How I treat myeloproliferative neoplasms in pregnancy.

ABSTRACT: Although myeloproliferative neoplasms (MPNs) are traditionally considered diseases of adults in their sixth or seventh decade, these conditions do occur in young patients; for example, for essential thrombocythemia, in particular, there is a second peak in women of reproductive age. Therefore, pregnancy is an uncommon but not rare occurrence and clinical challenge in some scenarios. Here, we discuss in detail our local approach to the management of pregnancy in patients with MPN while taking a case-based approach. We include relevant updates in the field and point to a future research strategy that should be internationally focused to obtain as much information in as short a time as possible.

The mesenchymal morphology of cells expressing the EML4-ALK V3 oncogene is dependent on phosphorylation of Eg5 by NEK7.

Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) oncogenic fusion proteins are found in approximately 5% of non-small cell lung cancers. Different EML4-ALK fusion variants exist with variant 3 (V3) being associated with a significantly higher risk than other common variants, such as variant 1 (V1). Patients with V3 respond less well to targeted ALK inhibitors, have accelerated rates of metastasis, and have poorer overall survival. A pathway has been described downstream of EML4-ALK V3 that is independent of ALK catalytic activity but dependent on the NEK9 and NEK7 kinases. It has been proposed that assembly of an EML4-ALK V3-NEK9-NEK7 complex on microtubules leads to cells developing a mesenchymal-like morphology and exhibiting enhanced migration. However, downstream targets of this complex remain unknown. Here, we show that the microtubule-based kinesin, Eg5, is recruited to interphase microtubules in cells expressing EML4-ALK V3, whereas chemical inhibition of Eg5 reverses the mesenchymal morphology of cells. Furthermore, we show that depletion of NEK7 interferes with Eg5 recruitment to microtubules in cells expressing EML4-ALK V3 and cell length is reduced, but this is reversed by coexpression of a phosphomimetic mutant of Eg5, in a site, S1033, phosphorylated by NEK7. Intriguingly, we also found that expression of Eg5-S1033D led to cells expressing EML4-ALK V1 adopting a more mesenchymal-like morphology. Together, we propose that Eg5 acts as a substrate of NEK7 in cells expressing EML4-ALK V3 and Eg5 phosphorylation promotes the mesenchymal morphology typical of these cells.

The burden of grief: A scoping review of nurses' and physicians' experiences throughout the COVID-19 pandemic.

Coping with loss is an unfortunate reality faced by healthcare professionals, and the COVID-19 pandemic exacerbated this challenge for those who worked on the frontlines. Our scoping review aimed to comprehensively map the existing literature pertaining to the experiences of grief among nurses and physicians in the context of the pandemic. Six bibliographic databases were searched in 2022, and a targeted search of gray literature and citation chasing was also performed. After screening a total of 2920 records, we included 173 evidence sources in this review. Data was both analyzed descriptively (e.g., frequency counts and percentages) and using a qualitative content analysis approach. Our findings illuminate the myriad losses experienced by nurses and physicians throughout the pandemic. While the literature portrays the coping mechanisms healthcare professionals have developed personally, there is a pronounced need for increased institutional support to alleviate the burdens they carry.

Autoantibodies identify primary Sjögren's syndrome in patients lacking serum IgG specific for Ro/SS-A and La/SS-B.

OBJECTIVE: Identify autoantibodies in anti-Ro/SS-A negative primary Sjögren's syndrome (SS). METHODS: This is a proof-of-concept, case-control study of SS, healthy (HC) and other disease (OD) controls. A discovery dataset of plasma samples (n=30 SS, n=15 HC) was tested on human proteome arrays containing 19 500 proteins. A validation dataset of plasma and stimulated parotid saliva from additional SS cases (n=46 anti-Ro+, n=50 anti-Ro-), HC (n=42) and OD (n=54) was tested on custom arrays containing 74 proteins. For each protein, the mean+3 SD of the HC value defined the positivity threshold. Differences from HC were determined by Fisher's exact test and random forest machine learning using 2/3 of the validation dataset for training and 1/3 for testing. Applicability of the results was explored in an independent rheumatology practice cohort (n=38 Ro+, n=36 Ro-, n=10 HC). Relationships among antigens were explored using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) interactome analysis. RESULTS: Ro+ SS parotid saliva contained autoantibodies binding to Ro60, Ro52, La/SS-B and muscarinic receptor 5. SS plasma contained 12 novel autoantibody specificities, 11 of which were detected in both the discovery and validation datasets. Binding to ≥1 of the novel antigens identified 54% of Ro- SS and 37% of Ro+ SS cases, with 100% specificity in both groups. Machine learning identified 30 novel specificities showing receiver operating characteristic area under the curve of 0.79 (95% CI 0.64 to 0.93) for identifying Ro- SS. Sera from Ro- cases of an independent cohort bound 17 of the non-canonical antigens. Antigenic targets in both Ro+ and Ro- SS were part of leukaemia cell, ubiquitin conjugation and antiviral defence pathways. CONCLUSION: We identified antigenic targets of the autoantibody response in SS that may be useful for identifying up to half of Ro seronegative SS cases.

Perinatal outcomes in women with sickle cell disease: a matched cohort study from London, UK.

There are limited data on contemporary outcomes for women with sickle cell disease (SCD) in pregnancy. We conducted a single-site matched cohort study, comparing 131 pregnancies to women with SCD between 2007 and 2017 to a comparison group of 1310 pregnancies unaffected by SCD. Restricting our analysis to singleton pregnancies that reached 24 weeks of gestation, we used conditional Poisson regression to estimate adjusted risk ratios (aRRs) for perinatal outcomes. Infants born to mothers with SCD were more likely to be small for gestational age [aRR 1·69, 95% confidence interval (CI) 1·13-2·48], preterm (aRR 2·62, 95% CI 1·82-3·78) and require Neonatal Unit (NNU) admission (aRR 3·59, 95% CI 2·18-5·90). Pregnant women with SCD were at higher risk of pre-eclampsia/eclampsia (aRR 3·53, 95% CI 2·00-6·24), more likely to receive induction of labour (aRR 2·50, 95% CI 1·82-1·76) and caesarean birth (aRR 1·44, 95% CI 1·18-1·76). In analysis stratified by genotype, the risk of adverse outcomes was highest in haemoglobin SS (HbSS) pregnancies (n = 80). There was no strong evidence that haemoglobin SC (HbSC) pregnancies (n = 46) were at higher risk of preterm birth, caesarean delivery, or NNU admission. Pre-eclampsia/eclampsia was more frequently observed in HbSC pregnancies. Despite improvements in the care of pregnant women with SCD, the increased risk of adverse perinatal outcomes remains.

Maternal iron deficiency anaemia in pregnancy: Lessons from a national audit.

We describe the management and the prevalence of iron deficiency anaemia (IDA) during pregnancy by comparison to standards. A cross-sectional national cohort study of women who had given birth six weeks prior to data collection was conducted at maternity units in the UK and Ireland. Participating centres collected data from 10 consecutive pregnant women. Analysis was descriptive to define the prevalence of IDA in pregnancy and the puerperium, and to compare the outcomes in women who had IDA with women who did not have anaemia anytime during pregnancy. Eighty-six maternity units contributed data on 860 pregnancies and births. The overall prevalence of IDA during pregnancy was 30.4% and in the puerperium 20%. Anaemic women were more likely to be from ethnic minorities, odds ratio 2.23 (1.50, 3.32). Adherence to national guidance was suboptimal, and the prevalence of anaemia in pregnancy remains very high. There is pressing need to explore barriers to early identification and effective management of iron deficiency. IDA should be considered a major public health problem in the UK.

Multifaceted Public Health Response to a COVID-19 Outbreak Among Meat-Processing Workers, Utah, March-June 2020.

OBJECTIVE: To identify potential strategies to mitigate COVID-19 transmission in a Utah meat-processing facility and surrounding community. DESIGN/SETTING: During March-June 2020, 502 workers at a Utah meat-processing facility (facility A) tested positive for SARS-CoV-2. Using merged data from the state disease surveillance system and facility A, we analyzed the relationship between SARS-CoV-2 positivity and worker demographics, work section, and geospatial data on worker residence. We analyzed worker survey responses to questions regarding COVID-19 knowledge, beliefs, and behaviors at work and home. PARTICIPANTS: (1) Facility A workers (n = 1373) with specimen collection dates and SARS-CoV-2 RT-PCR test results; (2) residential addresses of all persons (workers and nonworkers) with a SARS-CoV-2 diagnostic test (n = 1036), living within the 3 counties included in the health department catchment area; and (3) facility A workers (n = 64) who agreed to participate in the knowledge, attitudes, and practices survey. MAIN OUTCOME MEASURES: New cases over time, COVID-19 attack rates, worker characteristics by SARS-CoV-2 test results, geospatially clustered cases, space-time proximity of cases among workers and nonworkers; frequency of quantitative responses, crude prevalence ratios, and counts and frequency of coded responses to open-ended questions from the COVID-19 knowledge, attitudes, and practices survey. RESULTS: Statistically significant differences in race (P = .01), linguistic group (P < .001), and work section (P < .001) were found between workers with positive and negative SARS-CoV-2 test results. Geographically, only 6% of cases were within statistically significant spatiotemporal case clusters. Workers reported using handwashing (57%) and social distancing (21%) as mitigation strategies outside work but reported apprehension with taking COVID-19-associated sick leave. CONCLUSIONS: Mitigating COVID-19 outbreaks among workers in congregate settings requires a multifaceted public health response that is tailored to the workforce. IMPLICATIONS FOR POLICY AND PRACTICE: Tailored, multifaceted mitigation strategies are crucial for reducing COVID-19-associated health disparities among disproportionately affected populations.

The use of third-party packed red blood cells during ex situ normothermic machine perfusion of organs for transplantation: Underappreciated complexities?

Ex situ normothermic machine perfusion (NMP) is being used increasingly in the assessment of higher risk deceased donor organs and to facilitate prolonged organ storage. Third-party packed red blood cells (pRBCs) are often used as an oxygen carrier in the perfusate of ex situ NMP. Despite the increasing interest in NMP, comparatively little attention has been paid to the appropriate selection of pRBCs. This includes the choice of ABO blood group and Rhesus D status, the need for special requirements for selected recipients, and the necessity for traceability of blood components. Flushing organs with cold preservation solution after NMP removes the overwhelming majority of third-party allogeneic pRBCs, but residual pRBCs within the organ may have biologically relevant effects following implantation as they enter the recipient's circulation. This review considers these issues, and suggests that national transplant and blood transfusion agencies work together to develop a co-ordinated approach within each country. This is especially important given the possibility of organ re-allocation between centers after ex situ NMP, and the ongoing development of organ perfusion hubs.

Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability.

Nitric oxide (NO) regulates neuronal function and thus is critical for tuning neuronal communication. Mechanisms by which NO modulates protein function and interaction include posttranslational modifications (PTMs) such as S-nitrosylation. Importantly, cross signaling between S-nitrosylation and prenylation can have major regulatory potential. However, the exact protein targets and resulting changes in function remain elusive. Here, we interrogated the role of NO-dependent PTMs and farnesylation in synaptic transmission. We found that NO compromises synaptic function at the Drosophila neuromuscular junction (NMJ) in a cGMP-independent manner. NO suppressed release and reduced the size of available vesicle pools, which was reversed by glutathione (GSH) and occluded by genetic up-regulation of GSH-generating and de-nitrosylating glutamate-cysteine-ligase and S-nitroso-glutathione reductase activities. Enhanced nitrergic activity led to S-nitrosylation of the fusion-clamp protein complexin (cpx) and altered its membrane association and interactions with active zone (AZ) and soluble N-ethyl-maleimide-sensitive fusion protein Attachment Protein Receptor (SNARE) proteins. Furthermore, genetic and pharmacological suppression of farnesylation and a nitrosylation mimetic mutant of cpx induced identical physiological and localization phenotypes as caused by NO. Together, our data provide evidence for a novel physiological nitrergic molecular switch involving S-nitrosylation, which reversibly suppresses farnesylation and thereby enhances the net-clamping function of cpx. These data illustrate a new mechanistic signaling pathway by which regulation of farnesylation can fine-tune synaptic release.

Kv3.1 and Kv3.3 subunits differentially contribute to Kv3 channels and action potential repolarization in principal neurons of the auditory brainstem.

KEY POINTS: Kv3.1 and Kv3.3 subunits are highly expressed in the auditory brainstem, with little or no mRNA for Kv3.2 or Kv3.4. Changes in Kv3 currents and action potential (AP) firing were analysed from wild-type, Kv3.1 and Kv3.3 knockout (KO) mice. Both Kv3.1 and Kv3.3 immunostaining was present and western blots confirmed loss of subunit protein in the respective KO. Medial nucleus of the trapezoid body (MNTB) AP repolarization utilized Kv3.1 and/or Kv3.3; while in the lateral superior olive (LSO) Kv3.3 was essential. Voltage-gated calcium currents were unchanged between the genotypes. But APs evoked higher [Ca2+ ]i in LSO than MNTB neurons; and were highest in the Kv3.3KO, consistent with longer AP durations. High frequency stimulation increased AP failure rates and AP latency in LSO neurons from the Kv3.3KO, underlining the physiological consequences for binaural integration. LSO neurons require Kv3.3 for functional Kv3 channels, while MNTB neurons can utilize either Kv3.1 or Kv3.3 subunits. ABSTRACT: Kv3 voltage-gated potassium channels mediate action potential (AP) repolarization. The relative importance of Kv3.1 and Kv3.3 subunits for assembly of functional channels in neurons of the auditory brainstem was examined from the physiological perspective that speed and precision of AP firing are crucial for sound source localization. High levels of Kv3.1 and Kv3.3 mRNA and protein were measured, with no evidence of compensation by Kv3.2 or Kv3.4 in the respective knockout (KO) mouse. Using the KOs, composition of Kv3 channels was constrained to either Kv3.1 or Kv3.3 subunits in principal neurons of the medial nucleus of the trapezoid body (MNTB) and lateral superior olive (LSO); while TEA (1 mm) was employed to block Kv3-mediated outward potassium currents in voltage- and current clamp experiments. MNTB neuron APs (half-width 0.31 ± 0.08 ms, n = 25) were fast, reliable, and showed no distinction between channels assembled from Kv3.1 or Kv3.3 subunits (in the respective KO). LSO AP half-widths were also fast, but absolutely required Kv3.3 subunits for fast repolarization (half-widths: 0.25 ± 0.08 ms, n = 19 wild-type, 0.60 ± 0.17 ms, n = 21 Kv3.3KO, p = 0.0001). The longer AP duration increased LSO calcium influx and AP failure rates, and increased AP latency and jitter during high frequency repetitive firing. Both Kv3.1 and Kv3.3 subunits contribute to Kv3 channels in the MNTB (and compensate for each other in each KO); in contrast, LSO neurons require Kv3.3 subunits for fast repolarization and to sustain AP firing during high frequency stimulation. In conclusion, Kv3 channels exhibit both redundancy and Kv3.3 dominance between the brainstem nuclei involved in sound localization.

First Mildly Ill, Nonhospitalized Case of Coronavirus Disease 2019 (COVID-19) Without Viral Transmission in the United States-Maricopa County, Arizona, 2020.

BACKGROUND: Coronavirus disease 2019 (COVID-19) causes a range of illness severity. Mild illness has been reported, but whether illness severity correlates with infectivity is unknown. We describe the public health investigation of a mildly ill, nonhospitalized COVID-19 case who traveled to China. METHODS: The case was a Maricopa County resident with multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive specimens collected on 22 January 2020. Contacts were persons exposed to the case on or after the day before case diagnostic specimen collection. Contacts were monitored for 14 days after last known exposure. High-risk contacts had close, prolonged case contact (≥ 10 minutes within 2 m). Medium-risk contacts wore all US Centers for Disease Control and Prevention-recommended personal protective equipment during interactions. Nasopharyngeal and oropharyngeal (NP/OP) specimens were collected from the case and high-risk contacts and tested for SARS-CoV-2. RESULTS: Paired case NP/OP specimens were collected for SARS-CoV-2 testing at 11 time points. In 8 pairs (73%), ≥ 1 specimen tested positive or indeterminate, and in 3 pairs (27%) both tested negative. Specimens collected 18 days after diagnosis tested positive. Sixteen contacts were identified; 11 (69%) had high-risk exposure, including 1 intimate contact, and 5 (31%) had medium-risk exposure. In total, 35 high-risk contact NP/OP specimens were collected for SARS-CoV-2 testing; all 35 pairs (100%) tested negative. CONCLUSIONS: This report demonstrates that SARS-CoV-2 infection can cause mild illness and result in positive tests for up to 18 days after diagnosis, without evidence of transmission to close contacts. These data might inform public health strategies to manage individuals with asymptomatic infection or mild illness.

How we manage Philadelphia-negative myeloproliferative neoplasms in pregnancy.

The combined incidence of classical Philadelphia-negative myeloproliferative neoplasm (MPN) is 6-9/100 000 with a peak frequency between 50 and 70 years. MPN is less frequent in women of reproductive age. However, for essential thrombocythaemia (ET) in particular there is a second peak in women of reproductive age and 15% of polycythaemia vera (PV) patients are less than 40 years of age at the time of diagnosis. Thus these diseases are encountered in women of reproductive potential and may be diagnosed in pregnancy or in women being investigated for recurrent pregnancy loss. The incidence of MPN pregnancies is 3·2/100 000 maternities per year in the UK. The majority of data regarding Philadelphia-negative MPNs relates to patients with ET, for which the literature suggests significant maternal morbidity and poor fetal outcome; specifically maternal thrombosis and haemorrhage, miscarriage, pre-eclampsia, intrauterine growth restriction (IUGR), stillbirth and premature delivery as summarised in the recent systematic review and meta-analysis in Blood, 2018, 132, 3046. The literature for PV is more sparse but increasing and is concordant with ET pregnancy outcomes. The literature regarding primary myelofibrosis (PMF) is even more scarce. Treatment options include aspirin, venesection, low molecular weight heparin (LMWH) and cytoreductive therapy. Data and management recommendations are often extrapolated from other pro-thrombotic conditions or from ET to PV and PMF. Women of reproductive age with a diagnosis of MPN should receive information and assurance regarding management and outcome of future pregnancies. From pre-conceptual planning to the post-partum period, women should have access to joint care from an obstetrician with experience of high-risk pregnancies and a haematologist in a multidisciplinary setting. This paper provides an update with regards to Philadelphia-negative MPN in pregnancy, details local practise in an internationally recognised centre for patients with MPN and outlines a future research strategy.

Position paper on International Collaboration for Transfusion Medicine (ICTM) Guideline 'Red blood cell specifications for patients with hemoglobinopathies: a systematic review and guideline'.

The International Collaboration for Transfusion Medicine Guidelines (ICTMG) has published guidance on transfusion for haemoglobinopathies. To give a UK perspective on this guidance, each of the recommendations in the ICTMG guideline were reviewed and the applicability for transfusion practice in the UK considered with reference to relevant published British Society for Haematology (BSH) guidelines and national standards . There was much consensus; however, there was disparity surrounding the recommendations for routinely extended matching in those with alloimmunisation.

Blood component use in critical care in patients with COVID-19 infection: a single-centre experience.

There has been a significant surge in admissions to critical care during the coronavirus disease 2019 (COVID-19) pandemic. At present, the demands on blood components have not been described. We reviewed their use during the first 6 weeks of the outbreak from 3 March 2020 in a tertiary-level critical care department providing venovenous extracorporeal membrane oxygenation (vv-ECMO). A total of 265 patients were reviewed, with 235 not requiring ECMO and 30 requiring vv-ECMO. In total, 50 patients required blood components during their critical care admission. Red cell concentrates were the most frequently transfused component in COVID-19-infected patients with higher rates of use during vv-ECMO. The use of fresh frozen plasma, cryoprecipitate and platelet transfusions was low in a period prior to the use of convalescent plasma.

Trends in COVID-19 Incidence After Implementation of Mitigation Measures - Arizona, January 22-August 7, 2020.

Mitigating the spread of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), requires individual, community, and state public health actions to prevent person-to-person transmission. Community mitigation measures can help slow the spread of COVID-19; these measures include wearing masks, social distancing, reducing the number and size of large gatherings, pausing operation of businesses where maintaining social distancing is challenging, working from or staying at home, and implementing certain workplace and educational institution controls (1-4). The Arizona Department of Health Services' (ADHS) recommendations for mitigating exposure to SARS-CoV-2 were informed by continual monitoring of patient demographics, SARS-CoV-2 community spread, and the pandemic's impacts on hospitals. To assess the effect of mitigation strategies in Arizona, the numbers of daily COVID-19 cases and 7-day moving averages during January 22-August 7, 2020, relative to implementation of enhanced community mitigation measures, were examined. The average number of daily cases increased approximately 151%, from 808 on June 1, 2020 to 2,026 on June 15, 2020 (after stay-at-home order lifted), necessitating increased preventive measures. On June 17, local officials began implementing and enforcing mask wearing (via county and city mandates),* affecting approximately 85% of the state population. Statewide mitigation measures included limitation of public events; closures of bars, gyms, movie theaters, and water parks; reduced restaurant dine-in capacity; and voluntary resident action to stay at home and wear masks (when and where not mandated). The number of COVID-19 cases in Arizona peaked during June 29-July 2, stabilized during July 3-July 12, and further declined by approximately 75% during July 13-August 7. Widespread implementation and enforcement of sustained community mitigation measures informed by state and local officials' continual data monitoring and collaboration can help prevent transmission of SARS-CoV-2 and decrease the numbers of COVID-19 cases.

Measles Outbreak at a Privately Operated Detention Facility: Arizona, 2016.

BACKGROUND: We describe a measles outbreak and control measures implemented at a privately operated detention facility housing US Immigration and Customs Enforcement detainees in 2016. METHODS: Case-patients reported fever and rash and were either laboratory-confirmed or had an epidemiological link to a laboratory-confirmed case-patient. Immunoglobulin G (IgG) avidity and plaque reduction neutralization tests distinguished between primary acute and reinfection case-patients. Measles-specific IgG was measured to assess detainee immunity levels. We compared attack rates (ARs) among detainees and staff, between IgG-negative and IgG-positive detainees, and by detainee housing units and sexes. RESULTS: We identified 32 measles case-patients (23 detainees, 9 staff); rash onsets were during 6 May-26 June 2016. High IgG avidity and neutralizing-antibody titers >40000 to measles (indicating reinfection) were identified in 18 (95%) and 15 (84%) of 19 tested case-patients, respectively. Among 205 unit A detainees tested for presumptive immunity, 186 (91%) had detectable IgG. Overall, the AR was 1.65%. ARs were significantly higher among detainees in unit A (7.05%) compared with units B-F (0.59%), and among male (2.33%) compared with female detainees (0.38%); however, ARs were not significantly different between detainees and staff or between IgG-negative and IgG-positive detainees. Control measures included the vaccination of 1424 of 1425 detainees and 190 of 510 staff, immunity verification for 445 staff, case-patient isolation, and quarantine of affected units. CONCLUSIONS: Although ARs were low, measles outbreaks can occur in intense-exposure settings, despite a high population immunity, underscoring the importance of high vaccination coverage and containment in limiting measles transmission.

Risk of venous thromboembolism in pregnant women with essential thrombocythemia: a systematic review and meta-analysis.

We performed a meta-analysis to evaluate the risk of venous thromboembolism (VTE) in pregnant women with essential thrombocythemia. Twenty-one trials and 756 pregnancies met inclusion criteria. The absolute VTE risk in the antepartum period is not above a threshold where low-molecular-weight heparin (LMWH) prophylaxis is clearly indicated or below a threshold where LMWH should be withheld (2.5%; 95% CI, 1.3-4.3). Postpartum, the absolute VTE risk is above a threshold where postpartum LMWH prophylaxis should be considered (4.4%; 95% CI, 1.2-9.5).

The relationship between aerobic fitness and low-flow-mediated constriction in older adults.

PURPOSE: Aerobic fitness is directly related to favorable vasodilatory (i.e., flow-mediated dilation; FMD) and vasoconstrictor functions (i.e., low-flow-mediated constriction; L-FMC) in young adults. Furthermore, aerobically fit older adults (OA) have larger FMD responses than their less fit peers. However, the relationship between aerobic fitness and vasoconstrictor responsiveness is unknown in OA. We hypothesized that OA who are more aerobically fit will exhibit a greater L-FMC response than their less fit counterparts. METHODS: Forty-seven healthy OA (67 ± 5 years) were divided into less (LF; n = 27) and more aerobically fit (MF; n = 20) groups based on peak oxygen consumption (VO2peak). VO2peak was determined from an incremental maximal cycle ergometer test via indirect calorimetry. FMD and L-FMC were assessed in the brachial artery via high-resolution duplex ultrasonography. RESULTS: VO2peak (18.3 ± 3.2 versus 29.1 ± 5.8 ml/kg/min; P < 0.001) and L-FMC were both greatest in the MF versus LF groups (-1.2 ± 0.9 vs. - 0.5 ± 0.6%; P = 0.01). Furthermore, the MF group had an enhanced FMD response (5.6 ± 1.5 versus 3.9 ± 1.2%; P < 0.001). In the pooled sample, there was a negative correlation (r = - 0.52; P < 0.001) between VO2peak (22.9 ± 7.0 ml/kg/min) and L-FMC (-0.8 ± 0.8%). CONCLUSIONS: In an older population, greater aerobic fitness was associated with a more favorable vasoconstrictor response to low-flow conditions. Interventional or longitudinal aerobic exercise training studies are warranted in this population to determine the impact of training-induced increases in VO2peak on L-FMC.

Is seniority of emergency physician associated with the weekend mortality effect? An exploratory analysis of electronic health records in the UK.

OBJECTIVE: Admission to hospital over a weekend is associated with increased mortality, but the underlying causes of the weekend effect are poorly understood. We explore to what extent differences in emergency department (ED) admission and discharge processes, severity of illness and the seniority of the treating physician explain the weekend effect. METHODS: We analysed linked ED attendances to hospital admissions to Cambridge University Hospital over a 7-year period from 1 January 2007 to 31 December 2013, with 30-day in-hospital death as the primary outcome and discharge as a competing risk. The primary exposure was day of the week of arrival. Subdistribution hazards models controlled for multiple confounders, including physician seniority, calendar year, mode of arrival, triage category, referral from general practice, sex, arrival time, prior attendances and admissions, diagnosis group and age. RESULTS: 229 401 patients made 424 845 ED attendances, of which 158 396 (37.3%) were admitted to the hospital. The case-mix of admitted patients was more ill at weekends: 2530 (6.4%) admitted at a weekend required immediate resuscitation compared with 6450 (5.4%) admitted on a weekday (p<0.0001). Senior doctors admitted 24.8% of patients on weekdays and 24.0% at weekends, but junior doctors admitted 61.7% of patients on weekdays and 44.2% at weekends. 3947 (3.3%) patients admitted on a weekday and 1454 (3.7%) patients admitted at a weekend died within 30 days. In the adjusted subdistribution hazards model, the HR of in-hospital death was 1.11 (95% CI 1.04 to 1.18) for weekend arrivals. After controlling for confounders, the in-hospital mortality of patients admitted by junior doctors was greater at the weekend (adjusted HR (aHR) 1.15, 95% CI 1.06 to 1.24). In-hospital mortality for patients admitted by senior doctors was not statistically different at the weekend (aHR 1.08, 95% CI 0.98 to 1.19). CONCLUSIONS: Our findings suggest that the weekend effect was driven by a higher proportion of admitted patients requiring immediate resuscitation at the weekend. Junior doctors admitted a lower proportion of relatively healthy patients at the weekend compared with the weekday, thus diluting the risk pool of weekday admissions and contributing to the weekend effect. Senior doctors' admitting behaviour did not change at the weekend, and the corresponding weekend effect was reduced.

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A theory-driven tailored intervention developed in partnership with the community used evidence-based practices to (a) increase knowledge about colon cancer and screening and (b) assist patients in completing screenings. During the 16 months of delivery screening, patient navigators integrated into gastroenterology clinics met all goals, which included (a) enrolling an ethnically diverse group of participants ( N = 415) through inreach (clinic-referred patients who did not schedule appointments) and community outreach, (b) facilitating screening completions for 217 of the 358 (61%) patients identified as needing screening, and (c) obtaining satisfaction ratings from 89% of participants. A random sample ( N = 214) of nonnavigated patients matched on gender and age revealed no differences between navigated and nonnavigated patients on polyps detected. Navigated males (but not females) were significantly less likely than nonnavigated males to have either poor or only fair bowel preparation quality (odds ratio = .418, p = .020, 95% confidence interval [.197, .885]). Low-quality bowel preparation can lead to incomplete readings of the colon or cancelling a colonoscopy. This intervention demonstrates that evidence-based patient navigator programs are effective in increasing screening among a hard-to-reach population and improving bowel preparation quality for males.