Prospective Longitudinal Study Research Articles

Extremes of baseline cognitive function determine the severity and outcomes of delirium: findings from a prospective longitudinal cohort study

AbstractBackgroundEpidemiological studies have shown the bidirectional relationship between dementia and delirium to be complex and non‐linear. This has implications for mechanistic studies investigating the extent to which any pathophysiology might be specific to delirium, or shared with dementia. While delirium is associated with long‐term dementia risk and cognitive decline, this association may be independent of classical Alzheimer’s pathology in oldest‐old patients.MethodThe Delirium and Population Health informatics (DELPHIC) study prospectively followed a population‐representative sample of 1510 individuals aged ≥70 years living in London, UK. We performed cognitive assessments at baseline, two years, and ascertained delirium symptoms during incident hospitalisation in 209 participants across 371 episodes.ResultBetter baseline cognitive function was generally associated with a lower likelihood of delirium. However, during delirium episodes, there was a U‐shaped relationship between baseline cognition and delirium symptom severity; participants with the lowest and highest baseline cognition experienced the most severe delirium and arousal deficits (baseline z‐score ‐2: mean MDAS 15; baseline z‐score +2: mean MDAS 11). At follow‐up, we observed the largest cognitive decline in participants with better baseline cognition experiencing delirium (2.2SD decline vs 0.8SD without delirium).ConclusionThese findings imply that delirium pathophysiology research should take into account differences in baseline cognition, for example by defining pre‐existing subclinical dementia pathology. We suggest the need for prospective, serial pathophysiological studies to consider the temporal sequence of delirium‐related neural damage. In this way, we could differentiate which mechanisms are unique to delirium, and which might interact with pre‐existing dementia pathophysiology to result in long‐term cognitive deficits.

Most caregivers who choose tube feeding for a relative with advanced dementia don’t want it for themselves

AbstractBackgroundAlthough long‐term enteral feeding in advanced dementia is not advocated, a significant proportion of people with severe dementia (PWSDs) receive nasogastric tube (NGT) feeding. Often, in the absence of advanced care planning by the PWSDs, their caregivers may need to make pivotal decisions on the issue. Hence, we assessed perceptions of caregivers of PWSDs regarding NGT feeding and the association between caregiver factors and NGT feedingMethodCommunity‐dwelling PWSDs with a FAST 6c score or higher, were recruited as part of the PISCES study, a prospective longitudinal cohort study. Their informal primary caregivers (family members in regular contact with the PWSDs and involved in main decision‐making process) were surveyed.Result215 caregivers of PWSDs enrolled in the study, of which 9.8% (n = 21) utilised NGT for their PWSD. Most (90.5%) caregivers of PWSDs receiving NGT reported that they understood the risks and benefits of NGT; most (85.8%) also agreed with the decision for NGT and reported that they believed it would allow the PWSD to live longer (85.7%). However, only 28.6% of caregivers wanted to be tube‐fed themselves if positions were reversed and 52.4% felt that tube feeding had reduced PWSDs’ quality of life. Comparing caregivers of PWSDs with and without NGT, there was no significant difference in their understanding of the natural course of dementia with only half of each group acknowledging that dementia can cause death (NGT 57.1% vs non‐NGT 56.1%, p = 0.969), nor difference in their knowledge of the PWSDs’ prognosis with majority indicating that they did not know how long the PWSD would live (NGT 85.7% vs non‐NGT 90.7%, p = 0.337). There was also no significant difference in their goals of care for the PWSDs with comfort reported as the primary goal for both groups (NGT 90.5% vs non‐NGT 92.3%, p = 0.773).ConclusionThere is a dissonance between caregivers’ self‐reported understanding and support of NGT use, and their preferences for NGT themselves, its perceived effect on PWSDs’ quality of life and goals of care. Further in‐depth qualitative exploration of the reasons underlying this discordance can provide more clarity on the issue.

Cognitive function in older adults with hearing loss; outcomes for treated versus untreated groups at 3‐year follow‐up.

AbstractBackgroundHearing loss has been identified as the largest potentially modifiable risk factor for dementia and affects 50% adults aged 50‐64 years, and 70% aged 70 years and older. The quality of evidence the effect of hearing aid use on cognition in older adults is currently poor due to methodological limitations. Few studies have objectively studied these outcomes beyond 6‐12 months. This prospective longitudinal observational cohort study investigated the effects of hearing aid use on cognitive performance in older adults over 3 years.Method183 first‐time hearing aid users aged 60 years and older with mild to severe hearing loss were assessed using gold standard measures before hearing aid fitting, with subsets of this group re‐assessed after 18 and 36 months as they reached these timepoints. Outcomes for the treatment group were compared with those of participants of a large longitudinal cohort study of community‐living older adults (AIBL) using the same measures. Objective assessment measures included cognitive function, hearing loss, hearing aid use, genetic phenotyping, and speech perception. Subjective measures included hearing disability, mood, quality of life, social isolation, and loneliness.ResultThe treatment group showed good hearing aid compliance, significant improvement in speech perception (quiet and noise) and decreased self‐reported listening disability despite further significant hearing loss over the 3‐year follow‐up. There was significant improvement in cognitive performance from baseline for the treatment group versus the comparative group for working memory, attention, psychomotor function, and visual learning. Comparatively, AIBL participants showed statistically significant decline across all cognitive functions.ConclusionOlder adults with untreated hearing loss are expected to decline cognitively at 2‐5 times the rate of adults without hearing loss. Comparatively, cognitive performance in treated participants in this study instead improved after 3 years of hearing aid use, while the comparative group declined. These results suggest that treatment of hearing loss with hearing aids may delay cognitive decline.

Burden of systemic lupus erythematosus in clinical practice: baseline data from the SLE Prospective Observational Cohort Study (SPOCS) by interferon gene signature

ObjectiveThe longitudinal Systemic Lupus Erythematosus Prospective Observational Cohort Study (SPOCS) aims to assess SLE disease course overall and according to type I interferon 4 gene signature (IFNGS). Here, we describe...

Clinical prediction model for interdisciplinary biopsychosocial rehabilitation in osteoarthritis patients.

Osteoarthritis (OA) is a heterogenous condition, in which different subgroups are present. Individualized interdisciplinary multimodal pain treatments (IMPT) based on the biopsychosocial model have resulted in positive improvement of pain, health and disability in OA patients. Moreover, predictive factors for treatment success of IMPT in different musculoskeletal pain populations have been examined, but a clinical prediction model which informs whether an OA patient is expected to benefit or not from IMPT is currently lacking. The aim was to develop and internally validate a clinical prediction model to inform patient-tailored care based on identified predictors for positive or negative outcomes of IMPT in patients with OA. Longitudinal prospective cohort study. Center for Integral Rehabilitation at six locations in the Netherlands. Chronic OA patients. Data in this study were collected during January 2019 until January 2022. Participants underwent a 10-week IMPT program based on the biopsychosocial model. Treatment success was defined by a minimal decrease from baseline of 9 points on the Pain Disability Index (PDI). Candidate predictors were selected by experts in IMPT and literature review. Backward logistic regression analysis was performed to develop the clinical predication model and bootstrap validation was performed for internal validation. Overall, 599 OA patients were included, of which 324 experienced treatment success. Thirty-four variables were identified as possible predictors for good IMPT outcome. Age, gender, number of pain locations, PDI baseline score, maximal pain severity, use of pain medication and alcohol, work ability, brief illness perceptions questionnaire subscales timeline, consequences, identity and treatment control, pain catastrophizing scale and self-efficacy questionnaire score were found as predictors for treatment success. The internally validated model has an acceptable discriminative power of 0.71. This study reports a specific clinical prediction model for good outcome of IMPT in patients with OA. The internally validated model has an acceptable discriminative power of 0.71. After external validation, this model could be used to develop a clinically useful decision tool.

Different typologies of neighborhood resources are associated with cognitive function

AbstractBackgroundNeighborhood resources (NRes) such as libraries, grocery stores, and child/family centers may promote cognitive health via opportunities for cognitive stimulation and other health benefits. Resources are distributed differently across neighborhoods, but many studies examine effects of individual NRes on health outcomes. This study uses typologies of NRes and examines whether different types of NRes patterns contribute to Black‐White disparities in cognitive function.MethodThis cross‐sectional study of 462 non‐Hispanic Black and White older adults (Mage = 63.6; 53% Black) was drawn from the Michigan Cognitive Aging Project, a regionally‐representative, prospective longitudinal study of adults transitioning to late life in the Detroit metropolitan area. Participants’ current addresses were geocoded and linked to neighborhood data from the National Neighborhood Data Archive for the year 2017. First, a latent class analysis (LCA) using Mplus identified typological classes of NRes using fifteen indicators across all 2,813 census tracts in Michigan. Next, path analysis estimated associations among race, NRes class, and global cognition, operationalized as a composite of five factor scores (episodic memory, executive function, processing speed, language, visuospatial ability). Models adjusted for age, sex/gender, education, and population size.ResultLCA indicated three classes of NRes: low‐resourced (48%), well‐resourced (42%), and highly‐resourced (10%) neighborhoods. Black participants had lower cognitive health and were more likely to live in low‐resourced or highly‐resourced neighborhoods than White participants. White participants were more likely to live in well‐resourced neighborhoods than Black participants. Surprisingly, living in well‐resourced neighborhoods was associated with worse cognition, compared to living in low‐resourced neighborhoods, but this association was only found among Black participants (βBlack = ‐.181, βWhite = .008). Living in highly‐resourced neighborhoods was not associated with cognition, but only 4% of the sample lived in these neighborhoods.ConclusionParadoxical findings suggest additional work is needed to better disentangle the role of NRes in cognitive disparities. Findings may be driven by factors such as racial residential differences (i.e., home rental and homeownership) and/or access to resources within a neighborhood, as well as neighborhood social climate. This study adds to—and highlights the need for more comprehensive models in—research on neighborhoods and ADRD inequalities.

Impact of Remdesivir on inflammatory and prognostic markers of COVID-19: Findings of an event-monitoring study.

Remdesivir is currently approved for treating hospitalised patients with COVID-19. However, it is a priority to monitor its safety and effectiveness in various clinical settings. This study was undertaken to assess the impact of remdesivir on inflammatory and prognostic markers of COVID-19. A hospital-based prospective longitudinal study was conducted over two months comprising event monitoring of COVID-19 patients administered remdesivir as per standard guidelines. The demographic details, risk factors and all baseline parameters were collected. The patients were followed up for the appearance of any adverse drug reactions (ADRs) after the start of remdesivir therapy from Day 1 to discharge or death every day. Repeat Lab tests were done on days 2, 4, 6 and 10 days to assess the impact of remdesivir on inflammatory and prognostic markers of COVID-19 over time. Significant predictors of survival in the cohort were also assessed. A total of 60 COVID-19 patients were administered remdesivir. The mean age of the patients was 59.2 (+13.7) years. There was a significant improvement in the serum creatinine (decreased from 0.9 to 0.7 mg/dL), lymphocyte count {decreased from 9.2 to 7.3 (109 cells/L)} and serum sodium (increased from 134.6 to 137.4) of the patients over six days after the administration of remdesivir. The significant survival predictors were multiple organ failure (P 0.046) and WBC count on Day 10 (P 0.001). Remdesivir administration improved the prognostic biomarker profile in COVID-19 patients.

Anatomic acromioclavicular and Coracoclavicular ligament reconstruction with allograft is effective for the management of non-acute acromioclavicular dislocations

Objectiveto analyze the short-term outcomes of an anatomical technique that reconstructs both the acromioclavicular and coracoclavicular ligaments with the help of a tendon allograft for the management of non-acute acromioclavicular dislocations. Methodsthis is a prospective longitudinal study of a case series of subjects with symptomatic non-acute (>3 weeks) acromioclavicular dislocations surgically managed with an anatomical reconstruction of both the acromioclavicular and coracoclavicular ligaments using tibial tendon allografts. Outcomes were assessed with simple standardized radiographs and with the Constant-Murley, American Shoulder and Elbow Surgeons (ASES)-shoulder and Quick-DASH (Disabilities of the Arm, Shoulder and Hand) scales; also, the acromioclavicular joint stability and the scapulothoracic kinematics were assessed. Resultsa total of 19 subjects were assessed. There were no intraoperative or early postoperative complications. After a minimum two year follow-up (mean 3.12 years, [standard deviation 1.10 years]), there were significant improvements in all three of the scales: The Constant-Murley score increased from 65.4 (13.0) preoperatively to 92.6 (11.2) at the end of follow-up (p<0.001); the Quick-DASH score improved from 21.3 (6.73) to 13.0(4.58) (p<0.001); and the ASES-shoulder score increased from 56.6 (14.6) to 91.0 (9.86) (p<0.001). The AC joint was stable in both the vertical and the horizontal plane, without residual scapulothoracic dysfunction in 18/19 subjects at the end of follow-up. Only one patient presented a poor functional outcome, with loss of reduction, instability and persistent symptoms. Another subject suffered loss of reduction, though without functional repercussions. Two subjects had asymptomatic distal clavicle osteolysis and two developed radiographic osteoarthritis and were also asymptomatic. Moderate widening of the tunnels was observed in most patients: tunnel size after surgery was 5.1 (0.3) mm versus 5.8 (1.1) mm at the end of follow-up (p = 0.001) but widening was not correlated to final function. Conclusionsthe anatomical reconstruction of the acromioclavicular and coracoclavicular ligament complexes with a tendon allograft yields excellent clinical outcomes when used in subjects with symptomatic non-acute acromioclavicular dislocations. Secondary tunnel widening, distal clavicle osteolysis and osteoarthritis might be of concern but do not affect clinical outcomes.

Mild Behavioral impairment (MBI) and late-life psychiatric disorders: Differential clinical features and outcomes.

Mild Behavioral Impairment (MBI) refers to a late-onset neurobehavioral syndrome in which neuropsychiatric symptoms (NPS) represent early markers of dementia. Though being a promising diagnostic category for neurobiological research, in daily clinical practice, the boundaries and relationships between MBI and late-life psychiatric disorders are yet to be established. Particularly, no studies have been conducted so far on the prognostic implications of an MBI diagnosis in the psychogeriatric context.For these reasons, since June 2020, we are conducting a prospective longitudinal study on MBI in psychogeriatric patients. On June 2022, 144 elderly patients (≥50 years) referred to the outpatient clinic of the 2nd Psychiatric Unit of the University of Pisa had been recruited. Patients had been diagnosed with a primary psychiatric disorder (N=73, 50.6%), MBI (N=40, 27.8%) or dementia (N=31, 21.5%). Patients with MBI showed a significantly higher age at onset of psychiatric disorders and depressive episodes than patients diagnosed with primary psychiatric disorders. MCI and vascular leukoencephalopathy were also more common in patients with MBI. Moreover, compared to primary psychiatric disorders, MBI was associated with a significantly higher psychopathology severity, especially in the apathy and negative symptoms domain.Preliminary longitudinal analyses were also performed on a subsample of 83 patients followed-up for at least 3 months (on average for one year): at baseline 44 patients had been diagnosed with primary mood disorders including 23 patients in remission and 21 patients with current mood episodes; 22 patients had MBI and 17 were diagnosed with dementia. While at follow-up patients with mood episodes showed a significant decrease in psychopathology severity and increase in global functioning, those with MBI had no significant improvements.In conclusion, MBI is a common condition in psychogeriatric settings and shows distinctive clinical features that may help differential diagnosis. Moreover, the presence of MBI in patients with late-life psychiatric disorders may affect both clinical and functional outcomes. The recognition of patients with MBI symptoms, including apathy, might be useful for the early detection of individuals with poor prognosis.

Maternal psychological distress and children's adjustment problems: Mediation by household chaos.

Research over many decades has considered the crucial role of maternal psychological distress (e.g., depression, anxiety) for children's psychological adjustment (externalizing and internalizing problems), suggesting bidirectional influences over time. However, little is known about the extent to which household chaos (e.g., noise, disorganization, lack of calm) may mediate this mutual association, despite an understanding that chaos is a powerful stressor in the home. Conducting secondary data analysis in a large scale, prospective longitudinal study of families with children-the U.K.'s Millennium Cohort Study-we accounted for stability in both maternal psychological distress and children's internalizing and externalizing problems and examined the extent to which household chaos mediated the mutual association between maternal psychological distress and children's behaviors. Using what we term a mutual-mediation model, we found that both maternal psychological distress and children's adjustment problems predicted household chaos at Age 5, and in turn, that chaos predicted maternal psychological distress and child adjustment problems at Age 7. We found a dominance of children's externalizing problems in the prediction of household chaos, and all pathways were strongest for maternal psychological distress and externalizing problems compared to child internalizing problems. Our findings suggest that research would be well-minded to consider both child and parent effects on household chaos, as well as its mediation potential. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The role of multimorbidity and socio-economic characteristics as potential risk factors for Long Covid: evidence from the multilevel analysis of the Survey of Health, Ageing and Retirement in Europe's corona surveys (2020-2021).

A substantial proportion of individuals continue experiencing persistent symptoms following the acute stage of their Covid-19 illness. However, there is a shortage of population-based studies on Long Covid risk factors. To estimate the prevalence of Long Covid in the population of middle-aged and older Europeans having contracted Covid-19 and to assess the role of multimorbidity and socio-economic characteristics as potential risk factors of Long Covid. A population-based longitudinal prospective study involving a sample of respondents 50 years and older (n= 4,004) from 27 countries who participated in the 2020 and 2021 Survey of Health, Ageing and Retirement in Europe (SHARE), in particular the Corona Surveys. Analyses were conducted by a multilevel (random intercept) hurdle negative binomial model. Overall, 71.6% (95% confidence interval = 70.2-73.0%) of the individuals who contracted Covid-19 had at least one symptom of Long Covid up to 12 months after the infection, with an average of 3.06 (standard deviation = 1.88) symptoms. There were significant cross-country differences in the prevalence of Long Covid and number of symptoms. Higher education and being a man were associated with a lower risk of Long Covid, whilst being employed was associated with a higher risk of having Long Covid. Multimorbidity was associated with a higher number of symptoms and older age was associated with a lower number of symptoms. Our results provide evidence on the substantial burden of Long Covid in Europe. Individuals who contracted Covid-19 may require long-term support or further medical intervention, putting additional pressure on national health care systems.

Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia: Long-term results of endoscopic treatment.

Background and study aims This longitudinal prospective study evaluated the long-term outcome of endoscopic treatment of gastrointestinal bleeding in hereditary hemorrhagic telangiectases (HHT), its safety and outcome predictors. Patients and methods Consecutive patients with HHT and either anemia disproportionate to epistaxis or overt gastrointestinal bleeding received endoscopic treatment of gastrointestinal telangiectases with argon plasma coagulation (APC). Hemoglobin levels and transfusion requirements were evaluated before and after treatment. Treatment effectiveness was classified as: 1) complete: hemoglobin level during the follow-up ≥9 g/dL; 2) complete with recurrence: hemoglobin ≥9 g/dL for at least 12 months with subsequent drop to <9 g/dL; or 3) absent: no improvement of hemoglobin level. Adverse events (AEs) were classified as mild, moderate, severe or fatal. Correlations were searched between treatment outcome and demographic/genetic characteristics, number, size and site of telangiectases, and hepatic arterio-venous malformations grade. Results Forty-seven patients with HHT were enrolled. At median follow-up of 134 months (range 20-243 months), 41 of 47 patients showed treatment response (complete or with recurrence) after one (14/47) or more (27/47) endoscopic treatments. Median hemoglobin levels were 7.0 g/dL and 11.9 g/dL at baseline and at the end of follow-up, respectively. Transfusion requirement decreased from 22.8 to 7.3 red cell unit/year. A higher baseline number of telangiectases was associated with a lower chance of response ( P =0.008). Only one severe AE (0.4%, jejunal perforation) was recorded. Conclusions Endoscopic treatment of gastrointestinal teleangiectases for gastrointestinal bleeding in patients with HHT is effective in the long term and safe.

Neurocognitive function and health-related quality of life in adolescents and young adults with CHD with pulmonary valve dysfunction.

Neurocognitive impairment and quality of life are two important long-term challenges for patients with complex CHD. The impact of re-interventions during adolescence and young adulthood on neurocognition and quality of life is not well understood. In this prospective longitudinal multi-institutional study, patients 13-30 years old with severe CHD referred for surgical or transcatheter pulmonary valve replacement were enrolled. Clinical characteristics were collected, and executive function and quality of life were assessed prior to the planned pulmonary re-intervention. These results were compared to normative data and were compared between treatment strategies. Among 68 patients enrolled from 2016 to 2020, a nearly equal proportion were referred for surgical and transcatheter pulmonary valve replacement (53% versus 47%). Tetralogy of Fallot was the most common diagnosis (59%) and pulmonary re-intervention indications included stenosis (25%), insufficiency (40%), and mixed disease (35%). There were no substantial differences between patients referred for surgical and transcatheter therapy. Executive functioning deficits were evident in 19-31% of patients and quality of life was universally lower compared to normative sample data. However, measures of executive function and quality of life did not differ between the surgical and transcatheter patients. In this patient group, impairments in neurocognitive function and quality of life are common and can be significant. Given similar baseline characteristics, comparing changes in neurocognitive outcomes and quality of life after surgical versus transcatheter pulmonary valve replacement will offer unique insights into how treatment approaches impact these important long-term patient outcomes.

HIV-negative encephalitis and meningoencephalitis in the elderly

Introduction. The elderly are at a higher risk of infectious pathologies, which represent the third cause of primary mortality over 65 years and the leading cause of incidental mortality. The aim of a prospective longitudinal study conducted from April 1, 2012 to August 31, 2015 was to compare the epidemiological, clinical, biological, and etiological characteristics of encephalitis and meningoencephalitis in the elderly with those of young adults. Methods. Patients aged over 28 days with suggestive symptoms of encephalitis were included from three medical departments (resuscitation, infectious diseases, and pediatrics) based on established inclusion and exclusion criteria. Patients seropositive for HIV and children under 15 years of age were excluded. Based on age, two groups were formed: group A (under 65 years old) and group B (65 years old and above), and were compared epidemiologically, clinically, and in terms of evolution. Results. Out of 141 files that met the inclusion criteria, 38 were excluded (age ≤ 15 years). The average age for groups A and B were 36.27 ± 13.9 years (extremes: 17-64 years) and 72.55 ± 5.6 years (range: 66-83 years), respectively. In group B, progressive onset was the main feature (54.5%), associated with behavioral disorders (81.8%) and focal neurological disorders (81.8%). A significant part of these patients also had respiratory signs (36.8%), while in group A, behavioral disorders, focal and diffuse neurological disorders represented 49.6%, 45.5%, and 29.3% of cases, respectively. Out of 92 (65.2%) patients in group A, 44 (47.8%) had confirmed and/or probable viral etiologies, 31 (33.7%) had confirmed and/or probable bacterial etiologies, 3 (3.3%) had parasitic etiologies, 29 had confirmed co-infections, and 42 (45.7%) were treatable. Conclusion: The study highlights the frequency of encephalitis and meningoencephalitis of viral origin in the elderly. The diagnosis remains difficult and any neurological sign recent onset and evolving in a febrile context should suggest the diagnosis.

Significance of serum sestrin2 as a biomarker of severity and functional outcome in acute intracerebral hemorrhage: a prospective observational longitudinal study

BackgroundSestrin2 is a highly conserved stress-inducible protein with neuroprotective properties. Herein, we investigated the prognostic significance of serum sestrin2 in human intracerebral hemorrhage (ICH).MethodsIn this prospective observational longitudinal study, we enrolled 126 patients with supratentorial ICH as cases together with 126 healthy individuals as controls. Severity indicators were National Institutes of Health Stroke Scale (NIHSS) and hematoma volume. Prognostic parameters were early neurologic deterioration (END) and post-stroke 6-month poor prognosis [modified Rankin Scale (mRS) scores of 3–6]. Multivariate analysis was performed to assess relations of serum sestrin2 levels to severity and prognosis.ResultsPatients had statistically significantly higher serum sestrin2 levels than controls. Serum sestrin2 levels of patients were independently correlated with NIHSS scores and hematoma volume, as well as were substantially elevated in order of mRS scores from 0 to 6. Serum sestrin2 was identified as an independent predictor of END and poor prognosis. Based on the receiver operating characteristic curve, serum sestrin2 had a similar predictive ability for END and poor prognosis, as compared to NIHSS scores and hematoma volume. Prediction models of END and poor prognosis, in which serum sestrin2, NIHSS scores and hematoma volume were integrated, were visually described via nomogram, were reliable and stable under calibration curve and were of clinical benefit using decision curve analysis. Also, prediction model of poor prognosis showed dramatically higher discriminatory efficiency than any of NIHSS scores, hematoma volume and serum sestrin2.ConclusionSerum sestrin2 levels, which are obviously increased following acute ICH, are independently related to illness severity and poor clinical outcomes, substantializing serum sestrin2 as a clinically valuable prognostic biomarker of ICH.

Hemophilia A Research Program (HARP): A Novel Study Design for a Multicenter and Decentralized Prospective Observational Longitudinal Cohort Study in Hemophilia A

Background: Hemophilia A is a rare X-linked bleeding disorder caused by factor VIII (FVIII) deficiency. There is a compelling need in hemophilia to better understand the causes of bleeding in females and the factors underlying FVIII inhibitor development. To meet this need we are establishing a new NHLBI funded Hemophilia A Analytical Cohort Research Program (HARP) as part of a public-private partnership to support an Intergenerational Precision Medicine Program for the study of factor VIII (FVIII) immunogenicity in severe hemophilia A (Harpf8.org). The HARP objectives are: 1) Longitudinal assessment of bleeding in females with a severe hemophilia A genotype beginning in pregnancy; 2) Longitudinal assessment of anti-FVIII antibody formation in severe hemophilia A from birth through at least the first 2 years of life; 3) Studies of causes of bleeding in females with a severe hemophilia A genotype; 4) Studies of the immune response to FVIII in severe hemophilia A; 5) Development of a well-curated annotated data set of genetic, hemophilia, immune, environmental, psychosocial, and quality of life metrics; 6) Development of a multi-omics and immunologic biospecimen resource; and 7) Development of the hemophilia analytical Portal (F8portal.org). Study design: The HARP is a multicenter and decentralized prospective observational longitudinal cohort study beginning in pregnancy. It will follow 50 mother-baby pairs where the babies have severe hemophilia A and the mothers have a severe hemophilia A genotype. The private Clinical Consortium (CC) will oversee the study throughout the U.S., including sites that care for the mothers (up to 200 sites) and sites that care for the child (up to 70 sites). The CC will also conduct decentralized aspects of the study including collection of patient reported outcomes and local sample collection. The primary maternal endpoint is primary postpartum hemorrhage; the primary pediatric endpoint is rate of development of humoral immune response to FVIII and proportion that progress to clinical inhibitors. Mother and child secondary endpoints reflect the diverse research the HARP resource will support. Inclusion criteria for the pregnant person are: Pregnant and prior to 37 weeks gestation, known or at-risk to have a severe hemophilia A genotype, pregnant with a fetus at-risk for severe hemophilia A, ability to give informed consent, and &amp;gt; 18 years old. Inclusion criteria for the child are: severe hemophilia A, born to a person in the study. Exclusion/discontinuation criteria are: Presence of another significant bleeding disorder in mother or child; mother age &amp;lt;18 years; no fetus is at-risk to inherit severe hemophilia A; the child does not have severe hemophilia A; the child has a severe immune disorder; the mother or child participates in another study with blood collection volumes that exceed safety limits; mother's or child's healthcare will be outside the U.S.; the mother is a prisoner; any other reason that in the opinion of the investigator a subject is unsuitable for the study Summary: The HARP innovates in multiple areas of clinical study design to conduct a national prospective longitudinal intergenerational study in a rare disorder beginning in pregnancy. The structure includes a new multidisciplinary CC, systematic inclusion of Lived Experience Experts, strategies for broad community engagement, recruitment, and retention, and decentralized operations. This cohort will enable deep characterization, including genomics and other -omics, on pregnancy-associated bleeding and drivers of FVIII inhibitors in hemophilia A. The HARP Shareable Resource will be comprised of well annotated data and biological samples accessible to researchers through a portal, F8portal.org, and a linked biorepository.

The yield of early-pregnancy homeostasis of model assessment -insulin resistance (HOMA-IR) for predicting gestational diabetes mellitus in different body mass index and age groups

BackgroundEarly prediction of gestational diabetes mellitus(GDM) can be beneficial for lifestyle modifications to prevent GDM. The aim of this study was to investigate the predictive values of Homeostasis of Model Assessment -Insulin Resistance (HOMA-IR) in early pregnancy to predict GDM development in different body mass index (BMI) and age risk categories.Materials and methodsThis study is part of the Qazvin Maternal and Neonatal Metabolic Study (QMNMS) in Iran (2018–2021). In this prospective longitudinal study, pregnant women with a gestational age ≤ 14 weeks were enrolled in the study using convenience sampling method and were followed up until delivery to investigate risk factors for maternal and neonatal complications. Data collection was done using questionnaires. Serum sampling was done at a gestational age ≤ 14 weeks and sera were frozen until the end of study. GDM was diagnosed at 24–28 weeks of pregnancy using 75gr oral glucose tolerance test. Fasting blood glucose and insulin were measured in sera taken during early pregnancy in 583 participants. The Mann-Whitney U test, independent t-test, and Chi-square test were used for comparing variables between groups. The logistic regression analysis was used to examine the independent association of HOMA-IR with GDM development and receiver operating characteristic analysis was used for finding the best cut-off of HOMA-IR for predicting GDM.ResultsGDM was developed in 90 (15.4%) of the participants. The third HOMA-IR tertile was independently associated with 3.2 times higher GDM occurrence (95% CI:1.6–6.2, P = 0.001). Despite the high prevalence of GDM in advanced maternal age (GDM rate = 28.4%), HOMA-IR had no association with GDM occurrence in this high-risk group. In both normal BMI and overweight/obese groups, HOMA-IR was a moderate predictor of GDM development (AUC = 0.638, P = 0.005 and AUC = 0.622, P = 0.008, respectively). However, the best cut-off for predicting GDM was 2.06 (sensitivity 67.5%, specificity 61.1%) in normal BMI and 3.13 (sensitivity 64.6%, specificity61.8%) in overweight/obese BMI.ConclusionThe present study revealed the necessity of considering the BMI and age risk groups when using the HOMA-IR index to predict GDM. Using lower cut-offs is more accurate for women with a normal BMI. In the advanced maternal age, there is no yield of HOMA-IR for predicting GDM.

Assessing the Effects of 0.3% Carboxymethylcellulose Tear Substitute Treatment on Symptoms and Signs of Dry Eye Disease in Elderly Population: A Prospective Longitudinal Study

Background: We aimed to evaluate the effects of 0.3% carboxymethylcellulose (CMC) tear substitute treatment in dry eye disease (DED), as well as treatment compliance and adverse events (AEs). Methods: In this prospective, longitudinal study, a total of 30 eyes receiving 0.3% CMC tear substitute four times daily for DED were evaluated. Clinical endpoints included an ocular surface disease index (OSDI) questionnaire, average non-invasive tear film break-up time (A-NIBUT), lipid layer thickness (LLT), and a Schirmer test with anesthesia (ST). Treatment compliance and AEs were also assessed. All evaluations were performed at 2, 4, and 12 weeks of follow-up. Results: At the end of the follow-up, significant improvement was observed in all clinical endpoints with the following mean values: ΔOSDI questionnaire of −22.53 ± 14.68 points, ΔA-NIBUT of 4.81 ± 2.88 s, ΔLLT of 5.63 ± 6.53 nm, and ΔST of 2.8 ± 2.1 mm (p &lt; 0.001 for all comparisons). Although repeated measures analysis showed that all clinical endpoints presented statistically significant differences (p &lt; 0.001 for all comparisons LLTBaseline–LLT2-weeks (p = 0.460) and LLT4-weeks–LLT12-weeks (p = 0.071) were the only pairs of measures that reported non-statistically significant differences). In addition, treatment compliance was 94.3 ± 5.2% and transient AEs related to the use of 0.3% CMC tear substitute were reported. Conclusions: 0.3% CMC tear substitute treatment seems to achieve beneficial effects on the OSDI questionnaire, A-NIBUT, LLT, and ST. However, further studies at this concentration are needed to confirm these results.

Benefit of Inpatient Pain Plan Utilization on Hospital Length of Stay in Adolescents and Young Adults with Sickle Cell Disease

Introduction Vaso-occlusive crisis (VOC) is the most common manifestation of sickle cell disease (SCD) and the most common cause for emergency department (ED) visits and hospital admissions. VOC accounts for approximately 230,000 annual admissions in children with SCD. Patients with SCD face inconsistent analgesic management, leading to high inpatient healthcare utilization and financial burden for healthcare institutions. Furthermore, patients describe their pain management as the area of their care in most need of improvement. A prospective longitudinal cohort study showed that implementation of individualized pain plans in adult patients with SCD significantly decreased the duration of VOC hospital stays by 1.2 days. A similar study in children showed no change in duration of hospital stay, however the study was limited by a small sample size. We hypothesized parallel results to the prior adult study in adolescent and young adult (AYA) SCD patients. Methods At UCSF Benioff Children's Hospital Oakland, we implemented inpatient pain plans for SCD patients with frequent VOC admissions (i.e., &amp;gt;1 VOC admission in the prior year or complicated VOC admission history). Pain plans are individualized and embedded into the patient's electronic health record. These plans include detailed daily analgesic recommendations with the general recommendation for discharge on day 5 of the pain plan. After IRB approval, we performed a retrospective chart review of SCD patients with individualized inpatient pain plans initiated between November 2017 and April 2022. We recorded baseline demographic information including age at pain plan initiation, SCD genotype and sex. We assessed length of inpatient hospitalization for VOC admissions in the year prior and the year after pain plan initiation for each individual patient. We also noted number of admissions secondary to VOC during this two year time period. Results Twenty-six patients with SCD and individualized pain plans were identified (Table 1). Average length of hospital stay for VOC was significantly decreased in the year after inpatient pain plan initiation (Table 2). There was a trend towards increased admissions due to VOC in the year after inpatient pain plan initiation (Table 2). Conclusions Similar to the prior adult study in SCD patients, we found significantly reduced inpatient length of hospitalization after initiation of an inpatient pain plan for AYA patients with SCD and VOC. Although there was a trend towards increased hospitalizations in the year after inpatient pain plan initiation, this was likely secondary to the average patient age with an expected increased in VOC year over year. The National Heart, Lung, and Blood Institute (NHLBI) SCD guidelines recommend an individualized prescribing and monitoring protocol be written by a SCD provider and used in patients withVOC to promote effective, timely, and safe analgesic management. We further demonstrate that individualized pain plans for AYA patients with SCD can decrease length of hospital stay due to VOC, likely secondary to more effective pain management recommendations that have been prior agreed upon by the patient/family and SCD provider. We currently are calculating morphine equivalents and hypothesize total opioid utilization will be concomitantly decreased due to this significantly decreased length of hospitalization.

Hepatitis B Reactivation without Hepatitis Is a Common Event in Adolescent/Adult Patients of Acute Lymphoblastic Leukemia with Occult Hepatitis B (OHBI) Treated on Pediatric Protocols and Warrants Prophylactic Antivirals: A Prospective Cohort Study

Introduction: Patients with occult Hepatitis B infection(OHBI) (HBsAg negative but HBcIgG &amp;/or anti-HBs positive in the absence of immunization) are at an increased risk of Hepatitis B(HBV) reactivation while on and after chemotherapy. It can present over a spectrum ranging from asymptomatic or mild transaminitis to fatal hepatitis, affect the dose intensity of chemotherapy and compromise outcomes. The reported risk of reactivation is variable (1-24%, Yeo, 2009), and depends on the type of therapy and the method used to detect reactivation. Antiviral prophylaxis is recommended in patients with OHBI who are treated with antiCD20 monoclonal antibodies and those who undergo allogeneic stem-cell transplant, however this has not been evaluated in patients treated on pediatric-inspired ALL protocols comprising of several immunosuppressive drugs.. Methods: This was a prospective longitudinal cohort study conducted at a single tertiary care center in India between October 2017 to July 2021 (CTRI/2017/01/007747). The primary objective was to study the incidence of HBV reactivation in patients with OHBI on ALL protocol, and secondary objectives were to study the incidence of OHBI, HBV related hepatitis and its impact on chemotherapy intensity. Newly diagnosed patients with ALL/LBL, aged ≥15 years were screened for the presence of OHBI. Patients with OHBI were considered for enrollment into the prospective part of the study if they were treated on intense protocol (modified BFM-90 ALL protocol), had normal liver function tests, and no co-infection with HCV, HIV or history of HBV vaccination. Liver functions were monitored twice weekly during the induction/reinduction phase, prior to the early and delayed intensification and once every 2-3 months during the maintenance phase. HBV DNA copies by quantitative PCR (threshold for detection 20 units/ml), were measured at baseline, week 4, week 8, week 20, 32, week 48, completion of maintenance and every 3-6 months for 1 year. If a patient developed hepatitis, serum was collected for HBV DNA levels, HBsAg, HB core IgM antibody, IgM HAV antibody, IgM HEV, HCV and CMV DNA levels. HBV reactivation was defined as- either increase in serum HBV DNA level to more than 1 log higher than that of baseline or any copy numbers if it was negative at baseline. Seventy five patients with OHBI were to be studied to detect a true incidence of &amp;gt;10% HBV reactivation at a one-sided significance level of 5% and 90% power (Fleming's design) Results: A total of 566 patients were screened for the study, and 172(30.4% (95% C.I. (26.6-34.4)) patients were diagnosed with OHBI. 74 patients were enrolled in the prospective part of the study (Fig 1). The baseline characteristics of the study population are summarized in Table 1. HBV DNA was detectable at baseline in only 2(2.3%) patients. 51 patients (68.9%) completed all phases of treatment. The median follow-up was 21.6 months (range 0.03-53.5 months). A total of 402 HBV DNA tests were done in this cohort with an average of 5 tests per patient. HBV reactivation occurred in 5 patients ((6.7% 95% C.I.(1.03-12.47)), none of these patients developed hepatitis during HBV reactivation. In all the patients, reactivation occurred during the maintenance phase. All of these patients were started on antivirals (Entecavir). Overall 15(20.3%) patients developed hepatitis during the study period and CMV viremia was the cause for hepatitis in 4(26.7%) patients and HCV infection was the cause in 1 (6.6%) patient. Median AST, ALT during the episodes of hepatitis were 363 and 459 respectively (range AST 150-3490, range ALT 218-1950). Two(2.7%) patients had a delay in administration of chemotherapy due to hepatitis and median duration of delay was 21 days (range 18-24). Conclusion: We conclude that the risk of HBV reactivation is significant in adolescent/adult ALL patients with OHBI treated on pediatric inspired ALL protocols. HBV related hepatitis is a late event, and monitoring with liver function tests alone is not sufficient. The use of prophylactic antivirals is justified in patients with ALL.