Cortical cell assemblies and their underlying connectivity: An in silico study.

Recent developments in experimental techniques have enabled simultaneous recordings from thousands of neurons, enabling the study of functional cell assemblies. However, determining the patterns of synaptic connectivity giving rise to these assemblies remains challenging. To address this, we developed a complementary, simulation-based approach, using a detailed, large-scale cortical network model. Using a combination of established methods we detected functional cell assemblies from the stimulus-evoked spiking activity of 186,665 neurons. We studied how the structure of synaptic connectivity underlies assembly composition, quantifying the effects of thalamic innervation, recurrent connectivity, and the spatial arrangement of synapses on dendrites. We determined that these features reduce up to 30%, 22%, and 10% of the uncertainty of a neuron belonging to an assembly. The detected assemblies were activated in a stimulus-specific sequence and were grouped based on their position in the sequence. We found that the different groups were affected to different degrees by the structural features we considered. Additionally, connectivity was more predictive of assembly membership if its direction aligned with the temporal order of assembly activation, if it originated from strongly interconnected populations, and if synapses clustered on dendritic branches. In summary, reversing Hebb's postulate, we showed how cells that are wired together, fire together, quantifying how connectivity patterns interact to shape the emergence of assemblies. This includes a qualitative aspect of connectivity: not just the amount, but also the local structure matters; from the subcellular level in the form of dendritic clustering to the presence of specific network motifs.

Penny-wise and pound-foolish: the challenges of preoperative anaemia management.

The timely correction of anaemia before major surgery is important for optimising perioperative patient outcomes. However, multiple barriers have precluded the global expansion of preoperative anaemia treatment programmes, including misconceptions about the true cost/benefit ratio for patient care and health system economics. Institutional investment and buy-in from stakeholders could lead to significant cost savings through avoided complications of anaemia and red blood cell transfusions, and through containment of direct and variable costs of blood bank laboratories. In some health systems, billing for iron infusions could generate revenue and promote growth of treatment programmes. The aim of this work is to galvanise integrated health systems worldwide to diagnose and treat anaemia before major surgery.

Patients' Choice, Consent, and Ethics in Patient Blood Management.

The goal of patient blood management (PBM) is to optimize clinical outcomes for individual patients by managing their blood as a precious and unique resource to be safeguarded and managed judiciously. A corollary to successful PBM is the minimization or avoidance of blood transfusion and stewardship of donated blood. The first is achieved by a multidisciplinary approach with personalized management plans shared and decided on with the patient or their substitute. It follows that the physician-patient relationship is an integral component of medical practice and the fundamental link between patient and doctor based on trust and honest communication. Central to PBM is accurate and timely diagnosis based on sound physiology and pathophysiology as the bedrock on which scientifically based medicine is founded. PBM in all disease contexts starts with the questions, "What is the status of the patient's blood?" "If there are specific abnormalities in the blood, how should they be managed?" and "If allogeneic blood transfusion is considered, is there no reasonable alternative therapy?" There are compelling scientific reasons to implement a nontransfusion default position when there is clinical uncertainty and questionable evidence of clinical efficacy for allogeneic blood transfusion due to known potential hazards. Patients must be informed of their diagnosis, the nature, severity and prognosis of the disease, and treatment options along with risks and benefits. They should be involved in decision-making regarding their management. However, as part of this process, there are multifaceted medical, legal, ethical, and economic issues, encompassing shared decision-making, patient choice, and informed consent. Furthermore, variability in patient circumstances and preferences, the complexity of medical science, and the workings of health care systems in which consent takes place can be bewildering, not only for the patient but also for clinicians obtaining consent. Adding "patient" to the concept of blood management differentiates it from "donor" blood management to avoid confusion and the perception that PBM is a specific medical intervention. Personalized PBM is tailoring the PBM to the specific characteristics of each patient. With this approach, there should be no difficulty addressing the informed consent and ethical aspects of PBM. Patients can usually be reassured that there is nothing out of order with their blood, in which case the focus of PBM is to keep it that way. In some circumstances, a hematologist may be involved as a patient's blood advocate when abnormalities require expert involvement while the primary disease is being managed.

Patient Blood Management: Improving Outcomes for Millions While Saving Billions. What Is Holding It Up?

Patient blood management (PBM) offers significantly improved outcomes for almost all medical and surgical patient populations, pregnant women, and individuals with micronutrient deficiencies, anemia, or bleeding. It holds enormous financial benefits for hospitals and payers, improves performance of health care providers, and supports public authorities to improve population health. Despite this extraordinary combination of benefits, PBM has hardly been noticed in the world of health care. In response, the World Health Organization (WHO) called for its 194 member states, in its recent Policy Brief, to act quickly and decidedly to adopt national PBM policies. To further support the WHO's call to action, this article addresses 3 aspects in more detail. The first is the urgency from a health economic perspective. For many years, growth in health care spending has outpaced overall economic growth, particularly in aging societies. Due to competing economic needs, the continuation of disproportionate growth in health care spending is unsustainable. Therefore, the imperative for health care leaders and policy makers is not only to curb the current spending rate relative to the gross domestic product (GDP) but also to simultaneously improve productivity, quality, safety of patient care, and the health status of populations. Second, while PBM meets these requirements on an exceptional scale, uptake remains slow. Thus, it is vital to identify and understand the impediments to broad implementation. This includes systemic challenges such as the so-called "waste domains" of failure of care delivery caused by malfunctions of health care systems, failure of care coordination, overtreatment, and low-value care. Other impediments more specific to PBM are the misperception of PBM and deeply rooted cultural patterns. Third, understanding how the 3Es-evidence, economics, and ethics-can effectively be used to motivate relevant stakeholders to take on their respective roles and responsibilities and follow the urgent call to implement PBM as a standard of care.

Physician autonomy and patient rights: lessons from an enforced blood transfusion and the role of patient blood management.

This article provides an ethical and medico-legal analysis of ruling no. 465 of 30 May 2018 issued by the Court of Termini Imerese (Palermo) and confirmed on appeal on 11 November 2020, which, in the absence of similar historical precedents in Europe, convicted a medical doctor of a crime of violent assault for having ordered the administration of a blood transfusion to a patient specifically declining blood transfusion on religious grounds. We analyse the Court's decision regarding the identification of assault in performing the blood transfusion and its decision not to accept exculpatory urgent 'necessity' as a defence. In addition, we present an updated revision of the current standard of care in transfusion medicine as well as the ethical principles governing the patient's declining of transfusion. In doing so, we highlight that respect for the patient's self-determination in declining transfusions and respect for the professional autonomy of the doctor protecting the safety and life of the patient could be equally satisfied by applying the current peer-reviewed evidence.

Place of birth and outcomes associated with large volume transfusion: an observational study.

BACKGROUND: Guidelines recommend that women at high risk of postpartum haemorrhage deliver at facilities able to handle heavy bleeding. However postpartum haemorrhage is often unexpected. This study aims to compare outcomes and health service use related to transfusion of ≥4 units of red blood cells between women delivering in tertiary and lower level hospitals. METHODS: The study population was women giving birth in public hospitals in New South Wales, Australia, between July 2006 and December 2010. Data were obtained from linked hospital, birth and blood bank databases. The exposure of interest was transfusion of four or more units of red cells during admission for delivery. Outcomes included maternal morbidity, length of stay, neonatal morbidity and need for other blood products or transfer to higher care. Multivariable regression models were developed to predict need of transfusion of ≥4 units of red cells using variables known early in pregnancy and those known by the birth admission. RESULTS: Data were available for 231,603 births, of which 4309 involved a blood transfusion, with 1011 (0.4%) receiving 4 or more units. Women giving birth in lower level and/or smaller hospitals were more likely to receive ≥4 units of red cells. Women receiving ≥4 units in tertiary settings were more likely to receive other blood products and have longer hospital stays, but morbidity, readmission and hysterectomy rates were similar. Although 46% of women had no identifiable risk factors early in pregnancy, 20% of transfusions of ≥4 units occurred within this group. By the birth admission 70% of women had at least one risk factor for requiring ≥4 units of red cells. CONCLUSIONS: Overall outcomes for women receiving ≥4 units of red cells were comparable between tertiary and non-tertiary facilities. This is important given the inability of known risk factors to predict many instances of postpartum haemorrhage.

Reflections on pandemics and the 60th anniversary of the University of New South Wales Medical School.

In March 1961 the University of New South Wales enrolled the first students into the new faculty of medicine that is now ranked 4th in Australia and 59th in the world. The author was fortunate to be a member of that pioneering group and looks back in gratitude to all the visionary and committed academics and mentors, who made this happen. Many of the foundation academics were fellows of the Royal Australasian College of Physicians, with two becoming University of New South Wales deans of medicine. One-quarter of the foundation year's graduates became fellows of the college and the first PhD medical graduate, Professor John Chalmers AC, became president of the college.

Systematic reviews and meta-analyses comparing mortality in restrictive and liberal haemoglobin thresholds for red cell transfusion: an overview of systematic reviews.

BACKGROUND: There are no overviews of systematic reviews investigating haemoglobin thresholds for transfusion. This is important as the literature on transfusion thresholds has grown considerably in recent years. Our aim was to synthesise evidence from systematic reviews and meta-analyses of the effects of restrictive and liberal transfusion strategies on mortality. METHODS: This was a systematic review of systematic reviews (overview). We searched MEDLINE, Embase, Web of Science Core Collection, PubMed, Google Scholar, and the Joanna Briggs Institute EBP Database, from 2008 to 2018. We included systematic reviews and meta-analyses of randomised controlled trials comparing mortality in patients assigned to red cell transfusion strategies based on haemoglobin thresholds. Two independent reviewers extracted data and assessed methodological quality. We assessed the methodological quality of included reviews using AMSTAR 2 and the quality of evidence pooled using an algorithm to assign GRADE levels. RESULTS: We included 19 systematic reviews reporting 33 meta-analyses of mortality outcomes from 53 unique randomised controlled trials. Of the 33 meta-analyses, one was graded as high quality, 15 were moderate, and 17 were low. Of the meta-analyses presenting high- to moderate-quality evidence, 12 (75.0%) reported no statistically significant difference in mortality between restrictive and liberal transfusion groups and four (25.0%) reported significantly lower mortality for patients assigned to a restrictive transfusion strategy. We found few systematic reviews addressed clinical differences between included studies: variation was observed in haemoglobin threshold concentrations, the absolute between group difference in haemoglobin threshold concentration, time to randomisation (resulting in transfusions administered prior to randomisation), and transfusion dosing regimens. CONCLUSIONS: Meta-analyses graded as high to moderate quality indicate that in most patient populations no difference in mortality exists between patients assigned to a restrictive or liberal transfusion strategy. TRIAL REGISTRATION: PROSPERO CRD42019120503.

Patient blood management: The best approach to transfusion medicine risk management.

In advanced health systems it is increasingly important to offer effective medical services that have high quality and safety standards. We present an overview of the direct hazards and the indirect hazards associated with blood transfusions. Our aim is to focus on the potential medico-legal impacts of these hazards in the context of clinical risk management, incorporating the accumulating evidence from Patient Blood Management programs. The direct or deterministic hazards of transfusion refer to scenarios where the mechanisms for post transfusion damage are clearly traceable to the blood transfused in a 1:1 cause and effect manner. The indirect hazards can be defined as probabilistic and are associated with transfusion through epidemiological studies. The implementation of Patient Blood Management programs demonstrates that the use of a blood transfusion is not always necessary or unavoidable but can be considered modifiable. Review of the literature confirms that transfusion should not be the default option to manage anemia or blood loss. Instead, accumulating evidence demonstrates that a patient-centred, proactive approach to managing a patient's own blood is the new standard of care. It thus follows, an adverse transfusion event, where the transfusion was avoidable through the application of patient blood management, may constitute a profile for medical professional medical negligence. In an effort to maximise patient safety, transfusion medicine practice culture needs to shift towards a patient blood management approach, with hospitals implementing it as an important tool to minimize the risks of allogeneic blood transfusion.

Essential Role of Patient Blood Management in a Pandemic: A Call for Action.

The World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a pandemic. Global health care now faces unprecedented challenges with widespread and rapid human-to-human transmission of SARS-CoV-2 and high morbidity and mortality with COVID-19 worldwide. Across the world, medical care is hampered by a critical shortage of not only hand sanitizers, personal protective equipment, ventilators, and hospital beds, but also impediments to the blood supply. Blood donation centers in many areas around the globe have mostly closed. Donors, practicing social distancing, some either with illness or undergoing self-quarantine, are quickly diminishing. Drastic public health initiatives have focused on containment and "flattening the curve" while invaluable resources are being depleted. In some countries, the point has been reached at which the demand for such resources, including donor blood, outstrips the supply. Questions as to the safety of blood persist. Although it does not appear very likely that the virus can be transmitted through allogeneic blood transfusion, this still remains to be fully determined. As options dwindle, we must enact regional and national shortage plans worldwide and more vitally disseminate the knowledge of and immediately implement patient blood management (PBM). PBM is an evidence-based bundle of care to optimize medical and surgical patient outcomes by clinically managing and preserving a patient's own blood. This multinational and diverse group of authors issue this "Call to Action" underscoring "The Essential Role of Patient Blood Management in the Management of Pandemics" and urging all stakeholders and providers to implement the practical and commonsense principles of PBM and its multiprofessional and multimodality approaches.

Channelling medical truths from Sir William Osler.

Dr James L. T. Isbister (JLT), a graduate of the University of Adelaide, came to Sydney as a clinical pathologist at Sydney Hospital in 1897 and subsequently was a general practitioner in North Sydney and honorary surgeon and gynaecologist at Royal North Shore Hospital from 1900. He owned the first motor vehicle in North Sydney and he was Mary MacKillops's local doctor during her last years at the Sisters of St Joseph of the Sacred Heart convent in North Sydney. On a visit to the United Kingdom in 1908, he met Sir William Osler, a meeting that clearly impacted on his thinking that has been channelled down the Isbister medical family for over a century. JLT was a founding member of the Royal Australasian College of Surgeons with a grandson, Peter, also becoming a fellow. His son, James, daughter-in-law, Clair, and grandson, James, became fellows of the Royal Australasian College of Physicians. More recently, his great-grand daughter is currently an advanced college trainee. In this historical perspective, JLT's grandson confirms that Osler's medical truths have been channelled, added to and practised by JLT and his descendants.

Observational studies - should we simply ignore them in assessing transfusion outcomes?

BACKGROUND: As defined by evidence-based medicine randomized controlled trials rank higher than observational studies in the hierarchy of clinical research. Accordingly, when assessing the effects of treatments on patient outcomes, there is a tendency to focus on the study method rather than also appraising the key elements of study design. A long-standing debate regarding findings of randomized controlled trials compared with those of observational studies, their strengths and limitations and questions regarding causal inference, has recently come into focus in relation to research assessing patient outcomes in transfusion medicine. DISCUSSION: Observational studies are seen to have limitations that are largely avoided with randomized controlled trials, leading to the view that observational studies should not generally be used to inform practice. For example, observational studies examining patient outcomes associated with blood transfusion often present higher estimates of adverse outcomes than randomized controlled trials. Some have explained this difference as being a result of observational studies not properly adjusting for differences between patients transfused and those not transfused. However, one factor often overlooked, likely contributing to these variances between study methods is different exposure criteria. Another common to both study methods is exposure dose, specifically, measuring units transfused during only a part of the patient's hospital stay. When comparing the results of observational studies with randomized controlled trials assessing transfusion outcomes it is important that one consider not only the study method, but also the key elements of study design. Any study, regardless of its method, should focus on accurate measurement of the exposure and outcome variables of interest. Failure to do so may subject the study, regardless of its type, to bias and the need to interpret the results with caution.

Age of blood and adverse outcomes in a maternity population.

BACKGROUND: In recent times there has been debate around whether longer storage time of blood is associated with increased rates of adverse outcomes after transfusion. It is unclear whether results focused on cardiac or critically ill patients apply to a maternity population. This study investigates whether older blood is associated with increased morbidity and readmission in women undergoing obstetric transfusion. STUDY DESIGN AND METHODS: Women giving birth in hospitals in New South Wales, Australia, between July 2006 and December 2010 were included in the study population if they had received between 1 and 4 red blood cell units during the birth admission. Information on women's characteristics, transfusions, and outcomes were obtained from five routinely collected data sets including blood collection, birth, and hospitalization data. Generalized propensity score methods were used to determine the effect of age of blood on rates of severe morbidity and readmission, independent of confounding factors. RESULTS: Transfusion data were available for 2990 women, with a median age of blood transfused of 20 days (interquartile range, 14-27 days). There were no differences in the maximum age of blood transfused between women with and without severe morbidity (21 [14-28] days vs. 22 [15-30] days) and in women readmitted or not (22 [14-28] days vs. 22 [16-30] days). After potential confounding factors were considered, no relationship was found between the age of blood transfused and rates of severe morbidity and readmission. CONCLUSION: Among women receiving low-volume transfusions during a birth admission, there was no evidence of increased rates of adverse outcomes after transfusion with older blood.

Clustering and control for adaptation uncovers time-warped spike time patterns in cortical networks in vivo.

How information in the nervous system is encoded by patterns of action potentials (i.e. spikes) remains an open question. Multi-neuron patterns of single spikes are a prime candidate for spike time encoding but their temporal variability requires further characterisation. Here we show how known sources of spike count variability affect stimulus-evoked spike time patterns between neurons separated over multiple layers and columns of adult rat somatosensory cortex in vivo. On subsets of trials (clusters) and after controlling for stimulus-response adaptation, spike time differences between pairs of neurons are "time-warped" (compressed/stretched) by trial-to-trial changes in shared excitability, explaining why fixed spike time patterns and noise correlations are seldom reported. We show that predicted cortical state is correlated between groups of 4 neurons, introducing the possibility of spike time pattern modulation by population-wide trial-to-trial changes in excitability (i.e. cortical state). Under the assumption of state-dependent coding, we propose an improved potential encoding capacity.

Interruption of long-term warfarin is not necessary in patients undergoing total hip arthroplasty.

INTRODUCTION: The management of anticoagulation in patients undergoing arthroplasty remains a challenge. Guidelines for perioperative management of long-term warfarin recommend discontinuation of warfarin preoperatively in low risk patients. We hypothesised that patients who had their warfarin continued during the perioperative period would have shorter hospital stay and no significant increase risk of surgical complications compared to patients who had their warfarin interrupted. METHODS: This was a retrospective review of 20 consecutive patients receiving long-term warfarin who underwent total hip replacement without stopping warfarin. As a control group, we collected same data from 20 age and gender matched patients also on long term warfarin but their warfarin was stopped prior to surgery and restarted postoperatively. RESULTS: There was no significant difference in age, BMI or comorbidities between the 2 groups. There was a statistically significant difference between the two groups in postoperative INR (P < 0.0001) levels. The mean drop in Hb postoperatively was 25.95 g/L in the warfarin group and 35.7 g/L in the control group, which was statistically significant (P = 0.0066). Hospital stay was statistically significant with shorted stay observed in the warfarin group (P = 0.0447). The odds ratio for developing a postoperative complication was 1.5882 which was not statistically significant (P = 0.6346). CONCLUSION: Our results support the hypothesis that it is safe to continue warfarin in patients on long term anticoagulation undergoing total hip replacement. Continuation of warfarin was associated with significantly shorter hospital stay and less INR fluctuations. There was no significant increase in the risk of complications or blood transfusion.