Burden of Infection in Patients With and Without Secondary Immunodeficiency Disease Following Diagnosis of a Mature B Cell Malignancy.

BACKGROUND: This retrospective cohort study compared patient characteristics and burden of infection in patients with mature B cell malignancies with and without secondary immunodeficiency disease (SID). PATIENTS AND METHODS: Data were extracted from the Humedica database (H-DB) and Guardian Research Network (GRN) database from October 1, 2015 to March 10, 2020, including a 6-month pre-index period (PIP) and 12-month follow-up. Patients aged ≥18 years diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma, multiple myeloma, or non-Hodgkin's lymphoma in the PIP were stratified into 2 cohorts: SID (hypogammaglobulinemia [using ICD-10-CM codes] or serum IgG levels <5.0 g/L, both with signs and symptoms of SID or at least 1 infection) and no-SID. Patients with SID or primary immunodeficiency diseases in the PIP were excluded. RESULTS: Overall, 2221 patients with SID (H-DB/GRN: n = 1959/262), and 19,141 patients without SID (n = 17,598/1543) were included. Baseline characteristics were similar across cohorts. At 12-month follow-up, significantly more patients with SID had experienced ≥1 infection and ≥1 severe bacterial infection than those without SID (both P < .001). H-DB/GRN mean (standard deviation) number of severe bacterial infections was 7.6 (9.9)/2.9 (2.7) for the SID cohort versus 5.2 (6.8)/2.4 (2.2) for the no-SID cohort. CONCLUSION: This study confirms that patients with mature B cell malignancies and SID face a significantly higher burden of infections than those without SID.

[Dementia Prevention]. / Demenzprävention.

Dementia is common and will continue to grow in importance and numbers in the future. However, as causal treatment is not possible in most cases, prevention is particularly important. This is not only aimed at cognitively healthy people, but is also a central element in all phases of the disease.

Health care resource utilization and costs among patients with spasticity or cervical dystonia.

BACKGROUND: Spasticity and cervical dystonia (CD) are movement disorders with considerable direct and indirect health care cost implications. Although several studies have discussed their clinical impact, few have calculated the economic burden of these disorders. OBJECTIVE: To assess the all-cause health care resource utilization (HCRU) and costs in adults and children with spasticity or CD. METHODS: This retrospective, observational cohort-based study was conducted using administrative insurance claims from the IQVIA PharMetrics Plus database from October 1, 2015, to December 31, 2019. Patients were selected based on International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes for first evidence of spasticity (associated with a spasticity etiology) or CD (index date) during the selection window, from April 1, 2016, through December 31, 2018. Cases were stratified into 3 mutually exclusive cohorts: adult patients with spasticity, pediatric patients with spasticity, and patients with CD; those with spasticity who had a history of stroke or cerebral palsy were also evaluated in subcohorts. Patients without evidence of spasticity or CD during the study period were identified as a matched comparator group and were randomly assigned an index date. Patients with spasticity were matched 1:1 to the comparator group based on age, sex, index year, and payer type using descriptive analyses. RESULTS: 215,739 adult patients with spasticity, 29,644 pediatric patients with spasticity, and 9,035 adult patients with CD were identified after matching. Adult patients with spasticity and CD had mean (SD) ages of 48.4 (15.6) years and 48.0 (13.1) years, respectively. Stroke was identified in 31.9% (n = 68,928) of adult patients with spasticity, and cerebral palsy was identified in 11.3% (n = 3,364) of pediatric patients with spasticity. Adult and pediatric patients with spasticity and patients with CD had significantly higher HCRU (including mean number of outpatient, emergency department, and inpatient visits and proportions of patients with prescription fills) and higher mean total health care costs per patient (adult patients with spasticity $29,912 vs $7,464; pediatric patients with spasticity $16,089 vs $2,963; and patients with CD $20,168 vs $7,141) than matched comparators (all P<0.0001). CONCLUSIONS: The management of patients with spasticity or CD results in considerably higher health care expenses. Within managed health care systems, more effective management of spasticity and CD in adult and pediatric patients represents a significant opportunity for cost savings.

Investigating Real-World Benztropine Usage Patterns in Movement Disorders: Claims Analysis and Health Care Provider Survey Results.

Objective: To evaluate real-world treatment patterns for patients initiating benztropine and to understand treatment approaches in patients with drug-induced movement disorders from a health care provider perspective.Methods: A retrospective claims analysis was conducted among patients with evidence of benztropine initiation from January 2017 through March 2020 to assess treatment patterns and patient health care resource utilization. Subsequently, a 30-minute, United States-based online survey fielded from December 2021 to January 2022 was sent to physicians, nurse practitioners, and physician assistants who reported a primary care or psychiatry specialty currently treating drug-induced movement disorders and prescribed benztropine.Results: The health care claims analysis included 112,542 patients. Polypharmacy and multiple comorbidities were frequent characteristics in this population; 54.1% of patients had ≥ 2 comorbidities at baseline, and 59.1% had claims for > 10 medications. Benztropine was used for > 3 months in > 50% of the population. Health care costs and resource utilization were high, with mean all-cause pharmacy and outpatient costs totaling $11,755. Survey results from 349 primary care or psychiatry health care providers indicated that benztropine is often used in non-tardive dyskinesia drug-induced movement disorders but frequently continued for > 3 months or used in tardive dyskinesia. In this study, psychiatry providers prescribed benztropine in line with guideline recommendations more often than primary care providers; however, < 40% indicated familiarity with 2020 American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia.Conclusions: These complementary analyses suggest that benztropine is used long-term in non-tardive dyskinesia drug-induced movement disorders and in tardive dyskinesia despite risks of worsening tardive dyskinesia or adverse effects.Prim Care Companion CNS Disord 2023;25(4):22m03472. Author affiliations are listed at the end of this article.

Botulinum Toxin Utilization, Treatment Patterns, and Healthcare Costs Among Patients with Spasticity or Cervical Dystonia in the US.

INTRODUCTION: Spasticity and cervical dystonia (CD) are movement disorders with considerable direct and indirect healthcare cost implications. Although several studies have discussed their clinical impact, few have calculated the economic burden of these disorders. This study aimed to understand treatment/injection patterns of botulinum toxins type A (BoNT-As) and the characteristics, healthcare resource utilization (HCRU), and costs among patients with spasticity or CD. METHODS: Retrospective analyses were conducted using administrative healthcare claims from the IQVIA PharMetrics® Plus database, from October 1, 2015 to December 31, 2019. Eligible patients were selected based on Healthcare Common Procedure Coding System codes for BoNT-A (index date) and ICD-10 diagnosis codes for spasticity or CD with 6 months of continuous enrollment pre-index and 12 months post-index. Patients were stratified into adult spasticity, pediatric spasticity, and CD cohorts, and were evaluated for injection patterns, HCRU, and costs in the post-index period. RESULTS: Overall, 2452 adults with spasticity, 1364 pediatric patients with spasticity, and 1529 adults with CD were included. Total mean all-cause healthcare costs were US$42,562 (adult spasticity), $54,167 (pediatric spasticity), and $25,318 (CD). Differences were observed in the cost of BoNT-A injection visits between toxins, with abobotulinumtoxinA (aboBoNT-A) having the lowest injection cost across all indications. CONCLUSIONS: AboBoNT-A had the lowest injection visit costs across indications. These results are suggestive of real-world resource utilization patterns and costs, and, while helpful in informing insurers' BoNT-A management strategies, further research into cost differences is warranted.

Spasticity is an abnormal, involuntary muscle tightness due to extended muscle contraction. This resistance in movement can be caused by stroke, multiple sclerosis, or traumatic injuries to the brain or spinal cord. Cervical dystonia is a form of sustained involuntary muscle contractions that result in abnormal or repetitive muscle movements in the neck and upper shoulders. Spasticity and cervical dystonia are both associated with significant decrease in quality of life and work productivity as well as significant economic burden. It is therefore important to understand how disease management impacts these patients. Many studies have shown that botulinum toxins type A (BoNT-As) are safe and effective in reducing muscle tightness and improving normal range of motion. This study was conducted to better understand BoNT-A injection patterns, use of healthcare services, and the resulting costs in patients with spasticity or cervical dystonia.

Lithium Therapy in Old Age: Recommendations from a Delphi Survey.

INTRODUCTION: While lithium (Li) has been well established for the treatment of bipolar disorder, geriatric patients require special attention when it comes to issues of drug safety. Declining renal function, amongst other medical conditions, and polypharmacy may pose increased risks. Only a few previous studies have addressed the management of Li in geriatric patients. METHODS: Twenty-four German medical experts on geriatric medicine and Li treatment participated in a Delphi survey, consisting of two rounds of questionnaires and a final formulation of treatment recommendations. Three major issues of Li therapy were outlined: initiation of treatment, monitoring of ongoing therapy, and withdrawal due to medical reasons. Final recommendations were consented to at a threshold of at least 80% expert agreement. RESULTS: Final consensus was achieved on 21 clinical recommendations. The approved recommendations covered aspects of necessary laboratory checks, concomitant medication, and target Li serum concentration in geriatric patients. Concerning the termination of Li therapy, an agreement was reached on the appropriate time span for tapering and on potential alternatives to Li. No consensus was achieved on whether concomitant dementia or frailty should be considered contraindications for Li treatment and the appropriate threshold of the estimated glomerular function rate for withdrawing Li. CONCLUSION: According to the view of German experts, Li may be used in geriatric patients, but it should be monitored carefully. However, the lack of consent in several specific treatment situations underlines the need for research on specific issues of Li therapy.

Disentangling the relationship of subjective cognitive decline and depressive symptoms in the development of cognitive decline and dementia.

INTRODUCTION: Subjective cognitive decline (SCD) and depressive symptoms (DS) frequently co-occur prior to dementia. However, the temporal sequence of their emergence and their combined prognostic value for cognitive decline and dementia is unclear. METHODS: Temporal relationships of SCD, DS and memory decline were examined by latent difference score modeling in a high-aged, population-based cohort (N = 3217) and validated using Cox-regression of dementia-conversion. In 334 cognitively unimpaired SCD-patients from memory-clinics, we examined the association of DS with cognitive decline and with cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. RESULTS: In the population-based cohort, SCD preceded DS. High DS were associated with increased risk of dementia conversion in individuals with SCD. In SCD-patients from memory-clinics, high DS were associated with greater cognitive decline. CSF Aß42 predicted increasing DS. DISCUSSION: SCD typically precedes DS in the evolution to dementia. SCD-patients from memory-clinics with DS may constitute a high-risk group for cognitive decline. HIGHLIGHTS: Subjective cognitive decline (SCD) precedes depressive symptoms (DS) as memory declines. Emerging or persistent DS after SCD reports predict dementia. In SCD patients, more amyloid pathology relates to increasing DS. SCD patients with DS are at high risk for symptomatic progression.

A Comparison of Operational Definitions for Mild Cognitive Impairment.

BACKGROUND: Consideration of many tests from different cognitive domains in defining mild cognitive impairment (MCI) is clinical routine, but guidelines for a neuropsychological operationalization of MCI are lacking. OBJECTIVE: Among different operational MCI criteria, to identify those which are best in predicting either conversion to dementia, or a biomarker profile indicative for Alzheimer's disease (AD). METHODS: Memory clinic patients without dementia (N = 558; mean age = 66; up to 3 years of follow-up; n = 360 with baseline CSF biomarkers) were included in an observational study using most liberal criteria of cognitive impairment. Four operational definitions of MCI were retrospectively applied: 1) amnestic MCI (CERAD word list delayed recall), 2) CERAD total score, 3) comprehensive criteria and 4) base rate corrected CERAD. We compared their accuracy in predicting incident all-cause dementia or AD dementia within three years, or a concurrent CSF Aß42/tau-ratio indicative of AD. RESULTS: The four definitions overlapped considerably, classified 35-58% of the original sample as impaired and were associated with markedly increased PPVs regarding incident all-cause dementia (39-46% versus 26% of the original sample), AD dementia and AD biomarker positivity. The base rate corrected MCI definition had the highest prognostic accuracy. CONCLUSION: he operational criteria examined seem suitable to specify MCI in memory clinic settings, as they identify subjects at high risk of clinical progression. Depending on the neuropsychological battery in use, one or several of these criteria could help to calibrate the clinical judgment of test results, reduce false-positive decisions, and define risk-enriched groups for clinical trials.

Health care resource utilization in the management of patients with Arginase 1 Deficiency in the US: a retrospective, observational, claims database study.

BACKGROUND: Arginase 1 Deficiency (ARG1-D) is an inherited metabolic disease that leads to significant morbidity. AIMS: Despite the recognized burden of disease, information on health care resource utilization (HCRU) among patients with ARG1-D is lacking. We, therefore, sought to evaluate HCRU in ARG1-D relative to non-ARG1-D cohort. MATERIALS AND METHODS: Patients with ≥2 ICD-10-CM diagnosis codes for ARG1-D were identified (first diagnosis code = index date) using professional fee claims linked with prescription claims. Patients with ARG1-D were matched 1:1 to a comparator cohort of patients with other medical conditions. Matching variables included age, sex, index year, payer type (Medicare, Medicaid, third party) and geographic region. RESULTS: A total of 77 patients met the inclusion criteria for the ARG1-D cohort, with a median age of 15 years, 52% <18 years, and 52% male. Several concurrent diagnoses were recorded at a higher frequency in the ARG1-D cohort versus the matched comparator (spasticity 7 times higher; developmental delay ∼2 times higher; intellectual disability 5 times higher; and seizures 8 times higher). Emergency room visits occurred twice as often, laboratory tests were performed 1.5 times more often, hospitalization was required 3 times more often, and mean length of stay was longer for patients with ARG1-D than the comparator cohort (2.4 days vs. 0.3 days). LIMITATIONS: A relatively short study period while the burden of ARG1-D increases over a lifetime due to disease progression. CONCLUSIONS: Patients with ARG1-D had significantly greater HCRU compared with those without the disease; they presented with a more extensive comorbidity profile, accessed the health care system more frequently, required more intense monitoring and management, and had more frequent and longer hospitalizations relative to the comparator group. These findings demonstrate a high health burden in ARG1-D that is not mitigated by standard-of-care measures and emphasize the need for improved treatment options.

Myeloid cell tropism enables MHC-E-restricted CD8+ T cell priming and vaccine efficacy by the RhCMV/SIV vaccine.

The strain 68-1 rhesus cytomegalovirus (RhCMV)-based vaccine for simian immunodeficiency virus (SIV) can stringently protect rhesus macaques (RMs) from SIV challenge by arresting viral replication early in primary infection. This vaccine elicits unconventional SIV-specific CD8+ T cells that recognize epitopes presented by major histocompatibility complex (MHC)-II and MHC-E instead of MHC-Ia. Although RhCMV/SIV vaccines based on strains that only elicit MHC-II- and/or MHC-Ia-restricted CD8+ T cells do not protect against SIV, it remains unclear whether MHC-E-restricted T cells are directly responsible for protection and whether these responses can be separated from the MHC-II-restricted component. Using host microRNA (miR)-mediated vector tropism restriction, we show that the priming of MHC-II and MHC-E epitope-targeted responses depended on vector infection of different nonoverlapping cell types in RMs. Selective inhibition of RhCMV infection in myeloid cells with miR-142-mediated tropism restriction eliminated MHC-E epitope-targeted CD8+ T cell priming, yielding an exclusively MHC-II epitope-targeted response. Inhibition with the endothelial cell-selective miR-126 eliminated MHC-II epitope-targeted CD8+ T cell priming, yielding an exclusively MHC-E epitope-targeted response. Dual miR-142 + miR-126-mediated tropism restriction reverted CD8+ T cell responses back to conventional MHC-Ia epitope targeting. Although the magnitude and differentiation state of these CD8+ T cell responses were generally similar, only the vectors programmed to elicit MHC-E-restricted CD8+ T cell responses provided protection against SIV challenge, directly demonstrating the essential role of these responses in RhCMV/SIV vaccine efficacy.

Healthcare resource utilization, total costs, and comorbidities among patients with myotonic dystrophy using U.S. insurance claims data from 2012 to 2019.

BACKGROUND: Myotonic dystrophy (DM) is a rare, inherited disorder with multi-systemic effects that impact the skeletal muscles, eyes, heart, skin and gastrointestinal, endocrine, respiratory, and central nervous systems. DM is divided into two subtypes: DM1 can present from early childhood through adulthood and also has a congenital form (cDM) while DM2 typically manifests during mid-adulthood. Both forms are progressive with no approved treatments, and unmet need for disease-modifying therapies remains high. This study interrogated health insurance claims data to explore the clinical experience, healthcare resource utilization (HCRU), and all-cause costs for DM. RESULTS: A total of 8541 patients with DM and 242 patients with cDM and their matched controls were selected from a database of over 200 million claimants. HCRU and all-cause costs, including pharmacy, outpatient, and inpatient services, were analyzed across four years in 12-month follow-up periods. Mean all-cause costs per DM patient were high in each of the four periods (range $14,640-$16,704) and showed a steady increase from 13 to 23 months on, while the control group mean costs declined from $9671 in the first 12 months after the index event, to approach the US population average ($5193) over time. For cDM, the highest mean costs were in the first 12-months ($66,496 vs. $2818 for controls), and remained high (above $17,944) across all subsequent periods, while control mean costs approached $0. For DM and cDM, HCRU was higher compared to controls across all study periods and all-cause healthcare costs were mostly driven by inpatient and outpatient encounters. Analysis of all diagnosis codes over the study period (comorbidities) demonstrated an elevated comorbidity profile consistent with the clinical profile of DM. CONCLUSIONS: This study is among the first to utilize claims data to increase understanding of the clinical experience and health economic outcomes associated with DM. The markedly elevated HCRU patterns and comorbidity profile presented here add to the broad body of scientific and clinical knowledge on DM. These insights can inform clinical care and support the development of disease modifying and/or symptom-targeting therapies that address the multi-systemic, progressive nature of DM.

Don't forget about tau: the effects of ApoE4 genotype on Alzheimer's disease cerebrospinal fluid biomarkers in subjects with mild cognitive impairment-data from the Dementia Competence Network.

ApoE4, the strongest genetic risk factor for Alzheimer's disease (AD), has been shown to be associated with both beta-amyloid (Aß) and tau pathology, with the strongest evidence for effects on Aß, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aß42, total tau (t-tau), phospho-tau181 (p-tau), and with the progression of decline in a large cohort of MCI subjects, both progressors to AD and other dementias, as well as non-progressors. We analyzed associations of CSF Aß42, p-tau and t-tau with ApoE4 allele frequency cross-sectionally and longitudinally over 3 years of follow-up in 195 individuals with a diagnosis of MCI-stable, MCI-AD converters and MCI progressing to other dementias from the German Dementia Competence Network. In the total sample, ApoE4 carriers had lower concentrations of CSF Aß42, and increased concentrations of t-tau and p-tau compared to non-carriers in a gene dose-dependent manner. Comparisons of these associations stratified by MCI-progression groups showed a significant influence of ApoE4 carriership and diagnostic group on all CSF biomarker levels. The effect of ApoE4 was present in MCI-stable individuals but not in the other groups, with ApoE4 + carriers having decreased CSF Aß 42 levels, and increased concentration of t-tau and p-tau. Longitudinally, individuals with abnormal t-tau and Aß42 had a more rapid progression of cognitive and clinical decline, independently of ApoE4 genotype. Overall, our results contribute to an emerging framework in which ApoE4 involves mechanisms associated with both CSF amyloid-ß burden and tau aggregation at specific time points in AD pathogenesis.

Cognitive profiles of patients with mild cognitive impairment due to Alzheimer's versus Parkinson's disease defined using a base rate approach: Implications for neuropsychological assessments.

INTRODUCTION: Large studies on cognitive profiles of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD-MCI) compared to Parkinson's disease (PD-MCI) are rare. METHODS: Data from two multicenter cohort studies in AD and PD were merged using a unified base rate approach for the MCI diagnosis. Cognitive profiles were compared using scores derived from the Consortium to Establish a Registry for Alzheimer's Disease battery. RESULTS: Patients with AD-MCI showed lower standardized scores on all memory test scores and a language test. Patients with PD-MCI showed lower standardized scores in a set-shifting measure as an executive task. A cross-validated logistic regression with test scores as predictors was able to classify 72% of patients correctly to AD-MCI versus PD-MCI. DISCUSSION: The applied test battery successfully discriminated between AD-MCI and PD-MCI. Neuropsychological test batteries in clinical practice should always include a broad spectrum of cognitive domains to capture any cognitive changes.