Enhancing the implementation of provider-to-provider telehealth in rural and remote areas: A mixed methods study protocol.

Background: Virtual healthcare solutions are proposed as a way to combat the inequity of access to healthcare in rural and remote areas, and to better support the front-line providers who work in these areas. Rural provider-to-provider telehealth (RPPT) connects rural and remote clinicians to a 'hub' of healthcare specialists who can increase access to emergency and specialised healthcare via an integrated model. Reported benefits for the place-based provider include enhanced knowledge, expanded professional development opportunities, improved scope of practice, and increased confidence in treating more complex cases. These reported benefits could have implications for supporting and futureproofing our health workforce in terms of productivity, burnout, recruitment, and retention. Methods: The research uses an explanatory sequential mixed methods approach across multiple phases to evaluate the current implementation of Western Australia Country Health Service's (WACHS) Command Centre (CC) services and explore factors associated with their differential use. The primary population of interest and participants in this study are the place-based providers in country Western Australia (WA). Patient data constitutes the secondary population, informing the access and reach of CC services into country WA. Data collection will include service data, an online survey, and semi-structured interviews with the primary population. The data will be interpreted to inform evidence-based strategies and recommendations to improve the implementation and sustainment of RPPT. Discussion: Innovative and sustained workforce models and solutions are needed globally. Virtual healthcare, including provider-to-provider models, demonstrate potential, especially in rural and remote areas, designed to increase access to specialised expertise for patients and to support the local workforce. This research will generate new data around behaviour, perceptions, and value from the WACHS rural and remote workforce about provider-to-provider telehealth, to explore the implementation and investigate strategies for the long-term sustainment of RPPT services.

Firefighters' exposure to per-and polyfluoroalkyl substances (PFAS) as an occupational hazard: A review.

The term "firefighter" and "cancer" have become so intertwined in the past decade that they are now nearly inseparable. Occupational exposure of firefighters to carcinogenic chemicals may increase their risk of developing different types of cancer. PFAS are one of the major classes of carcinogenic chemicals that firefighters are exposed to as occupational hazard. Elevated levels of PFAS have been observed in firefighters' blood serum in recent studies. Possible sources of occupational exposure to PFAS include turnout gear, aqueous film-forming foam, and air and dust at both the fire scene and fire station. Preliminary discussion on PFAS includes definition, classification, and chemical structure. The review is then followed by identifying the sources of PFAS that firefighters may encounter as an occupational hazard. The structural properties of the PFAS used in identified sources, their degradation, and exposure pathways are reviewed. The elevated level of PFAS in the blood serum and how this might associate with an increased risk of cancer is discussed. Our review shows a significant amount of PFAS on turnout gear and their migration to untreated layers, and how turnout gear itself might be a potential source of PFAS exposure. PFAS from aqueous film-forming foams (AFFF), air, and dust of fire stations have been already established as potential exposure sources. Studies on firefighters' cancer suggest that firefighters have a higher cancer risk compared to the general population. This review suggests that increased exposure to PFAS as an occupational hazard could be a potential cancer risk for firefighters.

Patient reported preferences for sleep interventions among women receiving buprenorphine for opioid use disorder.

Aim: Among individuals receiving medication for OUD (MOUD), insomnia is highly prevalent and increases the risk for negative OUD outcomes. However, little is known about MOUD patient-reported preferences for insomnia treatments among women with OUD. This mixed-methods study explored acceptability of and patient preferences for sleep interventions among women in OUD treatment. Methods: This is an analysis from an ongoing cross-sectional survey and interview study investigating the relationship between sleep and OUD recovery. The parent study is actively enrolling non-pregnant women between 18-45 years stabilized on buprenorphine from an outpatient program. Participants complete measures including the Insomnia Severity Index (ISI), with scores of ≥10 identifying clinically significant insomnia symptoms. A sub-sample who met this threshold completed semi-structured interviews. Descriptive statistics were generated for survey responses, and applied thematic analysis was used for interview data. Results: Participants selected for the qualitative interview (n = 11) highlighted prior positive and negative experiences with sleep treatments, challenges with employing non-pharmacological sleep strategies, and preferences for both medical and behavioral sleep interventions while in recovery. Women emphasized the need for flexibility of sleep therapy sessions to align with ongoing social determinants (e.g., caregiving responsibilities) as well as for sleep medications without sedating effects nor risk of dependency. Conclusions: Many women receiving MOUD have concomitant insomnia symptoms, and desire availability of both pharmacologic and behavioral sleep interventions within the OUD treatment setting. Qualitative findings underscore the need for evidence-based sleep interventions that account for the unique socioenvironmental factors that may impact strategy implementation in this population.

A cycle-consistent adversarial network for brain PET partial volume correction without prior anatomical information.

PURPOSE: Partial volume effect (PVE) is a consequence of the limited spatial resolution of PET scanners. PVE can cause the intensity values of a particular voxel to be underestimated or overestimated due to the effect of surrounding tracer uptake. We propose a novel partial volume correction (PVC) technique to overcome the adverse effects of PVE on PET images. METHODS: Two hundred and twelve clinical brain PET scans, including 50 18F-Fluorodeoxyglucose (18F-FDG), 50 18F-Flortaucipir, 36 18F-Flutemetamol, and 76 18F-FluoroDOPA, and their corresponding T1-weighted MR images were enrolled in this study. The Iterative Yang technique was used for PVC as a reference or surrogate of the ground truth for evaluation. A cycle-consistent adversarial network (CycleGAN) was trained to directly map non-PVC PET images to PVC PET images. Quantitative analysis using various metrics, including structural similarity index (SSIM), root mean squared error (RMSE), and peak signal-to-noise ratio (PSNR), was performed. Furthermore, voxel-wise and region-wise-based correlations of activity concentration between the predicted and reference images were evaluated through joint histogram and Bland and Altman analysis. In addition, radiomic analysis was performed by calculating 20 radiomic features within 83 brain regions. Finally, a voxel-wise two-sample t-test was used to compare the predicted PVC PET images with reference PVC images for each radiotracer. RESULTS: The Bland and Altman analysis showed the largest and smallest variance for 18F-FDG (95% CI: - 0.29, + 0.33 SUV, mean = 0.02 SUV) and 18F-Flutemetamol (95% CI: - 0.26, + 0.24 SUV, mean = - 0.01 SUV), respectively. The PSNR was lowest (29.64 ± 1.13 dB) for 18F-FDG and highest (36.01 ± 3.26 dB) for 18F-Flutemetamol. The smallest and largest SSIM were achieved for 18F-FDG (0.93 ± 0.01) and 18F-Flutemetamol (0.97 ± 0.01), respectively. The average relative error for the kurtosis radiomic feature was 3.32%, 9.39%, 4.17%, and 4.55%, while it was 4.74%, 8.80%, 7.27%, and 6.81% for NGLDM_contrast feature for 18F-Flutemetamol, 18F-FluoroDOPA, 18F-FDG, and 18F-Flortaucipir, respectively. CONCLUSION: An end-to-end CycleGAN PVC method was developed and evaluated. Our model generates PVC images from the original non-PVC PET images without requiring additional anatomical information, such as MRI or CT. Our model eliminates the need for accurate registration or segmentation or PET scanner system response characterization. In addition, no assumptions regarding anatomical structure size, homogeneity, boundary, or background level are required.

Toward the future of firefighter gear: Assessing fluorinated and non-fluorinated outer shells following simulated on-the-job exposures.

In 2022, the occupation of firefighting was categorized as a "Group 1" carcinogen, meaning it is known to be carcinogenic to humans. The personal protective equipment that structural firefighters wear is designed to safeguard them from thermal, physical, and chemical hazards while maintaining thermo-physiological comfort. Typically, the outer layer of structural turnout gear is finished with a durable water and oil-repellent (DWR) based on per- and polyfluoroalkyl substances (PFAS) that helps limit exposure to water and hazardous liquids. The PFAS-based aqueous emulsion typically used in DWR finishes is highly persistent and can cause various health problems if absorbed into the body through ingestion, inhalation, and/or dermal absorption. In response, the U.S. Fire Service has begun using non-PFAS water repellants in firefighter turnout gear. This study aims to evaluate the performance of both traditional PFAS-based and alternative non-PFAS outer shell materials. The study involved exposing both PFAS-based and non-PFAS DWR outer shell materials in turnout composites to simulated job exposures (i.e., weathering, thermal exposure, and laundering) that artificially aged the materials. After exposures, samples were evaluated for repellency, durability, thermal protection, and surface chemistry analysis to determine any potential performance trade-offs that may exist. Non-PFAS outer shell fabrics were found not to be diesel/oil-repellent, posing a potential flammability hazard if exposed to diesel and subsequent flame on an emergency response. Both PFAS-based and non-PFAS sets of fabrics performed similarly in terms of thermal protective performance, tearing strength, and water repellency. The surface analysis suggests that both PFAS and non-PFAS chemistries can degrade and shed from fabrics during the aging process. The study indicates that firefighters should be educated and trained regarding the potential performance trade-offs, such as oil absorption and flammability concerns when transitioning to non-PFAS outer shell materials.

Identifying the top research priorities in medically not yet explained symptoms (MNYES): a James Lind Alliance priority setting partnership.

OBJECTIVES: This study establishes research priorities for medically not yet explained symptoms (MNYES), also known as persistent physical symptoms or medically unexplained symptoms, from the perspective of patients, caregivers and clinicians, in a priority setting partnership (PSP) following the James Lind Alliance (JLA) approach. Research into such symptoms in general has been poorly funded over the years and so far has been primarily researcher-led with minimal input from patients, caregivers and clinicians; and sometimes has been controversial. DESIGN: JLA PSP method. The PSP termed these symptoms MNYES. METHODS: The study was conducted according to the JLA's detailed methodology for conducting priority setting exercises. It involved five key stages: defining the appropriate term for the conditions under study by the PSP Steering Group; gathering questions on MNYES from patients, caregivers and clinicians in a publicly accessible survey; checking these research questions against existing evidence; interim prioritisation in a second survey; and a final multi-stakeholder consensus meeting to determine the top 10 unanswered research questions using the modified nominal group methodology. RESULTS: Over 700 responses from UK patients, caregivers and clinicians were identified in the two surveys and charities contributed from a broad range of medical specialties and primary care. The final top 10 unanswered research questions cover, among others: treatment strategies, personalisation of treatment, collaborative care pathways, training for clinicians and outcomes that matter to patients. INTERPRETATION: The top 10 unanswered research questions are expected to generate much needed, relevant and impactful research into MNYES.

Effect of a brief motivational interview and text message intervention targeting tobacco smoking, alcohol use and medication adherence to improve tuberculosis treatment outcomes in adult patients with tuberculosis: a multicentre, randomised controlled trial of the ProLife programme in South Africa.

OBJECTIVE: To investigate the effectiveness of a complex behavioural intervention, ProLife, on tuberculosis (TB) treatment success, medication adherence, alcohol use and tobacco smoking. DESIGN: Multicentre, individual, randomised controlled trial where participants were assigned (1:1) to the ProLife intervention or usual care. SETTING: 27 primary care clinics in South Africa. PARTICIPANTS: 574 adults starting treatment for drug-sensitive pulmonary TB who smoked tobacco or reported harmful/hazardous alcohol use. INTERVENTIONS: The intervention, delivered by lay health workers (LHWs), consisted of three brief motivational interviewing (MI) sessions, augmented with short message service (SMS) messages, targeting medication adherence, alcohol use and tobacco smoking. OUTCOME MEASURES: The primary outcome was successful versus unsuccessful TB treatment at 6-9 months, from TB records. Secondary outcomes were biochemically confirmed sustained smoking cessation, reduction in the Alcohol Use Disorder Identification Test (AUDIT) score, improved TB and antiretroviral therapy (ART) adherence and ART initiation, each measured at 3 and 6 months by questionnaires; and cure rates in patients who had bacteriology-confirmed TB at baseline, from TB records. RESULTS: Between 15 November 2018 and 31 August 2019, 574 participants were randomised to receive either the intervention (n=283) or usual care (n=291). TB treatment success rates did not differ significantly between intervention (67.8%) and control (70.1%; OR 0.9, 95% CI 0.64% to 1.27%). There was no evidence of an effect at 3 and 6 months, respectively, on continuous smoking abstinence (OR 0.65, 95% CI 0.37 to 1.14; OR 0.76, 95% CI 0.35 to 1.63), TB medication adherence (OR 1.22, 95% CI 0.52 to 2.87; OR 0.89, 95% CI 0.26 to 3.07), taking ART (OR 0.79, 95% CI 0.38 to 1.65; OR 2.05, 95% CI 0.80 to 5.27) or AUDIT scores (mean score difference 0.55, 95% CI -1.01 to 2.11; -0.04, 95% CI -2.0 to 1.91) and adjusting for baseline values. Cure rates were not significantly higher (OR 1.16, 95% CI 0.83 to 1.63). CONCLUSIONS: Simultaneous targeting of multiple health risk behaviours with MI and SMS using LHWs may not be an effective approach to improve TB outcomes. TRIAL REGISTRATION NUMBER: ISRCTN62728852.

An Analysis of Over-the-Counter Cannabidiol Products in the United Kingdom.

Introduction: Over-the-counter cannabidiol (CBD) products have seen unprecedented recent growth in the United Kingdom. However, analysis of these predominantly unregulated products from other countries tells us that they are often mislabeled or contain unlabeled and potentially dangerous chemicals. Thus, the aim of the present study was to analyze CBD oils available in the United Kingdom. Materials and Methods: Phytocannabinoids, residual solvent, and heavy metals were measured blinded in 29 widely available CBD products by an independent testing facility using high-performance liquid chromatography with diode-array detection for cannabinoids, Headspace-gas chromatography-flame ionization detector and gas chromatography-mass spectrometry for residual solvents, and inductively coupled plasma-mass spectrometry for heavy metals. Results: The mean advertised CBD content was 4.5%, and the actual mean measured CBD content of products was 3.2% (p=0.053, Mann-Whitney test). Only 11/29 (38%) products were within 10% of the advertised CBD content. Fifty five percent of products had measurable levels of the controlled substances Δ9-tetrahydrocannabinol (mean content 0.04%) or cannabinol (mean content 0.01%), as well as most other phytocannabinoid compounds including cannabidiolic acid (CBDA), cannabidivarin (CBDV), and cannabidivarin acid (CBDVA). Detectable levels of N-pentane, ethanol, isopropanol, heptane, lead, and arsenic were found in many of the CBD products, but these were within acceptable levels. Conclusions: As demonstrated in other countries, the quality of over-the-counter CBD products in the United Kingdom can be substandard, particularly with regard to CBD content, and often contains levels of controlled substances. We recommend that these products be more strictly regulated for consumer welfare.

Application of Machine Learning Techniques to an Agent-Based Model of Pantoea.

Agent-based modeling (ABM) is a powerful simulation technique which describes a complex dynamic system based on its interacting constituent entities. While the flexibility of ABM enables broad application, the complexity of real-world models demands intensive computing resources and computational time; however, a metamodel may be constructed to gain insight at less computational expense. Here, we developed a model in NetLogo to describe the growth of a microbial population consisting of Pantoea. We applied 13 parameters that defined the model and actively changed seven of the parameters to modulate the evolution of the population curve in response to these changes. We efficiently performed more than 3,000 simulations using a Python wrapper, NL4Py. Upon evaluation of the correlation between the active parameters and outputs by random forest regression, we found that the parameters which define the depth of medium and glucose concentration affect the population curves significantly. Subsequently, we constructed a metamodel, a dense neural network, to predict the simulation outputs from the active parameters and found that it achieves high prediction accuracy, reaching an R 2 coefficient of determination value up to 0.92. Our approach of using a combination of ABM with random forest regression and neural network reduces the number of required ABM simulations. The simplified and refined metamodels may provide insights into the complex dynamic system before their transition to more sophisticated models that run on high-performance computing systems. The ultimate goal is to build a bridge between simulation and experiment, allowing model validation by comparing the simulated data to experimental data in microbiology.

Expanding Advocacy to the Grassroots Level: The New York State Model.

New York State has achieved pharmacy practice advancement legislation more slowly than other states. Despite the benefits of pharmacy advocacy in shaping legislation, in New York State advocacy activities have generally been limited to once per year during Lobby Day. Implementation of a grassroots advocacy infrastructure has been able to organize and sustain legislative engagement among members of our professional organization, with more than 100 legislative visits completed since creation of the Grassroots Advocacy Committee. A committee with infrastructure including a buddy system and legislative visit tracking process and educational programs, such as simulation training, have reduced the perceived burdens of participation. Other pharmacy organizations who have identified advocacy as a priority can utilize these tools to organize their members to support legislative goals.

Towards Better Delivery of Cannabidiol (CBD).

Cannabidiol (CBD) has substantial therapeutic potential, but its development as an effective drug by the pharmaceutical industry is hindered by intrinsic characteristics such as low bioavailability, low water solubility, and variable pharmacokinetic profiles. Importantly, lack of patentability of the drug substance also limits the likelihood of an expensive, full development programme in anything other than orphan indications. Potential avenues to overcome these issues with CBD include self-emulsifying drug delivery systems, improved crystal formulations and other solid-state delivery formulations, which are mostly in the pre-clinical or early clinical stages of development. This review identifies issues compromising current delivery of solid-state CBD, and how advanced pharmaceutical development strategies can enable CBD to realise the full potential as a successful therapeutic agent.

NUFEB: A massively parallel simulator for individual-based modelling of microbial communities.

We present NUFEB (Newcastle University Frontiers in Engineering Biology), a flexible, efficient, and open source software for simulating the 3D dynamics of microbial communities. The tool is based on the Individual-based Modelling (IbM) approach, where microbes are represented as discrete units and their behaviour changes over time due to a variety of processes. This approach allows us to study population behaviours that emerge from the interaction between individuals and their environment. NUFEB is built on top of the classical molecular dynamics simulator LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator), which we extended with IbM features. A wide range of biological, physical and chemical processes are implemented to explicitly model microbial systems, with particular emphasis on biofilms. NUFEB is fully parallelised and allows for the simulation of large numbers of microbes (107 individuals and beyond). The parallelisation is based on a domain decomposition scheme that divides the domain into multiple sub-domains which are distributed to different processors. NUFEB also offers a collection of post-processing routines for the visualisation and analysis of simulation output. In this article, we give an overview of NUFEB's functionalities and implementation details. We provide examples that illustrate the type of microbial systems NUFEB can be used to model and simulate.

Individual Based Model Links Thermodynamics, Chemical Speciation and Environmental Conditions to Microbial Growth.

Individual based Models (IbM) must transition from research tools to engineering tools. To make the transition we must aspire to develop large, three dimensional and physically and biologically credible models. Biological credibility can be promoted by grounding, as far as possible, the biology in thermodynamics. Thermodynamic principles are known to have predictive power in microbial ecology. However, this in turn requires a model that incorporates pH and chemical speciation. Physical credibility implies plausible mechanics and a connection with the wider environment. Here, we propose a step toward that ideal by presenting an individual based model connecting thermodynamics, pH and chemical speciation and environmental conditions to microbial growth for 5·105 individuals. We have showcased the model in two scenarios: a two functional group nitrification model and a three functional group anaerobic community. In the former, pH and connection to the environment had an important effect on the outcomes simulated. Whilst in the latter pH was less important but the spatial arrangements and community productivity (that is, methane production) were highly dependent on thermodynamic and reactor coupling. We conclude that if IbM are to attain their potential as tools to evaluate the emergent properties of engineered biological systems it will be necessary to combine the chemical, physical, mechanical and biological along the lines we have proposed. We have still fallen short of our ideals because we cannot (yet) calculate specific uptake rates and must develop the capacity for longer runs in larger models. However, we believe such advances are attainable. Ideally in a common, fast and modular platform. For future innovations in IbM will only be of use if they can be coupled with all the previous advances.

Correction to: A formulation of neem and hypericum oily extract for the treatment of the wound myiasis by Wohlfahrtia magnifica in domestic animals.

The given names and family names of the authors of the originally published version of this article was inadvertently interchanged. Correct presentation of the author names are presented here.

ImPROving TB outcomes by modifying LIFE-style behaviours through a brief motivational intervention followed by short text messages (ProLife): study protocol for a randomised controlled trial.

BACKGROUND: South Africa is among the seven highest tuberculosis (TB) burden countries. Harmful lifestyle behaviours, such as smoking and alcohol, and poor adherence to medication can affect clinical outcomes. Modification of these behaviours is likely to improve TB treatment outcomes and has proven possible using motivational interviewing (MI) techniques or use of short message service (SMS) text messaging. There have been no studies assessing the effect of combined MI and SMS interventions on multiple lifestyle factors and TB treatment outcomes. METHODS: This is a prospective, multicentre, two-arm individual randomised controlled trial looking at the effectiveness and cost-effectiveness of a complex behavioural intervention (the ProLife programme) on improving TB and lifestyle-related outcomes in three provinces of South Africa. The ProLife programme consists of an MI counselling strategy, delivered by lay health workers, augmented with subsequent SMS. We aim to recruit 696 adult participants (aged 18 years and over) with drug-sensitive pulmonary TB who are current smokers and/or report harmful or hazardous alcohol use. Patients will be consecutively enrolled at 27 clinics in three different health districts in South Africa. Participants randomised individually to the intervention arm will receive three MI counselling sessions one month apart. Each MI session will be followed by twice-weekly SMS messages targeting treatment adherence, alcohol use and tobacco smoking, as appropriate. We will assess the effect on TB treatment success, using standard World Health Organization (WHO) treatment outcome definitions (primary outcome), as well as on a range of secondary outcomes including smoking cessation, reduction in alcohol use, and TB medication and anti-retroviral therapy adherence. Secondary outcomes will be measured at the three-month and six-month follow-ups. DISCUSSION: This trial aligns with the WHO agenda of integrating TB care with the care for chronic diseases of lifestyle, such as provision of smoking cessation treatments, and with the use of digital technologies. If the ProLife programme is found to be effective and cost-effective, the programme could have significant implications for TB treatment globally and could be successfully implemented in a wide range of TB treatment settings. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN62728852. Registered on 13 April 2018.

A formulation of neem and hypericum oily extract for the treatment of the wound myiasis by Wohlfahrtia magnifica in domestic animals.

Untreated, traumatic, or wound myiases can cause severe consequences to animal health and welfare as well as economic losses to livestock productions. For healing myiasis-caused wounds, disinfectant such as creolin is wrongly but currently used in association with insecticides. Though effective, creolin is highly toxic to the patients, is inadequate with respect to the repellent effect, and may delay the healing of treated wounds. In this uncontrolled study, the efficacy of the patented plant-derived formulation 1 Primary Wound Dressing© (1-PWD), composed of neem oil (Azadirachta indica A. Juss.) and the oily extract of Hypericum perforatum (L.) flowers, has been investigated. Forty-four domestic animals of different species suffering from wound myiasis lasting for up to 25 days, at different parts of the body, were enrolled in the study. No systemic or local antibiotic or disinfectants' treatment was administered. Larvae recovered on open wounds and adults reared from mature larvae were identified as Wohlfahrtia magnifica. All the treated wounds healed in a range of 10 to 32 days without further infestation. None of the recruited animals presented bacterial complications. Data herein presented indicate that the tested natural plant-derived formulation is able to manage the infestation caused by W. magnifica larvae and the healing process of traumatic infested wounds in several domestic animal species, without any side effect on the living tissue and without the need to use local or systemic chemical or other products.

Pyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia among older adults. Accumulation of amyloid-ß (Aß) in the brain is considered central in AD pathogenesis and its understanding crucial for developing new diagnostic and therapeutic approaches. Recent literature suggests that ageing may induce post translational modifications in Aß, in the form of spontaneous amino acid modifications, which enhance its pathogenic properties, contributing to its aggregation.In this study, we have investigated whether the isoaspartate (IsoD-Aß) and pyroglutamate (pE3-Aß) modified forms of Aß are significantly associated with AD pathology or represent markers of ageing. Cerebral neocortex of 27 AD cases, 32 old controls (OC) and 11 young controls (YC) was immunostained for pE3-Aß and IsoD-Aß, quantified as protein load and correlated with other Aß forms and p-TAU. IsoD-Aß and pE3-Aß were detected at low levels in non-demented controls, and significantly increased in AD (p ≤ 0.001), with a characteristic deposition of IsoD-Aß in blood vessel walls and pE3-Aß within neurons. Both AD and OC showed positive associations between IsoD-Aß and Aß (p = 0.003 in AD and p = 0.001 in OC) and between IsoD-Aß and pE3-Aß (p = 0.001 in AD and OC). This last association was the only significant pE3-Aß correlation identified in AD, whereas in the control cohorts pE3-Aß also correlated with Aß and AßPP (p = 0.001 in OC and p = 0.010 in YC).Our analyses suggest that IsoD-Aß accumulation starts with ageing; whereas pE3-Aß deposition is more closely linked to AD. Our findings support the importance of age-related modifications of Aß in AD pathogenesis.

Mitochondrial Genetic Diversity and Phylogeography of Mus musculus castaneus in Northern Punjab, Pakistan.

Regions of Iran, Afghanistan, Pakistan and northwestern India have been proposed as the place of origin of Mus musculus castaneus. But despite the fact that Pakistan encompasses an important part of its range, M. m. castaneus populations in Pakistan have not been the subject of intensive genetic and biogeographic studies, except for a very small number of samples included in past studies. We studied genetic variation in M. m. castaneus (CAS) from northern Punjab Province, Pakistan, by using cytochrome b (Cytb) analysis in a sample of 98 individuals. Median-joining network revealed four well differentiated CAS sub-lineages coexisting within a small geographical region; these had previously been thought to have largely non-overlapping geographic distributions. Moreover, haplotypes from Pakistan occupied a central position in the network and all identified global haplotypes were also present in Pakistan. All identified CAS sub-lineages proved to be highly diverse on the basis of haplotype and nucleotide diversity indices. Tajima's D test and Fu's Fs tests of neutrality suggest recent population expansions in all sub-lineages. Expansion times were estimated as 21,760-134,930, 10,800-64,400 and 4950-30,665 ybp using substitution rates of 2.5%, 5% and 11%, respectively. Our results support the hypothesis that northern Punjab Province in Pakistan is the most likely source area for M. m. castaneus, and that the CAS sub-lineages in this region have undergone rapid population expansion events at different time periods, which appear to have benefitted from human-mediated transport, although one of them clearly predates the establishment of human settlements in this region.