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

The Enhanced Danger of Physicians’ Off-Label Prescribing

The COVID-19 pandemic represents a major challenge to both technologically advanced and resource-poor countries. There are currently no effective treatments for severe disease other than supportive care and advanced life support measures, including the use of mechanical ventilators. With the urgency and necessity bred from desperation, there have been many calls to utilize unproven therapies, such as hydroxychloroquine, for which little evidence of efficacy exists. We have previously argued that such off-label use, while legal, is problematic (and even dangerous) and have suggested several regulatory remedies that could protect patients and advance their interests while preserving the reasonable authority of physicians to do what they and their patients think is the best course of action. In this essay we ask whether the special conditions existing in a public healthcare crisis, such as the current pandemic, would justify a relaxing of our argument and permit ongoing unregulated off-label use. We outline at least four areas of concern, all of which can be exacerbated by the widespread distress and despair amongst doctors, patients and other stakeholders. We contend that, if anything, these conditions warrant even more caution and scrutiny of this practice

Impact of Modifiable Bleeding Risk Factors on Major Bleeding in Patients With Atrial Fibrillation Anticoagulated With Rivaroxaban.

Background Reducing major bleeding events is a challenge when managing anticoagulation in patients with atrial fibrillation. This study evaluated the impact of modifiable and nonmodifiable bleeding risk factors in patients with atrial fibrillation receiving rivaroxaban and estimated the impact of risk factor modification on major bleeding events. Methods and Results Modifiable and nonmodifiable risk factors associated with major bleeding events were identified from the XANTUS (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation) prospective registry data set (6784 rivaroxaban-treated patients). Parameters showing univariate association with bleeding were used to construct a multivariable model identifying independent risk factors. Modeling was used to estimate attributed weights to risk factors. Heavy alcohol use (hazard ratio [HR]=2.37; 95% CI 1.24-4.53); uncontrolled hypertension (HR after parameter-wise shrinkage=1.79; 95% CI 1.05-3.05); and concomitant treatment with antiplatelets, nonsteroidal anti-inflammatory drugs, or paracetamol (HR=1.80; 95% CI 1.24-2.61) were identified as modifiable, independent bleeding risk factors. Increasing age (HR=1.25 [per 5-year increment]; 95% CI 1.12-1.38); heart failure (HR=1.97; 95% CI 1.36-2.86); and vascular disease (HR=1.91; 95% CI 1.32-2.77) were identified as nonmodifiable bleeding risk factors. Overall, 128 (1.9%) patients experienced major bleeding events; of these, 11% had no identified bleeding risk factors, 50% had nonmodifiable bleeding risk factors only, and 39% had modifiable bleeding risk factors (with or without nonmodifiable risk factors). The presence of 1 modifiable bleeding risk factor doubled the risk of major bleeding. Conclusions Elimination of modifiable bleeding risk factors is a potentially effective strategy to reduce bleeding risk in atrial fibrillation patients receiving rivaroxaban. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01606995

Neodymium isotopic composition and concentration in the western North Atlantic Ocean: results from the GEOTRACES GA02 section

The neodymium (Nd) isotopic composition of seawater is commonly used as a proxy to study past changes in the thermohaline circulation. The modern database for such reconstructions is however poor and the understanding of the underlying processes is incomplete. Here we present new observational data for Nd isotopes and concentrations from twelve seawater depth profiles, which follow the flow path of North Atlantic Deep Water (NADW) from its formation region in the North Atlantic to the northern equatorial Atlantic. Samples were collected during two cruises constituting the northern part of the Dutch GEOTRACES transect GA02 in 2010. The results show that the different water masses in the subpolar North Atlantic Ocean, which ultimately constitute NADW, have the following Nd isotope characteristics: Upper Labrador Sea Water (ULSW), εNd = -14.2 ± 0.3; Labrador Sea Water (LSW), εNd = -13.7 ± 0.9; Northeast Atlantic Deep Water (NEADW), εNd = -12.5 ± 0.6; Northwest Atlantic Bottom Water (NWABW), εNd = -11.8 ± 1.4. In the subtropics, where these source water masses have mixed to form NADW, which is exported to the global ocean, upper-NADW is characterised by εNd values of -13.2 ± 1.0 (2sd) and lower-NADW exhibits values of εNd = -12.4 ± 0.4 (2sd). While both signatures overlap within error, the signature for lower-NADW is significantly more radiogenic than the traditionally used value for NADW (εNd = -13.5) due to the dominance of source waters from the Nordic Seas (NWABW and NEADW). Comparison between the concentration profiles and the corresponding Nd isotope profiles with other water mass properties such as salinity, silicate concentrations, neutral densities and chlorofluorocarbon (CFC) concentration provides novel insights into the geochemical cycle of Nd and reveals that different processes are necessary to account for the observed Nd characteristics in the subpolar and subtropical gyres and throughout the vertical water column. While our data set provides additional insights into the contribution of boundary exchange in areas of sediment resuspension, the results for open ocean seawater demonstrate, at an unprecedented level, the suitability of Nd isotopes to trace modern water masses in the strongly advecting western Atlantic Ocean

Stapled Porcine Pericardium Displays Lower Infectivity In Vitro Than Native and Sutured Porcine Pericardium.

Biological xenografts using tubulized porcine pericardium are an alternative to replace infected prosthetic graft. We recently reported an innovative technique using a stapled porcine pericardial bioconduit for immediate vascular reconstruction in emergency. The objective of this study is to compare the growth and adherence to grafts of bacteria and yeast incubated with stapled porcine pericardium, sutured or naked pericardium. One square centimeter of porcine pericardial patches, with or without staples or sutures, was incubated with 10 <sup>5</sup> colony forming units of Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, and Candida albicans for 1, 6, and 24 h. The medium was collected to quantify planktonic microorganisms, while grafts were sonicated to quantify adherent microorganisms. Dacron and Dacron Silver were analyzed in parallel as synthetic reference prostheses. Stapled porcine pericardium reduced the growth and the adherence of E coli (2- to 30-fold; P < 0.0005), S aureus (11- to 1000-fold; P < 0.0006), S epidermidis (>500-fold; P < 0.0001), and C albicans (12- to 50-fold; P < 0.0001) when compared to medium alone (growth) and pericardium or Dacron (adherence). Native and sutured porcine pericardium interfered with the growth and the adherence of E coli and C albicans, and Dacron with that of S epidermidis. As expected, Dacron Silver was robustly bactericidal. Stapled porcine pericardium exhibited a lower susceptibility to infection by bacteria and yeasts in vitro when compared to the native and sutured porcine pericardium. Stapled porcine pericardium might be a good option for rapid vascular grafting without increasing infectivity

Impact of gender: Rivaroxaban for patients with atrial fibrillation in the XANTUS real-world prospective study.

BACKGROUND: The XANTUS study (NCT01606995) demonstrated low rates of stroke and major bleeding in patients with atrial fibrillation (AF) receiving rivaroxaban in clinical practice for the prevention of thromboembolic events (N = 6784). HYPOTHESIS: Because previous real-world studies have not reported gender-dependent responses to rivaroxaban treatment, this sub-analysis of the XANTUS study investigated the effect of gender on outcomes. METHODS: The centrally adjudicated outcomes were compared between genders. Primary outcomes were major bleeding and all-cause death. Secondary outcomes included symptomatic thromboembolic events. Multivariable Cox regression analysis was performed to assess the effect of risk factors on outcomes between genders. RESULTS: A total of 2765 female and 4016 male patients were included in the analysis. Baseline characteristics were generally similar. No nominally significant interaction between gender and risk factors for the study outcomes was observed. Rates of major bleeding, all-cause death and symptomatic thromboembolic events in patients with non-valvular AF receiving rivaroxaban for stroke prevention were similar in men and women; no significant differences in risk factors for these outcomes were observed between genders. CONCLUSIONS: Further research is needed to better characterize the relative importance of different risk factors on outcomes in men vs women and to determine whether gender differences exist in patients treated with non-vitamin K antagonist oral anticoagulants

Impact of the COVID-19 pandemic on Swiss pregnant and breastfeeding women - a cross-sectional study covering the first pandemic wave.

Information on the impact of the COVID-19 pandemic on pregnancy and breastfeeding experiences, as well as on perinatal mental health in Switzerland is limited. In Switzerland, there are few national studies and little information. Using an anonymous online survey accessible after the first wave of the outbreak in Switzerland, we have investigated how this pandemic affected pregnant and breastfeeding women. Among women who completed the survey, 69.0% (1050/1518) indicated the first wave of the pandemic affected their personal habits, 61.0% (689/1131) were affected in their work and 40.0% (632/1573) reported impaired relations with healthcare services (different denominators correspond to the number of participants who answered the question). 36.8% (110/299) of women reported an impact of the pandemic on their current pregnancy experience or breastfeeding experience (8.2%, 46/555). Overall, 11.6% (170/1467) of participants who completed the validated screening tests for mental health symptoms (Edinburgh Postnatal Depression Scale, Generalized Anxiety Disorder 7, Perceived Stress Scale) presented a score compatible with symptoms of major depression, severe anxiety or high perceived stress, which is higher than in the pre-pandemic period according to literature. Risk factors independently associated with impaired mental health were being hospitalized, having symptoms of COVID-19, living with a person with COVID-19 symptoms, having comorbidities, having experienced reduced healthcare services, having restricted usual activities and being a housewife. Protective factors independently associated were a high level of education and living with a partner. Our findings suggest that the COVID-19 pandemic might have significantly affected the well-being and mental health of pregnant and breastfeeding women, directly in the case of exposure, and indirectly as a result of the potential modifications in their life habits and in healthcare facilities