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The number of retail pharmacies in Balingasag, Misamis Oriental have increased due to the promising economic development of the municipality. Despite customers having wide alternative options to choose, service quality-implementation by respective pharmacies have perhaps executed inconsistently leading to a poor outlook of the stores service. The main objective of this study is to assess the service quality and performance efficiency of pharmacies surrounding the central area of the municipality of Balingasag using Analytical Hierarchy Process (AHP). We discuss in this paper the analysis of criterion prioritization through expert judgments, identify retail pharmacies with high and low performance efficiency of service quality. Criteria considered in formulating the AHP architecture is based on the retail service quality scale of Dabholkar et al. (1996) including workplace hygiene, understanding, accessibility, reliability, guidance, policy, and problem – solving. Based on experts’ judgments using pairwise comparison, different performance indicators have been evaluated: the most prioritized criterion among the seven (7) criteria is ‘problem-solving’ with a criterion weight of 0.22 while the least prioritized criterion is ‘accessibility’ with a criterion weight of 0.05. Empirical evaluation integrated with the obtained criterion weights showed that among ten (10) retail pharmacies; nine (9) pharmacies have good performance quality, while the remaining pharmacy have an acceptable performance in service quality implementation. The result of this study gives emphasis that ‘problem-solving’ criterion in the implementation of service quality should be strengthened by retail pharmacies to subsequently improve its service quality performance and competitive positioning.

Background It has been theorized that hallucinations, a common symptom of schizophrenia, are caused by failures in reality monitoring. The paracingulate sulcus (PCS) has been implicated as a brain structure supporting reality monitoring with the absence or shorter length of PCS associated with an occurrence of hallucinations in schizophrenia. The absence or shorter length of PCS has been associated with an occurrence of hallucinations. There are inconsistent findings in the literature regarding the role of the asymmetry of this structure for hallucinations. Here, we investigated the length of the PCS and cortical thickness of surrounding structures in patients with a lifetime history of auditory verbal hallucinations (AVH). Design Seventy-seven patients and twenty-eight healthy controls (HC) underwent an anatomical MRI scan. PCS length and cortical thickness were estimated using Mango brain visualization and FreeSurfer, respectively. Patients with AVH (n = 45) and patients without AVH were compared (n = 32) to the controls. Results PCS length significantly differed between HC and patient groups (F(2,102) = 3.57, P = .032) in the left but not in the right sulcus. We found significantly longer PCS between HC and AVH group but no difference between patient groups. Similarly, we found significant thinning of cortical structures including structures surrounding anterior parts of PCS between HC and patients either in general or per group, but no significant differences were observed between patient groups. Conclusions PCS length in the left hemisphere is shorter in schizophrenia patients with hallucinations as compared to HC subjects. The patient group without hallucinations was in between those 2 groups. Cortical thickness of neighboring areas of PCS is diminished in patient groups relative to the healthy comparison subjects. The role of lateralization and functional involvement of the PCS region in processes underlying hallucinations, such as reality monitoring, needs further clarification.

This study aims to describe the application of Human Resource Management (HRM) in recruiting employees to improve performance, analysis of HRM in efforts to develop human resources to improve employee performance, HRM analysis has an impact on recruitment and efforts in HR development to improve employee performance in the start-up sector Cool Kids at Ambon City Centre Mall. This study uses a descriptive qualitative approach. This research approach was carried out at Cool Kids in Ambon City Centre Mall with data collection techniques in the form of interviews, observation, documentation and accommodation methods. The results of this study are expected that the recruitment system carried out is not fully maximized, so using the human resource management recruitment model can be carried out effectively. In an effort to develop of human resources, this has been carried out in accordance with the procedures for implementing employee education and training programs, but this has not yet been implemented informally. HR development and recruitment have an impact on improving employee performance which has not been fully implemented, this is due to the knowledge, abilities and skills of employees not all of them can master them effectively.

Introduction Une collaboration efficace et soutenue entre cliniciens et professionnels en santé publique peut améliorer la santé des individus et la santé de la population. Le concept de santé publique clinique favorise cette collaboration entre médecine clinique et santé publique et permet de relever des défis complexes en matière de santé. Dans ce commentaire, nous décrivons le concept de santé publique clinique, les types de problèmes complexes qui nécessitent une collaboration entre les professionnels responsables de la santé des individus et ceux responsables de la santé de la population, de même que les obstacles à la santé publique clinique et les applications de la santé publique clinique qui ont émergé pendant la pandémie de COVID-19. Argumentaire Il existe une complémentarité entre la médecine clinique, qui est axée sur la santé des individus, et la santé publique, qui est axée sur la promotion et la protection de la santé des populations. Une collaboration entre ces deux disciplines est nécessaire pour résoudre les problèmes de santé complexes. Pour ce faire, toutefois, il convient de s’attaquer aux obstacles relatifs aux disciplines, ainsi qu’aux obstacles culturels et financiers qui empêchent une collaboration accrue et durable en la matière. Les succès récents, particulièrement durant la pandémie de COVID-19, constituent un modèle de collaboration de ce type entre cliniciens et praticiens en santé publique. Conclusion Une approche en matière de santé publique qui favorise une collaboration permanente entre cliniciens et professionnels en santé publique pour lutter contre des menaces sanitaires complexes aura plus d’impact que la somme de ses parties.

As health systems face increasing demands, non-medical prescribing is a workforce redesign strategy adopted within some services. Despite successful implementation in other professional groups, non-medical prescribing within speech pathology (SP) has not yet been described.To provide a descriptive account of the development and planned implementation of two SP prescribing models.The evolution of two SP-led prescribing models, including relevant training and credentialing, for use of (1) nystatin oral drops (100,000 units/mL); and (2) lidocaine (lignocaine) and phenylephrine nasal spray (5 mg/500 μg/spray), in the outpatient setting is detailed. Challenges to implementation are outlined.The development of relevant governance structures, a research evidenced-based project evaluation framework, and an overview of training pathways and credentialing was successfully completed. However, implementation of the models was unable to be achieved. A thorough review of the requirements and a discussion of contextual considerations that had a negative influence on the implementation of SP-led prescribing within this specific service context is provided.The successful implementation of SP-led prescribing is complex and highly context dependent. This work offers a discussion and review of the complexities of introducing a non-medical prescribing model in an outpatient hospital setting.What is already known on the subject Allied Health prescribing is an emerging practice area aiming to reduce current pressures on health services. SP-led prescribing has not been thoroughly investigated in the Australian context. What this study adds to existing knowledge This study describes the development of a SP-led prescribing process in the outpatient setting, and a thorough review and discussion of the drivers and barriers to the model's implementation. What are the potential or actual clinical implications of this work? The successful implementation of SP-led prescribing was identified to be complex from a legislative and operational perspective, as well as being highly context dependent. This study further highlights the importance of a thorough context evaluation and workflow mapping prior to full-scale implementation of SP prescribing trials.

Although existing studies of audiology first point of contact clinics which screen for retrocochlear pathology have demonstrated positive clinical outcomes, they have provided limited information regarding service impacts. Thus, this study aimed to evaluate both the clinical and health service outcomes of an audiology first point of contact (FPOC) clinic for adults referred to ENT services with suspected retrocochlear pathology.Retrospective cohort study.All 1123 patients referred to the clinic over a 6-year period (2013-2019).Most (73.7%) of the 1123 patients referred to the Retrocochlear Clinic were managed and discharged by the audiologist and did not require ENT appointment. Almost half (43.1%) were directly referred for MRI imaging, of which 4 (1.1%) were diagnosed with Vestibular Schwannoma. Waiting times for first appointments significantly (This audiology FPOC Retrocochlear Clinic was shown to be a safe and effective alternative service model.

NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, γδ + , and CD8 + T cell-mediated immune responses to environmental stressors such as viral or bacterial infections and oxidative stress. However, aberrant NKG2D signaling has also been associated with chronic inflammatory and autoimmune diseases, and as such NKG2D is thought to be an attractive target for immune intervention. Here, we describe a comprehensive small-molecule hit identification strategy and two distinct series of protein–protein interaction inhibitors of NKG2D. Although the hits are chemically distinct, they share a unique allosteric mechanism of disrupting ligand binding by accessing a cryptic pocket and causing the two monomers of the NKG2D dimer to open apart and twist relative to one another. Leveraging a suite of biochemical and cell-based assays coupled with structure-based drug design, we established tractable structure–activity relationships with one of the chemical series and successfully improved both the potency and physicochemical properties. Together, we demonstrate that it is possible, albeit challenging, to disrupt the interaction between NKG2D and multiple protein ligands with a single molecule through allosteric modulation of the NKG2D receptor dimer/ligand interface.

Background Sub-valvular aortic stenosis is a rare disorder that has a prevalence of 6.5% of all adult congenital heart diseases. The hemodynamic changes that occur in pregnancy with the resultant increase in cardiac output may not well be tolerated by a pregnant woman with sub-valvular aortic stenosis. Case presentation We report the case of a 34-year-old para 7 (6 alive + 1 dead) who has been experiencing intermittent episodes of easy fatigability on moderate exertion since childhood and had survived 6 prior pregnancies. During her last pregnancy, she started experiencing chest pain, palpitations, dyspnea, orthopnea, and pre-syncope at 36 weeks and had a caesarean section at 37 weeks on account of fetal distress. The post-delivery cardiac evaluation showed severe sub-valvular Aortic stenosis and a ventricular septal defect. Conclusion Sub-valvular Aortic stenosis may progress slowly in adults and may be tolerated during pregnancy. Despite the rare presentation and contraindication of pregnancy in such a patient, she extraordinarily survived the pregnancy with a healthy baby. Routine cardiovascular assessment during prenatal, ante-natal and post-natal care is highly advocated particularly so in resource-poor settings.

Supplementary Figure S6 from Caspase-8 Promotes Cell Motility and Calpain Activity under Nonapoptotic Conditions

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Significant caspase-8 activity has been found in normal and certain tumor cells, suggesting that caspase-8 possesses an alternative, nonapoptotic function that may contribute to tumor progression. In this article, we report that caspase-8 promotes cell motility. In particular, caspase-8 is required for the optimal activation of calpains, Rac, and lamellipodial assembly. This represents a novel nonapoptotic function of caspase-8 acting at the intersection of the caspase-8 and calpain proteolytic pathways to coordinate cell death versus cell motility signaling. (Cancer Res 2006; 66(8): 4273-8)

Supplementary Figure S8 from Caspase-8 Promotes Cell Motility and Calpain Activity under Nonapoptotic Conditions

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Supplementary Figure S1 from Caspase-8 Promotes Cell Motility and Calpain Activity under Nonapoptotic Conditions

Supplementary Figure Legends S1-S10 from Caspase-8 Promotes Cell Motility and Calpain Activity under Nonapoptotic Conditions

Parathyroid adenomas weighing more than 3.5 g are reported variously as “atypical”, “large” or “giant” parathyroid adenomas. All such adenomas are rare variants accounting for no more than 1.5% of all parathyroid adenomas. Large parathyroid adenomas are often associated with more severe form of the disease, including osteitis fibrosa cystica (OFC) and share many biochemical, histological, and molecular features of both benign and malignant parathyroid neoplasms, and are considered a distinct clinical entity. However, the pathogenesis of oversized parathyroid adenomas and the often-associated skeletal phenotype remains unclear. We present 5 cases of primary hyperparathyroidism (PHPT) with OFC, an uncommon manifestation of contemporary PHPT, associated with larger parathyroid adenomas, seen in the Bone and Mineral Disorders Clinic of the Henry Ford Health in the last 30 years to illustrate the critical role of vitamin D nutrition in the pathogenesis of both the OFC and adenoma size. The estimated prevalence of OFC was very low 0.2%, 5 of the >3000 surgically confirmed cases of PHPT seen during this time. The mean ± SD values were: age: 36.8 ± 22.1 years (4 of the 5 10 years of follow-up. Because OFC is a very rare in the West, but very common areas of endemic vitamin D deficiency, we also examined the relationship between vitamin D nutrition, as assessed by serum 25-hydroxyvitamin D level, and parathyroid adenoma weight as well as prevalence of OFC in two large secularly diverse cohorts of patients with PHPT (Detroit, USA and Chandigarh, India). Based on this relationship and the relative prevalence of OFC in these two large cohorts, we propose that vitamin D nutrition (and perhaps calcium nutrition) best explains both the adenoma size and prevalence of OFC.

Older age is associated with worsened outcome after mild traumatic brain injury (mTBI) and a higher risk of developing persistent post-traumatic complaints. However, the effects of mTBI sequelae on brain connectivity at older age and their association with post-traumatic complaints remain understudied.We analyzed multi-echo resting-state functional magnetic resonance imaging data from 25 older adults with mTBI (mean age: 68 years, SD: 5 years) in the subacute phase (mean injury to scan interval: 38 days, SD: 9 days) and 20 age-matched controls. Severity of complaints (e.g. fatigue, dizziness) was assessed using self-reported questionnaires. Group independent component analysis was used to identify intrinsic connectivity networks (ICNs). The effects of group and severity of complaints on ICNs were assessed using spatial maps intensity (SMI) as a measure of within-network connectivity, and (static) functional network connectivity (FNC) as a measure of between-network connectivity.Patients indicated a higher total severity of complaints than controls. Regarding SMI measures, we observed hyperconnectivity in left-mid temporal gyrus (cognitive-language network) and hypoconnectivity in the right-fusiform gyrus (visual-cerebellar network) that were associated with group. Additionally, we found interaction effects for SMI between severity of complaints and group in the visual(-cerebellar) domain. Regarding FNC measures, no significant effects were found.In older adults, changes in cognitive-language and visual(-cerebellar) networks are related to mTBI. Additionally, group-dependent associations between connectivity within visual(-cerebellar) networks and severity of complaints might indicate post-injury (mal)adaptive mechanisms, which could partly explain post-traumatic complaints (such as dizziness and balance disorders) that are common in older adults during the subacute phase.

Understanding the relationship between incursions of insect pests and established populations is critical to implementing effective control. Studies of genetic variation can provide powerful tools to examine potential invasion pathways and longevity of individual pest outbreaks. The major fruit fly pest in eastern Australia, Queensland fruit fly Bactrocera tryoni (Froggatt), has been subject to significant long‐term quarantine and population reduction control measures in the major horticulture production areas of southeastern Australia, at the species southern range limit. Previous studies have employed microsatellite markers to estimate gene flow between populations across this region. In this study, we used an independent genetic marker, mitochondrial DNA (mtDNA) sequences, to screen genetic variation in established and adjacent outbreak populations in southeastern Australia. During the study period, favorable environmental conditions resulted in multiple outbreaks, which appeared genetically distinctive and relatively geographically localized, implying minimal dispersal between simultaneous outbreaks. Populations in established regions were found to occur over much larger areas. Screening mtDNA (female) lineages proved to be an effective alternative genetic tool to assist in understanding fruit fly population dynamics and provide another possible molecular method that could now be employed for better understanding of the ecology and evolution of this and other pest species.

EXTRACT The object of this thesis is to study the operation of welfare-orientated legislation in the juvenile delinquency and child neglect jurisdiction. Most of the statutes are in similar terms, so the study the been conducted with reference to the Child Welfare Act 1960 (Tas.). However, the concepts, as distinct from details of procedure, will often apply more widely and will be appropriate to other jurisdictions having similar legislation. Generally, the approach has been to examine the actual operation of the statute, from the inception of tho legal process to the completion of any order that may be made by the Children's Court. This includes not only the judicial role of the Court, but also the execution of the order by an executive agency. Essentially the child welfare legislation aims to remove children from the processes of the ordinary criminal law. A child is to be treated as misguided and in need assistance. The Children's Court must look to his future welfare as the primary consideration in sentencing. Conceptually it is similar to the parene patriae doctrine of the ancient Chancery jurisdiction over children, but with the important distinction that the modern Children's Court is a creature of statue and has only the power conferred by statute. If the Court is to fulfill the aim of this concept it must dispense personal- ized justice. In each case the order mat met the individual circumstances of the child defendant. For the achievement of this goal, the statute provides for simple discharge without the recording of a conviction, the imposition of supervision orders, which may be conditional and finally for declaration of the child as a ward of the State. If the Court is uncertain as to the course it should adopt and requires further information, the child may be remanded in care for up to three month for further assessment. This thesis examines the operation of each of these orders in regard to both dilinquent and neglected children. It follows that if the order is to be peculiar to the needs of each defendant the court must have enough background information about the defendant to make the appropriate assessment. Social backqround investigation and reports are therefore an integral part of the juvenile justice. system. The nature of these reports is considered together with their legal status. Of special interest in this context is considered, together they should be revealed to the parties concerned. · This problem is also examined. The thesis then proceeds to a study of the manner in which the order, once made, is put into effect by the executive agency, namely, the Department of Social Welfare. This includes both residential and non-residential care and the legal status and rights of the child parents during the operation o£ the programme.. It may be thought that the personality and rights of both child and parents are subrogated to the unfettered control and discretion of the public service department. This aspect or the system has also been studied. Since the report of the Kilbrandon committee in 1964, the idea of the juvenile panel has received extensive consideration and has actually been introduced in South Australia. This system is examined and compared with the traditional judicial system. Another innovation is the family court concept. This has also been studied and compared with the system created by the Child Welfare act. Chapter 7 sets out the conclusions of the study, that whilst the Children's court system is not free from defects, it is the most preferable of the alternatives yet available

Compared with conventional coagulation tests and factor-specific assays, viscoelastic hemostatic assays (VHAs) can provide a more thorough evaluation of clot formation and lysis but have several limitations including clot deformation. In this proof-of-concept study, we test a noncontact technique, termed resonant acoustic rheometry (RAR), for measuring the kinetics of human plasma coagulation. Specifically, RAR utilizes a dual-mode ultrasound technique to induce and detect surface oscillation of blood samples without direct physical contact and measures the resonant frequency of the surface oscillation over time, which is reflective of the viscoelasticity of the sample. Analysis of RAR results of normal plasma allowed defining a set of parameters for quantifying coagulation. RAR detected a flat-line tracing of resonant frequency in hemophilia A plasma that was corrected with the addition of tissue factor. Our RAR results captured the kinetics of plasma coagulation and the newly defined RAR parameters correlated with increasing tissue factor concentration in both healthy and hemophilia A plasma. These findings demonstrate the feasibility of RAR as a novel approach for VHA, providing the foundation for future studies to compare RAR parameters to conventional coagulation tests, factor-specific assays, and VHA parameters.

Nous sommes heureux que notre article sur la santé publique clinique1 ait reçu l’appui du Dr Shah2, qui mentionne également des éléments historiques importants au sujet de la santé publique clinique. Le Dr Shah a été le premier directeur d’un nouveau programme de résidence lancé en 1976 à l’Université de Toronto, soit le programme de résidence en médecine communautaire, qui porte maintenant le nom de programme de résidence en santé publique et en médecine préventive. Même s’il prétend ne pas avoir « su rassembler les cliniciens et les professionnels de la santé publique pour définir les éléments communs et les synergies nécessaires »2, nous sommes d’avis qu’il n’a pas échoué, car ses efforts ont inspiré ses étudiants (dont plusieurs ont corédigé l’article en question1). Tirant parti de son héritage important, les générations suivantes de cliniciens et de professionnels en santé publique ont fait des avancées sur le plan d’une collaboration efficace entre médecine clinique et santé publique.

We are pleased that our paper on clinical public health1 received support from Dr. Shah,2 who also provides important historical aspects of clinical public health. Dr. Shah was the inaugural director of a newly created residency program (Community Medicine, now known as Public Health and Preventive Medicine) at the University of Toronto in 1976. Although he claims to have failed to “bring clinicians and public health professionals together to define the common elements and synergy needed,”2 we believe he did not fail, because his efforts ignited sparks among his students (including several co-authors of this paper1). Building on his important legacy, subsequent generations of clinicians and public health professionals have made strides towards effective collaboration of clinical medicine and public health.

Tramps ants are a constant biosecurity threat to Australia. Red Imported Fire Ant Solenopsis invicta was detected in Sydney, New South Wales in 2014, and a successful eradication program was undertaken. Stratified surveillance was conducted as part the program, and allowed for scenario tree analysis to statistically support the claim of freedom. Our analysis demonstrated a mean probability of freedom was 93.1%, 99.5% and > 99.9% after one, two or three surveys for two nests within 2 km of the detection. We demonstrated > 99.9% probability of freedom after three surveys if for a threshold value of five nests were present. Our analysis was the basis of declaring Sydney free from S. invicta. Sydney was declared free 18 months after the first detection of S. invicta.

Funder: Wellcome Clinical PhD fellowship, Funder: Wellcome PhD Studentship, Funder: Jean Shank/Pathological Society Intermediate Fellowship, Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.

In this paper, it is argued that the industrial revolution in eighteenth century Great Britain had its origins in the arrival of 100,000–140,000 Protestant refugees in England and Ireland in the sixteenth, seventeenth and eighteenth centuries. Specifically, it is argued that their arrival prompted both Schmooklerian pull and push factors. The pull factor was the thousands of refugee merchants and ship owners/captains to England and Ireland resulting in the creation of the Protestant International (1550-1750). This increased the demand for tradables which in turn spurred invention and innovation among refugees (push factor) and their descendants as well as in the local population. These factors were self-reinforcing, leading in time to the industrial revolution. The result is a novel account of the origins of the industrial revolution, one that is consistent with competing explanations.

The challenge of data availability for accurately assessing a location's level of corrosivity has lingered for so long and as such, researchers are constantly seeking factors with great influence that can assist in describing how corrosive a location will be toward buried oil and gas infrastructure. Alternative measures are required for making rapid and realistic investment decisions because accumulating these factors to make perfect sense is sometimes time-consuming and expensive. Using MATLAB mathematical computational analysis, this study capitalizes on this gap to build a 3D corrosivity signature and model for Delta state, Nigeria to aid in rapid and realistic investment decision-making. The soil pH and resistivity were identified as key variables that determine the extent of corrosion in this investigation. Vertical Electrical Soundings were utilized to collect soil resistivity data, which was then combined with the soil pH to create a 3D corrosivity signature and model with a 98% R-square factor. During the study, potential limitations were found, and recommendations were made.

If the Muldergate-era journalist Eschel M. Rhoodie could, in 1967, describe Namibia (then South West Africa) as ‘Africa’s last frontier’, then the Caprivi Strip (modern-day Zambezi region) was the ...

This study was set to assess factors that drive adoption of six climate smart agriculture technologies in Buhera and Chiredzi districts of Zimbabwe using a sample size of 240 households. Multivariate probit analysis was used to determine factors that influence smallholder farmers' decision to adopt climate smart agriculture technologies. The study finds that age, gender, education of household head, household size, membership to social group, land size, land ownership, and training influence adoption of the six climate smart agriculture technologies. Therefore, policies that allow an improvement in land size and ownership should be given full support by both government and NGO community. The study further recommends that there should be more trainings on benefits of various climate smart agriculture technologies. Farmers should further be encouraged to participate in social groups for easy access to extension information on climate smart agriculture.

Multi-Disease Predictive Analytics (MDPA) models simultaneously predict the risks of multiple diseases in patients and are valuable in early diagnoses. Patients tend to have multiple diseases simultaneously or develop multiple complications over time, and MDPA models can learn and effectively utilize such correlations between diseases. Data from large-scale Electronic Health Records (EHR) can be used through Multi-Label Learning (MLL) methods to develop MDPA models. However, data-driven approaches for MDPA face the challenge of data imbalance, because rare diseases tend to have much less data than common diseases. Insufficient data for rare diseases makes it difficult to leverage correlations with other diseases. These correlations are studied and recorded in biomedical literature but are rarely utilized in predictive analytics. This article presents a novel method called Knowledge-Aware Approach (KAA) that learns clinical correlations from the rapidly growing body of clinical knowledge. KAA can be combined with any data-driven MLL model for MDPA to refine the predictions of the model. Our extensive experiments, on real EHR data, show that the use of KAA improves the predictive performance of commonly used MDPA models, particularly for rare diseases. KAA is also found to be superior to existing general approaches of combining clinical knowledge with data-driven models. Further, a counterfactual analysis shows the efficacy of KAA in improving physicians’ ability to prescribe preventive treatments.

Purpose: Early evidence supports the safety and efficiency of extended scope speech-language pathology (SLP) clinics designed to manage low risk ear nose and throat (ENT) outpatient referrals, howe...

Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes.