The Case for Legal Regulation of Physicians’ Off-Label Prescribing

Deafness has been associated with poor abilities to deal with digits in the context of arithmetic and memory, and language modality-specific differences in the phonological similarity of digits have been shown to influence short-term memory (STM). Therefore, the overall aim of the present thesis was to find out whether language modality-specific differences in phonological processing between sign and speech can explain why deaf signers perform at lower levels than hearing peers when dealing with digits. To explore this aim, the role of phonological processing in digit-based arithmetic and memory tasks was investigated, using both behavioural and neuroimaging methods, in adult deaf signers and hearing non-signers, carefully matched on age, sex, education and non-verbal intelligence. To make task demands as equal as possible for both groups, and to control for material effects, arithmetic, phonological processing, STM and working memory (WM) were all assessed using the same presentation and response mode for both groups. The results suggested that in digit-based STM, phonological similarity of manual numerals causes deaf signers to perform more poorly than hearing non-signers. However, for  digit-based WM there was no difference between the groups, possibly due to differences in allocation of resources during WM. This indicates that similar WM for the two groups can be generalized from lexical items to digits. Further, we found that in the present work deaf signers performed better than expected and on a par with hearing peers on all arithmetic tasks, except for multiplication, possibly because the groups studied here were very carefully matched. However, the neural networks recruited for arithmetic and phonology differed between groups. During multiplication tasks, deaf signers showed an increased  reliance on cortex of the right parietal lobe complemented by the left inferior frontal gyrus. In contrast, hearing non-signers relied on cortex of the left frontal and parietal lobes during multiplication. This suggests that while hearing non-signers recruit phonology-dependent arithmetic fact retrieval processes for multiplication, deaf signers recruit non-verbal magnitude manipulation processes. For phonology, the hearing non-signers engaged left lateralized frontal and parietal areas within the classical perisylvian language network. In deaf signers, however, phonological processing was limited to cortex of the left occipital lobe, suggesting that sign-based phonological processing does not necessarily activate the classical language network. In conclusion, the findings of the present thesis suggest that language modality-specific differences between sign and speech in different ways can explain why deaf signers perform at lower levels than hearing non-signers on tasks that include dealing with digits.Dövhet har kopplats till bristande förmåga att hantera siffror inom områdena aritmetik och minne. Särskilt har språkmodalitetsspecifika skillnader i fonologisk likhet för siffror visat sig påverka korttidsminnet. Det övergripande syftet med den här avhandlingen var därför att undersöka om språkmodalitetsspecifika skillnader i fonologisk bearbetning mellan teckenoch talspråk kan förklara varför döva presterar sämre än hörande på sifferuppgifter. För att utforska det området undersöktes fonologisk bearbetning i sifferbaserade minnesuppgifter och aritmetik med hjälp av både beteendevetenskapliga metoder och hjärnavbildning hos grupper av teckenspråkiga döva och talspråkiga hörande som matchats noggrant på ålder, kön, utbildning och icke-verbal intelligens. För att testförhållandena skulle bli så likartade som möjligt för de båda grupperna, och för att förebygga materialeffekter, användes samma presentations- och svarssätt för båda grupperna. Resultaten visade att vid sifferbaserat korttidsminne påverkas de dövas prestation av de tecknade siffrornas fonologiska likhet. Däremot fanns det ingen skillnad mellan grupperna gällande sifferbaserat arbetsminne, vilket kan bero på att de båda grupperna fördelar sina kognitiva resurser på olika sätt. Dessutom fann vi att den grupp teckenspråkiga döva som deltog i studien presterade bättre på aritmetik än vad tidigare forskning visat och de skiljde sig bara från hörande på multiplikationsuppgifter, vilket kan bero på att grupperna var så noggrant matchade. Däremot fanns det skillnader mellan grupperna i vilka neurobiologiska nätverk som aktiverades vid aritmetik och fonologi. Vid multiplikationsuppgifter aktiverades cortex i höger parietallob och vänster frontallob för de teckenspråkiga döva, medan cortex i vänster frontal- och parietallob aktiverades för de talspråkiga hörande. Detta indikerar att de talspråkiga hörande förlitar sig på fonologiberoende minnesstrategier medan de teckenspråkiga döva förlitar sig på ickeverbal magnitudmanipulering och artikulatoriska processer. Under den fonologiska uppgiften aktiverade de talspråkiga hörande vänsterlateraliserade frontala och parietala områden inom det klassiska språknätverket. För de teckenspråkiga döva var fonologibearbetningen begränsad till cortex i vänster occipitallob, vilket tyder på att teckenspråksbaserad fonologi inte behöver aktivera det klassiska språknätverket. Sammanfattningsvis visar fynden i den här avhandlingen att språkmodalitetsspecifika skillnader mellan tecken- och talspråk på olika sätt kan förklara varför döva presterar sämre än hörande på vissa sifferbaserade uppgifter

Can a nudge keep you warm? Using nudges to reduce excess winter deaths: insight from the Keeping Warm in Later Life Project (KWILLT)

Nudges are interventions that aim to change people's behaviour through changing the environment in which they choose rather than appealing to their reasoning. Nudges have been proposed as of possible use in relation to health-related behaviour. However, nudges have been criticized as ethically dubious because they bypass peoples reasoning and (anyway) are of little help in relation to affecting ill-health that results from social determinants, such as poverty. Reducing the rate of excess winter deaths (EWDs) is a public health priority; however, EWD seems clearly to be socially determined such that nudges arguably have little role. This article defends two claims: (i) nudges could have a place in tackling even the heavily socially determined problem of EWD. We draw on evidence from an empirical study, the Keeping Warm in Later Life Project (KWILLT), to argue that in some cases the risk of cold is within the person’s control to some extent such that environmental modifications to influence behaviour such as nudges are possible. (ii) Some uses of behavioural insights in the form of nudges are acceptable, including some in the area of EWD. We suggest a question-based framework by which to judge the ethical acceptability of nudges

Development Of An In Silico Kir Genotyping Algorithm And Its Application To Population And Cancer Immunogenetic Analyses

Gene content determination and variant calling in the complex KIR genomic region are useful for immune system function analysis, pathogenesis and disease risk factor elucidation, immunotherapy development, evolutionary investigations, and human migration modeling. Sequence-specific oligonucleotide and sequence-specific primer PCR methods are the de facto standards for KIR presence/absence identification, but the current platforms are unsuitable for SNP calling, impractical for KIR typing large cohorts of DNA samples, and inapplicable for typing repositories in which sequence data, but not cells or cell analytes, are available. Alternative typing methods, such as in silico sequence-based typing, can address the problems associated with amplicon-based approaches. However, common next generation sequencing technologies that map short reads to a reference genome exhibit high rates of read mismapping in regions containing loci that are homologous, polymorphic, and variable in content. I developed a novel approach for rescuing KIR genotyping function from sequence read alignment data files exclusively, with no requirement for additional DNA or amplification reactions. This Sequence Read Remapping And Motif Counting (SeRRAMC) approach utilizes a pattern-matching algorithm to select mapped reads containing oligomotifs that uniquely discriminate the variants of a single KIR gene and remap the selected reads to the consensus coding sequence of the respective KIR. The process dramatically reduces read mismapping to near zero, thereby enabling high confidence KIR typing and variant calling from short sequence reads. I used this approach for an analysis of KIR variation in 2535 modern humans across 26 populations from around the world, plus three Neandertals and a Denisovan. The results identified 175 unique KIR genotypes, the four most frequent of which vary significantly across modern humans, and found 36 population-associated nonsynonymous single base polymorphisms. On average, African and Far Eastern genomes encode fewer KIR genes but a greater number of population-correlated variants, while South Asians have higher gene content with moderate variation. Archaic humans match European and South Asian genotypes at some key polymorphic sites and African genotypes at others. I also applied the SeRRAMC method to an analysis of 5489 germline exomes from cancer patients spanning 22 disease groups. After stratifying the samples by race and ethnicity, the results show no significant correlations between KIR gene content and cancer but did identify a transmembrane domain polymorphism in the KIR3DL3 framework gene associated with melanoma and another variant in the KIR3DP1 pseudogene associated with prostate adenocarcinoma. The analysis also revealed significant batch effects due to disparities in the lengths of sequence reads produced by different sequencing centers. SeRRAMC processing is the first approach to enable these types of immunogenetic analyses. It also offers the first solution for quantifying KIR-specific gene transcripts from RNAseq data and for calling structural variants from de novo sequence assemblies generated by third generation single molecule or synthetic long read sequencing technologies

Evidence-Based Medicine and the Law: The Courts Confront Clinical Practice Guidelines

This article examines how courts are likely to apply evidence-based medicine, and particularly clinical practice guidelines (CPGs), in healthcare litigation involving quality-of-care and entitlement-to-benefits (coverage) claims. Exploring the “politics” of the current situation, it observes that, just as clinicians have been reluctant to use CPGs in practice, courts have been, and likely will continue to be, slow to apply them in deciding cases., The article analyzes extant and proposed statutory approaches to legitimizing and promoting courts’ use of CPGs. It concludes by renewing the author’s earlier and controversial proposal to establish a voluntary federal program for certifying guidelines and directing courts to give certified CPGs greater weight in healthcare litigation

The Rayed Head and Stepped Platform: A Core Symbol of the Southern Andean Iconographic Series

This paper will explore various manifestations of the Rayed Head motif that is found on textiles produced by the Nasca, Sihuas, and Pucara cultures during the Early Intermediate Period (200 BCE – 600 CE), in the southern Andean region of South America. The Brooklyn Museum’s famous Nasca mangle, also known as “The Paracas Textile,” features repeating images of the Rayed Head motif on its interior cotton panel. Sihuas mantles also display distinctive manifestations of the motif in the form of a large rectangular head with highly stylized features and surrounded by radiating appendages. The late textile scholar and archaeologist Joerg Haeberli has pointed out many similarities between Sihuas and Nasca textiles such as their weaving techniques and iconography (including the Rayed Head), and has proposed that the valleys of Arequipa and the south coast were linked during the late Early Horizon and Early Intermediate Period, perhaps due to dispersed Nasca enclaves in Arequipa. Utilizing textiles in the Brooklyn Museum and other public and private collections, the author will further explore this regional relationship as well as a similar iconographic correspondence with the Rayed Head motif found on Pucara-style objects associated with the Yaya-Mama (Father-Mother) religious tradition in the Lake Titicaca of Peru and Bolivia