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e to development of primary headache syndromes.Network analyses inform complex systems such as human brain connectivity, but this approach is seldom applied to gold-standard histopathology. Here, we use two complimentary computational approaches to model microscopic progression of the main subtypes of tauopathy versus TDP-43 proteinopathy in the human brain. Digital histopathology measures were obtained in up to 13 gray matter (GM) and adjacent white matter (WM) cortical brain regions sampled from 53 tauopathy and 66 TDP-43 proteinopathy autopsy patients. First, we constructed a weighted non-directed graph for each group, where nodes are defined as GM and WM regions sampled and edges in the graph are weighted using the group-level Pearson's correlation coefficient for each pairwise node comparison. Additionally, we performed mediation analyses to test mediation effects of WM pathology between anterior frontotemporal and posterior parietal GM nodes. We find greater correlation (i.e., edges) between GM and WM node pairs in tauopathies compared with TDP-43 pe matter (WM) pathology influences cortical spread of disease in tauopathies that is less evident in TDP-43 proteinopathies. These data support the hypothesis that there are neuropathologic signatures of cellular degeneration within neurocognitive networks for specific protienopathies. These distinctive patterns of cellular pathology can guide future efforts to develop tissue-sensitive imaging and biological markers with diagnostic and prognostic utility for FTLD. Moreover, our novel computational approach can be used in future work to model various neurodegenerative disorders with mixed proteinopathy within the human brain connectome.

Depression is associated with socioeconomic disadvantage. However, whether and how depression exerts a causal effect on employment remains unclear. We used Mendelian randomisation (MR) to investigate whether depression affects employment and related outcomes in the UK Biobank dataset.

We selected 227 242 working-age participants (40-64 in men, 40-59 years for women) of white British ethnicity/ancestry with suitable genetic data in the UK Biobank study. We used 30 independent genetic variants associated with depression as instruments. We conducted observational and two-sample MR analyses. Outcomes were employment status (employed vs not, and employed vs sickness/disability, unemployment, retirement or caring for home/family); weekly hours worked (among employed); Townsend Deprivation Index; highest educational attainment; and household income.

People who had experienced depression had higher odds of non-employment, sickness/disability, unemployment, caring for home/family and early retirement. Depression or household income, but power was low. Effective treatment of depression might have important economic benefits to individuals and society.

To examine if there is a social gradient in early childhood head injuries among UK children.

Cross-sectional study, using data from the UK Millennium Cohort Study (MCS). The second, third and fourth sweeps of the MCS were analysed separately, when children were 3, 5 and 7 years old. Logistic regression models were used to explore the associations between head injuries and family socioeconomic position (social class, household income, maternal education and area deprivation).

The unadjusted analyses showed different associations with socioeconomic indicators at different ages. At age 3 and 5 years, head injuries were associated with higher area deprivation, lower household income and parents not being in work or in the routine social class. At age 5 years head injuries were also associated with lower maternal education. At age 7 years only associations with area deprivation and maternal education were found. In adjusted analyses (mutually adjusted for all four socioeconomic indicators, maternal age, child age and child sex), the following associations were observed at ages 3 and 5 years, higher levels of area deprivation were related to higher odds of head injuries. At age 3 years only, lower levels of maternal education were related to lower odds of head injuries. No social gradients were observed. At age 7 years, there were no significant associations between head injuries and any of the SEP measures.

We observed no social gradients in early childhood head injuries. However, at ages 3 and 5 years, head injuries were more frequently reported for children living in more deprived areas.

We observed no social gradients in early childhood head injuries. However, at ages 3 and 5 years, head injuries were more frequently reported for children living in more deprived areas.

Poly (ADP-ribose) polymerase inhibitors have transformed the management landscape for patients with ovarian cancer, demonstrating remarkable improvements in progression-free survival and overall survival. Unfortunately, most relapses are due to an acquired mechanism of resistance to these agents. We hypothesize that secondary cytoreductive surgery, removing resistant clones, might help to overcome the development of resistance to poly (ADP-ribose) polymerase inhibitors, prolonging their therapeutic effect.

To determine the efficacy of olaparib beyond progression compared with standard platinum-based chemotherapy in patients with recurrent ovarian cancer progressed during or after poly (ADP-ribose) polymerase inhibitor maintenance therapy after secondary cytoreductive surgery.

Olaparib administered beyond progression is more effective in increasing progression-free survival and progression-free survival 2 compared with second-line platinum-based chemotherapy in patients after secondary cytoreductive surg 2024. Results will be presented in 2026.

EudraCT 2021-000245-41 NCT05255471.

EudraCT 2021-000245-41 NCT05255471.To explore the molecular pathogenesis of primary hyperparathyroidism (PHPT), we investigated the proliferation and apoptosis of parathyroid cells in a rabbit model of diet-induced PHPT. A total of 120 adult Chinese rabbits were randomly divided into normal diet (CaP, 10.7) group (control group) or a high-phosphate diet (CaP, 17) group (experimental group). The thyroid and parathyroid complexes were harvested for 1-month interval from month 1 to month 6. The expression of proliferation markers, including proliferating cell nuclear antigen (PCNA) and cyclin-D1, and B cell lymphoma-2 (Bcl-2), were evaluated by immunohistochemistry in thyroid and parathyroid tissues. Apoptosis was quantified by DNA-fragment terminal labeling. Our results demonstrated that parathyroid cells in the experimental group started proliferating from the end of the 2nd month, the expression of PCNA, Bcl-2, and cyclin-D1 were significantly higher in the PHPT group than those of the control group (p less then 0.05). Furthermore, the apoptosis index (AI) was positively correlated with the glandular cell count and expression of PCNA in the 6th month in the PHPT group. Overall, our results suggested that excessive proliferation and apoptosis of parathyroid cells may contribute to the pathogenesis of PHPT through PCNA-related, Bcl-2-related, and cyclin-D1-related pathways.

To assess associations between occupational exposures to pesticides and other chemicals and motor neuron disease (MND).

A population-based case-control study that included 319 MND cases (64% male/36% female) recruited through the New Zealand MND Association complemented with hospital discharge data, and 604 controls identified from the Electoral Roll. For each job held, a questionnaire collected information on 11 exposure categories (dust, fibres, tobacco smoke, fumes, gas, fumigants, oils/solvents, acids/alkalis, pesticides, other chemicals and animals/animal products). ORs were estimated using logistic regression adjusting for age, sex, ethnicity, socioeconomic status, education, smoking, alcohol consumption, physical activities, head/spine injury and other occupational exposures.

Two exposure categories were associated with increased MND risks pesticides (OR 1.70, 95% CI 1.17 to 2.48) and fumigants (OR 3.98, 95% CI 1.81 to 8.76), with risks increasing with longer exposure duration (p<0.01). Associations were also observed for methyl bromide (OR 5.28, 95% CI 1.63 to 17.15), organochlorine insecticides (OR 3.28, 95% CI 1.18 to 9.07), organophosphate insecticides (OR 3.11, 95% CI 1.40 to 6.94), pyrethroid insecticides (OR 6.38, 95% CI 1.13 to 35.96), inorganic (copper) fungicides (OR 4.66, 95% CI 1.53 to 14.19), petrol/diesel fuel (OR 2.24, 95% CI 1.27 to 3.93) and unspecified solvents (OR 1.91, 95% CI 1.22 to 2.99). In women, exposure to textile fibres (OR 2.49, 95% CI 1.13 to 5.50), disinfectants (OR 9.66, 95% CI 1.29 to 72.44) and cleaning products (OR 3.53, 95% CI 1.64 to 7.59) were also associated with MND; this was not observed in men (OR 0.80, 95% CI 0.44 to 1.48; OR 0.72, 95% CI 0.29 to 1.84; OR 0.57, 95% CI 0.21 to 1.56, respectively).

This study adds to the evidence that pesticides, especially insecticides, fungicides, and fumigants, are risk factors for MND.

This study adds to the evidence that pesticides, especially insecticides, fungicides, and fumigants, are risk factors for MND.

The aim was to examine exposure-response relations between surgery for subacromial impingement syndrome (SIS) and intensities of lifting/carrying and pushing/pulling loads during a 10-year time window.

We conducted a register-based cohort study (2003-2008), comprising persons born in Denmark (1933-1977) with ≥5 years of work experience (N=2 374 403). Information on surgery for SIS was retrieved from the Danish National Patient Register (N=14 188). Occupational mechanical exposures comprising lifting/carrying loads ≥10 kg and pushing/pulling loads ≥50 kg were assessed by combining individual register-based job codes with our expert-based Shoulder job exposure matrix. We created three intensity-specific exposure duration variables by dividing the intensity for lifting/carrying and pushing/pulling loads into three categories (low, medium and high), and summed up number of years in each exposure category for a 10-year time window. Triparanol The associations were analysed using logistic regression technique equivalent to discrete survival analysis.

The adjusted OR (OR

) increased with both exposure duration and intensity of lifting/carrying and pushing/pulling. For lifting/carrying, the OR

reached a maximum of 1.78 (95% CI 1.66 to 1.89), 2.52 (95% CI 2.32 to 2.74) and 2.96 (95% CI 2.53 to 3.47) after 10 years of exposures for the three exposure intensities. For pushing/pulling, maximum OR

was 1.44 (95% CI 1.31 to 1.58), 1.68 (95% CI 1.58 to 1.79) and 1.72 (95% CI 1.50 to 2.00), respectively.

We found exposure-response relations for lifting/carrying and pushing/pulling across the 10-year time window. The risk was especially pronounced for lifting/carrying compared with pushing/pulling. We did not find indications of safe exposure intensities.

We found exposure-response relations for lifting/carrying and pushing/pulling across the 10-year time window. The risk was especially pronounced for lifting/carrying compared with pushing/pulling. We did not find indications of safe exposure intensities.