Nevin Manimala

J Periodontol. 2024 Nov 20. doi: 10.1002/JPER.24-0264. Online ahead of print.

ABSTRACT

BACKGROUND: The present study aimed to investigate changes in intranetwork functional connectivity (FC) and internetwork FC in middle-aged and elderly individuals with normal cognition (NC) and varying degrees of periodontitis to determine the effects of periodontitis on brain function.

METHODS: Periodontal findings and resting-state functional magnetic resonance imaging data were acquired from 51 subjects with NC. Independent component analysis and correlation analysis were used for the statistical analysis of the data.

RESULTS: Differences in intranetwork FC were observed among groups in the anterior default-mode network (aDMN), dorsal attention network and dorsal sensorimotor network (dSMN). Compared with the nonperiodontitis (NP) group or the mild-periodontitis group, the analysis of internetwork FC showed increased FC between the auditory network and the ventral attention network (VAN), between the aDMN and the salience network (SN), and between the SN and the VAN and decreased FC between the posterior default-mode network and the right frontoparietal network in the moderate-to-severe periodontitis group. Additionally, internetwork FC between the dSMN and the VAN was also increased in the moderate-to-severe periodontitis group compared to the NP group. The altered intra- and internetwork FC were significantly correlated with the periodontal clinical index.

CONCLUSION: Our results confirmed that periodontitis was associated with both intra- and internetwork FC changes even in NC. The present study indicates that periodontitis might be a potential risk factor for brain damage and provides a theoretical clue and a new treatment target for the early prevention of Alzheimer disease.

PLAIN LANGUAGE SUMMARY: Recent research has proposed that periodontitis is a potential risk factor for Alzheimer disease (AD). However, the relationship between periodontitis and the brain function of middle-aged and elderly individuals with normal cognition (NC) remains unclear. Analyzing the effect of periodontitis on brain function in the NC stage can provide clues to AD development and help achieve early prevention of dementia. The present study aimed to investigate changes in brain functional connectivity (FC) in NC with different severity of periodontitis to determine the effects of periodontitis on brain function. Both changed intranetwork FC and internetwork FC were found in the moderate-to-severe periodontitis group, and periodontitis was associated with brain network function impairment in NC. The present study indicates that periodontitis might be a potential risk factor for brain damage even in NC stage, and provides a theoretical clue and a new treatment target for the early prevention of AD.

PMID:39565645 | DOI:10.1002/JPER.24-0264

FASEB J. 2024 Nov 30;38(22):e70160. doi: 10.1096/fj.202401704R.

ABSTRACT

Disease-specific oligomers Tau assay system is anticipated in Alzheimer disease (AD) to elucidate their etiological roles. We developed a highly sensitive and selective ELISA for high-molecular-weight oligomer tau (HMWoTau) with LLOQ of 0.3 pg/well for the first time, using a novel mouse monoclonal antibody APNmAb005. The target molecule was identified as HMWoTau with circa 2000 kD as a minimum size and the more oligomerized species (>5000 kD), in combination analysis with Size-Exclusion-Chromatography and Sucrose-Density-Gradient-Centrifugation for both recombinant human (rh) Tau-derived aggregates and AD brain-lysates in PBS(-). HMWoTau was labeled by Thioflavin S and visualized as a homogeneous globular particle (about 30 nm in diameter) by two different technologies of atomic force microscopy and dSTORM-Nanoimager. Specific quantitation was also confirmed by immune-absorption, rhHMWoTau-spiked, and cross-reactivity studies. APNmAb005 failed to detect the HMWoTau signal by treatment with DTT/SDS under no influence on the pan-tau antibody, indicating its conformation-specific recognition. APNmAb005-ELISA showed AD-specific and statistically significant ELISA signals from 1 ng brain lysate protein/well. Analysis of the frontal neocortex (N = 40, Braak stage I-VI) by ELISA revealed the detection-limit levels of HMWoTau species at stage I-III, and drastic and statistically significant increases at stage V/VI (AD). By contrast, total Tau and p181 Tau showed 1/4-1/5 levels of AD even at Stage I, while both tau species also showed a statistically significant increase in AD. In sum, our novel APNmAb005-ELISA clarified the disease-specific increase in HMWoTau species and will be useful for not only further etiological elucidation but also the potential diagnostics in AD and relevant tauopathy.

PMID:39565643 | DOI:10.1096/fj.202401704R

JAMA Netw Open. 2024 Nov 4;7(11):e2446336. doi: 10.1001/jamanetworkopen.2024.46336.

ABSTRACT

IMPORTANCE: The Oral Rheumatoid Arthritis Trial Surveillance demonstrated an increased cancer risk among patients with rheumatoid arthritis (RA) taking tofacitinib compared with those taking tumor necrosis factor inhibitors (TNFis). Although international cohort studies have compared cancer outcomes between TNFis, non-TNFi drugs, and Janus kinase inhibitor (JAKis), their generalizability to US patients with RA is limited.

OBJECTIVE: To assess the comparative safety of TNFis, non-TNFi drugs, and JAKis among US patients with RA (ie, the cancer risk associated with the use of these drugs among these patients).

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used US administrative claims data from Merative Marketscan Research Databases from November 1, 2012, to December 31, 2021. Follow-up occurred up to 2 years after initiation of biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs). Participants included individuals aged 18 to 64 years with RA, identified using at least 2 RA International Classification of Diseases, Ninth Revision or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnostic codes on or before the date of TNFi, non-TNFi, or JAKi initiation (“index date”). Statistical analysis took place from June 2022 to September 2024.

EXPOSURES: New initiations of TNFis, abatacept, interleukin 6 inhibitors (IL-6is), rituximab, or JAKis. Individuals could contribute person-time to more than 1 treatment exposure if treatment escalation mimicked typical clinical practice but were censored if they switched to a previously trialed medication class.

MAIN OUTCOMES AND MEASURES: Incident cancer, excluding nonmelanoma skin cancer, after at least 90 days and within 2 years of initiation of biologic or targeted synthetic DMARDs. Outcomes were associated with the most recent drug exposure.

RESULTS: Of the 25 305 individuals who initiated treatment and who met the inclusion criteria, most were female (19 869 [79%]), had a median age of 50 years (IQR, 42-56 years), and were from the South US (12 516 [49%]). Of a total 27 661 drug exposures, drug initiations consisted of 20 586 TNFi exposures (74%), 2570 JAKi exposures (9%), 2255 abatacept exposures (8%), 1182 rituximab exposures (4%), and 1068 IL-6i exposures (4%). Multivariable Cox proportional hazards regression analysis showed that rituximab was associated with a higher risk of incident cancer compared with TNFis (hazard ratio [HR], 1.91; 95% CI, 1.17-3.14), followed by abatacept (HR, 1.47; 95% CI, 1.03-2.11), and JAKis (HR, 1.36; 95% CI, 0.94-1.96).

CONCLUSIONS AND RELEVANCE: In this cohort study of individuals with RA and new biologic or targeted synthetic DMARD exposures, individuals initiating rituximab, abatacept, and JAKis demonstrated higher incidence rates and statistically significantly increased risks of incident cancers compared with those initiating TNFis in the first 2 years after initiation of biologic or targeted synthetic DMARDs. Given the limitations of administrative claims data and confounding by indication, it is likely that these patients may have a higher disease burden, resulting in channeling bias. To better understand these associations, larger studies with longer follow-up time are needed.

PMID:39565623 | DOI:10.1001/jamanetworkopen.2024.46336

JAMA Netw Open. 2024 Nov 4;7(11):e2446345. doi: 10.1001/jamanetworkopen.2024.46345.

ABSTRACT

IMPORTANCE: The American College of Surgeons (ACS) operative standards were established to detail critical elements of cancer surgery, reduce technical variation, and improve outcomes. Two of the 6 operative standards target adequate axillary surgery for breast cancer. The potential association of the operative standards with short-term oncologic outcomes, such as nodal yield and nodal positivity rates, is currently unknown.

OBJECTIVE: To evaluate the potential association of the ACS operative standards with short-term oncologic outcomes in breast cancer.

DESIGN, SETTING, AND PARTICIPANTS: A cohort study was performed using data on 1 201 317 women 18 years or older who underwent sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) for invasive breast cancer from January 1, 2012, to December 31, 2020. Patients were identified using the National Cancer Database (NCDB), a clinical oncology database encompassing approximately 70% of new cancer diagnoses, sourced from hospital registry data from 1317 facilities. Statistical analysis was performed from October 2023 to June 2024.

EXPOSURE: Sentinel lymph node biopsy or ALND.

MAIN OUTCOMES AND MEASURES: Reliability-adjusted facility-level lymph node yield and nodal positivity rate for each procedure were calculated using generalized linear mixed models, Poisson regression, and logistic regression with facility-level random intercepts.

RESULTS: The cohort included 1 201 317 women with a median age of 62 years (IQR, 53-70 years). Facility-level nodal yield ranged from 1 to 6 for SLNB and from 6 to 22 for ALND. Median facility-level nodal yield for SLNB was 2.6 (IQR, 2.3-3.0) and the nodal positivity rate for SLNB was 12.2% (IQR, 11.0%-13.7%), with rates ranging from 6% to 21%. A weak correlation between facility-level lymph node yield and nodal positivity was observed (Spearman correlation coefficient, 0.17). Median nodal upstaging rate (≥4 positive nodes) for ALND was 30.5% (IQR, 26.5%-35.0%), with rates ranging from 11% to 54%; median nodal yield was 12.2 (IQR, 10.9-13.6). A strong correlation between nodal yield and nodal upstaging rates was observed (Spearman correlation coefficient, 0.53).

CONCLUSIONS AND RELEVANCE: In this cohort study of women undergoing axillary surgery for invasive breast cancer, facility-level variation in lymph node yield was present for both SLNB and ALND, which could potentially be improved through the ACS operative standards. However, this variation had mixed associations with nodal positivity and upstaging rates, suggesting the association of the ACS operative standards with oncologic outcomes may be mixed.

PMID:39565622 | DOI:10.1001/jamanetworkopen.2024.46345

Clin Exp Dermatol. 2024 Nov 20:llae498. doi: 10.1093/ced/llae498. Online ahead of print.

ABSTRACT

BACKGROUND: The lack of dermatological knowledge by non-dermatologists is exposed by the increasing number of requests made for inpatient dermatological consultations. Patients have been commenced on inappropriate treatment because of poor dermatology training.

OBJECTIVES: To determine the burden and accuracy of inpatient dermatology referrals.

METHODS: A retrospective cohort study using paper inpatient dermatology referrals from one Health Board between June 2007 and July 2021. Data analysis included timing of referrals; referring speciality; diagnosis and treatment. Descriptive statistics, using Excel, were used for analyses.

RESULTS: The average number of referrals per year was 106 (79-166). The most frequent day of referral was Monday (26%). Most referrals were from medical teams (73%).Differential diagnosis was suggested by the referring team in 59% of referrals. In only 29% of referrals the dermatology team agreed with the differential diagnosis. There was discrepancy in the correctness of diagnosis in all categories, however the paediatricians were most likely to offer a correct differential (44%). In 44% of referrals treatment was commenced by the referring team, most commonly antibiotics.

CONCLUSIONS: There is an extra burden on dermatology teams to cover inpatients. Our figures highlight two important issues – the need for better dermatological education in medical schools to improve diagnosis accuracy and management of conditions as well as the need to recognise the need for an inpatient dermatology service to review inpatient referrals and advise in diagnosis and management of dermatology cases on the wards, and to protect the service from being uncoupled from the main hospital.

PMID:39565592 | DOI:10.1093/ced/llae498

Methods Mol Biol. 2025;2871:179-191. doi: 10.1007/978-1-0716-4217-7_17.

ABSTRACT

The planarian Schmidtea mediterranea shows nutrient-dependent whole-body plasticity. Starvation leads to body size reduction, while feeding triggers growth. The balance of cell proliferation and cell death controls cell number, driving organismal body size. Here, we uncovered the role of FoxO in controlling cell death through TUNEL and caspase-3 assays and bak qPCR detection in foxO RNAi planarians.

PMID:39565589 | DOI:10.1007/978-1-0716-4217-7_17

Radiol Med. 2024 Nov 20. doi: 10.1007/s11547-024-01931-7. Online ahead of print.

ABSTRACT

OBJECTIVE: The purpose of this study is to demonstrate the consistency and reproducibility of quantitative SPECT/CT by evaluating the maximum SUV (SUV_max) in normal bone, to provide the reference value of metastatic lesions, and to evaluate the clinical implication of SUV_max changes of osseous metastasis during treatment.

MATERIAL AND METHODS: This prospective imaging sub-study was performed as part of a phase 2 clinical trial of patients with metastatic castration-resistant prostate cancer (mCRPC) randomized to the combination of pembrolizumab plus radium-223 or to radium-223 alone (NCT03093428). The maximum standardized uptake value (SUV_max) and mean Hounsfield Unit (HU_mean) of normal bone as well as metastases were measured using a 1.5 cm region of interest (ROI) on CT and xSPECT Quant reconstruction on the baseline study (S₀) and restaging scans. The most tracer-avid metastatic lesion in each patient on S₀ was selected as a target lesion, and changes of SUV_max and HU_mean of the target lesion were compared on the first restaging scan (S₁). Correlations between the percentage changes of SUV_max of the target lesion with alkaline phosphatase (ALP) and prostate-specific antigen (PSA) were assessed.

RESULTS: Twenty-one patients were enrolled on the imaging sub-study of which 15 had paired baseline S₀ and S₁ data. On S₀, the median SUV_max and HU_mean of normal bone was 5.85 g/mL (0.42-14.98) and 133.03 (range, 28.47-461.91), respectively. The median SUV_max and HU_mean of metastasis were 42.2 g/mL (range, 17.96-143.36) and 549.58 (177.87-1107.64), respectively. There was significant reduction in SUV_max (- 40.1%, range – 86.2 to + 23.5%), p < 0.001) and increase in HU_mean (+ 8.3%, range – 11.3 to + 61.7%, p = 0.0479, Wilcoxon signed-rank test) of target lesions between S₀ and S₁. Spearman correlation between the percentage changes of SUV_max of a target lesion and both serum PSA (r = 0.33, p = 0.226) and ALP (r = 0.45, p = 0.094) were not statistically significant.

CONCLUSION: Quantitative SPECT/CT provides consistent and objective imaging parameters, which can help monitor tumor burden. The median SUVmax of metastasis at baseline was roughly 7.2-fold higher than normal bone. Quantitative SPECT/CT may help visualize the early osteoblastic treatment response in prostate cancer patients treated with radium-223 alone or combined with pembrolizumab.

PMID:39565570 | DOI:10.1007/s11547-024-01931-7

Drugs Real World Outcomes. 2024 Nov 20. doi: 10.1007/s40801-024-00452-z. Online ahead of print.

ABSTRACT

BACKGROUND: Hemophilia A (HA) treatment strategies aim to manage bleeding episodes and improve patients’ quality of life. This study investigates the effectiveness of a preventative approach using intermediate-dose prophylaxis with standard half-life FVIII products in reducing bleeding rates and enhancing the quality of life for patients with severe HA.

METHODS: A 4-year prospective longitudinal study followed 35 patients with severe HA (without FVIII inhibitors) who transitioned from a reactive treatment approach to intermediate-dose prophylaxis in Taiwan from 2014 until 2018. The study tracked annual bleeding rates (ABR) and annual joint bleeding rates (AjBR) alongside associated costs and patient-reported quality-of-life measures.

RESULTS: Prophylaxis significantly reduced both ABR and AjBR compared with the previous treatment. After one year, ABR and AjBR decreased by 76.9% and 72.5%, respectively, with further reductions to 91.0% and 90.8% after 4 years (p < 0.001). While the average annual cost of factor VIII concentrate increased by 41.0% in the first year, the incremental cost-effectiveness ratio demonstrated ongoing benefits from ABR avoidance over the 4 years. Additionally, patients reported significant improvements in quality-of-life measures following the switch to prophylaxis (p = 0.036).

CONCLUSION: Intermediate-dose prophylaxis effectively reduced bleeding rates and improved quality of life in patients with severe HA. Despite initial cost increases, the intervention became cost effective over time. This study provides valuable data for healthcare policymakers, highlighting the long-term benefits of prophylaxis as a preventative approach for managing bleeding and improving overall well-being in patients with severe HA.

PMID:39565566 | DOI:10.1007/s40801-024-00452-z

Qual Life Res. 2024 Nov 20. doi: 10.1007/s11136-024-03837-3. Online ahead of print.

ABSTRACT

PURPOSE: To develop the Norwegian value set for the EQ-5D-5L based on interviews with a representative sample of the Norwegian adult population.

METHODS: Random and quota sampling were used to recruit the sample of adults (age> 18 years) representative of the Norwegian general population. Data collection followed EQ-VT 2.1 undertaken before and after the COVID-19 pandemic from November 2019 to December 2022, using PC-assisted and video conferencing interviews, respectively. Each respondent valued 10 health states using composite time trade-off (cTTO) and 7 health states using a discrete choice experiment (DCE). Different statistical models were assessed for logical consistency and predictive accuracy using cTTO and DCE data alone or in combination as hybrid models.

RESULTS: Of the 1,321 respondents, 1,237 met inclusion criteria. All statistical models demonstrated logical consistency. The weighted hybrid model combining both cTTOand DCE data was preferred and had the highest predictive accuracy. Predicted values ranged from -0.453 to 1, and the dimension of anxiety/depression was the most highly valued by respondents, followed by pain/discomfort, self-care, mobility, and usual activities. These findings are not dissimilar to those for most Western European countries, and regression coefficients are closest to those for other Scandinavian countries.

CONCLUSION: This study provides the Norwegian value set for the EQ-5D-5L based on health state values obtained from members of the adult general population in Norway. This is an important contribution to economic evaluation and the broader application ofthe EQ-5D-5L in Norway including clinical and health services research, and quality measurement.

PMID:39565555 | DOI:10.1007/s11136-024-03837-3

Qual Life Res. 2024 Nov 20. doi: 10.1007/s11136-024-03831-9. Online ahead of print.

ABSTRACT

PURPOSE: Adults with arthritis experience poor health-related quality of life (HRQOL), though research often focuses on single HRQOL outcomes or summary scores. We aimed to identify HRQOL profiles in adults with different arthritis types and determine risk and protective factors.

METHODS: Data including PROMIS-29 Profile v2.1 and PROMIS Short Form v2.0 – Emotional Support 4a were collected through a national foundation’s online survey of adults with arthritis in the U.S. We used latent profile analysis (LPA) to characterize the heterogeneity in arthritis patients by clustering them into HRQOL profiles, based on statistical model fit and clinical interpretability. We fit a multinomial logistic regression model with HRQOL profile assignment as the outcome to determine associations with protective and risk factors.

RESULTS: We included 25,305 adults with arthritis. The LPA results favored a five-HRQOL profile solution (entropy = 0.83). While some profiles displayed better HRQOL in some domains, 93% of the sample displayed impacted pain and physical functioning. One profile (20%) displayed mean T-scores nearly 2 standard deviations below the population mean. Despite poor physical HRQOL outcomes, one profile (10%) displayed average mental health. All demographic and clinical factors contributed significantly to the model, including risk factors (arthritis types, work status) and protective factors (more emotional support, starting exercise).

CONCLUSION: We identified profiles with consistently impacted HRQOL in arthritis, though one displayed average mental health functioning despite poor physical functioning. These results highlight the value of considering the patient’s HRQOL experience alongside treatment options, and the potentially positive impact of non-pharmacological interventions.

PMID:39565554 | DOI:10.1007/s11136-024-03831-9