The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart abnormalities: A systematic review and meta-analysis.

OBJECTIVES: To determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated with extra-cardiac malformations (ECMs) and CHA dependent upon anatomical subclassification. METHODS: A systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010-February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF-PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747. RESULTS: Overall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%-21.6%), 9.3% (95% CI, 6.6%-12.3%) and 35.9% (95% CI, 21.0%-52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%-65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%). CONCLUSION: The likelihood of a monogenic aetiology in fetuses with multi-system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions.

Combined effects of loneliness and inflammation on depression in people with HIV.

OBJECTIVE: Loneliness is prevalent in people with HIV (PWH) and associated with adverse health-related consequences, including depression. Chronic inflammation has been linked to depression in PWH, though its association with loneliness is less well established. Simultaneous examination of inflammation, loneliness and depression is needed to clarify these relationships. This study investigated the relationship between loneliness and inflammation, and the effects of loneliness and inflammation on depression in PWH. METHODS: 82 PWH who were on suppressive ART (mean age [SD] = 53.2 [9.0]) completed the UCLA Loneliness Scale-Version 3 and the Center for Epidemiologic Studies Depression Scale as part of a comprehensive evaluation. Biomarkers of systemic inflammation (CRP, IL-6, CCL2/MCP-1, sCD14) and coagulation (D-dimer) were measured in blood using commercial immunoassays. RESULTS: Multivariable linear regression analyses revealed that higher D-dimer, CCL2/MCP-1, and sCD14 were significant predictors of loneliness (ps < .05) while accounting for relevant covariates. Stepwise multiple linear regression models that included loneliness, biomarkers, and their interactions as predictors of depressive symptoms revealed significant main effects of loneliness and CCL2/MCP-1 levels (ps < .05), and a significant loneliness by D-dimer interaction (p < .05) whereby higher D-dimer was associated with increased depressive symptoms only at higher levels of loneliness. CONCLUSIONS: Increased coagulation activity is associated with loneliness, and in the context of loneliness, may increase risk for depression. Increased inflammation was associated with depression suggesting potentially dissociable underlying biological processes. To the extent that these processes are modifiable, such findings could have important implications in the treatment of loneliness and depression in PWH.

Causalgia: A Review of Nerve Resection, Amputation, Immunotherapy, and Amputated Limb CRPS II Pathology.

BACKGROUND: Causalgia and complex regional pain syndrome (CRPS) type II with nerve injury can be difficult to treat. Surgical peripheral nerve denervation for causalgia has been largely abandoned by pain clinicians because of a perception that this may aggravate a central component (anesthesia dolorosa). METHODS: We selectively searched Pubmed, Cochrane, MEDLINE, EMBASE, CINAHL Plus, and Scopus from 1947 for articles, books, and book chapters for evidence of surgical treatments (nerve resection and amputation) and treatment related to autoimmunity and immune deficiency with CRPS. RESULTS: Reviews were found for the treatment of causalgia or CRPS type II (n = 6), causalgia relieved by nerve resection (n = 6), and causalgia and CRPS II treated by amputation (n = 8). Twelve reports were found of autoimmunity with CRPS, one paper of these on associated immune deficiency and autoimmunity, and two were chosen for discussion regarding treatment with immunoglobulin and one by plasma exchange. We document a report of a detailed and unique pathological examination of a CRPS type II affected amputated limb and related successful treatment with immunoglobulin. CONCLUSIONS: Nerve resection, with grafting, and relocation may relieve uncomplicated causalgia and CRPS type II in some patients in the long term. However, an unrecognized and treatable immunological condition may underly some CRPS II cases and can lead to the ultimate failure of surgical treatments.

Transarterial chemoembolisation for very early and early stage hepatocellular carcinoma: single-centre experience.

AIM: To evaluate the safety and efficacy of transarterial chemoembolisation (TACE) in patients with very early and early stage hepatocellular carcinoma (VES-HCC). MATERIALS AND METHODS: A retrospective analysis was performed for all TACE procedures done at King's College Hospital, a tertiary liver centre, for VES-HCC during a 5-year period (January 2014-December 2018). Patients with solitary tumours ≤5 cm and patients with 2-3 tumours (each ≤3 cm) were included. RESULTS: Two hundred and thirty-seven eligible patients were included. Technical success was achieved in 233 (98.3%) procedures. TACE using drug-eluting beads (DEB-TACE) was performed in 192 (82.4%) procedures. A complete response was achieved in 109 (45.9%) patients. The recurrence rate was 44% (48 cases), during a median imaging follow-up of 31.9 months (IQR 15.9-44.7). Median overall survival was 71.1 months (95% confidence interval [CI]: 62.9-79.3). Median recurrence-free survival was 58.9 months (95% CI: 47.1-70.7). Sixty-six (27.8%) patients eventually underwent transplantation, and six (2.5%) patients underwent surgical resection. Mild, moderate, and severe adverse events were encountered in 2.9%, 5.4%, and 0.8% of cases, respectively. No 30-day mortality was encountered. CONCLUSION: DEB-TACE is safe and effective for treating VES-HCC patients, who are unsuitable for thermal ablation or surgery, and may offer comparable survival benefit. It can also be used as a bridge to transplantation for these patients.

Intensive Care Interventions Among Children With Toxicologic Exposures to Cardiovascular Medications.

OBJECTIVES: Interventions requiring a PICU are rare in toxicologic exposures, but cardiovascular medications are high-risk exposures due to their hemodynamic effects. This study aimed to describe prevalence of and risk factors for PICU interventions among children exposed to cardiovascular medications. DESIGN: Secondary analysis of Toxicology Investigators Consortium Core Registry from January 2010 to March 2022. SETTING: International multicenter research network of 40 sites. PATIENTS: Patients 18 years old or younger with acute or acute-on-chronic toxicologic exposure to cardiovascular medications. Patients were excluded if exposed to noncardiovascular medications or if symptoms were documented as unlikely related to exposure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,091 patients in the final analysis, 195 (17.9%) received PICU intervention. One hundred fifty-seven (14.4%) received intensive hemodynamic interventions and 602 (55.2%) received intervention in general. Children less than 2 years old were less likely to receive PICU intervention (odds ratio [OR], 0.42; 95% CI, 0.20-0.86). Exposures to alpha-2 agonists (OR, 2.0; 95% CI, 1.11-3.72) and antiarrhythmics (OR, 4.26; 95% CI, 1.41-12.90) were associated with PICU intervention. In the sensitivity analysis removing atropine from the composite outcome PICU intervention, only exposures to calcium channel antagonists (OR, 2.12; 95% CI, 1.09-4.11) and antiarrhythmics (OR, 4.82; 95% CI, 1.57-14.81) were independently associated with PICU intervention. No independent association was identified between PICU intervention and gender, polypharmacy, intentionality or acuity of exposure, or the other medication classes studied. CONCLUSIONS: PICU interventions were uncommon but were associated with exposure to antiarrhythmic medications, calcium channel antagonists, and alpha-2 agonists. As demonstrated via sensitivity analysis, exact associations may depend on institutional definitions of PICU intervention. Children less than 2 years old are less likely to require PICU interventions. In equivocal cases, age and exposure to certain cardiovascular medication classes may be useful to guide appropriate disposition.

Performance-enhancing drugs and the Olympics.

The rules of fair play in sport generally prohibit the use of performance-enhancing drugs (PEDs). The World Anti-Doping Agency (WADA) oversees global antidoping regulations and testing for elite athletes participating in Olympic sports. Efforts to enforce antidoping policies are complicated by the diverse and evolving compounds and strategies employed by athletes to gain a competitive edge. Now between the uniquely proximate 2021 Tokyo and 2022 Beijing Olympic Games, we discuss WADA's efforts to prevent PED use during the modern Olympic Games. Then, we review the major PED classes with a focus on pathophysiology, complexities of antidoping testing, and relevant toxicities. Providers from diverse practice environments are likely to care for patients using PEDs for a variety of reasons and levels of sport; these providers should be aware of common PED classes and their risks.

Binge Drinking Relates to Worse Neurocognitive Functioning Among Adults Aging with HIV.

OBJECTIVE: Given the aging population of people with HIV (PWH), along with increasing rates of binge drinking among both PWH and the general older adult population, this study examined the independent and interactive effects of HIV, binge drinking, and age on neurocognition. METHOD: Participants were 146 drinkers stratified by HIV and binge drinking status (i.e., ≥4 drinks for women and ≥5 drinks for men within approximately 2 h): HIV+/Binge+ (n = 30), HIV-/Binge+ (n = 23), HIV+/Binge- (n = 55), HIV-/Binge- (n = 38). All participants completed a comprehensive neuropsychological battery measuring demographically-corrected global and domain-specific neurocognitive T scores. ANCOVA models examined independent and interactive effects of HIV and binge drinking on neurocognitive outcomes, adjusting for overall alcohol consumption, lifetime substance use, sex, and age. Subsequent multiple linear regressions examined whether HIV/Binge group moderated the relationship between age and neurocognition. RESULTS: HIV+/Binge+ participants had worse global neurocognition, processing speed, delayed recall, and working memory than HIV-/Binge- participants (p's < .05). While there were significant main effects of HIV and binge drinking, their interaction did not predict any of those neurocognitive outcomes (p's > .05). Significant interactions between age and HIV/Binge group showed that HIV+/Binge+ participants demonstrated steeper negative relationships between age and neurocognitive outcomes of learning, delayed recall, and motor skills compared to HIV-/Binge- participants (p's < .05). CONCLUSIONS: Results showed adverse additive effects of HIV and binge drinking on neurocognitive functioning, with older adults demonstrating the most vulnerability to these effects. Findings support the need for interventions to reduce binge drinking, especially among older PWH.

Shotgun metagenome sequencing of a Sudanese toombak snuff tobacco: genetic attributes of a high tobacco-specific nitrosamine containing smokeless tobacco product.

The most alarming aspect of the Sudanese toombak smokeless tobacco is that it contains high levels of highly toxic tobacco-specific nitrosamines (TSNAs). Understanding the microbiology of toombak is of relevance because TSNAs are an indirect result of microbial-mediated nitrate reductions. We conducted shotgun metagenomic sequencing on a toombak product for which relevant features are presented here. The microbiota was composed of over 99% Bacteria. The most abundant taxa included Actinobacteria, specifically the genera Enteractinococcus and Corynebacterium, while Firmicutes were represented by the family Bacillaceae and the genus Staphylococcus. Selected gene targets were nitrate reduction and transport, antimicrobial resistance, and other genetic transference mechanisms. Canonical nitrate reduction and transport genes (i.e. nar) were found for Enteractinococcus and Corynebacterium while various species of Staphylococcus exhibited a notable number of antimicrobial resistance and genetic transference genes. The nitrate reduction activity of the microbiota in toombak is suspected to be a contributing factor to its high levels of TSNAs. Additionally, the presence of antimicrobial resistance and transference genes could contribute to deleterious effects on oral and gastrointestinal health of the end user. Overall, the high toxicity and increased incidences of cancer and oral disease of toombak users warrants further investigation into the microbiology of toombak.

Daily Cannabis Use is Associated With Lower CNS Inflammation in People With HIV.

OBJECTIVE: Recent cannabis exposure has been associated with lower rates of neurocognitive impairment in people with HIV (PWH). Cannabis's anti-inflammatory properties may underlie this relationship by reducing chronic neuroinflammation in PWH. This study examined relations between cannabis use and inflammatory biomarkers in cerebrospinal fluid (CSF) and plasma, and cognitive correlates of these biomarkers within a community-based sample of PWH. METHODS: 263 individuals were categorized into four groups: HIV- non-cannabis users (n = 65), HIV+ non-cannabis users (n = 105), HIV+ moderate cannabis users (n = 62), and HIV+ daily cannabis users (n = 31). Differences in pro-inflammatory biomarkers (IL-6, MCP-1/CCL2, IP-10/CXCL10, sCD14, sTNFR-II, TNF-α) by study group were determined by Kruskal-Wallis tests. Multivariable linear regressions examined relationships between biomarkers and seven cognitive domains, adjusting for age, sex/gender, race, education, and current CD4 count. RESULTS: HIV+ daily cannabis users showed lower MCP-1 and IP-10 levels in CSF compared to HIV+ non-cannabis users (p = .015; p = .039) and were similar to HIV- non-cannabis users. Plasma biomarkers showed no differences by cannabis use. Among PWH, lower CSF MCP-1 and lower CSF IP-10 were associated with better learning performance (all ps < .05). CONCLUSIONS: Current daily cannabis use was associated with lower levels of pro-inflammatory chemokines implicated in HIV pathogenesis and these chemokines were linked to the cognitive domain of learning which is commonly impaired in PWH. Cannabinoid-related reductions of MCP-1 and IP-10, if confirmed, suggest a role for medicinal cannabis in the mitigation of persistent inflammation and cognitive impacts of HIV.

The resilience of the developing reading system: multi-modal evidence of incident and recovery after a pediatric stroke.

Decades of neuroscientific findings have elucidated the highly specialized brain areas involved in reading, especially along the ventral occipitotemporal stream where the critical step of recognizing words occurs. We report on a 14-year-old female with temporary dyslexia after a left ventral occipitotemporal ischemic stroke. Our longitudinal multimodal findings show that the resolution of the reading impairment was associated with heightened activity in the left posterior superior and inferior temporal gyri. Our findings highlight the role of the left inferior temporal gyrus in reading and the importance of perilesional and ipsilateral cortical areas for functional recovery after childhood stroke.

Industrial workwear for hot workplace environments: thermal management attributes.

Personal protective clothing (PPC) is critical for worker safety and wellbeing from both protection and thermal management perspectives, particularly as PPC typically covers more than 90% of the body. Research of PPC in low-risk categories such as mining, oil, gas, and construction and their thermal management attributes is limited, although these industries represent a significant proportion of the industrial workforce, work across a broad range of major industries, and frequently work in hot and/or humid thermal environments. This study evaluated and characterized the thermal management attributes of a selection of commercial low-level risk PPC ensembles currently used around the world as well as a civilian/corporate wear ensemble, using a sweating thermal manikin. The results demonstrate that there are substantially poorer thermal attributes for the PPC ensembles. Predicted Heat Strain Index (PHS) results for hot conditions reveal significantly lower duration limited exposure (DLE) and considerably greater body water loss for the wearers of PPC. Opportunities to substantially reduce PPC material mass and improve construction for these low-level risk categories in order to enhance thermal management performance are identified. Relationships between the thermal attributes of PPC and civilian clothing, and their garment construction, fit, and material characteristics are identified, providing new and important knowledge for current performance and direction for development of new improved PPC. This study provides researchers, developers, and garment designers with valuable insights for future improvement of PPC to create improved PPC for industrial workwear worn in hot environments.

Microbial communities and gene contributions in smokeless tobacco products.

Smokeless tobacco products (STP) contain bacteria, mold, and fungi due to exposure from surrounding environments and tobacco processing. This has been a cause for concern since the presence of microorganisms has been linked to the formation of highly carcinogenic tobacco-specific nitrosamines. These communities have also been reported to produce toxins and other pro-inflammatory molecules that can cause mouth lesions and elicit inflammatory responses in STP users. Moreover, microbial species in these products could transfer to the mouth and gastrointestinal tract, potentially altering the established respective microbiotas of the consumer. Here, we present the first metagenomic analysis of select smokeless tobacco products, specifically US domestic moist and dry snuff. Bacterial, eukaryotic, and viral species were found in all tobacco products where 68% of the total species was comprised of Bacteria with 3 dominant phyla but also included 32% Eukarya and 1% share abundance for Archaea and Viruses. Furthermore, 693,318 genes were found to be present and included nitrate and nitrite reduction and transport enzymes, antibiotic resistance genes associated with resistance to vancomycin, ß-lactamases, their derivatives, and other antibiotics, as well as genes encoding multi-drug transporters and efflux pumps. Additional analyses showed the presence of endo- and exotoxin genes in addition to other molecules associated with inflammatory responses. Our results present a novel aspect of the smokeless tobacco microbiome and provide a better understanding of these products' microbiology. KEY POINTS: • The findings presented will help understand microbial contributions to overall STP chemistries. • Gene function categorization reveals harmful constituents outside canonical forms. • Pathway genes for TSNA precursor activity may occur at early stages of production. • Bacteria in STPs carry antibiotic resistance genes and gene transfer mechanisms.

Integrating animal welfare into disaster management using an 'all-hazards' approach.

Statistics show that disasters have expanded in scope and scale, with impacts on both humans and animals. As animals are valued not only for their economic value, but also for their companionship, people sometimes risk their lives to protect them, and emergency responders are expected to safeguard their welfare during emergencies. This paper discusses experiences from different regions of the world in animal disaster risk reduction and management in terms of legislation, funding streams, planning, capacity development, and communications. It is widely recognised that human, animal and environmental well-being are interconnected; therefore, as this is the case, and as veterinarians are at the forefront in ensuring animal welfare, they should be involved throughout the disaster management cycle. While animals and their welfare should always be considered in national disaster management plans, sub-regional authorities must be empowered to integrate animal welfare principles when responding to emergencies and implementing risk reduction programmes. Capacity development is key for Veterinary Services personnel who work in the fields of disaster management and risk reduction. Training tools and curricula developed by different organisations are available to foster skills such as incident coordination, risk communication, or response planning using tools such as the Livestock Emergency Guidelines and Standards (LEGS). Intergovernmental organisations also play a significant role in setting the standards and frameworks within which professionals operate.

Les données statistiques montrent un accroissement de l'amplitude et de la portée des catastrophes ainsi que l'impact qu'elles peuvent avoir sur les populations humaines et animales. La valeur des animaux n'étant pas seulement économique mais également affective, en cas de catastrophe c'est parfois au péril de leur vie que des personnes tentent de sauver animaux et il est attendu des services de secours d'urgence qu'ils prennent en compte le bien-être animal lors de leurs interventions. Les auteurs examinent l'expérience acquise dans diverses régions du monde en matière de réduction et de gestion des risques de catastrophes affectant les animaux, notamment en termes de législation, de mécanismes de financement, de planification, de renforcement des capacités et de communication. Il est désormais établi que le bien-être humain et animal et la qualité environnementale sont étroitement interconnectés ; par conséquent, il est important que les vétérinaires, qui assurent en première ligne la protection du bien-être animal, soient également associés à toutes les phases du cycle de la gestion des catastrophes. S'il est indispensable que les plans nationaux de gestion des catastrophes prennent en compte les animaux et leur bien-être, les autorités locales devraient également être habilitées à intégrer les principes du bien-être animal lors des interventions d'urgence et de la mise en œuvre des programmes de réduction des risques. Il est crucial de renforcer les capacités des personnels des Services vétérinaires qui travaillent dans les domaines de la gestion des catastrophes et de la réduction des risques. Un certain nombre d'outils et de programmes de formation conçus par différentes organisations sur la base des Normes et directives pour l'aide d'urgence à l'élevage (LEGS) permettent de mettre en place des compétences spécialisées dans la coordination en cas d'incidents, la communication sur les risques et la planification des interventions d'urgence. Les organisations intergouvernementales jouent également un rôle important en établissant les normes et les cadres d'intervention applicables aux professionnels.

Los datos estadísticos demuestran que tanto el alcance como la escala de los desastres van en aumento y repercuten en poblaciones tanto humanas como animales. A veces las personas arriesgan la vida para proteger a sus animales, pues el apego a ellos responde no solo a su valor económico, sino también a consideraciones afectivas. Por este motivo, del personal que interviene en situaciones de emergencia se espera que salvaguarde también el bienestar de los animales. Los autores describen experiencias de distintas regiones del mundo en materia de reducción y gestión del riesgo de desastre ganadero, deteniéndose en aspectos como la legislación, los flujos de financiación, la planificación, la adquisición de medios de acción y las comunicaciones. Poca duda cabe de que el bienestar humano, el animal y el ambiental están conectados entre sí. Si tal es el caso, y dado que los veterinarios son los primeros responsables de velar por el bienestar animal, es obvio que habría que integrarlos en todas las fases del ciclo de gestión de desastres. A la vez que en los planes nacionales de gestión de desastres siempre se debe tener presente la cuestión de los animales y su bienestar, también es preciso que las autoridades de ámbito infrarregional estén capacitadas para integrar los principios del bienestar animal en la respuesta a situaciones de emergencia y en los programas de reducción del riesgo que implanten. La adquisición de capacidad es un elemento clave para el personal de los Servicios Veterinarios que trabaja en la gestión de desastres y la reducción del correspondiente riesgo. Existen herramientas de formación y planes de estudios elaborados por diversas organizaciones que sirven para potenciar competencias como las de coordinación en caso de incidente, comunicación del riesgo o planificación de la respuesta con empleo de las directrices y normas para emergencias ganaderas (Livestock Emergency Guidelines and Standards, LEGS). Las organizaciones intergubernamentales cumplen también una importante función a la hora de establecer las normas y marcos de referencia que encuadran la labor de los profesionales.

Phase I study of emactuzumab single agent or in combination with paclitaxel in patients with advanced/metastatic solid tumors reveals depletion of immunosuppressive M2-like macrophages.

BACKGROUND: Emactuzumab is a monoclonal antibody against the colony-stimulating factor-1 receptor and targets tumor-associated macrophages (TAMs). This study assessed the safety, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of emactuzumab, as monotherapy and in combination with paclitaxel, in patients with advanced solid tumors. PATIENTS AND METHODS: This open-label, phase Ia/b study comprised two parts (dose escalation and dose expansion), each containing two arms (emactuzumab, every 2 or 3 weeks, as monotherapy or in combination with paclitaxel 80 mg/m2 weekly). The dose-escalation part explored the maximum tolerated dose and optimal biological dose (OBD). The dose-expansion part extended the safety assessment and investigated the objective response rate. A PK/PD analysis of serial blood, skin and tumor biopsies was used to explore proof of mechanism and confirm the OBD. RESULTS: No maximum tolerated dose was reached in either study arm, and the safety profile of emactuzumab alone and in combination does not appear to preclude its use. No patients receiving emactuzumab monotherapy showed an objective response; the objective response rate for emactuzumab in combination with paclitaxel was 7% across all doses. Skin macrophages rather than peripheral blood monocytes or circulating colony-stimulating factor-1 were identified as an optimal surrogate PD marker to select the OBD. Emactuzumab treatment alone and in combination with paclitaxel resulted in a plateau of immunosuppressive TAM reduction at the OBD of 1000 mg administered every 2 weeks. CONCLUSIONS: Emactuzumab showed specific reduction of immunosuppressive TAMs at the OBD in both treatment arms but did not result in clinically relevant antitumor activity alone or in combination with paclitaxel. (ClinicalTrials.gov Identifier: NCT01494688).

Deterministic entanglement of superconducting qubits by parity measurement and feedback.

The stochastic evolution of quantum systems during measurement is arguably the most enigmatic feature of quantum mechanics. Measuring a quantum system typically steers it towards a classical state, destroying the coherence of an initial quantum superposition and the entanglement with other quantum systems. Remarkably, the measurement of a shared property between non-interacting quantum systems can generate entanglement, starting from an uncorrelated state. Of special interest in quantum computing is the parity measurement, which projects the state of multiple qubits (quantum bits) to a state with an even or odd number of excited qubits. A parity meter must discern the two qubit-excitation parities with high fidelity while preserving coherence between same-parity states. Despite numerous proposals for atomic, semiconducting and superconducting qubits, realizing a parity meter that creates entanglement for both even and odd measurement results has remained an outstanding challenge. Here we perform a time-resolved, continuous parity measurement of two superconducting qubits using the cavity in a three-dimensional circuit quantum electrodynamics architecture and phase-sensitive parametric amplification. Using postselection, we produce entanglement by parity measurement reaching 88 per cent fidelity to the closest Bell state. Incorporating the parity meter in a feedback-control loop, we transform the entanglement generation from probabilistic to fully deterministic, achieving 66 per cent fidelity to a target Bell state on demand. These realizations of a parity meter and a feedback-enabled deterministic measurement protocol provide key ingredients for active quantum error correction in the solid state.

Pancreatic allograft thrombosis: Suggestion for a CT grading system and management algorithm.

Pancreatic allograft thrombosis (PAT) remains the leading cause of nonimmunologic graft failure. Here, we propose a new computed tomography (CT) grading system of PAT to identify risk factors for allograft loss and outline a management algorithm by retrospective review of consecutive pancreatic transplantations between 2009 and 2014. Triple-phase CT scans were graded independently by 2 radiologists as grade 0, no thrombosis; grade 1, peripheral thrombosis; grade 2, intermediate non-occlusive thrombosis; and grade 3, central occlusive thrombosis. Twenty-four (23.3%) of 103 recipients were diagnosed with PAT (including grade 1). Three (2.9%) grafts were lost due to portal vein thrombosis. On multivariate analysis, pancreas after simultaneous pancreas-kidney transplantation/solitary pancreatic transplantation, acute rejection, and CT findings of peripancreatic edema and/or inflammatory change were significant risk factors for PAT. Retrospective review of CT scans revealed more grade 1 and 2 thromboses than were initially reported. There was no significant difference in graft or patient survival, postoperative stay, or morbidity of recipients with grade 1 or 2 thrombosis who were or were not anticoagulated. Our data suggest that therapeutic anticoagulation is not necessary for grade 1 and 2 arterial and grade 1 venous thrombosis. The proposed grading system can assist clinicians in decision-making and provide standardized reporting for future studies.

Risk of pre-eclampsia in women taking metformin: a systematic review and meta-analysis.

AIMS: To perform meta-analyses of studies evaluating the risk of pre-eclampsia in high-risk insulin-resistant women taking metformin prior to, or during pregnancy. METHODS: A search was conducted of the Medline, EMBASE, Web of Science and Scopus databases. Both randomized controlled trials and prospective observational cohort studies of metformin treatment vs. placebo/control or insulin either prior to or during pregnancy were selected. The main outcome measure was the incidence of pre-eclampsia in each treatment group. RESULTS: Overall, in five randomized controlled trials comparing metformin treatment (n = 611) with placebo/control (n = 609), no difference in the risk of pre-eclampsia was found [combined/pooled risk ratio (RR), 0.86 (95% CI 0.33-2.26); P = 0.76; I2  = 66%]. Meta-analysis of four cohort studies again showed no significant effect [RR, 1.21 (95% CI 0.56-2.61); P = 0.62; I2  = 30%]. A meta-analysis of eight randomized controlled trials comparing metformin (n = 838) with insulin (n = 836), however, showed a reduced risk of pre-eclampsia with metformin [RR, 0.68 (95% CI 0.48-0.95); P = 0.02; I2  = 0%]. No heterogeneity was present in the metformin vs. insulin analysis of randomized controlled trials, whereas high levels of heterogeneity were present in studies comparing metformin with placebo/control. Pre-eclampsia was a secondary outcome in most of the studies. The mean weight gain from time of enrolment to delivery was lower in the metformin group (P = 0.05, metformin vs. placebo; P = 0.004, metformin vs. insulin). CONCLUSIONS: In studies randomizing pregnant women to glucose-lowering therapy, metformin was associated with lower gestational weight gain and a lower risk of pre-eclampsia compared with insulin.

Genotypes, phenotypes and whole genome sequence: Approaches from the My Life Our Future haemophilia project.

INTRODUCTION: Information from the genes encoding factor VIII (F8) and IX (F9) is used in reproductive planning and to inform inhibitor formation, bleeding severity and response to therapies. Advances in technology and our understanding of the human genome now allows more comprehensive methods to study genomic variation and its impact on haemophilia. AIMS: The My Life Our Future (MLOF) programme was begun in 2012 to provide genetic analysis and to expand research in haemophilia through a research repository. METHODS: MLOF enrolled haemophilia A and B patients followed at haemophilia treatment centers in the U.S., including, since 2015, known and potential genetic carriers. Initial F8 and F9 DNA analysis was performed utilizing a next generation sequencing approach which allowed simultaneous detection of F8 inversions and other variants. Candidate variants were confirmed using a second method and multiplex ligation-dependent probe amplification was used to detect structural variants. RESULTS: The initial phase of MLOF completed enrollment in December 2017 with 11,356 patients, genetic carriers, and potential carriers enrolled. In the 9453 subjects in whom analysis is complete, 687 unique previously unreported variants were found. Simultaneous sequencing of the F8 and F9 genes resulted in identification of non-deleterious variants previously reported as causative in haemophilia. DNA from 5141 MLOF subjects has undergone whole genome sequencing through the NHLBI TOPMed programme of the U.S. NIH. CONCLUSION: MLOF has provided genetic information for patients and their families to help inform clinical care and has established a repository of data and biospecimens to further advance haemophilia research.

Coherent singlet-triplet oscillations in a silicon-based double quantum dot.

Silicon is more than the dominant material in the conventional microelectronics industry: it also has potential as a host material for emerging quantum information technologies. Standard fabrication techniques already allow the isolation of single electron spins in silicon transistor-like devices. Although this is also possible in other materials, silicon-based systems have the advantage of interacting more weakly with nuclear spins. Reducing such interactions is important for the control of spin quantum bits because nuclear fluctuations limit quantum phase coherence, as seen in recent experiments in GaAs-based quantum dots. Advances in reducing nuclear decoherence effects by means of complex control still result in coherence times much shorter than those seen in experiments on large ensembles of impurity-bound electrons in bulk silicon crystals. Here we report coherent control of electron spins in two coupled quantum dots in an undoped Si/SiGe heterostructure and show that this system has a nuclei-induced dephasing time of 360 nanoseconds, which is an increase by nearly two orders of magnitude over similar measurements in GaAs-based quantum dots. The degree of phase coherence observed, combined with fast, gated electrical initialization, read-out and control, should motivate future development of silicon-based quantum information processors.

Donors With Immune Thrombocytopenia: Do They Pose a Risk to Transplant Recipients?

Transplant-mediated alloimmune thrombocytopenia (TMAT) from donors with immune thrombocytopenia (ITP) can result in significant bleeding complications in the recipient. The risk to a recipient of TMAT if they receive an organ from a donor with ITP is unknown. The outcomes of recipients of organs from deceased donors with ITP recorded in the UK Transplant Registry between 2000 and 2015 were reviewed. Twenty-one deceased organ donors had a predonation diagnosis of ITP. These donors were significantly more likely to have died from intracranial hemorrhage than were all other deceased organ donors (85% vs. 57%, p < 0.001). Organs from donors with ITP resulted in 49 organ transplants (31 kidney, 14 liver, four heart), with only one case of TMAT, which occurred in a liver transplant recipient and resulted in death from bleeding complications 18 days posttransplantation. The recipient of a kidney from the same organ donor was not affected. Unadjusted 5-year patient and graft survival was significantly worse for liver transplant recipients from donors with ITP compared with liver transplant recipients from donors without ITP (64% vs. 85%, p = 0.012). Organs from donors with ITP may be considered for transplantation, but livers should be used with caution.