Carbogen-Induced Respiratory Acidosis Blocks Experimental Seizures by a Direct and Specific Inhibition of NaV1.2 Channels in the Axon Initial Segment of Pyramidal Neurons.

Brain pH is a critical factor for determining neuronal activity, with alkalosis increasing and acidosis reducing excitability. Acid shifts in brain pH through the breathing of carbogen (5% CO2/95% O2) reduces seizure susceptibility in animal models and patients. The molecular mechanisms underlying this seizure protection remain to be fully elucidated. Here, we demonstrate that male and female mice exposed to carbogen are fully protected from thermogenic-triggered seizures. Whole-cell patch-clamp recordings revealed that acid shifts in extracellular pH (pHo) significantly reduce action potential firing in CA1 pyramidal neurons but did not alter firing in hippocampal inhibitory interneurons. In real-time dynamic clamp experiments, acidification reduced simulated action potential firing generated in hybrid model neurons expressing the excitatory neuron predominant NaV1.2 channel. Conversely, acidification had no effect on action potential firing in hybrid model neurons expressing the interneuron predominant NaV1.1 channel. Furthermore, knockdown of Scn2a mRNA in vivo using antisense oligonucleotides reduced the protective effects of carbogen on seizure susceptibility. Both carbogen-mediated seizure protection and the reduction in CA1 pyramidal neuron action potential firing by low pHo were maintained in an Asic1a knock-out mouse ruling out this acid-sensing channel as the underlying molecular target. These data indicate that the acid-mediated reduction in excitatory neuron firing is mediated, at least in part, through the inhibition of NaV1.2 channels, whereas inhibitory neuron firing is unaffected. This reduction in pyramidal neuron excitability is the likely basis of seizure suppression caused by carbogen-mediated acidification.SIGNIFICANCE STATEMENT Brain pH has long been known to modulate neuronal excitability. Here, we confirm that brain acidification reduces seizure susceptibility in a mouse model of thermogenic seizures. Extracellular acidification reduced excitatory pyramidal neuron firing while having no effect on interneuron firing. Acidification also reduced dynamic clamp firing in cells expressing the NaV1.2 channel but not in cells expressing NaV1.1 channels. In vivo knockdown of Scn2a mRNA reduced seizure protection of acidification. In contrast, acid-mediated seizure protection was maintained in the Asic1a knock-out mouse. These data suggest NaV1.2 channel as an important target for acid-mediated seizure protection. Our results have implications on how natural variations in pH can modulate neuronal excitability and highlight potential antiseizure drug development strategies based on the NaV1.2 channel.

Preexisting Neuropsychiatric Conditions and Associated Risk of Severe COVID-19 Infection and Other Acute Respiratory Infections.

Importance: Evidence indicates that preexisting neuropsychiatric conditions confer increased risks of severe outcomes from COVID-19 infection. It is unclear how this increased risk compares with risks associated with other severe acute respiratory infections (SARIs). Objective: To determine whether preexisting diagnosis of and/or treatment for a neuropsychiatric condition is associated with severe outcomes from COVID-19 infection and other SARIs and whether any observed association is similar between the 2 outcomes. Design, Setting, and Participants: Prepandemic (2015-2020) and contemporary (2020-2021) longitudinal cohorts were derived from the QResearch database of English primary care records. Adjusted hazard ratios (HRs) with 99% CIs were estimated in April 2022 using flexible parametric survival models clustered by primary care clinic. This study included a population-based sample, including all adults in the database who had been registered with a primary care clinic for at least 1 year. Analysis of routinely collected primary care electronic medical records was performed. Exposures: Diagnosis of and/or medication for anxiety, mood, or psychotic disorders and diagnosis of dementia, depression, schizophrenia, or bipolar disorder. Main Outcomes and Measures: COVID-19-related mortality, or hospital or intensive care unit admission; SARI-related mortality, or hospital or intensive care unit admission. Results: The prepandemic cohort comprised 11 134 789 adults (223 569 SARI cases [2.0%]) with a median (IQR) age of 42 (29-58) years, of which 5 644 525 (50.7%) were female. The contemporary cohort comprised 8 388 956 adults (58 203 severe COVID-19 cases [0.7%]) with a median (IQR) age of 48 (34-63) years, of which 4 207 192 were male (50.2%). Diagnosis and/or treatment for neuropsychiatric conditions other than dementia was associated with an increased likelihood of a severe outcome from SARI (anxiety diagnosis: HR, 1.16; 99% CI, 1.13-1.18; psychotic disorder diagnosis and treatment: HR, 2.56; 99% CI, 2.40-2.72) and COVID-19 (anxiety diagnosis: HR, 1.16; 99% CI, 1.12-1.20; psychotic disorder treatment: HR, 2.37; 99% CI, 2.20-2.55). The effect estimate for severe outcome with dementia was higher for those with COVID-19 than SARI (HR, 2.85; 99% CI, 2.71-3.00 vs HR, 2.13; 99% CI, 2.07-2.19). Conclusions and Relevance: In this longitudinal cohort study, UK patients with preexisting neuropsychiatric conditions and treatments were associated with similarly increased risks of severe outcome from COVID-19 infection and SARIs, except for dementia.

Regional citrate anticoagulation versus systemic heparin anticoagulation for continuous kidney replacement therapy in intensive care.

PURPOSE: Many intensive care units (ICUs) have transitioned from systemic heparin anticoagulation (SHA) to regional citrate anticoagulation (RCA) for continuous kidney replacement therapy (CKRT). We evaluated the clinical and health economic impacts of ICU transition to RCA. MATERIALS AND METHODS: We surveyed all adult general ICUs in England and Wales to identify transition dates and conducted a micro-costing study in eight ICUs. We then conducted an interrupted time-series analysis of linked, routinely collected health records. RESULTS: In 69,001 patients who received CKRT (8585 RCA, 60,416 SHA) in 181 ICUs between 2009 and 2017, transition to RCA was not associated with a change in 90-day mortality (adjusted odds ratio 0.98, 95% CI 0.89-1.08) but was associated with step-increases in duration of kidney support (0.53 days, 95% CI 0.28-0.79), advanced cardiovascular support (0.23 days, 95% CI 0.09-0.38) and ICU length of stay (0.86 days, 95% CI 0.24-1.49). The estimated one-year incremental net monetary benefit per patient was £ - 2376 (95% CI £ - 3841-£ - 911), with an estimated likelihood of cost-effectiveness of <0.1%. CONCLUSIONS: Transition to RCA was associated with significant increases in healthcare resource use, without corresponding clinical benefit, and is highly unlikely to be cost-effective over a one-year time horizon.

Neuropsychiatric Ramifications of Severe COVID-19 and Other Severe Acute Respiratory Infections.

Importance: Individuals surviving severe COVID-19 may be at increased risk of neuropsychiatric sequelae. Robust assessment of these risks may help improve clinical understanding of the post-COVID syndrome, aid clinical care during the ongoing pandemic, and inform postpandemic planning. Objective: To quantify the risks of new-onset neuropsychiatric conditions and new neuropsychiatric medication prescriptions after discharge from a COVID-19-related hospitalization, and to compare these with risks after discharge from hospitalization for other severe acute respiratory infections (SARI) during the COVID-19 pandemic. Design, Setting, and Participants: In this cohort study, adults (≥18 years of age) were identified from QResearch primary care and linked electronic health record databases, including national SARS-CoV-2 testing, hospital episode statistics, intensive care admissions data, and mortality registers in England, from January 24, 2020, to July 7, 2021. Exposures: COVID-19-related or SARI-related hospital admission (including intensive care admission). Main Outcomes and Measures: New-onset diagnoses of neuropsychiatric conditions (anxiety, dementia, psychosis, depression, bipolar disorder) or first prescription for relevant medications (antidepressants, hypnotics/anxiolytics, antipsychotics) during 12 months of follow-up from hospital discharge. Maximally adjusted hazard ratios (HR) with 95% CIs were estimated using flexible parametric survival models. Results: In this cohort study of data from 8.38 million adults (4.18 million women, 4.20 million men; mean [SD] age 49.18 [18.45] years); 16 679 (0.02%) survived a hospital admission for SARI, and 32 525 (0.03%) survived a hospital admission for COVID-19. Compared with the remaining population, survivors of SARI and COVID-19 hospitalization had higher risks of subsequent neuropsychiatric diagnoses. For example, the HR for anxiety in survivors of SARI was 1.86 (95% CI, 1.56-2.21) and for survivors of COVID-19 infection was 2.36 (95% CI, 2.03-2.74); the HR for dementia for survivors of SARI was 2.55 (95% CI, 2.17-3.00) and for survivors of COVID-19 infection was 2.63 (95% CI, 2.21-3.14). Similar findings were observed for all medications analyzed; for example, the HR for first prescriptions of antidepressants in survivors of SARI was 2.55 (95% CI, 2.24-2.90) and for survivors of COVID-19 infection was 3.24 (95% CI, 2.91-3.61). There were no significant differences observed when directly comparing the COVID-19 group with the SARI group apart from a lower risk of antipsychotic prescriptions in the former (HR, 0.80; 95% CI, 0.69-0.92). Conclusions and Relevance: In this cohort study, the neuropsychiatric sequelae of severe COVID-19 infection were found to be similar to those for other SARI. This finding may inform postdischarge support for people surviving SARI.

Heparin versus citrate anticoagulation for continuous renal replacement therapy in intensive care: the RRAM observational study.

BACKGROUND: In the UK, 10% of admissions to intensive care units receive continuous renal replacement therapy with regional citrate anticoagulation replacing systemic heparin anticoagulation over the last decade. Regional citrate anticoagulation is now used in > 50% of intensive care units, despite little evidence of safety or effectiveness. AIM: The aim of the Renal Replacement Anticoagulant Management study was to evaluate the clinical and health economic impacts of intensive care units moving from systemic heparin anticoagulation to regional citrate anticoagulation for continuous renal replacement therapy. DESIGN: This was an observational comparative effectiveness study. SETTING: The setting was NHS adult general intensive care units in England and Wales. PARTICIPANTS: Participants were adults receiving continuous renal replacement therapy in an intensive care unit participating in the Intensive Care National Audit & Research Centre Case Mix Programme national clinical audit between 1 April 2009 and 31 March 2017. INTERVENTIONS: Exposure - continuous renal replacement therapy in an intensive care unit after completion of transition to regional citrate anticoagulation. Comparator - continuous renal replacement therapy in an intensive care unit before starting transition to regional citrate anticoagulation or had not transitioned. OUTCOME MEASURES: Primary effectiveness - all-cause mortality at 90 days. Primary economic - incremental net monetary benefit at 1 year. Secondary outcomes - mortality at hospital discharge, 30 days and 1 year; days of renal, cardiovascular and advanced respiratory support in intensive care unit; length of stay in intensive care unit and hospital; bleeding and thromboembolic events; prevalence of end-stage renal disease at 1 year; and estimated lifetime incremental net monetary benefit. DATA SOURCES: Individual patient data from the Intensive Care National Audit & Research Centre Case Mix Programme were linked with the UK Renal Registry, Hospital Episode Statistics (for England), Patient Episodes Data for Wales and Civil Registrations (Deaths) data sets, and combined with identified periods of systemic heparin anticoagulation and regional citrate anticoagulation (survey of intensive care units). Staff time and consumables were obtained from micro-costing. Continuous renal replacement therapy system failures were estimated from the Post-Intensive Care Risk-adjusted Alerting and Monitoring data set. EuroQol-3 Dimensions, three-level version, health-related quality of life was obtained from the Intensive Care Outcomes Network study. RESULTS: Out of the 188 (94.9%) units that responded to the survey, 182 (96.8%) use continuous renal replacement therapy. After linkage, data were available from 69,001 patients across 181 intensive care units (60,416 during periods of systemic heparin anticoagulation use and 8585 during regional citrate anticoagulation use). The change to regional citrate anticoagulation was not associated with a step change in 90-day mortality (odds ratio 0.98, 95% confidence interval 0.89 to 1.08). Secondary outcomes showed step increases in days of renal support (difference in means 0.53 days, 95% confidence interval 0.28 to 0.79 days), advanced cardiovascular support (difference in means 0.23 days, 95% confidence interval 0.09 to 0.38 days) and advanced respiratory support (difference in means, 0.53 days, 95% CI 0.03 to 1.03 days) with a trend toward fewer bleeding episodes (odds ratio 0.90, 95% confidence interval 0.76 to 1.06) with transition to regional citrate anticoagulation. The micro-costing study indicated that regional citrate anticoagulation was more expensive and was associated with an estimated incremental net monetary loss (step change) of -£2376 (95% confidence interval -£3841 to -£911). The estimated likelihood of cost-effectiveness at 1 year was less than 0.1%. LIMITATIONS: Lack of patient-level treatment data means that the results represent average effects of changing to regional citrate anticoagulation in intensive care units. Administrative data are subject to variation in data quality over time, which may contribute to observed trends. CONCLUSIONS: The introduction of regional citrate anticoagulation has not improved outcomes for patients and is likely to have substantially increased costs. This study demonstrates the feasibility of evaluating effects of changes in practice using routinely collected data. FUTURE WORK: (1) Prioritise other changes in clinical practice for evaluation and (2) methodological research to understand potential implications of trends in data quality. TRIAL REGISTRATION: This trial is registered as ClinicalTrials.gov NCT03545750. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 13. See the NIHR Journals Library website for further project information.

Acute kidney injury, which prevents kidneys from working properly, is common in critically ill patients being treated in an intensive care unit. Patients with acute kidney injury are treated with a machine that takes over kidney functions, a process called continuous renal replacement therapy. Traditionally, as part of continuous renal replacement therapy, heparin (an anticoagulant that stops the blood from clotting) is added to the blood as it enters the continuous renal replacement therapy machine. Recently, citrate anticoagulation (an alternative to heparin) has been increasingly used in intensive care units in the UK. However, the increased use of citrate is happening without evidence that this is better for patients and cost-effective for the NHS. We aimed to find out whether or not changing to citrate anticoagulation for continuous renal replacement therapy is more beneficial than heparin anticoagulation for patients with acute kidney injury treated in an intensive care unit. We also looked at whether or not changing to citrate is cost-effective for the NHS. We used routinely collected data from the Intensive Care National Audit & Research Centre Case Mix Programme national clinical audit to identify 69,001 patients who received continuous renal replacement therapy in an intensive care unit in England or Wales between 1 April 2009 and 31 March 2017. To get a more comprehensive view of the long-term effects of changing to citrate, we 'linked' data from the 69,001 patients together with other routinely collected data sets to get information on their hospital admissions, longer-term kidney problems and survival after leaving the intensive care unit. We combined this information with a survey of anticoagulant use in intensive care units in England and Wales to compare patients who received continuous renal replacement therapy with heparin and citrate. We found that the change to citrate was not associated with a significant change in the death rate at 90 days, but that it was more expensive for hospitals. Our findings suggest that the change to citrate-based anticoagulation may have been premature and should cause clinicians in intensive care units that are still using systemic heparin anticoagulation to pause before making this change.

The novel persistent sodium current inhibitor PRAX-562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers.

OBJECTIVE: This study investigates the effects of PRAX-562 on sodium current (INa ), intrinsic neuronal excitability, and protection from evoked seizures to determine whether a preferential persistent INa inhibitor would exhibit improved preclinical efficacy and tolerability compared to two standard voltage-gated sodium channel (NaV ) blockers. METHODS: Inhibition of INa  was characterized using patch clamp analysis. The effect on intrinsic excitability was measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. Anticonvulsant activity was evaluated using the maximal electroshock seizure (MES) model, and tolerability was assessed by measuring spontaneous locomotor activity (sLMA). RESULTS: PRAX-562 potently and preferentially inhibited persistent INa induced by ATX-II or the SCN8A mutation N1768D (half-maximal inhibitory concentration [IC50 ] = 141 and 75 nmol·L-1 , respectively) relative to peak INa tonic/resting block (60× preference). PRAX-562 also exhibited potent use-dependent block (31× preference to tonic block). This profile is considerably different from standard NaV blockers, including carbamazepine (CBZ; persistent INa IC50 = 77 500 nmol·L-1 , preference ratios of 30× [tonic block], less use-dependent block observed at various frequencies). In contrast to CBZ, PRAX-562 reduced neuronal intrinsic excitability with only a minor reduction in action potential amplitude. PRAX-562 (10 mg/kg po) completely prevented evoked seizures without affecting sLMA (MES unbound brain half-maximal efficacious concentration = 4.3 nmol·L-1 , sLMA half-maximal tolerated concentration = 69.7 nmol·L-1 , protective index [PI] = 16×). In contrast, CBZ and lamotrigine (LTG) had PIs of approximately 5.5×, with significant overlap between doses that were anticonvulsant and that reduced locomotor activity. SIGNIFICANCE: PRAX-562 demonstrated robust preclinical anticonvulsant activity similar to CBZ but improved compared to LTG. PRAX-562 exhibited significantly improved preclinical tolerability compared with standard NaV blockers (CBZ and LTG), potentially due to the preference for persistent INa . Preferential targeting of persistent INa may represent a differentiated therapeutic option for diseases of hyperexcitability, where standard NaV blockers have demonstrated efficacy but poor tolerability.

Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH, which can reach as low as 6.0 to 6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly affects cardiac function. METHODS: We used genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole-organ level. Human induced pluripotent stem cell-derived cardiomyocytes as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and postconditioning therapeutic agents. RESULTS: Analysis of human complex trait genetics indicates that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using human induced pluripotent stem cell-derived cardiomyocytes in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacologic inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and 2 models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as preconditioning or postconditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no effect on cardiac ion channels regulating baseline electromechanical coupling and physiologic performance. CONCLUSIONS: Our data provide compelling evidence for a novel pharmacologic strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

Discovery of the First Orally Available, Selective KNa1.1 Inhibitor: In Vitro and In Vivo Activity of an Oxadiazole Series.

The gene KCNT1 encodes the sodium-activated potassium channel KNa1.1 (Slack, Slo2.2). Variants in the KCNT1 gene induce a gain-of-function (GoF) phenotype in ionic currents and cause a spectrum of intractable neurological disorders in infants and children, including epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Effective treatment options for KCNT1-related disease are absent, and novel therapies are urgently required. We describe the development of a novel class of oxadiazole KNa1.1 inhibitors, leading to the discovery of compound 31 that reduced seizures and interictal spikes in a mouse model of KCNT1 GoF.

Anxiety, depression and post-traumatic stress disorder management after critical illness: a UK multi-centre prospective cohort study.

BACKGROUND: Survivors of critical illness have significant psychopathological comorbidity. The treatments offered by primary health care professionals to affected patients are unstudied. AIM: To report the psychological interventions after GPs received notification of patients who showed severe symptoms of anxiety, depression or Post-Traumatic Stress Disorder. METHODS: Design: Multi-centre prospective cohort sub-study of the ICON study. SETTING: NHS primary care in the United Kingdom. PARTICIPANTS: Adult patients, November 2006-October 2010 who had received at least 24 h of intensive care, where the general practitioner recorded notification that the patient had reported severe symptoms or caseness using the Hospital Anxiety and Depression Scale (HADS) or the Post-Traumatic Stress Disorder Check List-Civilian (PCL-C). INTERVENTIONS: We notified general practitioners (GPs) by post if a patient reported severe symptoms or caseness and sent a postal questionnaire to determine interventions after notification. MAIN OUTCOME MEASURE: Primary or secondary healthcare interventions instigated by general practitioners following notification of a patient's caseness. RESULTS: Of the 11,726 patients, sent questionnaire packs containing HADS and PCL-C, 4361 (37%) responded. A notification of severe symptoms was sent to their GP in 25% (1112) of cases. Of notified GPs, 65% (725) responded to our postal questionnaire. Of these 37% (266) had no record of receipt of the original notification. Of the 459 patients where GPs had record of notification (the study group for this analysis), 21% (98) had pre-existing psychopathology. Of those without a pre-existing diagnosis 45% (162) received further psychological assessment or treatment. GP screening or follow-up alone occurred in 18% (64) whilst 27% (98) were referred to mental health services or received drug therapy following notification. CONCLUSIONS: Postal questionnaire identifies a burden of psychopathology in survivors of critical illness that have otherwise gone undiagnosed following discharge from an intensive care unit (ICU). After being alerted to the presence of psychological symptoms, GPs instigate treatment in 27% and augmented surveillance in 18% of cases. TRIAL REGISTRATION: ISRCTN69112866 (assigned 02/05/2006).

Trajectories of vital signs in patients with COVID-19.

BACKGROUND: The global pandemic of coronavirus disease 2019 (COVID-19) has placed a huge strain on UK hospitals. Early studies suggest that patients can deteriorate quickly after admission to hospital. The aim of this study was to model changes in vital signs for patients hospitalised with COVID-19. METHODS: This was a retrospective observational study of adult patients with COVID-19 admitted to one acute hospital trust in the UK (CV) and a cohort of patients admitted to the same hospital between 2013-2017 with viral pneumonia (VI). The primary outcome was the start of continuous positive airway pressure/non-invasive positive pressure ventilation, ICU admission or death in hospital. We used non-linear mixed-effects models to compare changes in vital sign observations prior to the primary outcome. Using observations and FiO2 measured at discharge in the VI cohort as the model of normality, we also combined individual vital signs into a single novelty score. RESULTS: There were 497 cases of COVID-19, of whom 373 had been discharged from hospital. 135 (36.2%) of patients experienced the primary outcome, of whom 99 died in hospital. In-hospital mortality was over 4-times higher in the CV than the VI cohort (26.5% vs 6%). For those patients who experienced the primary outcome, CV patients became increasingly hypoxaemic, with a median estimated FiO2 (0.75) higher than that of the VI cohort (estimated FiO2 of 0.35). Prior to the primary outcome, blood pressure remained within normal range, and there was only a small rise in heart rate. The novelty score showed that patients with COVID-19 deteriorated more rapidly that patients with viral pneumonia. CONCLUSIONS: Patients with COVID-19 who deteriorate in hospital experience rapidly-worsening respiratory failure, with low SpO2 and high FiO2, but only minor abnormalities in other vital signs. This has potential implications for the ability of early warning scores to identify deteriorating patients.

Hospital outcomes associated with new-onset atrial fibrillation during ICU admission: A multicentre competing risks analysis.

PURPOSE: New onset atrial fibrillation (NOAF) in critically ill patients has been associated with increased short-term mortality. Analyses that do not take into account the time-varying nature of NOAF can underestimate its association with hospital outcomes. We investigated the prognostic association of NOAF with hospital outcomes using competing risks methods. MATERIALS AND METHODS: We undertook a retrospective cohort study in three general adult intensive care units (ICUs) in the UK from June 2008 to December 2015. We excluded patients with known prior atrial fibrillation or an arrhythmia within four hours of ICU admission. To account for the effect of NOAF on the rate of death per unit time and the rate of discharge alive per unit time we calculated subdistribution hazard ratios (SDHRs). RESULTS: Of 7541 patients that fulfilled our inclusion criteria, 831 (11.0%) developed NOAF during their ICU admission. NOAF was associated with an increased duration of hospital stay (CSHR 0.68 (95% CI 0.63-0.73)) and an increased rate of in-hospital death per unit time (CSHR 1.57 (95% CI 1.37-1.1.81)). This resulted in a strong prognostic association with dying in hospital (adjusted SDHR 2.04 (1.79-2.32)). NOAF lasting over 30 min was associated with increased hospital mortality. CONCLUSIONS: Using robust methods we demonstrate a stronger prognostic association between NOAF and hospital outcomes than previously reported.

Prophylactic use of platelets in critically ill patients with thrombocytopaenia: A retrospective two-centre observational study.

PURPOSE: We report the use and effect of prophylactic platelet transfusions in critically ill thrombocytopaenic patients, comparing patients with or without bone marrow failure as a cause of thrombocytopaenia. METHODS: A retrospective observational study of admissions to three intensive care units (ICU) in the UK. We identified thrombocytopaenic patients who received a platelet transfusion and extracted the platelet count prior and subsequent to platelet transfusion. We grouped patients with or without suspected bone marrow failure, defined by a total white cell count ≤1.0 × 109/L. RESULTS: Of 11,757 admissions, 399 (3.4%) patients received a platelet transfusion for thrombocytopaenia. The median [IQR] platelet count prior to transfusion in patients without bone marrow failure was 42 [28-64] × 109/L versus 14 [7-24] × 109/L (p < .0001) in those with. The median [IQR] increment in platelets following transfusion was lower in patients with marrow failure (12 [-1-23] × 109/L) compared to those without (18 [5-36] × 109/L) (p = .006). CONCLUSIONS: Platelet transfusions were given at a higher median platelet count than suggested by guidelines. Patients with bone marrow failure were transfused at a lower threshold and experienced a smaller increment in platelet count when compared to patients without marrow failure.

GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons.

The binding of GABA (γ-aminobutyric acid) to extrasynaptic GABAA receptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes according to variation in chloride gradient. Here, using biophysically detailed neuron models, we predict that tonic inhibition can differentially modulate the excitability of neuron subtypes according to variation in electrophysiological properties. Surprisingly, tonic inhibition increased the responsiveness (or gain) in models with features typical for somatostatin interneurons but decreased gain in models with features typical for parvalbumin interneurons. Patch-clamp recordings from cortical interneurons supported these predictions, and further in silico analysis was then performed to seek a putative mechanism underlying gain modulation. We found that gain modulation in models was dependent upon the magnitude of tonic current generated at depolarized membrane potential-a property associated with outward rectifying GABAA receptors. Furthermore, tonic inhibition produced two biophysical changes in models of relevance to neuronal excitability: 1) enhanced action potential repolarization via increased current flow into the dendritic compartment, and 2) reduced activation of voltage-dependent potassium channels. Finally, we show theoretically that reduced potassium channel activation selectively increases gain in models possessing action potential dynamics typical for somatostatin interneurons. Potassium channels in parvalbumin-type models deactivate rapidly and are unavailable for further modulation. These findings show that GABA can differentially modulate interneuron excitability and suggest a mechanism through which this occurs in silico via differences of intrinsic electrophysiological properties.

Conditional Survival With Increasing Duration of ICU Admission: An Observational Study of Three Intensive Care Databases.

OBJECTIVES: Prolonged admissions to an ICU are associated with high resource utilization and personal cost to the patient. Previous reports suggest increasing length of stay may be associated with poor outcomes. Conditional survival represents the probability of future survival after a defined period of treatment on an ICU providing a description of how prognosis evolves over time. Our objective was to describe conditional survival as length of ICU stay increased. DESIGN: Retrospective observational cohort study of three large intensive care databases. SETTING: Three intensive care databases, two in the United States (Medical Information Mart for Intensive Care III and electronic ICU) and one in United Kingdom (Post Intensive Care Risk-Adjusted Alerting and Monitoring). PATIENTS: Index admissions to intensive care for patients 18 years or older. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 11,648, 38,532, and 165,125 index admissions were analyzed from Post Intensive Care Risk-Adjusted Alerting and Monitoring, Medical Information Mart for Intensive Care III and electronic ICU databases respectively. In all three cohorts, conditional survival declined over the first 5-10 days after ICU admission and changed little thereafter. In patients greater than or equal to 75 years old conditional survival continued to decline with increasing length of stay. CONCLUSIONS: After an initial period of 5-10 days, probability of future survival does not appear to decrease with increasing length of stay in unselected patients admitted to ICUs in United Kingdom and United States [corrected]. These findings were consistent between the three populations and suggest that a prolonged admission to an ICU is not a reason for a pessimism in younger patients but may indicate a poor prognosis in the older population.

Medical schools, primary care and family medicine: clerkship directors' perceptions of the current environment.

BACKGROUND: The culture at a medical school and the positive experiences in primary care clerkships influence student specialty choice. This choice is significant if the demand for primary care physicians is to be met. The aim of this study was to examine family medicine clerkship directors' perceptions of the medical school environment. METHODS: Data were collected as part of the 2015 Council of Academic Family Medicine Educational Research Alliance Family Medicine Clerkship Director survey. Questions asked included how clerkship directors perceived the environment of their medical school towards family medicine, has the environment towards family medicine changed between 2010 and 2015, do they take action to influence student attitudes towards family medicine and whether faculty members in other departments make negative comments about family medicine. RESULTS: The response rate was 79.4%. While most respondents indicated the environment of their medical school has become more positive towards family medicine, a majority of clerkship directors perceived the environment to be either very much against, slightly against or indifferent towards family medicine. Nearly one-half (41.4%) of the clerkship directors were notified more than once a year that a faculty member of another department made a negative comment about family medicine. Results varied among regions of the USA and between schools located in the USA and Canada. CONCLUSION: Family medicine clerkship directors often perceived negativity towards family medicine, a finding that may limit the effectiveness of academic health centres in their mission to better serve their community and profession.

Primary Care Tracks in Medical Schools.

INTRODUCTION: With the estimated future shortage of primary care physicians there is a need to recruit more medical students into family medicine. Longitudinal programs or primary care tracks in medical schools have been shown to successfully recruit students into primary care. The aim of this study was to examine the characteristics of primary care tracks in departments of family medicine. METHODS: Data were collected as part of the 2016 CERA Family Medicine Clerkship Director Survey. The survey included questions regarding the presence and description of available primary care tracks as well as the clerkship director's perception of impact. The survey was distributed via email to 125 US and 16 Canadian family medicine clerkship directors. RESULTS: The response rate was 86%. Thirty-five respondents (29%) reported offering a longitudinal primary care track. The majority of tracks select students on a competitive basis, are directed by family medicine educators, and include a wide variety of activities. Longitudinal experience in primary care ambulatory settings and primary care faculty mentorship were the most common activities. Almost 70% of clerkship directors believe there is a positive impact on students entering primary care. CONCLUSIONS: The current tracks are diverse in what they offer and could be tailored to the missions of individual medical schools. The majority of clerkship directors reported that they do have a positive impact on students entering primary care.