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Background: Lysosomal storage diseases (LSDs) are inherited metabolic disorders that may lead to severe multi-organ disease. Current ERTs are limited by anti-drug antibodies, the blood-brain barrier, and early disease onset and progression before ERT is started. We have opened a phase I clinical trial of enzyme replacement therapy (ERT) for fetuses with LSDs (NCT04532047). We evaluated the attitudes of parents and patients with LSDs towards fetal clinical trials and therapies.Methods: A multidisciplinary team designed a survey which was distributed by five international patient advocacy groups. We collected patients' demographic, diagnostic, and treatment information. Associations between respondent characteristics and attitudes towards fetal therapies/trials were analyzed using multivariate ordinal logistic regression.Results: The survey was completed by 181 adults from 19 countries. The majority of respondents were mothers from the United States. The most common diseases were MPS1 (26%), MPS3 (19%), and infantile-onset Pompe (14%). Most patients (88%) were diagnosed after birth, at a median of 21 months. Altogether, 65% of participating patients and children of participants had received ERT, 27% a stem cell transplant, and 4% gene therapy. We found that half (49%) of respondents were unlikely to terminate a future affected pregnancy, 55% would enroll in a phase I clinical trial for fetal ERT, and 46% would enroll in a fetal gene therapy trial. Respondents who received postnatal ERT were significantly more likely enroll in a trial for fetal ERT or gene therapy (ERT OR 4.48, 95% CI 2.13-9.44, p < 0.0001; gene therapy OR 3.03, 95% CI 1.43-6.43, p = 0.0038). Respondents who used clinicaltrials.gov as a main source of information were more likely to choose to participate in a fetal trial (ERT OR 2.43, 95% CI 1.18-5.01, p = 0.016; gene therapy OR 2.86, 95% CI 1.27-6.46, p = 0.011).Conclusions: Familiarity with postnatal ERT increased respondents' likelihood of pursuing fetal therapies. Families who use clinicaltrials.gov may be more receptive to innovative fetal treatments. The patient community has a favorable attitude towards fetal therapy; over half of respondents would enroll in a phase I clinical trial to assess the safety and efficacy of fetal ERT. [ABSTRACT FROM AUTHOR]

Background: Public health palliative care interventions are increasingly implemented, with growing recognition of the importance of building evidence to support their utility in end-of-life care. Previous efforts have focused on community outcomes. Aim: To examine the impact of public health palliative care on patterns of health service use at the end of life (primary) and explore which outcomes are being measured within this field of research (secondary). Design: Systematic review of studies reporting qualitative and quantitative data, analysed with a narrative synthesis method. Data sources: A systematic review conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses guideline was undertaken using six electronic databases (MEDLINE, CINAHL, EMBASE, PsycINFO, INFORMIT and COCHRANE) up to February 2020. Results: Searches yielded 2622 unique titles screened for eligibility, resulting in 35 studies measuring outcomes from a public health palliative care approach. Five (14%) studies assessed health system outcomes, and three reported some mixed evidence of impact, including reduced hospital emergency admissions, hospital bed days, hospital costs and increased home deaths. Most studies (86%) instead reported on conceptual (49%), knowledge (40%), programme participation (37%) and/or individual health outcomes (29%). Conclusion: The impact of public health palliative care is an evolving area of empirical inquiry with currently only limited evidence that it improves healthcare utilisation outcomes at the end of life, and limited focus on measurement of these outcomes. Further empirical studies are needed to support the reorientation of health services, which remains an important component in realising 'whole of system change' to bring about quality end-of-life care for all. [ABSTRACT FROM AUTHOR]

The article presents the discussion on expanding prenatal genetic testing (ePGT) in the US. Topics include requiring the involvement of a physician attesting to the patient's suffering; addressing the concerns ensuring longer-term consequences not including a widening of health disparities; and forcing sterilization policies targeting the already marginalized, reinforcing systemic racism, sexism, and ableism.

This paper attends to the sociality available in the clozapine clinic regimen and suggests that the social dimensions of clozapine treatment may be as important as the biochemical efficacy of clozapine. The clozapine clinic is where people diagnosed with chronic schizophrenia who take the antipsychotic clozapine go for routine monitoring of clozapine side effects, particularly haematological effects. Psychopharmaceutical treatments are often criticized for being reductionistic and dehumanizing, but clozapine clinics offer increased clinical contact in the age of deinstitutionalization. The inadvertent social benefits of biomedically reductive treatments have not previously been ethnographically attended to in the clozapine-only context. Drawing on 18 months of ethnographic fieldwork with 43 clozapine clients and 16 clinical caregivers in two clozapine clinics in the United Kingdom in Australia, I argue that routine clinical attachments in the clozapine clinic can serve a therapeutic role in terms of providing opportunities for clients' health agency, social competence and accountability. This socio-therapeutic quality appeared to be available because the clinical emphasis was not on psychotic illness. It depended, however, on reliable and familiar social exchanges inside the clinic and on the predictability of clinical activity. The importance of unemotional but unfailing relationships and rhythms in the clozapine clinic context echoes cross-cultural findings about how schizophrenia is managed more productively in environments that invite more neutral and equal social exchanges. [ABSTRACT FROM AUTHOR]

This paper explores the experiences of smoking and ‘vaping’ while being pharmaceutically treated for schizophrenia, as well as what the experiences of breathing smoke and vapour in and out can reveal about health ‘care’, toward the self and others. Drawing on ethnographic data collected over 2015-2016 in Australia and the UK, and particularly on patient experiences in the UK where electronic cigarettes had become an endorsed Nicotine Replacement Therapy, I argue that inhaling nicotine via e-cigarettes can, like tobacco cigarettes, be experienced in terms of temporal opportunities for self-reclamation and experiences of health. When patients opted to vape instead of smoke, their sense of self-reclamation allowed for shifted attention toward the movement and materiality of exhalations, and toward how second-hand vapour (compared to smoke) is socially received. Experiences of vaping were, however, contingent on the clinical endorsement of e-cigarettes and were inconsistent inside and outside of clinical spaces. Further consideration should be given to vaping as a harm minimisation tool in Western societies dealing with widening disparities in health. Ultimately, clozapine-treated schizophrenia patients continue to smoke or vape for reasons that speak to the desire to make ‘time’; to find connections to life rather than focusing on death. [ABSTRACT FROM AUTHOR]

Dengue fever is among the most widespread vector-borne infectious diseases. The primary vector of dengue is the Aedes aegypti mosquito. Ae. aegypti is prevalent in the tropics and sub-tropics and is closely associated with human habitats outside its native range of Africa. While long established in the southeastern United States of America where dengue is re-emerging, breeding populations have never been reported from California until the summer of 2013. Using 12 highly variable microsatellite loci and a database of reference populations, we have determined that the likely source of the California introduction is the southeastern United States, ruling out introductions from abroad, from the geographically closer Arizona or northern Mexico populations, or an accidental release from a research laboratory. The power to identify the origin of new introductions of invasive vectors of human disease relies heavily on the availability of a panel of reference populations. Our work demonstrates the importance of generating extensive reference databases of genetically fingerprinted human-disease vector populations to aid public health efforts to prevent the introduction and spread of vector-borne diseases. Author Summary: Dengue fever is a vector-borne disease that has dramatically increased in frequency and severity in recent decades, affecting over half of the world's population. The primary vector of dengue is Aedes aegypti. Breeding populations of this mosquito were reported for the first time in California in summer 2013, and the origin of these populations was unknown. We genotyped Ae. aegypti from California and compared their genetic composition and diversity against reference populations from Asia and the Americas, and with laboratory strains, to identify the source of this introduction. We identified the southeastern United States of America as the likeliest origin of California Ae. aegypti. This information will aid the design of containment, control, and elimination strategies to prevent the establishment of a permanent breeding vector population in the state. Note that the resolution achieved in tracking the origin of new disease-vector introductions is proportional to the completeness of the reference dataset. Our analysis was delayed to gather further data on regions close to California and would otherwise have been completed within a week. This work highlights the importance of having an extended dataset of human disease-vector genotypes in place prior to the occurrence of invasions that compromise public health. [ABSTRACT FROM AUTHOR]

Dengue fever is among the most widespread vector-borne infectious diseases. The primary vector of dengue is the Aedes aegypti mosquito. Ae. aegypti is prevalent in the tropics and sub-tropics and is closely associated with human habitats outside its native range of Africa. While long established in the southeastern United States of America where dengue is re-emerging, breeding populations have never been reported from California until the summer of 2013. Using 12 highly variable microsatellite loci and a database of reference populations, we have determined that the likely source of the California introduction is the southeastern United States, ruling out introductions from abroad, from the geographically closer Arizona or northern Mexico populations, or an accidental release from a research laboratory. The power to identify the origin of new introductions of invasive vectors of human disease relies heavily on the availability of a panel of reference populations. Our work demonstrates the importance of generating extensive reference databases of genetically fingerprinted human-disease vector populations to aid public health efforts to prevent the introduction and spread of vector-borne diseases. [ABSTRACT FROM AUTHOR]

Although anthropogenic impacts are often considered harmful to species, human modifications to the landscape can actually create novel niches to which other species can adapt. These 'domestication' processes are especially important in the context of arthropod disease vectors, where ecological overlap of vector and human populations may lead to epidemics. Here, we present results of a global genetic study of one such species, the dengue and yellow fever mosquito, Aedes aegypti, whose evolutionary history and current distribution have been profoundly shaped by humans. We used DNA sequences of four nuclear genes and 1504 single nucleotide polymorphism (SNP) markers developed with restriction-site associated DNA (RAD) sequencing to test the hypothesis that Ae. aegypti originated in Africa, where a domestic form arose and spread throughout the tropical and subtropical world with human trade and movement. Results confirmed African ancestry of the species, and supported a single subspeciation event leading to the pantropical domestic form. In addition, genetic data strongly supported the hypothesis that human trade routes first moved domestic Ae. aegypti out of Africa into the New World, followed by a later invasion from the New World into Southeast Asia and the Pacific. These patterns of domestication and invasion are relevant to many species worldwide, as anthropogenic forces increasingly impact evolutionary processes. [ABSTRACT FROM AUTHOR]

Understanding the processes bywhich species colonize and adapt tohuman habitats is particularly important in the case of disease-vectoring arthropods. The mosquito species Aedes aegypti, a major vector of dengue and yellow fever viruses, probably originated as a wild, zoophilic species in sub-Saharan Africa, where some populations still breed in tree holes in forested habitats. Many populations of the species, however, have evolved to thrive in human habitats and to bite humans. This includes some populationswithin Africa aswell as almost all those outside Africa. It is not clearwhether all domestic populations are genetically related and represent a single 'domestication' event, orwhether associationwith human habitats has developed multiple times independently within the species. To test the hypotheses above, we screened 24worldwide population samples of Ae. aegypti at 12 polymorphic microsatellite loci. We identified two distinct genetic clusters: one included all domestic populations outside of Africa and the other included both domestic and forest populations within Africa. This suggests that human association in Africa occurred independently from that in domestic populations across the rest of the world. Additionally, measures of genetic diversity support Ae. aegypti in Africa as the ancestral form of the species. Individuals from domestic populations outside Africa can reliably be assigned back to their population of origin, which will help determine the origins of new introductions of Ae. aegypti. [ABSTRACT FROM AUTHOR]

Genetic variants in SLC22A5, encoding the membrane carnitine transporter OCTN2, cause the rare metabolic disorder Carnitine Transporter Deficiency (CTD). CTD is potentially lethal but actionable if detected early, with confirmatory diagnosis involving sequencing of SLC22A5. Interpretation of missense variants of uncertain significance (VUSs) is a major challenge. In this study, we sought to characterize the largest set to date (n = 150) of OCTN2 variants identified in diverse ancestral populations, with the goals of furthering our understanding of the mechanisms leading to OCTN2 loss-of-function (LOF) and creating a protein-specific variant effect prediction model for OCTN2 function. Uptake assays with 14C-carnitine revealed that 105 variants (70%) significantly reduced transport of carnitine compared to wild-type OCTN2, and 37 variants (25%) severely reduced function to less than 20%. All ancestral populations harbored LOF variants; 62% of green fluorescent protein (GFP)-tagged variants impaired OCTN2 localization to the plasma membrane of human embryonic kidney (HEK293T) cells, and subcellular localization significantly associated with function, revealing a major LOF mechanism of interest for CTD. With these data, we trained a model to classify variants as functional (>20% function) or LOF (<20% function). Our model outperformed existing state-of-the-art methods as evaluated by multiple performance metrics, with mean area under the receiver operating characteristic curve (AUROC) of 0.895 ± 0.025. In summary, in this study we generated a rich dataset of OCTN2 variant function and localization, revealed important disease-causing mechanisms, and improved upon machine learning-based prediction of OCTN2 variant function to aid in variant interpretation in the diagnosis and treatment of CTD. [ABSTRACT FROM AUTHOR]

During summer 2010, Aedes aegypti mosquitoes were discovered in the Netherlands. Using genetic markers, we tracked the origin of these mosquitoes to a tire shipment from Miami, Florida, USA. Surveillance of tire exports from the United States should be included as part of a comprehensive surveillance system. During summer 2010, national surveillance activities detected Aedes aegypti mosquitoes in 2 tire yards in the Netherlands (1,2). Ae. aegypti mosquitoes are the principal worldwide vectors of dengue and yellow fever viruses, which cause a wide range of illnesses varying from asymptomatic to life threatening (3). Typically, these mosquitoes are found in tropical and subtropical regions throughout the world and had not been found in Europe since they were eliminated in the region shortly after World War II (3). [ABSTRACT FROM AUTHOR]

It is well recognised that antipsychotic treatments impact the whole body, not just the target area of the brain. For people with refractory schizophrenia on clozapine, the gold standard antipsychotic treatment in England and Australia, the separation of mental and physical regimes of health is particularly pronounced, resulting in multiple, compartmentalised treatment registers. Clinicians often focus on the mental health aspects of clozapine use, using physical indicators to determine whether treatment can continue. Our observations of 59 participants in England and Australia over 18 months revealed that patients did not observe this hierarchisation of mental treatments and physical outcomes. Patients often actively engaged in the management of their bodily symptoms, leading us to advance the figure of the active, rather than passive, patient. In our paper, we do not take the position that the facility for active management is a special one utilised only by these patients. We seek instead to draw attention to what is currently overlooked as an ordinary capacity to enact some sort of control over life, even under ostensibly confined and confining circumstances. We argue that clozapine-treated schizophrenia patients utilise the clinical dichotomy between mental and physical domains of health to rework what health means to them. This permits patients to actively manage their own phenomenological 'life projects' (Rapport, I am Dynamite: an Alternative Anthropology of Power, Routledge, London 2003), and forces us to reconsider the notion of clinical giveness of what health means. This making of one's own meanings of health may be critical to the maintenance of a sense of self. [ABSTRACT FROM AUTHOR]

Body size is a common focus of macroevolutionary, macroecological and palaeontological investigations. Here, we document body-size evolution in 19 species-level ostracod lineages from the deep Indian Ocean (Deep Sea Drilling Program Site 253) over the past 40 myr. Body-size trajectories vary across taxa and time intervals, but most lineages (16/19) show net gains in body size. Because many modern ostracod taxa are larger in colder parts of their geographical range, we compared the timing and magnitude of these size changes to established Cenozoic deep-water cooling patterns confirmed through δO measurements of benthic foraminifera in the samples studied. These data show a significant negative correlation between size changes and temperature changes (ostracods get larger as temperatures get colder), and that systematic size increases only occur during intervals of sustained cooling. In addition, statistical support for an explicit temperature-tracking model exceeds that of purely directional evolution. We argue that this Cope's Rule pattern is driven by secular changes in the environment, rather than any universal or intrinsic advantages to larger body sizes, and we note some difficulties in the attempts to link Cope's Rule to observations made within a single generation. [ABSTRACT FROM AUTHOR]

Background: Aedes aegypti is the most important vector of dengue fever in Brazil, where severe epidemics have recently taken place. Ae. aegypti in Brazil was the subject of an intense eradication program in the 1940s and 50s to control yellow fever. Brazil was the largest country declared free of this mosquito by the Pan-American Health Organization in 1958. Soon after relaxation of this program, Ae. aegypti reappeared in this country, and by the early 1980s dengue fever had been reported. The aim of this study is to analyze the present-day genetic patterns of Ae. aegypti populations in Brazil. Methodology/Principal Findings: We studied the genetic variation in samples of 11 widely spread populations of Ae. aegypti in Brazil based on 12 well-established microsatellite loci. Our principal finding is that present-day Brazilian Ae. aegypti populations form two distinct groups, one in the northwest and one in the southeast of the country. These two groups have genetic affinities to northern South American countries and the Caribbean, respectively. This is consistent with what has been reported for other genetic markers such as mitochondrial DNA and allele frequencies at the insecticide resistance gene, kdr. Conclusions/Significance: We conclude that the genetic patterns in present day populations of Ae. aegypti in Brazil are more consistent with a complete eradication of the species in the recent past followed by re-colonization, rather than the alternative possibility of expansion from residual pockets of refugia. At least two colonizations are likely to have taken place, one from northern South American countries (e.g., Venezuela) that founded the northwestern group, and one from the Caribbean that founded the southeastern group. The proposed source areas were never declared free of Ae. aegypti. Author Summary: The mosquito, Aedes aegypti, was historically very important as the major vector of yellow fever, whereas today it is most notorious for being the major transmitter of dengue fever. In the 1940s and 50s, the Pan-American Health Organization organized a campaign to eradicate Ae. aegypti from the New World. They were partly successful, with Brazil being the largest country to be declared free of Ae. aegypti. Within ten years of relaxation of control efforts, Ae. aegypti reappeared in Brazil and today is the vector of the most intense dengue epidemics in the New World. Here, we present population genetic data that are most consistent with the species having truly been eradicated from Brazil rather than simply pushed into small refugia as a consequence of the eradication campaign. The re-infestation most likely resulted from two sources: 1) from northern S. American countries like Venezuela into northwest Brazil and 2) from the Caribbean into the southeast of the country. [ABSTRACT FROM AUTHOR]

Background: Aedes aegypti is the most important vector of dengue fever in Brazil, where severe epidemics have recently taken place. Ae. aegypti in Brazil was the subject of an intense eradication program in the 1940s and 50s to control yellow fever. Brazil was the largest country declared free of this mosquito by the Pan-American Health Organization in 1958. Soon after relaxation of this program, Ae. aegypti reappeared in this country, and by the early 1980s dengue fever had been reported. The aim of this study is to analyze the present-day genetic patterns of Ae. aegypti populations in Brazil. Methodology/Principal Findings: We studied the genetic variation in samples of 11 widely spread populations of Ae. aegypti in Brazil based on 12 well-established microsatellite loci. Our principal finding is that present-day Brazilian Ae. aegypti populations form two distinct groups, one in the northwest and one in the southeast of the country. These two groups have genetic affinities to northern South American countries and the Caribbean, respectively. This is consistent with what has been reported for other genetic markers such as mitochondrial DNA and allele frequencies at the insecticide resistance gene, kdr. Conclusions/Significance: We conclude that the genetic patterns in present day populations of Ae. aegypti in Brazil are more consistent with a complete eradication of the species in the recent past followed by re-colonization, rather than the alternative possibility of expansion from residual pockets of refugia. At least two colonizations are likely to have taken place, one from northern South American countries (e.g., Venezuela) that founded the northwestern group, and one from the Caribbean that founded the southeastern group. The proposed source areas were never declared free of Ae. aegypti. [ABSTRACT FROM AUTHOR]