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Alzheimers disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimers disease. Here, we investigate whether genetic risk for Alzheimers disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimers Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Conversely, for the transition from A+T- to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05-2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27-2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05-6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87-3.49; P = 0.12). The genetic risk for late-onset Alzheimers disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimers disease, in addition to opening therapeutic windows for targeted interventions.

The uptake of human papilloma virus (HPV) and other adolescent vaccinations in special schools for young people with disability is significantly lower than in mainstream settings. This study explored the factors believed to influence parental decision making regarding vaccine uptake for students with intellectual disability and/or on the autism spectrum attending special schools in New South Wales, Australia, from the perspective of all stakeholders involved in the program. Focus groups and interviews were conducted with 40 participants, including parents, school staff, and immunisation providers. The thematic analysis identified two themes: (1) appreciating diverse parental attitudes towards vaccination and (2) educating parents and managing vaccination questions and concerns. While most parents were described as pro-vaccination, others were anti-vaccination or vaccination-hesitant, articulating a marked protectiveness regarding their child's health. Reasons for vaccine hesitancy included beliefs that vaccines cause autism, concerns that the vaccination may be traumatic for the child, vaccination fatigue following COVID-19, and assumptions that children with disability will not be sexually active. Special school staff regarded the vaccination information pack as inadequate for families, and nurses described limited educational impact resulting from minimal direct communication with parents. More effective communication strategies are needed to address vaccine hesitancy among parents with children with disability. [ABSTRACT FROM AUTHOR]

Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer's disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease. Lewy body diseases exhibit notable clinical and pathological heterogeneity. Here, the authors found three distinct trajectories of Lewy body pathology that are associated with different clinicopathological characteristics. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. Study Design In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into z scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning analysis. Study Results SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, (2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages than treatment-responsive cases (P  = .001). The GP-CX type presented earlier stages than the pure CX type (P  = .009). Conclusions The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker. [ABSTRACT FROM AUTHOR]

Background Antimicrobial resistance (AMR) in uropathogens has been increasing in Australia. Many nations observed heightened AMR during the coronavirus disease 2019 (COVID-19) pandemic, but it is not known how this may vary across clinical settings and in nations with lower infection rates. Methods We investigated the uropathogen composition and corresponding antibiotic resistance of 775 559 Australian isolates from the community, hospitals, and aged care facilities before (2016–2019) and during (2020–2022) the COVID-19 pandemic. A mathematical model was developed to predict the likelihood of resistance to currently recommended antibiotics for treating urinary tract infections (UTIs). Results Among uropathogens originating from the community, hospitals, and aged care facilities, Escherichia coli accounted for 71.4%, 57.6%, and 65.2%, respectively. During the COVID-19 pandemic period, there was an increase in UTIs caused by E coli across all settings. Uropathogens from aged care and hospitals frequently showed higher resistance to antibiotics compared to those isolated from the community. Interestingly, AMR among uropathogens showed a declining trend during the COVID-19 pandemic. Based on the resistance patterns of the past 3 years, our modeling predicted that 30%, 42.6%, and 38.8% of UTIs in the community, hospitals, and aged care facilities, respectively, would exhibit resistance to trimethoprim treatment as empirical therapy. In contrast, resistance to nitrofurantoin was predicted to be 14.6%, 26%, and 24.1% from these 3 respective settings. Conclusions Empirical therapy of UTIs in Australia with trimethoprim requires evaluation due to high rates of resistance observed across clinical settings. [ABSTRACT FROM AUTHOR]

Objectives: Paternalistic care behavior in health contexts reduces involvement in the decision-making process and dissatisfaction in healthcare, which may negatively influence older adults' mental health. This study comprised two main objectives: (1) to explore older adults' experiences of paternalistic behavior in the context of health services and (2) analyze the influence of paternalistic behavior on older adults' mental health. Methods: The sample involved 416 participants aged 65 to 81 (M = 70.1 ± 5.73) with three different nationalities (English, Brazilian ad Portuguese). All interviews went through content analysis. Results: For the first objective, content analysis identified seven themes: (1) perceived inattention to the uniqueness of each person (81%); (2) feeling a duality of supporting and suppressing independence (79%); (3) selective disclosure of information to keep the person's spirit up (74%); (4) feeling neglected (66%); (5) feeling unable to make decisions (64%); (6) receiving opposition to the person's requests (60%); and (7) routine actions being considered as the best action (57%). For the second objective, three main themes emerged: (1) feeling anxious and stressed (88%); (2) feeling frustration and despair (87%); and (3) feeling injustice and anger (72%). Conclusions: Healthcare paternalism negatively affects older adults' mental health, emphasizing the need for their agency, involvement in decisions, and personalized care. These findings highlight the negative influence of paternalistic behavior on the mental health of older adults and may contribute to future targeted interventions and policy programs among the older population. [ABSTRACT FROM AUTHOR]

The nonconsensual--yet legally enshrined and politically encouraged--child relinquishments seen within certain dystopian narratives (namely, Margaret Atwood's The Handmaid's Tale, and Lois Lowry's young adult novel The Giver) show us the nature and scope of the war crime of forced adoption. These texts contain representations of compulsory abandonments and harmful displacements which render the concept of legal or de facto adoption superfluous: prior to their conception, these chattel-infants are destined for familial and sociocultural transplantations, to be raised by privileged substitute carers. Both can be read as sharp critiques of such practices, presenting the reader with a new language with which to discuss the harms and injustices arising from the war crime of forced adoption, especially those seen recently within occupied Ukraine. [ABSTRACT FROM AUTHOR]