Need For Additional Therapy Research Articles

Prognostic implications of CK19 positivity in patients with early recurrent hepatocellular carcinoma after hepatic resection undergoing transarterial chemoembolization

BackgroundThis study aimed to compare the survival outcomes of transarterial chemoembolization (TACE) between patients with early recurrent hepatocellular carcinoma (rHCC) after hepatic resection, stratified by cytokeratin (CK) 19 expression.MethodsA retrospective analysis was conducted on 63 patients with early rHCC after hepatic resection who underwent TACE between January 2017 and December 2021. Patients were divided into two groups based on CK19 expression: CK19-negative (n=31) and CK19-positive (n=32). Overall survival (OS) and progression-free survival (PFS) were compared between the two groups using the Kaplan-Meier method and log-rank test. Cox regression analysis was performed to identify independent risk factors for OS and PFS.ResultsThe CK19-negative group demonstrated a significantly longer median OS compared to the CK19-positive group (635 days vs. 432 days, p=0.013). Similarly, the CK19-negative group had a longer median PFS than the CK19-positive group (291 days vs. 117 days, p=0.014). Multivariate Cox analysis identified Child-Pugh A grade, CK19-negative expression, and increased TACE sessions as protective factors for OS. No severe TACE-related adverse events were observed.ConclusionIn patients with early rHCC after hepatic resection, those with CK19-positive expression had poorer survival outcomes following TACE compared to CK19-negative patients. These findings suggest the need for additional therapies to improve survival in CK19-positive individuals.

Evaluation of treatment-related problems in hemodialysis patients in Egypt: a prospective observational study

BackgroundHemodialysis (HD) patients often have multiple comorbidities, leading to care from various prescribers and a complex medication regimen. Patients on HD are particularly vulnerable to treatment-related problems (TRPs). This study aimed to evaluate the impact of the lack of clinical pharmacy services on HD care by assessing the types and frequencies of TRPs encountered in HD units.Patients and methodsThis was a prospective observational study. Data were collected from medical records and medication reconciliation of HD patients attending to a large Hospital specialized in Nephrology and Urology at the Minia region in Egypt. The frequencies and percentages of demographic data were calculated. Standard multiple regression analysis was conducted to assess predictors of TRPs.ResultsA total of 103 patients were included. The mean age was 47.6 ± 15.1 years; patients had been on HD for 5.95 ± 5.04 years, had 2.47 ± 0.57 comorbidities and took 7.02 ± 1.35 different medications. Within the included patients, 121 TRPs were identified. The most common TRPs were the need for more frequent monitoring, followed by inappropriate dose/dosing frequency and the need for additional therapy (33.9%, 26.2%, and 15.5%, respectively). We did not identify any predictors of TRP in this study.ConclusionIn the Minia HD population of Egypt, TRPs affected 75% of the patients. Therefore, involving clinical pharmacy services to tailor the optimal management plan for each patient is crucial to reduce the frequency of TRPs in this vulnerable patient population.

Longevity and risk factors of CAD-CAM manufactured implant-supported all-ceramic crowns - A prospective, multi-center, practice-based cohort study

ObjectivesThe aim of this prospective, multi-center, practice-based cohort study was to analyze factors associated with the success of implant supported all-ceramic single-unit crowns, made by computer-aided-design/computer-aided-manufacturing (CAD-CAM). MethodsAll-ceramic crowns placed in a private practice-based research network (Ceramic Success Analysis, AG Keramik) were analyzed. Data from 567patients with CAD-CAM implant supported all-ceramic crowns placed between 2008–2023 by 54dentists were evaluated. Firstly, all crowns with at least one follow-up control were included (n = 907). Secondly, all crowns being followed up for ≥ 5years and all failures were included (n = 151). At the latest follow-up visit, crowns were considered as successful (not failed) if they were still in function without the need for additional therapy. Multi-level Cox proportional hazards models were used to evaluate the association between a range of predictors and time of success. ResultsWithin a mean follow-up period (SD) of 2.5 (2)years (first scenario) and 6.2 (1.2)years (second scenario) [maximum:12years], 27crowns failed (annual failure rate [AFR]:0.74 %). The main failure types were decementation, (n = 11), fracture of the ceramic (n = 4) or Ti-Base (n = 4). In 5-year-scenario, crowns fabricated in the laboratory had 26times lower failure rate than those fabricated chairside (95 %CI:0.0–0.7;p = 0.038). Furthermore, the use of a silane (HR:0.051;95 %CI:0.0–0.5;p = 0.014) and etching of the ceramic (HR:0.053;95 %CI:0.0–0.8;p = 0.035) resulted in a significantly higher risk for failure than their non-use. SignificanceFor CAD-CAM manufactured implant supported all-ceramic crowns, high success rates were found in up to 12-year evaluation. Furthermore, after 5years, no patient-or implant-level factors, but operative-level factor (i.e.fabrication method, use of silane/etching) were significantly associated with failure.The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00020271).

The Association between Drug-Related Problems and Length of Stay of Type 2 Diabetes Mellitus Patients.

Drug-related problems (DRPs) are treatment-related occurrences that affect therapeutic efficacy. In a previous study, approximately 279 out of 330 (84.5%) patients with type 2 diabetes mellitus (T2DM) had experienced at least one DRP, including non-optimal drug effects (n = 240, 52.7%) and indications without medication (n = 137, 30.1%). Patients who were hospitalised for 5-10 days had the highest number of DRPs. Therefore, this study investigates the association between DRPs and length of stay (LoS) in patients with T2DM. A cross-sectional study was conducted from January 2020 to May 2023 at Rumah Sakit Akademik, Universitas Gadjah Mada, Yogyakarta, Indonesia. Clinical pharmacists reviewed electronic health data to examine DRPs. The Fisher's exact test evaluated the association between DRPs and LoS. A total of 60.7% (n = 17) of the participants were females, with the majority falling into the age group ≥ 65 years old (n = 11, 29.7%). A significant portion experienced LoS > 7 days (n = 17, 60.7%). Antidiabetic monotherapy was predominant, and the categories of DRPs included adverse drug reaction (n = 15, 40.5%), dosage too high (n = 6, 16.2%), wrong drug (n = 6, 16.2%), non-adherence (n = 4, 10.8%), need for additional therapy (n = 4, 10.8%) and dosage too low (n = 2, 5.4%). A significant association was observed between non-adherence and LoS (P = 0.016). The possibility of experiencing LoS of 1-7 days increased by 3.43 times with improved non-adherence (OR = 3.43; 95% CI: 1.83, 6.39). In this context, non-adherence refers to DRPs associated with the non-compliance of patients with the prescribed treatment plan. This study concludes that non-adherence was significantly associated with hospital LoS.

The Current State of Systemic Therapy of Metastatic Uveal Melanoma.

Uveal melanoma (UM) is genetically a distinct tumor compared to cutaneous melanoma (CM), and due to its low mutational burden, it is far less perceptible to the immune system. Thus, treatments that have revolutionized the treatment of CM remain widely inefficient in metastatic UM or only demonstrate effectiveness in a small subpopulation of patients. To this end, the therapeutic benefit of immune checkpoint blockade is very limited and may come at the expense of severe immune-related adverse events that could potentially affect all organ systems. Notably, tebentafusp, an entirely novel class of anti-cancer drugs, has received official authorization for the treatment of metastatic UM. It is the first agent that demonstrated a survival advantage in a randomized controlled trial of metastatic UM patients. Despite the survival benefit and approval, the restriction of tebentafusp to HLA-A*02:01-positive patients and the low objective response rate indicate the persistent need for additional therapies. Thus, liver-directed therapies are commonly used for tumor control of hepatic metastases and represent a central pillar of the daily management of liver-dominant disease. Further, promising data from targeted therapies independent of MEK-inhibitors, such as the combination of darovasertib and crizotinib, raise hope for additional options in metastatic UM in the future. This narrative review provides a timely and comprehensive overview of the current treatment landscape for metastatic UM.

Fundamentals and recent advances in the evaluation and management of medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is a rare primary neuroendocrine thyroid carcinoma that is distinct from other thyroid or neuroendocrine cancers. Most cases of MTC are sporadic, although MTC exhibits a high degree of heritability as part of the multiple endocrine neoplasia syndromes. REarranged during Transfection (RET) mutations are the primary oncogenic drivers and advances in molecular profiling have revealed that MTC is enriched in druggable alterations. Surgery at an early stage is the only chance for cure, but many patients present with or develop metastases. C-cell-specific calcitonin trajectory and structural doubling times are critical biomarkers to inform prognosis, extent of surgery, likelihood of residual disease, and need for additional therapy. Recent advances in the role of active surveillance, regionally directed therapies for localized disease, and systemic therapy with multi-kinase and RET-specific inhibitors for progressive/metastatic disease have significantly improved outcomes for patients with MTC.

Pathological complete response to predict long term outcomes in the I-SPY2 TRIAL.

597 Background: The I-SPY2 platform trial uses pathologic complete response (pCR) to identify active agents in patients with stage 2/3 breast cancer. Only patients with HR+ HER2- tumors, and low risk 70-gene assay results are excluded. 2118 patients were enrolled from March 2010 through June 2022 with follow-up data from 2005 patients as of January 2024. We have reported the improved event-free (EFS) and distant-recurrence free (DRFS) survival for 950 patients (1) who achieved a pathological complete response (pCR). Here we report the outcomes for the additional 1055 patients not included in our initial report. Methods: Patients have been randomized to one of 25 arms. Residual Cancer Burden (RCB) assessment was performed by site pathologists who were trained to ensure uniform response classification; RCB 0 = pCR. EFS is defined as time to local or distant recurrence or death. DRFS is defined as time to distant recurrence or death. Patients without events were censored at time to last follow-up. Association between pCR and EFS/DRFS was assessed using Cox proportional hazard modeling with significance assessment using the log rank test. EFS and DRFS at 3 years are estimated using the Kaplan Meier method. Results: Median follow up was 3.3 years (0.05-10.2 y). There were 144 EFS and 123 DRFS events. pCR rates varied by subtype, but achieving pCR was associated with an EFS of 96% and DRFS of 96%. For patients without pCR the EFS was 82% and DRFS was 84% at 3 years. The relationship between pCR and EFS was significant and clinically impactful within each subtype. Conclusions: pCR continues to have a strong positive association with EFS and DRFS as in our initial report. It is notable that EFS for non-pCR patients improved to 82% from our initial report of 78%. Initially few patients received additional adjuvant therapy except for standard of care endocrine and HER2-targeted therapy. Increased adoption of post neoadjuvant therapy with the approval of several agents for patients with non-pCR likely contributed to this improvement. I-SPY also reported a shift in residual cancer burden for patients receiving investigational therapies, which also may improve outcome for non-pCR patients. Taken together, these data demonstrate the value of pCR as an early endpoint regardless of tumor type or drugs delivered. These findings emphasize the need for new agents that will allow all patients to achieve pCR and potentially avoid the need for additional therapy after surgery. 1. Yee, et al. JAMA Oncol 2020. 2. Symmans, et al. JAMA Oncol 2021. Clinical trial information: NCT01042379 . [Table: see text]

Pulmonary Surgical Margins for Metastatic Osteosarcoma: Is Negative Margin Enough?

BackgroundIn advanced osteosarcoma, the lung is the most frequent site of distant metastasis, with metastasectomy often used for local disease control. The influence of pulmonary resection margin length on outcomes for osteosarcoma has not been well explored. This study sought to evaluate the impact of margin length relative to tumor size on local recurrence and survival in lung-limited metastatic osteosarcoma. MethodsPatients with metastatic osteosarcoma who underwent lung resection between 2000 and 2020 were identified from a single institution. Clinicopathologic variables were collected. The margin length-to-tumor size ratio (MTR) was calculated per nodule and classified relative to an MTR of 0.5. The primary outcome was development of local recurrence per nodule. Multivariate logistic regression was used to investigate covariates. ResultsA total of 142 patients with 689 nodules met inclusion criteria, with mean age of 35.6 years (interquartile range [IQR], 20.9-46.6 years). Patients were predominantly male (n = 87; 61.3%) and White (n = 106; 72.5%). Most nodules (n = 644; 93.5%) were resected through thoracotomy. The mean tumor size was 0.8 cm (IQR, 0.5-1.70 cm), with an average margin length of 0.3 cm (IQR, 0.1-0.7 cm). Among all nodules, 299 (43.4%) had an MTR >0.5. Systemic therapy was received by 94 patients (66.2%) preoperatively and by 100 patients (70.4%) postoperatively. Importantly, the study found that an MTR >0.5 conferred a protective effect against disease recurrence (hazard ratio, 0.67; 95% CI, 0.52-0.87; P = .003). ConclusionsIn resected pulmonary metastatic osteosarcoma, a margin length greater than one-half the size of the pulmonary nodule is associated with a lower incidence of local disease recurrence. This finding has implications for the subsequent need for additional therapy and disease-free status, thus meriting attentive intraoperative consideration.

Diphenhydramine and Migraine Treatment Failure in Pediatric Patients Receiving Prochlorperazine.

The objectives are to determine whether diphenhydramine coadministered with prochlorperazine versus prochlorperazine only is associated with a difference in the risk of migraine treatment failure, as measured by the need for additional therapy, hospitalization rates, and 72-hour return rates, and to compare extrapyramidal adverse effects between groups. Retrospective cohort of patients aged 7 to 18 years treated in the emergency department for migraines using prochlorperazine with or without diphenhydramine between 2013 and 2019. Patients were included if they had International Classification of Diseases, Ninth or Tenth Revision, codes for migraine or unspecified headache and were treated with prochlorperazine as part of their initial migraine therapy. Data collected included demographics, medications administered, pain scores, neuroimaging, disposition, return visits, and documentation of extrapyramidal adverse effects. Multivariable logistic regression was used to estimate the association between diphenhydramine coadministration and each of the outcomes. A total of 1683 patients were included. Overall, 13% required additional therapy with a 16.7% admission rate and a 72-hour return rate of 5.3%. There was no association between initial treatment with diphenhydramine and the odds of additional therapy (adjusted odds ratio [aOR], 0.74 [95% confidence interval {CI}, 0.53-1.03]), admission rates (aOR, 1.22 [95% CI, 0.89-1.67]), or return visit rates (aOR, 0.91 [95% CI, 0.55-1.51]). Extrapyramidal adverse effects occurred in 2.4% of patients in the prochlorperazine group and 0% in the prochlorperazine with diphenhydramine group. There was no association between diphenhydramine coadministration and the need for additional therapy, 72-hour return visit rates or admission rates. Extrapyramidal effects did not occur in patients treated with diphenhydramine.

Biochemical Response of

BackgroundIn a subset of patients with oligorecurrent prostate cancer (PCa), salvage surgery with prostate-specific membrane antigen (PSMA) radioguided surgery (PSMA-RGS) seems to be of value. ObjectiveTo evaluate whether a lower level of postoperative prostate-specific antigen (PSA; <0.1 ng/ml) is predictive of therapy-free survival (TFS) following salvage PSMA-RGS. Design, setting, and participantsThis cohort study evaluated patients with biochemical recurrence after radical prostatectomy and oligorecurrent PCa on PSMA positron emission tomography treated with PSMA-RGS in three tertiary care centers (2014–2022). InterventionPSMA-RGS. Outcome measurements and statistical analysisPostsalvage surgery PSA response was categorized as <0.1, 0.1–<0.2, or >0.2 ng/ml. Kaplan-Meier and multivariable Cox regression models evaluated TFS according to PSA response. Results and limitationsAmong 553 patients assessed, 522 (94%) had metastatic soft tissue lesions removed during PSMA-RGS. At 2–16 wk after PSMA-RGS, 192, 62, and 190 patients achieved PSA levels of <0.1, 0.1–<0.2, and >0.2 ng/ml, respectively. At 2 yr of follow-up, TFS rate was 81.1% versus 56.1% versus 43.1% (p < 0.001) for patients with PSA <0.1 versus 0.1–<0.2 versus >0.2 ng/ml. In multivariable analyses, PSA levels of 0.1–0.2 ng/ml (hazard ratio [HR]: 1.9, confidence interval [CI]: 1.1–3.1) and ≥0.2 ng/ml (HR: 3.2, CI: 2.2–4.6, p < 0.001) independently predicted the need for additional therapy after PSMA-RGS. The main limitation is the lack of a control group. ConclusionsFor patients after salvage PSMA-RGS, a lower biochemical response (PSA <0.1 ng/ml) seems to predict longer TFS. This insight may help in counseling patients postoperatively as well as guiding the timely selection of additional therapy. Patient summaryWe studied what happened to prostate cancer patients in three European centers who had salvage surgery using a special method called prostate-specific membrane antigen–targeted radioguidance. We found that patients who had low prostate-specific antigen levels soon after surgery were less likely to need further treatment for a longer time.

Juvenile Myasthenia Gravis in North Texas: Clinical Features, Treatment Response, and Outcomes

BackgroundJuvenile myasthenia gravis (JMG) is a rare autoimmune disease that causes fatigable muscle weakness in children aged <18 years. There is currently no curative treatment or internationally accepted standard of care for JMG. The objective is to investigate relationships between clinical presentation, antibody status, severity of disease onset, electrodiagnostic evaluation, and response to therapy in JMG. MethodsThis study was a retrospective chart review. Congenital myasthenic syndromes were excluded. Data on demographics, treatments, and outcomes were collected. Disease severity was evaluated using Myasthenia Gravis Foundation of America (MGFA) clinical classifications. ResultsWe identified 84 patients with JMG at Children's Medical Center Dallas between January 2014 and February 2022. It was found that 52% of patients presented with ocular JMG (median onset age 4.5 years) and 48% with generalized JMG (median onset age 11.5 years); 81% tested positive for acetylcholine receptor antibodies. Patients were 17% non-Hispanic white, 29% Hispanic, 39% black, and 12% Asian. There was a significant difference in average MGFA scores between ethnicities (P = 0.047) and age groups (P = 0.004), with postpubertal patients having higher average MGFA scores than prepubertal patients. Seventy-one percent of patients who underwent thymectomy experienced a decrease in MGFA scores postprocedure. ConclusionsOur study showed that there were significant differences in disease severity between ethnicities and age groups and that most patients who underwent thymectomy showed clinical improvement. These outcomes highlight the need for additional therapies in the treatment of JMG and the importance of extending clinical trials to the pediatric population.

Evaluation of an enhanced depression and anxiety screening with targeted pharmacist intervention

BackgroundDepression is a major source of morbidity but often goes undiagnosed. Broader screening is recommended, and pharmacists could contribute. ObjectivesThis study aimed to assess the feasibility of community pharmacy depression and anxiety screening and describe the medication-related problems (MRPs) identified, pharmacist interventions, and provider responses for high-risk patients. MethodsThis pilot was conducted between October 2022 and January 2023 at an independently owned community pharmacy in the Midwest United States. Patients aged 18-45 years with ready prescriptions were identified through weekly reports, and tags were placed on prescription bags. A convenience sample of patients fluent in English were offered the Patient Health Questionnaire (PHQ2) and Generalized Anxiety Disorder (GAD2), with follow-up PHQ9 and GAD7 for at-risk individuals. High-risk individuals met with the pharmacist for consultation and recommendations were discussed. Descriptive statistics were calculated for participant demographics, questionnaire responses, MRPs, and provider responses. Patient profiles were examined 2 months after the workup to identify medication changes. ResultsA total of 29 patients volunteered to be screened for anxiety and depression; of these, 41% scored in the high-risk category for depression or anxiety and met with the pharmacist for the consultation. The pharmacist identified multiple MRPs. The most common was the need for additional therapy and inadequate dosages. Patients were reluctant for the pharmacist to follow up with their prescriber and were unreachable for telephone follow-up. Profiles reviewed 2 months after assessment showed half of the at-risk patients had one or more mental health medication changes. ConclusionCommunity pharmacists may have a role in the screening and management of patient mental health, although there were challenges with screening uptake and follow-up. The pharmacist identified multiple MRPs for this high-risk group for which greater routine monitoring and follow-up may be beneficial. More work seems needed to engage both patients and prescribers.

TNF Superfamily and ILC2 Activation in Asthma.

Eosinophilic asthma is the most prevalent and well-defined phenotype of asthma. Despite a majority of patients responding to corticosteroid therapy and T2 biologics, there remains a subset that have recurrent asthma exacerbations, highlighting a need for additional therapies to fully ameliorate airway eosinophilia. Group 2 innate lymphoid cells (ILC2) are considered key players in the pathogenesis of eosinophilic asthma through the production of copious amounts of type 2 cytokines, namely IL-5 and IL-13. ILC2 numbers are increased in the airways of asthmatics and with the greatest numbers of activated ILC2 detected in sputa from severe prednisone-dependent asthma with uncontrolled eosinophilia. Although epithelial-derived cytokines are important mediators of ILC2 activation, emerging evidence suggests that additional pathways stimulate ILC2 function. The tumor necrosis factor super family (TNFSF) and its receptors (TNFRSF) promote ILC2 activity. In this review, we discuss evidence supporting a relationship between ILC2 and TNFSF/TNFRSF axis in eosinophilic asthma and the role of this relationship in severe asthma with airway autoimmune responses.

Update on Endoscopic Treatments for Obesity.

Increased morbidity seen with rising obesity rates continues to place an unheralded burden on our health system. Lack of higher bariatric surgery utilization and limitations with lifestyle modification and pharmacotherapy highlights the need for additional therapies for obesity. Endoscopic bariatric and metabolic therapies (EBMT) are effective, safe treatments for obesity. Current FDA-approved EBMT are confined to gastric modalities while small bowel directed therapies are still considered investigational. This review highlights current modalities of EBMT. Many randomized controlled trials have been performed, including both open label and sham-controlled, which have demonstrated safety and efficacy of EBMT over lifestyle therapy alone. In addition, emerging evidence from clinical experience further supports EBMT for treatment of obesity. Current evidence supports the safety and efficacy of EBMT for obesity treatment in conjunction with lifestyle therapy. They can also be used concurrently with weight loss medications to increase total weight loss.

Risk factors for failing sub-Tenon’s triamcinolone acetonide for uveitic macular edema

BackgroundSub-Tenon’s triamcinolone acetonide (STA) is less effective than intravitreal corticosteroids in the treatment of uveitic macular edema (ME), but does have some relative advantages, including substantially lower cost and decreased risk of post-injection ocular hypertension. It would be useful for clinicians to know which eyes may respond well to STA and not necessarily require intravitreal therapy. The objective of this study is to identify risk factors for failing STA for the treatment of uveitic ME.Main bodyA retrospective cohort study was performed. Medical records were reviewed of patients who underwent STA for the treatment of uveitic ME between January 1, 2013, and July 31, 2022, at the University of Colorado Hospital. Uveitic ME was defined by a central subfield thickness (CST) greater than 320 μm or the presence of intra-retinal cystoid spaces on optical coherence tomography (OCT), or by the presence of petaloid macular leakage on fluorescein angiography (FA). Data collected included age, race/ethnicity, sex, history of diabetes mellitus, anatomic classification of uveitis, use of corticosteroids, use of immunomodulatory therapy, presence of intra-retinal fluid on OCT, CST on OCT, and presence of petaloid macular leakage on FA. STA failure was defined as the need for additional therapy within 12 weeks of STA due to persistent or worsening uveitic ME. One hundred eighty eyes from 131 patients were included. Forty-two eyes (23.3%) were considered treatment failures. In univariate and multivariable analysis, higher baseline CST was associated with a higher likelihood of failing STA (OR 1.17 for each 30 μm increase in CST, P = 0.016).ConclusionsSTA, while not as potent as intravitreal corticosteroids for the treatment of uveitic ME, was still an effective therapy, particularly for patients with lower baseline CST. Given its lower side effect profile and cost compared to intravitreal treatments, clinicians could consider STA as an initial treatment for mild uveitic ME.

Intranasal insulin attenuates hypoxia-ischemia-induced short-term sensorimotor behavioral disturbances, neuronal apoptosis, and brain damage in neonatal rats

There is a significant need for additional therapy to improve outcomes for newborns with acute Hypoxic-ischemic (HI) encephalopathy (HIE). New evidence suggests that insulin could be neuroprotective. This study aimed to investigate whether intranasal insulin attenuates HI-induced brain damage and neurobehavioral dysfunction in neonatal rats. Postnatal day 10 (P10), Sprague-Dawley rat pups were randomly divided into Sham + Vehicle, Sham + Insulin, HI + Vehicle, and HI + Insulin groups with equal male-to-female ratios. Pups either had HI by permanent ligation of the right common carotid artery followed by 90 min of hypoxia (8% O2) or sham surgery followed by room air exposure. Immediately after HI or Sham, pups were given fluorescence-tagged insulin (Alex-546-insulin)/vehicle, human insulin (25 μg), or vehicle in each nare under anesthesia. Shortly after administration, widespread Alex-546-insulin-binding cells were detected in the brain, primarily co-localized with neuronal nuclei-positive neurons on double-immunostaining. In the hippocampus, phospho-Akt was activated in a subset of Alex-546-insulin double-labeled cells, suggesting activation of the Akt/PI3K pathway in these neurons. Intranasal insulin (InInsulin) reduced HI-induced sensorimotor behavioral disturbances at P11. InInsulin prevented HI-induced increased Fluoro-Jade C+ degenerated neurons, cleaved caspase 3+ neurons, and volume loss in the ipsilateral brain at P11. There was no sex-specific response to HI or insulin. The findings confirm that intranasal insulin provides neuroprotection against HI brain injury in P10 rats associated with activation of intracellular cell survival signaling. If further pre-clinical research shows long-term benefits, intranasal insulin has the potential to be a promising non-invasive therapy to improve outcomes for newborns with HIE.

Symptomatic Alzheimer’s Disease Therapy Utilization in 3 National Cohorts

AbstractBackgroundAlthough the positive results of the first disease modifying therapies is anticipated to moderately slow disease progression, significant need remains for cognitive enhancers to address AD symptoms and improve quality of life. Despite potential benefits of current treatments, the literature suggests that a large percentage (40‐60%) of AD patients do not use symptomatic treatments for AD and treatment patterns may have considerable geographic variation.MethodPatients with AD (ICD‐10 code G30 or READ code for AD) in 2018‐2019, with ≥1‐year baseline period before index date (first AD diagnosis date during 2018‐2019) and ≥1‐year follow‐up after the index date were selected from the US Humana Research Database (Humana) and the UK Clinical Practice Research Datalink GOLD (CPRD). Patients with an AD diagnosis during the baseline period were excluded. Within the Japan Medical Data Vision (MDV) database, an ICD‐10 code for AD (G30) was required prior to/on the same date as the first provider visit with an associated prescription for a specified AD medication during the 2018‐2020 study period (defined as the index date). Patients with AD medication visits ≤6 months before the index date were excluded. Percentages of patients initiating donepezil, rivastigmine, galantamine, and memantine, median time on first therapy, and use of a second therapy were calculated.ResultAD therapy was initiated by 35,459, 8,901, and 51,115, patients in the US, UK, and Japan, respectively. Sixty‐three percent were female, in the US and UK, and 59% in Japan; mean age ranged from 81‐82 years. Donepezil was used most frequently (69%, 61%, and 50%), followed by memantine monotherapy (19%, 28%, and 22%) in the US, UK, and Japan, respectively. Median time on first therapy was 213, 334, and 111 days, and a second treatment was used by 30%, 12%, and 10%, respectively.ConclusionIn contemporary cohorts of US, UK, and Japanese individuals newly initiating symptomatic AD therapy, donepezil was the most frequently used therapy followed by memantine monotherapy. Time on first therapy was relatively short (&lt;1 year) and the majority of patients did not utilize a second therapy. These results underscore the unmet need for additional therapies to alleviate the significant burden of AD.

Patterns of use of symptomatic treatments for Alzheimer's disease dementia (AD)

BackgroundSymptomatic treatment for Alzheimer's disease (AD) dementia could temporarily slow symptom worsening and improve the quality of life for both AD dementia patients and their caregivers. A comprehensive evaluation of symptomatic treatment patterns using recent data for newly diagnosed AD dementia has not been performed and compared across different countries.MethodsThe drug name, time to the first therapy, duration, discontinuation or switches were described in newly diagnosed AD dementia patients in two databases (a major U.S. health plan [US] and UK-Clinical Practice Research Datalink [CPRD GOLD]). This analysis included patients with newly diagnosed AD dementia in 2018–2019, who initiated symptomatic AD drug therapy, with ≥ 1 year baseline period and ≥ 1 year of follow-up.ResultsOver median follow-ups of 698 and 645 days, 63% and 65% of AD dementia patients used symptomatic treatments, with 34% and 77% newly initiating therapy, constituting analytic samples of 7637 patients in the US database and 4470 patients in the CPRD, respectively. The median time to the first therapy was 14 days for US and 49 days for CPRD; donepezil ranked the as most frequently used (69% vs 61%), followed by memantine (19% vs 28%) in the US database and CPRD, respectively. Median time on first therapy was 213 and 334 days, and 30% and 12% of patients proceeded to a second treatment in the US and CPRD databases, respectively.ConclusionApproximately two thirds of newly diagnosed AD dementia patients utilized approved symptomatic treatment. Time on first therapy was relatively short (< 1 year) and the majority did not move to a second therapy, highlighting the need for better adherence and persistence to existing AD symptomatic therapies and the need for additional therapies to alleviate the significant burden of AD dementia.

The impact of worsening heart failure (WHF) status on subsequent outcomes among patients with HFrEF: History of WHF events is associated with worse subsequent outcomes regardless of extent of GDMT

Abstract Background Patients with worsening heart failure (WHF) have increased risk of future WHF events and death. Guideline directed medical therapy (GDMT) reduces this risk in clinical trials, but few patients in the real-world receive optimal GDMT, leaving its comparative effectiveness unclear. Methods Using Optum’s de-identified Clinformatics® Data Mart Database, we identified patients with heart failure with reduced ejection fraction (HFrEF) who filled HF prescriptions for components of GDMT ("Conventional GDMT:" i.e., ACEi or ARB, and beta-blocker) or first-line therapy from the most recent US guidelines ("2022 GDMT:" i.e., ARNi, MRA, beta-blocker, SGLT2i) between Jan2020 and Mar2022. The ongoing risk of HF hospitalizations (HFH), receipt of IV diuretics, and all-cause death, was assessed by history of (HFH, receipt of IV diuresis in past 12 months) WHF. Event rates reflect counts of first events, whereas cumulative incidence is first and recurrent events. Both are presented per 1,000 person-years. Results Conventional GDMT Cohort: Overall, 26,517 were in the cohort and 51% had WHF. Patients with and without WHF were alike in age (72 vs. 73 years) and a similar proportion were female (43% vs. 40%), and white (67% vs. 67%) (Table). Per 1,000 person-years, the event rates for death, HFH, and IV diuresis were 109, 404, and 106 among patients with WHF and 38, 194, and 29 among patients without WHF, respectively. The cumulative incidence, per 1,000 person-years, for HFH and IV diuretics use among those with WHF were 622 and 241 compared to 258 and 44 among those without WHF (Table). The time to WHF event or death was shorter for patients with WHF (Figure) and HR for all-cause death or WHF was 1.91 for those with WHF compared to those without. 2022 GDMT Cohort: There were 2,775 patients receiving 2022 GDMT and just under half (47%) had WHF. Patients with and without WHF were both an average of 66 years of age, one-third were female, and 60% were white (Table). The event rates (per 1,000 person-years) for death, HFH, and IV diuretic use among those with WHF were 176, 395, and 87 compared to 106, 179, and 40, among those without WHF, respectively (Table). The cumulative incidence (per 1,000 person-years) for HFH and IV diuresis were 577 and 157 among patients with WHF and 268 and 63 among patients without WHF. The time to WHF event or death was also shorter for patients with WHF (Figure). The HR for all-cause death or WHF event comparing patients with and without WHF was 2.28. Conclusion Our study quantified the excess risk of HF morbidity and all-cause death associated with WHF, regardless of extent of GDMT. WHF resulted in higher hospitalizations, morbidity, and deaths and was the strongest predictor of subsequent WHF and all-cause death. This places patients with WHF in a high-risk group. Results can help clinicians better assess the clinical trajectory of their patients and underscore the need for additional therapies and optimized care.Table.Patient CharacteristicsFigure.Clinical Trajectory

Efficacy of Empirical Radioiodine Therapy in Patients with Differentiated Thyroid Cancer and Elevated Serum Thyroglobulin without Evidence of Structural Disease: A Propensity Score Analysis.

We assessed the outcome of administration of empiric radioactive iodine (RAI) therapy to patients with differentiated thyroid cancer (DTC), in a propensity-score-matched cohort of patients with biochemical incomplete response (BIR) and without evidence of structural disease. We retrospectively evaluated 820 DTC patients without distant metastases, who underwent total thyroidectomy followed by RAI therapy, with available BIR at 12 months and follow-up evaluations. The patients were categorized according to the administration of empiric therapy (ET). To account for differences between patients with (n = 119) and without (n = 701) ET, a propensity-score-matched cohort of 119 ET and 119 no-ET patients was created. The need for additional therapy and the occurrence of structural disease were considered as end-points. During a median follow-up of 53 months (range 3-285), 57 events occurred (24% cumulative event rate). The rate of events was significantly higher in the no-ET compared to the ET patients (30% vs. 18% p < 0.001). The multivariate Cox analysis identified age (p < 0.01), pre-therapy Tg (p < 0.05) and empiric RAI therapy (p < 0.01) as predictors of outcome. The Kaplan-Meier analysis found that progression-free survival was lower in no-ET patients compared to the ET group (p < 0.01). In patients with DTC treated with surgery and RAI, and with biochemical incomplete response at the 12-month evaluation, their prognosis seemed to be affected by Tg values and the empiric treatment. The identification of candidates for this approach may improve prognosis.