Low Burden Research Articles

Monoclonal Antibody Delivery Using 3D Printed Biobased Hollow μNe3dle Arrays for the Treatment of Osteoporosis.

Transdermal microneedles have demonstrated promising potential as an alternative to typical drug administration routes for the treatment of various diseases. As microneedles offer lower administration burden with enhanced patient adherence and reduced ecological footprint, there is a need for further exploitation of microneedle devices. One of the main objectives of this work was to initially develop an innovative biobased photocurable resin with high biobased carbon content comprising isobornyl acrylate (IBA) and pentaerythritol tetraacrylate blends (50:50 wt/wt). The optimization of the printing and curing process resulted in μNe3dle arrays with durable mechanical properties and piercing capacity. Another objective of the work was to employ the 3D printed hollow μNe3dles for the treatment of osteoporosis in vivo. The 3D printed μNe3dle arrays were used to administer denosumab (Dmab), a monoclonal antibody, to osteoporotic mice, and the serum concentrations of critical bone minerals were monitored for six months to assess recovery. It was found that the Dmab administered by the 3D printed μNe3dles showed fast in vitro rates and induced an enhanced therapeutic effect in restoring bone-related minerals compared to subcutaneous injections. The findings of this study introduce a novel green approach with a low ecological footprint for 3D printing of biobased μNe3dles, which can be tailored to improve clinical outcomes and patient compliance for chronic diseases.

Outcomes of minimal residual disease at upfront debulking surgery compared with complete cytoreduction after neoadjuvant chemotherapy

ObjectiveThe aim of this study was to compare surgical complexity, post-operative complications, and survival outcomes between patients with minimal residual disease (completeness of cytoreduction (CC) score) CC-1 at the time...

Associations between psychosocial burden and prognostic biomarkers in patients with chronic coronary syndrome: a STABILITY substudy.

To investigate associations between psychosocial burden and biomarkers reflecting pathophysiological pathways in patients with chronic coronary syndrome. Psychosocial (PS) factors were collected from self-assessed questionnaires and biomarkers representing inflammation (high-sensitivity [hs]-C-reactive protein [CRP], interleukin-6 [IL-6], lipoprotein-associated phospholipase A2 [Lp-PLA2]) and cardiac injury/stress (hs-troponin T [hs-TnT], N-terminal pro-B type natriuretic peptide [NT-proBNP]) were measured in 12,492 patients with chronic coronary syndrome in the STABILITY trial. Associations between level of each psychosocial factor (never-rarely (reference), sometimes, often-always) and biomarkers were evaluated using linear models with adjusted geometric mean ratios (GMR). A score comprising four factors ('feeling down', 'loss of interest', financial stress', 'living alone') that previously demonstrated association with cardiovascular (CV) outcome was created, and categorized into three levels: low, moderate and high PS burden. Associations between PS score and biomarkers were evaluated similarly. Greater PS burden was significantly associated with a gradual increase in inflammatory biomarkers (GMR [95% CI] for moderate vs low PS burden; and high vs low PS burden): hs-CRP (1.09 [1.04-1.14]; 1.12 [1.06-1.17]), IL-6 (1.05 [1.02-1.07]; 1.08 [1.05-1.11]), LpPLA2 (1.01 [1.00 - 1.02]; 1.02 [1.01-1.04]) and cardiac biomarkers hs-TnT (1.03 [1.01-1.06]; 1.06 [1.03-1.09]) and NT-proBNP (1.09 [1.04-1.13]; 1.21 [1.15-1.27]). In patients with chronic coronary syndrome, greater psychosocial burden was associated with increased levels of inflammatory and cardiac biomarkers. While this observational study does not establish causal nature of these associations, the findings suggest inflammation and cardiac injury/stress as plausible pathways linking psychosocial burden to an elevated CV risk, that needs to be further explored.

Network proteomics of the Lewy body dementia brain reveals presynaptic signatures distinct from Alzheimer’s disease

Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimer’s disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinson’s disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or “modules” of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.

Burden of osteoarthritis in Indonesia: A Global Burden of Disease (GBD) study 2019.

Osteoarthritis (OA) is a complex and common condition, especially affecting the knees due to their weight-bearing role. Traditionally seen as a degenerative disease, OA is now understood to have both mechanical and inflammatory causes. Despite its increasing prevalence, there is limited data on OA in Indonesia, resulting in low awareness among clinicians and the public. The aim of this study was to describe the OA burden in Indonesia, focusing on its prevalence, incidence, and years lived with disability (YLD) from 1990 to 2019, using data from the Global Burden of Disease (GBD) study 2019. A descriptive cross-sectional study was conducted to examine the prevalence, incidence, and YLD of OA in Indonesia from the GBD study 2019. OA prevalence and YLD were compared to other countries according to similar social demographics and geographical proximity. OA YLD was also compared to the top causes of death and disability YLD in Indonesia. The study found that OA cases in Indonesia more than doubled from 1990 to 2019, with increases of 153.12% in males and 143.36% in females. Similar trends were observed for knee OA. The age-standardized prevalence rate in Indonesia increased by 11.03% in males and 8.42% in females, and these were higher compared to China, India, Singapore, and the global average. Younger people had a higher OA prevalence rate growth than older groups. The incidence rate for OA also rose significantly, with males seeing a 10.89% increase to 290 per 100,000 people and females with an 8.57% increase to 384 per 100,000 people. Despite lower overall burden rates compared to some countries, Indonesia experienced significant growth in YLD due to OA (12.16% in males and 9.65% in females) since 1990. Although OA was less burdensome than stroke, diabetes, low back pain, and chronic obstructive pulmonary disease (COPD), its YLD growth rate was higher. In conclusion, OA prevalence and incidence in Indonesia significantly increased from 1990 to 2019, with a notable rise among younger populations. OA had a higher YLD growth compared to several other major diseases in Indonesia, highlighting the need for early detection and preventive measures, particularly for the younger population.

Perceptions of prior authorization burden and solutions.

The prior authorization (PA) process consumes time and money on the part of patients, providers, and payers. While some research shows substantial possible savings in the PA process, identifying what different groups can do is not as well known. Thus, organizations have struggled to capture this opportunity. To understand different perspectives on PA burden and receptivity to possible changes in the PA process, we surveyed 1005 patients, 1010 provider employees, and 115 private payer employees. Patients reported the longest perceived wait times but indicated the highest perceived approval rates and lowest perceived burden. The relatively low burden for patients is because most do not have to engage in PA directly. Provider respondents reported spending time equivalent of more than 100 000 full-time registered nurses per year on prior authorization. Artificial intelligence (AI) represents a possible solution: 65% of private payer respondents reported that their organizations planned to incorporate AI into the process in the next 3 to 5 years. Intended adoption by provider respondents is much smaller (11%). Private payer respondents cited cybersecurity concerns and a lack of technical infrastructure as barriers; provider respondents cited lack of budget and limited trust in the technology.

Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic neoplasm: a HARMONY Alliance study.

Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients.

Estimating the risk of gastrointestinal illness associated with drinking tap water in Norway: a prospective cohort study

BackgroundThe delivery of safe drinking water has high public health relevance, as reflected in the Sustainable Development Goals (SDG6). Several precautionary actions have reduced the burden associated with infectious diseases in high-income countries; however, pollution in source waters, inadequate disinfection, and premise plumbing, along with an increased awareness that intrusion in the drinking water distribution system, represents risk factors for gastrointestinal illness linked to consume of drinking water. Sporadic cases of waterborne infections are expected to be underreported since a sick person is less likely to seek healthcare for a self-limiting gastrointestinal infection. Hence, knowledge on the true burden of waterborne diseases is scarce. The primary aim with the present study was to estimate the risk of gastrointestinal illness associated with drinking tap water in Norway.MethodsWe conducted a 12-month prospective cohort study where participants were recruited by telephone interview after invitation based on randomised selection. A start up e-survey were followed by 12 monthly SMS questionnaires to gather information on participants characteristics and drinking tap water (number of 0.2L glasses per day), incidence, duration and symptoms associated with gastrointestinal illness. Associations between the exposure of drinking tap water and the outcome of risk of acute gastrointestinal illness (AGI) were analysed with linear mixed effects models. Age, sex, education level and size of the drinking water supply were identified as potential confounders and included in the adjusted model.ResultsIn total, 9,946 persons participated in this cohort study, accounting for 11.5% of all invited participants. According to the data per person and month (99,446 monthly submissions), AGI was reported for 5,508 person-months (5.5 per 100 person-months). Severe AGI was reported in 819 person-months (0.8 per 100 person-months). Our study estimates that 2–4% of AGI in Norway is attributable to drinking tap water.ConclusionsThis is the largest cohort study in Norway estimating the burden of self-reported gastrointestinal infections linked to the amount of tap water drunk in Norway. The data indicate that waterborne AGI is not currently a burden in Norway, but the findings need to be used with caution. The importance of continued efforts and investments in the maintenance of drinking water supplies in Norway to address the low burden of sporadic waterborne cases and to prevent future outbreaks needs to be emphasised.

The impact of comorbidity burden on cardiac arrest mortality: A population-based cohort study

AimPatients experiencing cardiac arrest are often burdened with comorbidities that increase mortality. This study examined the impact of comorbidity burden on cardiac arrest mortality by quantifying biological interaction. MethodsNationwide population-based Danish cohort study of adult patients hospitalized for cardiac arrest during 1996–2021 and 5:1 matched comparisons from the general population (matched on age, sex, calendar year, and all Charlson Comorbidity Index comorbidities). Mortality rates and hazard ratios for the association between cardiac arrest and mortality was calculated according to comorbidity burden (none, low, moderate, severe). Biological interaction was examined by calculating interaction contrasts (difference in rate differences). ResultsFor no comorbidity burden, the 30-day mortality rate per 1,000 person-years was 18,110 in the cardiac arrest cohort and 24 in the comparison cohort (hazard ratio = 1,435). For low comorbidity burden, the 30-day mortality rate increased to 20,272 in the cardiac arrest cohort and 41 in the comparison cohort (hazard ratio = 504). The corresponding interaction contrast of 2,145 indicated that 11% of the mortality rate in patients with cardiac arrest and low comorbidity burden was explained by interaction between the two. This percentage increased to 20% for moderate and to 28% for severe comorbidity burden. Within 31–365-day follow-up, the percentage of the mortality rate explained by interaction was 28% for low, 38% for moderate, and 41% for severe comorbidity burden. The interaction effect was present for both out-of-hospital and in-hospital cardiac arrest. ConclusionsComorbidity burden interacted with cardiac arrest to increase mortality beyond that explained by their separate effects.

Prognostic implications, genomic and immune characteristics of lung adenocarcinoma with lepidic growth pattern

AimsConflicting data were provided regarding the prognostic impact and genomic features of lung adenocarcinoma (LUAD) with lepidic growth pattern (LP+A). Delineation of the genomic and immune characteristics of LP+A could...

Gestational PFAS exposure and newborn size: The modifying effect of cord blood fatty acids

Per- and polyfluoroalkyl substances (PFASs) can disrupt lipid metabolism, and changes in cord blood fatty acid composition have been observed in small newborns. Emerging evidence suggests that exposure to PFASs during pregnancy is linked to decreased newborn size, although the evidence is not consistent. The modifying effect of fatty acids on the associations of gestational PFAS exposure with newborn size is still unknown. Here we show that the nutritional status of the fetus, as indicated by the level of fatty acids in the cord blood, mitigates the adverse effects of gestational PFAS exposure on the size of the newborn. Our study confirms the adverse developmental effects of PFASs and identifies emerging short-chain PFASs as the primary drivers of reduced newborn size, despite their lower exposure burden compared to legacy PFASs. Additionally, we find the protective role of cord blood fatty acids, suggesting potential strategies for mitigating the detrimental effects of emerging environmental exposures on human health. Our findings provide new evidence of the potential toxicity of emerging PFASs and call for further toxicity evaluations of these pollutants for regulatory purposes. Future studies should consider the complex interaction between exposure and nutrition within the human body, particularly during the first thousand days of life, to promote lifelong health.

Evaluating the cost-effectiveness of Cy-Tb for LTBI in India: a comprehensive economic modelling analysis.

Latent tuberculosis infection (LTBI) remains a significant challenge, as there is no gold standard diagnostic test. Current methods used for identifying LTBI are the interferon-γ release assay (IGRA), which is based on a blood test, and the tuberculin skin test (TST), which has low sensitivity. Both these tests are inadequate, primarily because they have limitations with the low bacterial burden characteristic of LTBI. This highlights the need for the development and adoption of more specific and accurate diagnostic tests to effectively identify LTBI. Herein we estimate the cost-effectiveness of the Cy-Tb test as compared with the TST for LTBI diagnosis. An economic modelling study was conducted from a health system perspective using decision tree analysis, which is most widely used for cost-effectiveness analysis using transition probabilities. Our goal was to estimate the incremental cost and number of TB cases prevented from LTBI using the Cy-Tb diagnostic test along with TB preventive therapy (TPT). Secondary data such as demographic characteristics, treatment outcome, diagnostic test results and cost data for the TST and Cy-Tb tests were collected from the published literature. The incremental cost-effectiveness ratio was calculated for the Cy-Tb test as compared with the TST. The uncertainty in the model was evaluated using one-way sensitivity analysis and probability sensitivity analysis. The study findings indicate that for diagnosing an additional LTBI case with the Cy-Tb test and to prevent a TB case by providing TPT prophylaxis, an additional cost of 18658 Indian rupees (US${\$}$223.5) is required. The probabilistic sensitivity analysis indicated that using the Cy-Tb test for diagnosing LTBI was cost-effective as compared with TST testing. If the cost of the Cy-Tb test is reduced, it becomes a cost-saving strategy. The Cy-Tb test for diagnosing LTBI is cost-effective at the current price, and price negotiations could further change it into a cost-saving strategy. This finding emphasizes the need for healthcare providers and policymakers to consider implementing the Cy-Tb test to maximize economic benefits. Bulk procurements can also be considered to further reduce costs and increase savings.

Abstract Tu141: Effect of Epicardial Application of Oxygenated Hydrogel on Scar Burden in a Rat Model of Myocardial Infarction

Background: Epicardial application of a bioadhesive at the time of experimental myocardial infarction (MI) has been shown to reduce ventricular scar burden in mice. This study assessed the impact of an oxygenated hydrogel (O 2 -hydrogel) on post-infarct cardiac function and scar burden in rats. Method: Experimental MI was performed in Lewis rats (age 12-15 weeks) by permanent ligation of the anterior interventricular artery. There were 3 cohorts in this study: 1. MI followed by epicardial application of hydrogel, 2. MI followed by epicardial application of O 2 -hydrogel, and 3. MI with no treatment. Left ventricular (LV) function was evaluated by transthoracic echocardiography (TTE) at baseline, immediately post-MI, and 3 weeks post-MI. LV scar burden was evaluated with histopathology performed 3 weeks post-MI. Result: Twenty-four rats were analyzed (hydrogel, n= 8; O 2 -hydrogel, n= 9; untreated, n=7). LV fractional shortening (FS) measured by TTE 3 weeks post-MI was significantly reduced compared with baseline in untreated rats (44.6±12.4 to 22.3±4.9, P=0.043; Figure 1) and hydrogel treated rats (32.4±6.0 to 14.9±5.2, P=0.018). No significant change in FS was observed in the O 2 -hydrogel treatment cohort (39.0±13.9 to 38.1±12.6, P=0.859). LV scar burden in the O 2 -hydrogel cohort was significantly lower than in the hydrogel alone and untreated cohorts (11.9% vs 39.9% and 36.2%, respectively; Figure 2). Conclusion: In this rat model, epicardial application of O 2 -hydrogel at the time of experimental MI is associated with greater preservation of LV function and significantly lower scar burden than application of hydrogel alone or no treatment.

Effectiveness of preventive treatment among different age groups and Mycobacterium tuberculosis infection status: a systematic review and individual-participant data meta-analysis of contact tracing studies.

Tuberculosis is a preventable disease. However, there is debate regarding which individuals would benefit most from tuberculosis preventive treatment and whether these benefits vary in settings with a high burden and low burden of tuberculosis. We aimed to compare the effectiveness of tuberculosis preventive treatment in exposed individuals of differing ages and Mycobacterium tuberculosis infection status while considering tuberculosis burden of the settings. In this systematic review and individual-participant meta-analysis, we investigated the development of incident tuberculosis in people closely exposed to individuals with tuberculosis. We searched for studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase. We restricted our search to cohort studies; case-control studies and outbreak reports were excluded. Two reviewers evaluated titles, abstracts, and full text articles for eligibility. At each stage, two reviewers discussed discrepancies and re-evaluated articles until a consensus was reached. Individual-participant data and a pre-specified list of variables, including characteristics of the exposed contact, the index patient, and environmental characteristics, were requested from authors of all eligible studies; contacts exposed to a drug-resistant tuberculosis index patient were excluded. The primary study outcome was incident tuberculosis. We estimated adjusted hazard ratios (aHRs) for incident tuberculosis with mixed-effects Cox regression models with a study-level random effect. We estimated the number-needed-to-treat (NNT) to prevent one person developing tuberculosis. Propensity score matching procedures were used in all analyses. This study is registered with PROSPERO (CRD42018087022). After screening 25 358 records for eligibility, 439 644 participants from 32 cohort studies were included in the individual-participant data meta-analysis. Participants were followed for 1 396 413 person-years (median of 2·7 years [IQR 1·3-4.4]), during which 2496 people were diagnosed with incident tuberculosis. Overall, effectiveness of preventive treatment was 49% (aHR 0·51 [95% CI 0·44-0·60]). Participants with a positive tuberculin-skin-test (TST) or IFNγ release assay (IGRA) result at baseline benefitted from greater protection, regardless of age (0·09 [0·05-0·17] in children younger than 5 years, 0·20 [0·15-0·28] in individuals aged 5-17 years, and 0·17 [0·13-0·22] in adults aged 18 years and older). The effectiveness of preventive treatment was greater in high-burden (0·31 [0·23-0·40]) versus low-burden (0·58 [0·47-0·72]) settings. The NNT ranged from 9 to 34 depending on age among participants with a positive TST or IGRA in both high-burden and low-burden settings; among all contacts (regardless of TST or IGRA test result), the NNT ranged from 29 to 43 in high-burden settings and 213 to 455 in low-burden settings. Our findings suggest that a risk-targeted strategy prioritising contacts with evidence of M tuberculosis infection might be indicated in low-burden settings, and a broad approach including all contacts should be considered in high-burden settings. Preventive treatment was similarly effective among contacts of all ages. None.

Exploring Caregiving Burden and Family Resilience Among Caregivers of Young and Middle-Aged Stroke Survivors in China

Background: Stroke, characterized by high morbidity, disability, and mortality, has increasingly affected younger populations. In China, the proportion of strokes among individuals aged 40-64 has risen significantly. This study explored the caregiving burden and family resilience among caregivers of young and middle-aged first-stroke survivors, comparing caregivers of those with good versus poor functional outcomes. Methods: A cross-sectional survey was conducted from January to June 2024, involving 119 family caregivers of stroke survivors from two tertiary hospitals in Yancheng City, Jiangsu Province, China. Data were collected using the Modified Rankin Scale (mRS), Zarit Burden Interview (ZBI), and the Family Resilience Assessment Scale (FRAS-C). Independent t-tests and Pearson's correlation analysis were performed to examine differences in care burden and family resilience between caregiver groups. Results: Caregivers had an average ZBI score of 28.32±20.66, with 39.5% reporting no or minimal burden, 29.4% light burden, and 25.2% moderate burden. Caregivers of patients with mRS 0-2 had significantly lower care burdens (23.84 vs. 37.17, p<0.01) and higher family resilience (98.22 vs. 93.00, p<0.05) compared to those with mRS 3-5. Care burden was negatively correlated with family resilience (r=-0.243, p=0.008). Conclusion: Caregivers of young and middle-aged stroke survivors generally experienced mild to moderate care burden, while family resilience was moderate. Caregivers of survivors with better functional outcomes had lower care burdens and higher family resilience. These findings highlight the need for targeted interventions to support caregivers of survivors with poorer functional outcomes to enhance family resilience and reduce care burden.

Symptom Burden and Its Impact on Quality of Life in Patients With Moderate to Severe CKD: The International Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps)

Recent evidence suggests people with nondialysis chronic kidney disease (ND-CKD) experience a substantial burden of symptoms, but informative large-scale studies have been scarce. We assessed the prevalence of symptoms and the association of overall symptom burden with quality of life in patients with moderate to severe CKD. Cross-sectional study. 4,430 patients with ND-CKD stages 3-5 enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, France, and the United States between 2013 and2021. 13 individual patient-reported symptoms from the Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire and an overall symptom burden score (low, intermediate, and high). Physical and mental component summary scores (PCS and MCS) of the KDQOL-SF. Adjusted prevalence ratios and generalized estimating equations. Patients (mean age, 68 years; 40% women; mean baseline estimated glomerular filtration rate [eGFR], 30mL/min/1.73m2) were very much to extremely bothered by numerous symptoms ("soreness in muscles," 23%; "washed out or drained," 21%; "cramps, shortness of breath, dry skin, diminished sex life, or numbness in hands or feet," 14%-17%). The adjusted prevalences of "cramps," "washed out or drained," "lack of appetite," "nausea/upset stomach," and "sex life" were greater with more severe CKD and in women (except for "sex life"). A high overall symptom burden was more common in women, in France, and in patients with severe albuminuria and various comorbidities, but not with lower eGFR. The PCS and MCS scores were 13.4 and 7.7 points lower, respectively, for high versus low overall symptom burden. Generalizability limited to patients under nephrology care, residual confounding, and inaccurate Brazilian translation of some symptoms. The high symptom burden observed in this large cohort of ND-CKD patients across 3 diverse countries and its strong association with poorer health-related quality of life should inform clinical management of and clinical research in CKD. Little is known about symptoms in patients with non-dialysis-dependent chronic kidney disease (ND-CKD). In the Chronic Kidney Disease Outcomes and Practice Patterns Study, which enrolled 4,430 patients with CKD stages 3-5 in Brazil, France, and the United States, patients most often reported soreness in muscles, feeling washed out or drained, cramps, shortness of breath, dry skin, altered sex life, and numbness in hands or feet. Cramps, feeling washed out or drained, lack of appetite, and nausea were more often reported at lower levels of kidney function. The overall symptom burden was higher in women than men, in French than in Brazilian or US patients, and in those with severe albuminuria. The higher the symptom burden, the lower were the physical and mental health quality of life scores. The high symptom burden observed in this large cohort of ND-CKD patients across 3 diverse countries and its strong association with poorer health-related quality of life should inform clinical management of and clinical research in CKD.

A pharmacometric multistate model for predicting long-term treatment outcomes of patients with pulmonary TB.

Studying long-term treatment outcomes of TB is time-consuming and impractical. Early and reliable biomarkers reflecting treatment response and capable of predicting long-term outcomes are urgently needed. To develop a pharmacometric multistate model to evaluate the link between potential predictors and long-term outcomes. Data were obtained from two Phase II clinical trials (TMC207-C208 and TMC207-C209) with bedaquiline on top of a multidrug background regimen. Patients were typically followed throughout a 24 week investigational treatment period plus a 96 week follow-up period. A five-state multistate model (active TB, converted, recurrent TB, dropout, and death) was developed to describe observed transitions. Evaluated predictors included patient characteristics, baseline TB disease severity and on-treatment biomarkers. A fast bacterial clearance in the first 2 weeks and low TB bacterial burden at baseline increased probability to achieve conversion, whereas patients with XDR-TB were less likely to reach conversion. Higher estimated mycobacterial load at the end of 24 week treatment increased the probability of recurrence. At 120 weeks, the model predicted 55% (95% prediction interval, 50%-60%), 6.5% (4.2%-9.0%) and 7.5% (5.2%-10%) of patients in converted, recurrent TB and death states, respectively. Simulations predicted a substantial increase of recurrence after 24 weeks in patients with slow bacterial clearance regardless of baseline bacterial burden. The developed multistate model successfully described TB treatment outcomes. The multistate modelling framework enables prediction of several outcomes simultaneously, and allows mechanistically sound investigation of novel promising predictors. This may help support future biomarker evaluation, clinical trial design and analysis.

Clinical characteristics and complication risks in data-driven clusters among Chinese community diabetes populations.

Novel diabetes phenotypes were proposed by the Europeans through cluster analysis, but Chinese community diabetes populations might exhibit different characteristics. This study aims to explore the clinical characteristics of novel diabetes subgroups under data-driven analysis in Chinese community diabetes populations. We used K-means cluster analysis in 6369 newly diagnosed diabetic patients from eight centers of the REACTION (Risk Evaluation of cAncers in Chinese diabeTic Individuals) study. The cluster analysis was performed based on age, body mass index, glycosylated hemoglobin, homeostatic modeled insulin resistance index, and homeostatic modeled pancreatic β-cell functionality index. The clinical features were evaluated with the analysis of variance (ANOVA) and chi-square test. Logistic regression analysis was done to compare chronic kidney disease and cardiovascular disease risks between subgroups. Overall, 2063 (32.39%), 658 (10.33%), 1769 (27.78%), and 1879 (29.50%) populations were assigned to severe obesity-related and insulin-resistant diabetes (SOIRD), severe insulin-deficient diabetes (SIDD), mild age-associated diabetes mellitus (MARD), and mild insulin-deficient diabetes (MIDD) subgroups, respectively. Individuals in the MIDD subgroup had a low risk burden equivalent to prediabetes, but with reduced insulin secretion. Individuals in the SOIRD subgroup were obese, had insulin resistance, and a high prevalence of fatty liver, tumors, family history of diabetes, and tumors. Individuals in the SIDD subgroup had severe insulin deficiency, the poorest glycemic control, and the highest prevalence of dyslipidemia and diabetic nephropathy. Individuals in MARD subgroup were the oldest, had moderate metabolic dysregulation and the highest risk of cardiovascular disease. The data-driven approach to differentiating the status of new-onset diabetes in the Chinese community was feasible. Patients in different clusters presented different characteristics and risks of complications.

Enhancing the therapeutic potential of P29 protein-targeted monoclonal antibodies in the management of alveolar echinococcosis through CDC-mediated mechanisms.

Alveolar echinococcosis (AE) is a highly lethal helminth infection. Current chemotherapeutic strategies for AE primarily involve the use of benzimidazoles (BZs) such as mebendazole (MDZ) and albendazole (ABZ), which exhibit limited efficacy. In a previous study, the vaccine of recombinant Echinococcus granulosus P29 (rEgP29) showed significant immunoprotection against E. granulosus in both mice and sheep. In the current study, we utilized hybridoma technology to generate five monoclonal antibodies (mAbs) against P29, among which 4G10F4 mAb exhibited the highest antigen-specific binding capacity. This mAb was selected for further investigation of anti-AE therapy, both in vivo and in vitro. In vitro, 4G10F4 inhibited a noteworthy inhibition of E. multilocularis protoscoleces and primary cells viability through complement-dependent cytotoxicity (CDC) mechanism. In vivo, two experiments were conducted. In the first experiment, mice were intraperitoneally injected with Em protoscoleces, and subsequently treated with 4G10F4 mAb (2.5/5/10 mg/kg) at 12 weeks postinfection once per week for 8 times via tail vein injection. Mice that were treated with 4G10F4 mAb only in dosage of 5mg/kg exhibited a significant lower mean parasite burden (0.89±0.97 g) compared to isotype mAb treated control mice (2.21±1.30 g). In the second experiment, mice were infected through hepatic portal vein and treated with 4G10F4 mAb (5mg/kg) at one week after surgery once per week for 8 times. The numbers of hepatic metacestode lesions of the 4G10F4 treatment group were significantly lower in comparison to the isotype control group. Pathological analysis revealed severe disruption of the inner structure of the metacestode in both experiments, particularly affecting the germinal and laminated layers, resulting in the transformation into infertile vesicles after treatment with 4G10F4. In addition, the safety of 4G10F4 for AE treatment was confirmed through assessment of mouse weight and evaluation of liver and kidney function. This study presents antigen-specific monoclonal antibody immunotherapy as a promising therapeutic approach against E. multilocularis induced AE.

Real-World Analysis of Breast Cancer Patients Qualifying for Adjuvant CDK4/6 Inhibitors

BackgroundAdjuvant CDK4/6 inhibitors abemaciclib and ribociclib improved disease-free survival (DFS) added to endocrine therapy in hormone receptor (HR)-positive HER2-negative early breast cancer (EBC), in monarchE (NCT03155997) and NATALEE (NCT03701334) trials respectively. We assessed the proportion and outcome of EBC patients qualifying for adjuvant CDK4/6 inhibitors in the real-world. MethodsConsecutive female patients with HR-positive HER2-negative EBC between 1997 and 2017 from the Australian Capital Territory and South-East New South Wales Breast Cancer Treatment Group registry were analyzed. Patients eligible for abemaciclib had ≥4 axillary nodes involved or 1-3 nodes plus primary >5 cm or grade 3. Ribociclib eligibility was defined as node-positive and node-negative with primary >5 cm or >2 cm grade 3. ResultsOf 3840 patients, 671 (17.5%) were abemaciclib-eligible and 1587 (41.3%) ribociclib-eligible . The 5-year DFS was 77% and 94% in abemaciclib-eligible and noneligible registry patients respectively (HR 2.6, 95% CI 2.26-3.05, P < .001). The 5-year DFS was 86% and 97% in ribociclib-eligible and noneligible registry patients respectively (HR 1.92, 95% CI 1.67-2.19, P < .001). Compared with monarchE trial patients, abemaciclib-eligible registry patients were older (median 55 years in registry vs. 51 years in trial), with lower nodal burden (≥4 nodes in 44% in registry vs. 60% in trial). There were more stage III cancers in NATALEE trial patients (60%) than ribociclib-eligible registry patients (24%). ConclusionsMany women with EBC will qualify for adjuvant CDK4/6 inhibitors (17.5% abemaciclib, 41.3% ribociclib) with resource and workforce implications. In the real-world setting, a greater proportion of adjuvant CDK4/6-eligible patients have lower stage disease, therefore the absolute benefit from treatment may be smaller than estimated by the trials.