aspects of educational programs, report demographic and pertinent data on participants, and utilize established instruments to measure outcomes when conducting educational interventions on HCPs and students in this area.

Acyclovir-Induced Nephrotoxicity and Neurotoxicity: A Report of Two Cases.

Acyclovir is a widely used antiviral agent used to treat viral meningitis. Although well tolerated, on rare occasions, it can cause severe nephrotoxicity and neurotoxicity. It is recommended that the dose of intravenous acyclovir be calculated based on the ideal body weight for height rather than the actual weight in obese patients to avoid excessive dosage. We report two patients who developed severe acute kidney injury and neurological symptoms while on intravenous acyclovir therapy. The first patient was a 57-year-old obese woman known to have epilepsy who received a dose of intravenous acyclovir based on her actual weight of 80 kg and subsequently developed acyclovir-induced nephrotoxicity and increased seizure activity. The second patient was a 60-year-old, slightly overweight, man, who received a dose of intravenous acyclovir based on his actual weight of 80 kg and subsequently developed both acyclovir-induced nephrotoxicity and possible neurotoxicity. No other cause for the deterioration in renal function or neurological symptoms was identified, and there was rapid recovery within three days of stopping acyclovir therapy. This case report emphasizes the importance of monitoring renal function while patients are on intravenous acyclovir therapy and highlights the fact that even non-obese, overweight patients are at risk of toxicity when their actual body weight instead of their ideal body weight for height is used for intravenous acyclovir dose calculation.

Cost-effectiveness analysis of add-on pertuzumab to trastuzumab biosimilar and chemotherapy as neoadjuvant treatment for human epidermal growth receptor 2-positive early breast cancer patients in Singapore.

OBJECTIVES: The Asian PEONY trial showed that add-on pertuzumab to trastuzumab and chemotherapy significantly improved pathological complete response in the neoadjuvant treatment of patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC). This study evaluated the cost-effectiveness of pertuzumab as an add-on therapy to trastuzumab and chemotherapy for neoadjuvant treatment of patients with HER2+ EBC in Singapore. METHODS: A six-state Markov model was developed from the Singapore healthcare system perspective, with a lifetime time horizon. Model outputs were: costs; life-years (LYs); quality-adjusted LYs (QALYs); incremental cost-effectiveness ratios (ICERs). Sensitivity/scenario analyses explored model uncertainties. RESULTS: The base case projected the addition of pertuzumab to be associated with improved outcomes by 0.277 LYs and 0.271 QALYs, increased costs by S$1,387, and an ICER of S$5,121/QALY. The ICER was most sensitive to the pCR rate, and the probabilistic sensitivity analysis showed that add-on pertuzumab had an 81.3% probability of being cost-effective at a willingness-to-pay threshold of S$45,000/QALY gained. CONCLUSIONS: This model demonstrated that the long-term clinical impact of early pertuzumab use, particularly the avoidance of metastatic disease and thus avoidance of higher costs and mortality rates, make neoadjuvant pertuzumab a cost-effective option in the management of patients with HER2+ breast cancer in Singapore.

Dosimetric Validation for Prospective Clinical Trial of GRID Collimator-Based Spatially Fractionated Radiation Therapy: Dose Metrics Consistency and Heterogeneous Pattern Reproducibility.

PURPOSE: Dose heterogeneity within a tumor target is likely responsible for the biologic effects and local tumor control from spatially fractionated radiation therapy (SFRT). This study used a commercially available GRID-pattern dose mudulated nonuniform radiation therapy (GRID) collimator to assess the interplan variability of heterogeneity dose metrics in patients with various bulky tumor sizes and depths. METHODS AND MATERIALS: The 3-dimensional heterogeneity metrics of 14 bulky tumors, ranging from 155 to 2161 cm3 in volume, 6 to 23 cm in equivalent diameter, and 3 to 13 cm in depth, and treated with GRID collimator-based SFRT were studied. A prescription dose of 15 Gy was given at the tumor center with 6 MV photons. The dose-volume histogram indices, dose heterogeneity parameters, and peak/valley dose ratios were derived; the equivalent uniform doses of cancer cells with various radiosensitivities in each plan were estimated. To account for the spatial fractionation, high dose core number density of the tumor target was defined and calculated. RESULTS: Among 14 plans, the dose-volume histogram indices D5, D10, D50, D90, and D95 (doses covering 5%, 10%, 50%, 90%, and 95% of the target volume) were found within 10% variation. The dose ratio of D10/D90 also showed a moderate consistency (range, 3.9-5.0; mean, 4.4). The equivalent uniform doses were consistent, ranging from 4.3 to 5.5 Gy, mean 4.6 Gy, for radiosensitive cancer cells and from 5.8 to 6.9 Gy, mean 6.2 Gy, for radioresistant cancer cells. The high dose core number density was within 20% among all plans. CONCLUSIONS: GRID collimator-based SFRT delivers a consistent heterogeneity dose distribution and high dose core density across bulky tumor plans. The interplan reproducibility and simplicity of GRID therapy may be useful for certain clinical indications and interinstitutional clinical trial design, and its heterogeneity metrics may help guide multileaf-collimator-based SFRT planning to achieve similar or further optimized dose distributions.

Framework for Radiation Oncology Department-wide Evaluation and Implementation of Commercial Artificial Intelligence Autocontouring.

PURPOSE: Artificial intelligence (AI)-based autocontouring in radiation oncology has potential benefits such as standardization and time savings. However, commercial AI solutions require careful evaluation before clinical integration. We developed a multidimensional evaluation method to test pretrained AI-based automated contouring solutions across a network of clinics. METHODS AND MATERIALS: Curated data included 121 patient planning computed tomography (CT) scans with a total of 859 clinically approved contours used for treatment from 4 clinics. Regions of interest (ROIs) were generated with 3 commercial AI-based automated contouring software solutions (AI1, AI2, AI3) spanning the following disease sites: brain, head and neck (H&N), thorax, abdomen, and pelvis. Quantitative agreement between AI-generated and clinical contours was measured by Dice similarity coefficient (DSC) and Hausdorff distance (HD). Qualitative assessment was performed by multiple experts scoring blinded AI-contours using a Likert scale. Workflow and usability surveying was also conducted. RESULTS: AI1, AI2, and AI3 contours had high quantitative agreement in 27.8%, 32.8%, and 34.1% of cases (DSC >0.9), performing well in pelvis (median DSC = 0.86/0.88/0.91) and thorax (median DSC = 0.91/0.89/0.91). All 3 solutions had low quantitative agreement in 7.4%, 8.8%, and 6.1% of cases (DSC <0.5), performing worse in brain (median DSC = 0.65/0.78/0.75) and H&N (median DSC = 0.76/0.80/0.81). Qualitatively, AI1 and AI2 contours were acceptable (rated 1-2) with at most minor edits in 70.7% and 74.6% of ROIs (2906 ratings), higher for abdomen (AI1: 79.2%) and thorax (AI2: 90.2%), and lower for H&N (29.0/35.6%). An end-user survey showed strong user preference for full automation and mixed preferences for accuracy versus total number of structures generated. CONCLUSIONS: Our evaluation method provided a comprehensive analysis of both quantitative and qualitative measures of commercially available pretrained AI autocontouring algorithms. The evaluation framework served as a roadmap for clinical integration that aligned with user workflow preference.

Risk factors for a false negative Ortolani and Barlow examination in developmental dysplasia of the hip.

INTRODUCTION: Although universal screening by neonatal clinical examination with Ortolani and Barlow manoeuvres is widely adopted, its role as a sole screening tool is controversial due to its poor sensitivity and failure in identifying hip joints that eventually require surgical intervention. HYPOTHESIS: This study aims to identify risk factors for a false negative Ortolani and Barlow examination in neonatal screening for DDH. The hypothesis is that risk factors for developmental dysplasia of the hips could similarly be risk factors for a false negative Ortolani and Barlow examination. MATERIAL AND METHODS: In the 14-year retrospective cohort study, all newborn infants born in a single institution from 1st January 1999 to 31st December 2013 were screened clinically with the Ortolani/Barlow manoeuvre by a neonatologist. Infants with positive risk factors, despite a normal clinical examination, were then scheduled for bilateral hip ultrasound in the first three months of life and evaluated according to the Graf's method, Harcke's method of dynamic ultrasound screening and Terjesen's method of evaluation for femoral head coverage. RESULTS: A total of 164 infants with normal Ortolani and Barlow examinations were scheduled for bilateral hip ultrasound due to the presence of risk factors. Amongst these, 32 (19.5%) infants were evaluated to have an abnormal hip on ultrasound. Breech position was the only statistically significant risk factor for a false negative Ortolani/Barlow examination (14/34, 41.2% vs. 18/112, 13.8%; p<0.001). DISCUSSION: Sonographic hip examinations are recommended for all infants with breech presentation even if they have a normal Ortolani and Barlow examination. LEVEL OF EVIDENCE: III; case-control study.

Critical care delivery across health care systems in low-income and low-middle-income country settings: A systematic review.

Background: Prior research has demonstrated that low- and low-middle-income countries (LLMICs) bear a higher burden of critical illness and have a higher rate of mortality from critical illness than high-income countries (HICs). There is a pressing need for improved critical care delivery in LLMICs to reduce this inequity. This systematic review aimed to characterise the range of critical care interventions and services delivered within LLMIC health care systems as reported in the literature. Methods: A search strategy using terms related to critical care in LLMICs was implemented in multiple databases. We included English language articles with human subjects describing at least one critical care intervention or service in an LLMIC setting published between 1 January 2008 and 1 January 2020. Results: A total of 1620 studies met the inclusion criteria. Among the included studies, 45% of studies reported on pediatric patients, 43% on adults, 23% on infants, 8.9% on geriatric patients and 4.2% on maternal patients. Most of the care described (94%) was delivered in-hospital, with the remainder (6.2%) taking place in out-of-hospital care settings. Overall, 49% of critical care described was delivered outside of a designated intensive care unit. Specialist physicians delivered critical care in 60% of the included studies. Additional critical care was delivered by general physicians (40%), as well as specialist physician trainees (22%), pharmacists (16%), advanced nursing or midlevel practitioners (8.9%), ambulance providers (3.3%) and respiratory therapists (3.1%). Conclusions: This review represents a comprehensive synthesis of critical care delivery in LLMIC settings. Approximately 50% of critical care interventions and services were delivered outside of a designated intensive care unit. Specialist physicians were the most common health care professionals involved in care delivery in the included studies, however generalist physicians were commonly reported to provide critical care interventions and services. This study additionally characterised the quality of the published evidence guiding critical care practice in LLMICs, demonstrating a paucity of interventional and cost-effectiveness studies. Future research is needed to understand better how to optimise critical care interventions, services, care delivery and costs in these settings. Registration: PROSPERO CRD42019146802.

Race and sex differences in the longitudinal changes in multidimensional self-reported sleep health characteristics in aging older adults.

OBJECTIVES: We examined within-individual changes in self-reported sleep health as community-dwelling older adults age as well as potential differences in these changes by self-reported sex and racial identity. METHODS: Participants were from the United States and enrolled in the Rush Memory and Aging Project, Minority Aging Research Study, or Religious Orders Study (N = 3539, 20% Black, 75% female, mean 78years [range 65-103]), and they received annual, in-person clinical evaluations (median 5 visits [range 1-27]). A sleep health composite score measured the number of poor sleep characteristics among satisfaction, daytime sleepiness, efficiency, and duration. Mixed effects models estimated associations of age, race, sex, and their interactions on the composite and individual sleep measures, accounting for key confounders. RESULTS: As they aged, Black participants shifted from reporting two poor sleep characteristics to one poor sleep characteristic, while White participants shifted from one poor characteristic to two. Regardless of age, sex, and race, participants reported that they "often" felt satisfied with their sleep and "sometimes" had trouble staying asleep. Females over age 85 and males of all ages reported the most daytime sleepiness, and older White participants (>age 90) reported the most difficulty falling asleep. CONCLUSIONS: Although self-reported sleep characteristics were typically stable across age, identifying race and sex differences in self-reported sleep health can help guide future research to understand the mechanisms that underlie these differences.

The prognostic impact of t(11;14) in multiple myeloma: A real-world analysis from the Australian Lymphoma Leukaemia Group (ALLG) and the Australian Myeloma and Related Diseases Registry (MRDR).

The prognostic impact of t(11;14) in multiple myeloma (MM) needs to be better understood to inform future treatment decisions. The Australian Lymphoma Leukaemia Group embarked on a retrospective, observational cohort study using real-world data to interrogate treatment patterns and outcomes in 74 MM patients with t(11;14) [t(11;14)-MM] diagnosed over 10 years. This was compared to 159 and 111 MM patients with high-risk IgH translocations (IgH HR-MM) and hyperdiploidy (Hyperdiploid-MM), respectively, from the Australian Myeloma and Related Diseases Registry. No appreciable differences in age, gender, ISS, LDH levels, 1q21 or del(17p) status, or treatment patterns were observed between groups. Median PFS-1 was not different between groups but both t(11;14)-MM and IgH HR-MM had an inferior PFS-2 vs. Hyperdiploid-MM: median PFS-2 8.2 months, 10.0 months, and 19.8 months (p = 0.002), respectively. The 3-year OS were 69%, 71%, and 82% (p = 0.026), respectively. In the t(11;14)-MM group, gain or amplification of 1q21 at diagnosis predicted for poorer OS (HR 3.46, p = 0.002). Eleven patients had received venetoclax with 45% achieving better than a very good partial response. Results suggest that t(11;14) MM may confer an unfavorable risk profile and that the use of targeted therapies such as venetoclax earlier in the treatment algorithm should be explored.

Adherence to continuous positive airway pressure for the treatment of obstructive sleep apnea in neurodegenerative diseases: A systematic review.

Obstructive sleep apnea (OSA) is prevalent in patients with neurodegenerative diseases and is associated with worse outcomes. Positive airway pressure therapy has the potential to benefit these patients but can be challenging in this population. Our primary aim was to describe positive pressure therapy adherence. Secondarily, we aimed at identifying identify predictors of adherence to treatment in adults with neurodegenerative diseases and OSA, and report the effect of PAP adherence on outcomes such as cognitive function, quality of life and patient/caregiver satisfaction. We performed a systematic review of the literature and identified seventeen studies, eight reporting on adults with obstructive sleep apnea and mild cognitive impairment (MCI) and/or Alzheimer's disease (AD), 6 with Parkinson's disease (PD), and 3 with multiple system atrophy (MSA). Meta-analyses were not performed due to lack of systematic and standardized reporting of the primary outcome. Study duration ranged from 6 weeks to an average of 3.3 years. PAP adherence definition was widely variable between studies. Attrition rates ranged from 12% to 75%. In MCI/AD, adherence rates ranged from 28% to 61% (study duration range: 3 weeks to 3.3 years). Younger age, race (white) and better CPAP confidence scores at 1 week were associated with more CPAP use while APOE4 positive and unmarried individuals were more likely to abandon CPAP. In most studies, adherent patients had improvement in excessive daytime sleepiness, depressive symptoms, sleep quality, ability to manage daily activities and certain aspects of cognition (composite score or global cognition, psychomotor speed, executive function), as well as less cognitive decline over time. Caregiver satisfaction was also better in PAP adherent patients in one study. In PD, 15-25% of individuals refused treatment with PAP upfront, and attrition ranged from 8 to 75%. Adherent patients used their device for an average of 3h27 to 5h12 per night (study duration range: 6 weeks to 12 months). Longer disease duration, worse motor symptoms or sleep quality and lower % of REM sleep were identified as predictors of lower PAP adherence in a preliminary study, while race (non-white) and sex (women) were linked to lower adherence in a large retrospective study. In the study reporting the highest attrition rate (75%), individuals had lower educational levels. PAP adherence improved daytime sleepiness, anxiety symptoms, sleep architecture and quality and global non-motor symptoms. However, in one short-term (3 weeks) study, there was no improvement in neuropsychological testing composite score. Three studies on MSA patients suffering from sleep-disordered breathing showed that most patients are accepting of PAP (69-72%) with an average nightly use of 4h42 to 6h18. Floppy epiglottis was more frequently seen in patients discontinuing PAP in one study. In one study, four adults with MSA and long-term PAP use reported better sleep and improved vigilance. Survival time was no different between treated and untreated individuals. In conclusion, PAP therapy is challenging in patients with OSA and NDD, as evidenced by the considerable attrition and low adherence rates reported in this systematic review. There is emerging evidence proposing OSA a treatable target to prevent clinical and functional deterioration in patients with neurodegenerative diseases and addressing potential barriers to PAP adherence is paramount to maximize adherence. Our systematic review outlines several of these potential barriers, underscoring the need for future studies to standardize the definition of and explore long-term adherence to PAP therapy and assess interventions that can optimize adherence in this patient population.

Examining temporal features of BOLD-based cerebrovascular reactivity in clinical populations.

Background: Conventional cerebrovascular reactivity (CVR) estimation has demonstrated that many brain diseases and/or conditions are associated with altered CVR. Despite the clinical potential of CVR, characterization of temporal features of a CVR challenge remains uncommon. This work is motivated by the need to develop CVR parameters that characterize individual temporal features of a CVR challenge. Methods: Data were collected from 54 adults and recruited based on these criteria: (1) Alzheimer's disease diagnosis or subcortical Vascular Cognitive Impairment, (2) sleep apnea, and (3) subjective cognitive impairment concerns. We investigated signal changes in blood oxygenation level dependent (BOLD) contrast images with respect to hypercapnic and normocapnic CVR transition periods during a gas manipulation paradigm. We developed a model-free, non-parametric CVR metric after considering a range of responses through simulations to characterize BOLD signal changes that occur when transitioning from normocapnia to hypercapnia. The non-parametric CVR measure was used to examine regional differences across the insula, hippocampus, thalamus, and centrum semiovale. We also examined the BOLD signal transition from hypercapnia back to normocapnia. Results: We found a linear association between isolated temporal features of successive CO2 challenges. Our study concluded that the transition rate from hypercapnia to normocapnia was significantly associated with the second CVR response across all regions of interest (p < 0.001), and this association was highest in the hippocampus (R2 = 0.57, p < 0.0125). Conclusion: This study demonstrates that it is feasible to examine individual responses associated with normocapnic and hypercapnic transition periods of a BOLD-based CVR experiment. Studying these features can provide insight on between-subject differences in CVR.

Continuous positive airway pressure increases CSF flow and glymphatic transport.

Respiration can positively influence cerebrospinal fluid (CSF) flow in the brain, yet its effects on central nervous system (CNS) fluid homeostasis, including waste clearance function via glymphatic and meningeal lymphatic systems, remain unclear. Here, we investigated the effect of supporting respiratory function via continuous positive airway pressure (CPAP) on glymphatic-lymphatic function in spontaneously breathing anesthetized rodents. To do this, we used a systems approach combining engineering, MRI, computational fluid dynamics analysis, and physiological testing. We first designed a nasal CPAP device for use in the rat and demonstrated that it functioned similarly to clinical devices, as evidenced by its ability to open the upper airway, augment end-expiratory lung volume, and improve arterial oxygenation. We further showed that CPAP increased CSF flow speed at the skull base and augmented glymphatic transport regionally. The CPAP-induced augmented CSF flow speed was associated with an increase in intracranial pressure (ICP), including the ICP waveform pulse amplitude. We suggest that the augmented pulse amplitude with CPAP underlies the increase in CSF bulk flow and glymphatic transport. Our results provide insights into the functional crosstalk at the pulmonary-CSF interface and suggest that CPAP might have therapeutic benefit for sustaining glymphatic-lymphatic function.

Application of Modelling and Simulation Approaches to Predict Pharmacokinetics of Therapeutic Monoclonal Antibodies in Pediatric Population.

Ethical regulations and limited paediatric participants are key challenges that contribute to a median delay of 6 years in paediatric mAb approval. To overcome these barriers, modelling and simulation methodologies have been adopted to design optimized paediatric clinical studies and reduce patient burden. The classical modelling approach in paediatric pharmacokinetic studies for regulatory submissions is to apply body weight-based or body surface area-based allometric scaling to adult PK parameters derived from a popPK model to inform the paediatric dosing regimen. However, this approach is limited in its ability to account for the rapidly changing physiology in paediatrics, especially in younger infants. To overcome this limitation, PBPK modelling, which accounts for the ontogeny of key physiological processes in paediatrics, is emerging as an alternative modelling strategy. While only a few mAb PBPK models have been published, PBPK modelling shows great promise demonstrating a similar prediction accuracy to popPK modelling in an Infliximab paediatric case study. To facilitate future PBPK studies, this review consolidated comprehensive data on the ontogeny of key physiological processes in paediatric mAb disposition. To conclude, this review discussed different use-cases for pop-PK and PBPK modelling and how they can complement each other to increase confidence in pharmacokinetic predictions.