Nevin Manimala

JAMA Netw Open. 2024 Jun 3;7(6):e2415058. doi: 10.1001/jamanetworkopen.2024.15058.

ABSTRACT

IMPORTANCE: In 2018, the US Congress gave Medicare Advantage (MA) historic flexibility to address members’ social needs with a set of Special Supplemental Benefits for the Chronically Ill (SSBCIs). In response, the Centers for Medicare & Medicaid Services expanded the definition of primarily health-related benefits (PHRBs) to include nonmedical services in 2019. Uptake has been modest; MA plans cited a lack of evidence as a limiting factor.

OBJECTIVE: To evaluate the association between adopting the expanded supplemental benefits designed to address MA enrollees’ nonmedical and social needs and enrollees’ plan ratings.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study compared the plan ratings of MA enrollees in plans that adopted an expanded PHRB, SSBCI, or both using difference-in-differences estimators with MA Consumer Assessment of Health Care Providers and Systems survey data from March to June 2017, 2018, 2019, and 2021 linked to Medicare administrative claims and publicly available benefits and enrollment data. Data analysis was performed between April 2023 and March 2024.

EXPOSURE: Enrollees in MA plans that adopted a PHRB and/or SSBCI in 2021.

MAIN OUTCOMES AND MEASURES: Enrollee plan rating on a 0- to 10-point scale, with 0 indicating the worst health plan possible and 10 indicating the best health plan possible.

RESULTS: The study sample included 388 356 responses representing 467 MA contracts and 2558 plans in 2021. Within the weighted population of responders, the mean (SD) age was 74.6 (8.7) years, 57.2% were female, 8.9% were fully Medicare-Medicaid dual eligible, 74.6% had at least 1 chronic medical condition, 13.7% had not graduated high school, 9.7% were helped by a proxy, 45.1% reported fair or poor physical health, and 15.6% were entitled to Medicare due to disability. Adopting both a new PHRB and SSBCI benefit in 2021 was associated with an increase of 0.22 out of 10 points (95% CI, 0.4-4.0 points) in mean enrollee plan ratings. There was no association between adoption of only a PHRB (adjusted difference, -0.12 points; 95% CI, -0.26 to 0.02 points) or SSBCI (adjusted difference, 0.09 points; 95% CI, -0.03 to 0.21 points) and plan rating.

CONCLUSIONS AND RELEVANCE: Medicare Advantage plans that adopted both benefits saw modest increases in mean enrollee plan ratings. This evidence suggests that more investments in supplemental benefits were associated with improved plan experiences, which could contribute to improved plan quality ratings.

PMID:38837157 | DOI:10.1001/jamanetworkopen.2024.15058

JAMA Netw Open. 2024 Jun 3;7(6):e2415084. doi: 10.1001/jamanetworkopen.2024.15084.

ABSTRACT

IMPORTANCE: Global developmental delay (GDD) is characterized by a complex etiology, diverse phenotypes, and high individual heterogeneity, presenting challenges for early clinical etiologic diagnosis. Cognitive impairment is the core symptom, and despite the pivotal role of genetic factors in GDD development, the understanding of them remains limited.

OBJECTIVES: To assess the utility of genetic detection in patients with GDD and to examine the potential molecular pathogenesis of GDD to identify targets for early intervention.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter, prospective cohort study enrolled patients aged 12 to 60 months with GDD from 6 centers in China from July 4, 2020, to August 31, 2023. Participants underwent trio whole exome sequencing (trio-WES) coupled with copy number variation sequencing (CNV-seq). Bioinformatics analysis was used to unravel pathogenesis and identify therapeutic targets.

MAIN OUTCOMES AND MEASURES: The main outcomes of this study involved enhancing the rate of positive genetic diagnosis for GDD, broadening the scope of genetic testing indications, and investigating the underlying pathogenesis. The classification of children into levels of cognitive impairment was based on the developmental quotient assessed using the Gesell scale.

RESULTS: The study encompassed 434 patients with GDD (262 [60%] male; mean [SD] age, 25.75 [13.24] months) with diverse degrees of cognitive impairment: mild (98 [23%]), moderate (141 [32%]), severe (122 [28%]), and profound (73 [17%]). The combined use of trio-WES and CNV-seq resulted in a 61% positive detection rate. Craniofacial abnormalities (odds ratio [OR], 2.27; 95% CI, 1.45-3.56), moderate or severe cognitive impairment (OR, 1.69; 95% CI, 1.05-2.70), and age between 12 and 24 months (OR, 1.57; 95% CI, 1.05-2.35) were associated with a higher risk of carrying genetic variants. Additionally, bioinformatics analysis suggested that genetic variants may induce alterations in brain development and function, which may give rise to cognitive impairment. Moreover, an association was found between the dopaminergic pathway and cognitive impairment.

CONCLUSIONS AND RELEVANCE: In this cohort study of patients with GDD, combining trio-WES with CNV-seq was a demonstrable, instrumental strategy for advancing the diagnosis of GDD. The close association among genetic variations, brain development, and clinical phenotypes contributed valuable insights into the pathogenesis of GDD. Notably, the dopaminergic pathway emerged as a promising focal point for potential targets in future precision medical interventions for GDD.

PMID:38837156 | DOI:10.1001/jamanetworkopen.2024.15084

JAMA Psychiatry. 2024 Jun 5. doi: 10.1001/jamapsychiatry.2024.1310. Online ahead of print.

ABSTRACT

IMPORTANCE: Several psychotherapy protocols have been evaluated as adjuncts to pharmacotherapy for patients with bipolar disorder (BD). Little is known about their comparative effectiveness.

OBJECTIVE: To compare the effectiveness of 2 types of group psychotherapy, skill-oriented, material-based cognitive behavioral therapy (SEKT) and supportive, patient-centered, emotion-focused therapy (FEST), to prevent relapse in patients with euthymic BD.

DESIGN, SETTING, AND PARTICIPANTS: This was a large, observer-blind, randomized clinical trial conducted over 18 months (posttreatment after 6 months; follow-up at 12 and 18 months). In addition to psychiatric care as usual (including mood-stabilizing medication), each participant at 9 clinical outpatient units in Germany received 24 hours of group psychotherapy over 4, full-day sessions spread over 5 months. Patients with euthymic BD type 1 (BD 1) or BD type 2 (BD 2) between the ages of 18 and 50 years were randomly assigned to 1 of 2 forms of psychotherapy, SEKT or FEST. Independent clinicians blinded to patient grouping performed assessments using structured interviews (Structured Clinical Interview for DSM Disorders and Longitudinal Interval Follow-Up Evaluation) and self-rating and clinician rating for inclusion criteria and outcome. Kaplan-Meier survival curves were calculated for time to relapse. Cox proportional hazards statistics and propensity score matching were calculated for the multivariate analysis. Study data were analyzed from March 2020 to September 2022.

INTERVENTIONS: SEKT intervention is a structured cognitive behavioral therapy integrating elements of interpersonal social rhythm therapy, and of mindfulness-based cognitive therapy. FEST psychotherapy has its roots in emotion-focused, supportive, and nondirective therapy.

MAIN OUTCOMES AND MEASURES: Recurrence of a new affective episode assessed by blinded interviewer with the LIFE interview. In addition, self-rating and clinician rating of depressive and mania symptoms as well as level of social functioning were assessed.

RESULTS: Of 348 screened referrals, 305 patients (median [IQR] age, 34 [18-50] years; 162 male [53%]) with euthymic BD 1 or BD 2 were included in the study. A total of 207 patients (68%) had BD 1, 98 (32%) had BD 2, and 278 (91%) received psychiatric care. Both therapies were equally effective in preventing recurrence of a new episode. Outcome (higher rate of new episodes) was not predicted by kind of treatment (SEKT: 69 [49%] relapse; FEST: 63 [46%] relapse) but was predicted by BD 2, comorbidity, attending all sessions, and the interaction of type of treatment by BD 1 or 2. Patients with BD 2 had the highest rate of relapse (60 [61%] relapse), in particular, when treated by SEKT (39 [70%] relapse).

CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial revealed that a structured, skill-oriented, material-based cognitive behavioral therapy (SEKT) and a supportive, patient-centered, emotion-focused therapy (FEST) were equally effective in preventing relapse of affective episodes when delivered in a new, intensive group format. Additionally, there were baseline factors, in particular BD 2, that influenced outcomes.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02506322.

PMID:38837133 | DOI:10.1001/jamapsychiatry.2024.1310

J Osteopath Med. 2024 Jun 6. doi: 10.1515/jom-2023-0088. Online ahead of print.

ABSTRACT

CONTEXT: Fryette’s mechanics is taught as a simplistic model of coupled vertebral movement, fundamental in osteopathic practice. This study seeks to better understand the likelihood of Fryette’s model by calculating vertebral orientation in computed tomography (CT) scans. Given previous findings of low angular coupled movements during overall spinal motion, static calculations provide a unique perspective on the likelihood of Fryette’s mechanics.

OBJECTIVES: This analysis aims to evaluate the efficacy of Fryette’s principles in predicting vertebral positioning in CT scans by comparing their 3-dimensional (3D) orientation to movements described by Fryette.

METHODS: 3D models of 953 thoracic and lumbar vertebrae were obtained from 82 CT scans within the VerSe`20 open-source dataset. A stepwise algorithm generated three unique symmetry planes for each vertebra, offering 3D angular orientation with respect to the vertebral level below. A total of 422 vertebrae were omitted from the analysis due to the presence of pathologies significant enough to affect their motion, inaccurate symmetry plane calculations, or absence of vertebral level below. The remaining 531 vertebra were analyzed to compare quantitative coupled positioning against expected coupled spinal movements in line with Fryette’s mechanics. One-sample proportional z-scoring was implemented for all vertebral levels with an ∝=0.05 and a null hypothesis of Fryette’s primed positioning occurring by chance of 50 %. Further analysis was performed with individual z-scoring for each individual level to see which levels were statistically significant.

RESULTS: Data from the VerSe`20 dataset revealed that 56.9 % of successfully analyzed vertebrae demonstrated positions compatible with Fryette’s mechanics (p=0.0014, power=89 %). The 302 vertebral levels that did display coupled positioning consisted of Type I (166 vertebrae) and Type II (136 vertebrae) compatible with Fryette’s mechanics. Levels that demonstrated statistical significance consisted of T5 (p=0, power=99 %), T6 (p=0.0023, power=77 %), T7 (p=0.041, power=46 %), and T10 (p=0.017, power=60 %).

CONCLUSIONS: Our analysis suggests that the static positions of vertebrae in CT scans may align with Fryette’s descriptions, although not very often. Notably, vertebral levels T5-T7 and T10 exhibit strong evidence of their static positions aligning with expected movements, warranting further investigation into the Fryette phenomenon at these levels. Future studies should explore the dynamic implications of these findings to enhance our understanding of spinal biomechanics.

PMID:38837124 | DOI:10.1515/jom-2023-0088

Radiol Phys Technol. 2024 Jun 5. doi: 10.1007/s12194-024-00817-7. Online ahead of print.

ABSTRACT

Changing a window width (WW) alters appearance of noise and contrast of CT images. The aim of this study was to investigate the impact of adjusted WW for deep learning reconstruction (DLR) in detecting hepatocellular carcinomas (HCCs) on CT with DLR. This retrospective study included thirty-five patients who underwent abdominal dynamic contrast-enhanced CT. DLR was used to reconstruct arterial, portal, and delayed phase images. The investigation of the optimal WW involved two blinded readers. Then, five other blinded readers independently read the image sets for detection of HCCs and evaluation of image quality with optimal or conventional liver WW. The optimal WW for detection of HCC was 119 (rounded to 120 in the subsequent analyses) Hounsfield unit (HU), which was the average of adjusted WW in the arterial, portal, and delayed phases. The average figures of merit for the readers for the jackknife alternative free-response receiver operating characteristic analysis to detect HCC were 0.809 (reader 1/2/3/4/5, 0.765/0.798/0.892/0.764/0.827) in the optimal WW (120 HU) and 0.765 (reader 1/2/3/4/5, 0.707/0.769/0.838/0.720/0.791) in the conventional WW (150 HU), and statistically significant difference was observed between them (p < 0.001). Image quality in the optimal WW was superior to those in the conventional WW, and significant difference was seen for some readers (p < 0.041). The optimal WW for detection of HCC was narrower than conventional WW on dynamic contrast-enhanced CT with DLR. Compared with the conventional liver WW, optimal liver WW significantly improved detection performance of HCC.

PMID:38837119 | DOI:10.1007/s12194-024-00817-7

Breast Cancer Res Treat. 2024 Jun 5. doi: 10.1007/s10549-024-07386-8. Online ahead of print.

ABSTRACT

PURPOSE: While ¹⁸F-FDG PET/CT (FDG-PET/CT) is consensual for clinical stage ≥ IIB breast cancers (BC), its benefit for stage I or IIA HER2+ or triple-negative breast cancer (TNBC) patients lacks sufficient evidence. We reported a single-institution, retrospective study evaluating FDG-PET/CT impact on patient management and staging for stage I or IIA HER2+ or Triple-Negative BC.

METHODS: Patients who underwent FDG-PET/CT staging before any treatment between January 2015 and December 2020 at Oscar Lambret Center were included.

EXCLUSIONS: patients with symptoms or conventional imaging suggestive of metastatic dissemination, or with prior malignancies. Initial stage was determined from mammography, breast ultrasound, breast MRI, and clinical examination. Staging and therapeutic impact based on FDG-PET/CT findings collected, including intra- (modification of dose/site/strategy in a type of management previously indicated) and inter-modality (modification of planned treatment strategy) changes.

RESULTS: The cohort included 287 female patients with clinical stage I or IIA, HER2+ , or TNBC. Therapeutic impact observed for 18% of patients (n = 52), with 2% (n = 7) undergoing inter-modality change with omission of planned surgery. The impact on patient management was higher for stage IIA patients (20%, 47/237) than for stage I patients (10%, 5/50). Among stage IIA disease, changes in management were more important for T2N0 patients (22%, 44/205) than for T1N1 patients (9%, 3/32). While not statistically significant, trends suggest usefulness of FDG-PET/CT for T2N0 patients.

CONCLUSION: Considering substantial therapeutic implications, our study suggests the usefulness of FDG-PET/CT for patients with stage IIA, HER2-positive, or Triple-Negative BC with tumor size > 2 cm (T2N0).

PMID:38837087 | DOI:10.1007/s10549-024-07386-8

Breast Cancer Res Treat. 2024 Jun 5. doi: 10.1007/s10549-024-07263-4. Online ahead of print.

ABSTRACT

PURPOSE: Beta blockers (BBs) are commonly used cardiovascular medications, and their association with breast cancer outcomes has been examined in several previous observational studies and meta-analyses. In this study, an updated meta-analysis was undertaken to ascertain the association between BBs and both breast cancer death (BCD) and breast cancer recurrence (BCR).

METHODS: Articles were sourced from various databases up until the 14th of August 2023. Effect estimates were pooled using the random effects model, and the Higgins I² statistic was computed to ascertain heterogeneity. Subgroup analyses were conducted by the potential for immortal time bias (ITB), the exposure period (prediagnosis vs postdiagnosis), and type of BB (selective vs non-selective). Publication bias was assessed using funnel plots and Egger’s regression tests.

RESULTS: Twenty-four studies were included. Pooled results showed that there was no statistically significant association between BB use and both BCD (19 studies, hazard ratio = 0.90, 95% CI 0.78-1.04) and BCR (16 studies, HR = 0.87, 95% CI 0.71-1.08). After removing studies with ITB, the associations were attenuated towards the null. There was no effect modification for either outcome when stratifying by the exposure period or type of BB. There was clear evidence of publication bias for both outcomes.

CONCLUSION: In this meta-analysis, we found no evidence of an association between BB use and both BCD and BCR. Removing studies with ITB attenuated the associations towards the null, but there was no effect modification by the exposure period or type of BB.

PMID:38837086 | DOI:10.1007/s10549-024-07263-4

Bull Math Biol. 2024 Jun 5;86(7):82. doi: 10.1007/s11538-024-01307-y.

ABSTRACT

Many neurodegenerative diseases (NDs) are characterized by the slow spatial spread of toxic protein species in the brain. The toxic proteins can induce neuronal stress, triggering the Unfolded Protein Response (UPR), which slows or stops protein translation and can indirectly reduce the toxic load. However, the UPR may also trigger processes leading to apoptotic cell death and the UPR is implicated in the progression of several NDs. In this paper, we develop a novel mathematical model to describe the spatiotemporal dynamics of the UPR mechanism for prion diseases. Our model is centered around a single neuron, with representative proteins P (healthy) and S (toxic) interacting with heterodimer dynamics (S interacts with P to form two S’s). The model takes the form of a coupled system of nonlinear reaction-diffusion equations with a delayed, nonlinear flux for P (delay from the UPR). Through the delay, we find parameter regimes that exhibit oscillations in the P- and S-protein levels. We find that oscillations are more pronounced when the S-clearance rate and S-diffusivity are small in comparison to the P-clearance rate and P-diffusivity, respectively. The oscillations become more pronounced as delays in initiating the UPR increase. We also consider quasi-realistic clinical parameters to understand how possible drug therapies can alter the course of a prion disease. We find that decreasing the production of P, decreasing the recruitment rate, increasing the diffusivity of S, increasing the UPR S-threshold, and increasing the S clearance rate appear to be the most powerful modifications to reduce the mean UPR intensity and potentially moderate the disease progression.

PMID:38837083 | DOI:10.1007/s11538-024-01307-y

Invest New Drugs. 2024 Jun 5. doi: 10.1007/s10637-024-01450-2. Online ahead of print.

ABSTRACT

In the current in-vivo study we demonstrate the potential of the radiolabeled nanoparticle ¹⁷⁷Lu-SN201 as an effective anticancer treatment, as evidenced by significantly prolonged survival and reduced tumor burden in the aggressive, triple negative 4T1 murine breast cancer model. We show with high statistical significance that ¹⁷⁷Lu-SN201 is superior at suppressing the tumor growth not only compared to vehicle but also to the commonly used cancer drugs paclitaxel, niraparib, carboplatin, and the combination of the immune checkpoint inhibitors anti PD-1 and anti-CTLA-4. The dosing of the standard drugs were based on examples in the literature where good effects have been seen in various mouse models. The treatment is reasonably well-tolerated, as indicated by clinical chemistry of liver and renal function through the measurement of glutamate pyruvate alanine aminotransferase, alanine amino transferase, blood urea nitrogen, and creatinine levels in plasma samples, despite some weight loss. Overall, ¹⁷⁷Lu-SN201 presents as a promising therapeutic candidate for cancer treatment.

PMID:38837077 | DOI:10.1007/s10637-024-01450-2

Hernia. 2024 Jun 5. doi: 10.1007/s10029-024-03080-2. Online ahead of print.

ABSTRACT

Cord lipomas are frequent findings in laparoscopic inguinal hernia surgeries in male patients. The symptoms of lipoma and the potential benefits of removing them are often overlooked because the focus is on the primary pathology of the hernia itself. Current recommendations are to reduce this fatty content, when present. When inguinal cord lipomas are left untreated in inguinal hernia surgery they can potentially cause symptoms and be detected in follow-up imaging exams. The objective of this study was to study incidence of cord lipomas in a cohort operated on by a single group specializing in abdominal wall surgery, as well as to analyze the possible relationship of this finding with the patient’s symptoms, the characteristics of the operated hernia and postoperative outcome. This is a prospective study of male patients operated on for inguinal hernia laparoscopically or robotically in a single reference center. Of the total of 141 hernias, the distribution according to European Hernia Society classification showed that 45.4% were lateral, 19.1% medial and 35.5% mixed, highlighting a variety in the presentation of hernias. Analysis of the size of the hernias revealed that the majority (35.5%) were ≤ 1.5 cm. Inguinal cord lipoma was present in 64.5% of the samples, with no statistically significant association between the presence of the lipoma and an indirect hernia sac or obesity. The incidence of surgical site occurrences (SSO) was 9,2%, with seroma and hematoma. No recurrences were observed during follow-up, indicating a successful approach. There were no statistically significant relationships between SSO, the presence of lipoma and indirect hernial sac.

PMID:38837073 | DOI:10.1007/s10029-024-03080-2