Regional and bilateral MRI and gene signatures in facioscapulohumeral dystrophy: implications for clinical trial design and mechanisms of disease progression.

Identifying the aberrant expression of DUX4 in skeletal muscle as the cause of facioscapulohumeral dystrophy (FSHD) has led to rational therapeutic development and clinical trials. Several studies support the use of MRI characteristics and the expression of DUX4-regulated genes in muscle biopsies as biomarkers of FSHD disease activity and progression. We performed lower-extremity MRI and muscle biopsies in the mid-portion of the tibialis anterior (TA) muscles bilaterally in FSHD subjects and validated our prior reports of the strong association between MRI characteristics and expression of genes regulated by DUX4 and other gene categories associated with FSHD disease activity. We further show that measurements of normalized fat content in the entire TA muscle strongly predict molecular signatures in the mid-portion of the TA, indicating that regional biopsies can accurately measure progression in the whole muscle and providing a strong basis for inclusion of MRI and molecular biomarkers in clinical trial design. An unanticipated finding was the strong correlations of molecular signatures in the bilateral comparisons, including markers of B-cells and other immune cell populations, suggesting that a systemic immune cell infiltration of skeletal muscle might have a role in disease progression.

The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs.

Translational control is critical for cell fate transitions during development, lineage specification, and tumorigenesis. Here, we show that the transcription factor double homeobox protein 4 (DUX4), and its previously characterized transcriptional program, broadly regulates translation to change the cellular proteome. DUX4 is a key regulator of zygotic genome activation in human embryos, whereas misexpression of DUX4 causes facioscapulohumeral muscular dystrophy (FSHD) and is associated with MHC-I suppression and immune evasion in cancer. We report that translation initiation and elongation factors are disrupted downstream of DUX4 expression in human myoblasts. Genome-wide translation profiling identified mRNAs susceptible to DUX4-induced translation inhibition, including those encoding antigen presentation factors and muscle lineage proteins, while DUX4-induced mRNAs were robustly translated. Endogenous expression of DUX4 in human FSHD myotubes and cancer cell lines also correlated with reduced protein synthesis and MHC-I presentation. Our findings reveal that DUX4 orchestrates cell state conversion by suppressing the cellular proteome while maintaining translation of DUX4-induced mRNAs to promote an early developmental program.

Human DUX4 and porcine DUXC activate similar early embryonic programs in pig muscle cells: implications for preclinical models of FSHD.

Human DUX4 and its mouse ortholog Dux are normally expressed in the early embryo-the 4-cell or 2-cell cleavage stage embryo, respectively-and activate a portion of the first wave of zygotic gene expression. DUX4 is epigenetically suppressed in nearly all somatic tissue, whereas facioscapulohumeral dystrophy (FSHD)-causing mutations result in its aberrant expression in skeletal muscle, transcriptional activation of the early embryonic program and subsequent muscle pathology. Although DUX4 and Dux both activate an early totipotent transcriptional program, divergence of their DNA binding domains limits the use of DUX4 expressed in mice as a preclinical model for FSHD. In this study, we identify the porcine DUXC messenger ribonucleic acid expressed in early development and show that both pig DUXC and human DUX4 robustly activate a highly similar early embryonic program in pig muscle cells. These results support further investigation of pig preclinical models for FSHD.

DUX4-induced bidirectional HSATII satellite repeat transcripts form intranuclear double-stranded RNA foci in human cell models of FSHD.

The DUX4 transcription factor is normally expressed in the cleavage-stage embryo and regulates genes involved in embryonic genome activation. Misexpression of DUX4 in skeletal muscle, however, is toxic and causes facioscapulohumeral muscular dystrophy (FSHD). We recently showed DUX4-induced toxicity is due, in part, to the activation of the double-stranded RNA (dsRNA) response pathway and the accumulation of intranuclear dsRNA foci. Here, we determined the composition of DUX4-induced dsRNAs. We found that a subset of DUX4-induced dsRNAs originate from inverted Alu repeats embedded within the introns of DUX4-induced transcripts and from DUX4-induced dsRNA-forming intergenic transcripts enriched for endogenous retroviruses, Alu and LINE-1 elements. However, these repeat classes were also represented in dsRNAs from cells not expressing DUX4. In contrast, pericentric human satellite II (HSATII) repeats formed a class of dsRNA specific to the DUX4 expressing cells. Further investigation revealed that DUX4 can initiate the bidirectional transcription of normally heterochromatin-silenced HSATII repeats. DUX4-induced HSATII RNAs co-localized with DUX4-induced nuclear dsRNA foci and with intranuclear aggregation of EIF4A3 and ADAR1. Finally, gapmer-mediated knockdown of HSATII transcripts depleted DUX4-induced intranuclear ribonucleoprotein aggregates and decreased DUX4-induced cell death, suggesting that HSATII-formed dsRNAs contribute to DUX4 toxicity.

Changes in Healthcare During the Past 30 Years: Can the National Health Service in the United Kingdom Survive?

At the turn of the century, the National Health Service (NHS) in the United Kingdom (UK) was considered one of the top public healthcare systems in the world. Not only was it comprehensive and inclusive, but it was also free at the point of delivery for the entire UK population. It was also largely available to visitors and the families of residents that lived outside the UK. During the past 30 years, the NHS has received more and more funding both in cash terms and as a percentage of the gross national product. Despite this, the general consensus is that the NHS is delivering a poor service. The current government is facing unprecedented strike action from all areas of the workforce including doctors and nurses. This editorial asks the following questions: Where has the money gone? What has caused the current crisis? Can the current NHS model survive in today's highly technological healthcare environment?

Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction.

DUX4 activates the first wave of zygotic gene expression in the early embryo. Mis-expression of DUX4 in skeletal muscle causes facioscapulohumeral dystrophy (FSHD), whereas expression in cancers suppresses IFNγ induction of major histocompatibility complex class I (MHC class I) and contributes to immune evasion. We show that the DUX4 protein interacts with STAT1 and broadly suppresses expression of IFNγ-stimulated genes by decreasing bound STAT1 and Pol-II recruitment. Transcriptional suppression of interferon-stimulated genes (ISGs) requires conserved (L)LxxL(L) motifs in the carboxyterminal region of DUX4 and phosphorylation of STAT1 Y701 enhances interaction with DUX4. Consistent with these findings, expression of endogenous DUX4 in FSHD muscle cells and the CIC-DUX4 fusion containing the DUX4 CTD in a sarcoma cell line inhibit IFNγ induction of ISGs. Mouse Dux similarly interacted with STAT1 and suppressed IFNγ induction of ISGs. These findings identify an evolved role of the DUXC family in modulating immune signaling pathways with implications for development, cancers, and FSHD.

Risk Factors for Postoperative Infections in Cardiac Surgery Patients: A Retrospective Study.

Background and objective Cardiac surgery is one of the most common surgical procedures globally; its incidence has been on the rise due to the faster pace of population aging thanks to technological and epidemiological advances. Patients who undergo cardiac surgeries may face various postoperative complications that might affect their survival, and one of these major complications is infection. Nosocomial pneumonia, surgical site infection (SSI), mediastinitis, bacteremia, and sepsis are common infections encountered after surgeries. In this study, we aimed to determine the common risk factors related to postoperative infections at the King Faisal Cardiac Center from January 2014 to September 2020. Materials and methods  Records from 364 patients who underwent cardiac surgery and were aged above 18 years were assessed for postoperative infections in this retrospective cohort study. Patients who were immunosuppressed or had active systemic infections were excluded. Consent was waived by the Institutional Review Board. All procedures were performed at the King Faisal Cardiac Center, National Guard Hospital, Jeddah. Results Of the total 364 patients, 105 were women and 259 were men. The mean age of the cohort was 59 years (SD = 13) and the mean BMI was 29.1 kg/m2 (SD = 5.3). The study population showed a high prevalence of cardiac risk factors and diseases: diabetes (n = 244, 67%), hypertension (n = 230, 63%), dyslipidemia (n = 144, 40%), smoking (n = 80, 22%), heart failure (n = 41, 11%), and chronic obstructive pulmonary disease (n = 6, 1.6%). The overall rate of postoperative infection was 32.7% (n = 120), and 17 (14%) of these infected patients underwent reoperations for infection. Conclusion Based on a thorough analysis of 364 patients undergoing various cardiac surgical procedures, including a multivariate analysis accounting for preoperative factors, there was a significant association between postoperative infections and hypertension, diabetes, increased preoperative activated partial thromboplastin time, and elevated HbA1c.

DUX4 expression in cancer induces a metastable early embryonic totipotent program.

The transcription factor DUX4 regulates a portion of the zygotic gene activation (ZGA) program in the early embryo. Many cancers express DUX4 but it is unknown whether this generates cells similar to early embryonic stem cells. Here we identified cancer cell lines that express DUX4 and showed that DUX4 is transiently expressed in a small subset of the cells. DUX4 expression activates the DUX4-regulated ZGA transcriptional program, the subsequent 8C-like program, and markers of early embryonic lineages, while suppressing steady-state and interferon-induced MHC class I expression. Although DUX4 was expressed in a small number of cells under standard culture conditions, DNA damage or changes in growth conditions increased the fraction of cells expressing DUX4 and its downstream programs. Our demonstration that transient expression of endogenous DUX4 in cancer cells induces a metastable early embryonic stem cell program and suppresses antigen presentation has implications for cancer growth, progression, and immune evasion.

Validation of the association between MRI and gene signatures in facioscapulohumeral dystrophy muscle: implications for clinical trial design.

Identifying the aberrant expression of DUX4 in skeletal muscle as the cause of facioscapulohumeral dystrophy (FSHD) has led to rational therapeutic development and clinical trials. Several studies support the use of MRI characteristics and the expression of DUX4-regulated genes in muscle biopsies as biomarkers of FSHD disease activity and progression, but reproducibility across studies needs further validation. We performed lower-extremity MRI and muscle biopsies in the mid-portion of the tibialis anterior (TA) muscles bilaterally in FSHD subjects and validated our prior reports of the strong association between MRI characteristics and expression of genes regulated by DUX4 and other gene categories associated with FSHD disease activity. We further show that measurements of normalized fat content in the entire TA muscle strongly predict molecular signatures in the mid-portion of the TA. Together with moderate-to-strong correlations of gene signatures and MRI characteristics between the TA muscles bilaterally, these results suggest a whole muscle model of disease progression and provide a strong basis for inclusion of MRI and molecular biomarkers in clinical trial design.

Cerebral oximetry in adult cardiac surgery to reduce the incidence of neurological impairment and hospital length-of-stay: A prospective, randomized, controlled trial.

Background: Cerebral oximetry using near-infrared spectroscopy (NIRS) has been shown to reduce neurological dysfunction and hospital length-of-stay after adult cardiac surgery in some but not all studies. We audited maintaining cerebral saturations at or above baseline and showed improved neurological and length-of-stay outcomes. Our hypothesis for this study was that our NIRS protocol would improve neurological and length-of-stay outcomes. Methods: This prospective, single centre, double-blinded controlled study randomized 182 consecutive patients, scheduled for cardiac surgery using cardiopulmonary bypass. Participants were randomized by concealed envelope prior to anaesthesia. NIRS study group were managed perioperatively using our NIRS protocol of 8 interventions, increase cardiac output, normocapnia, increase mean arterial pressure, increase inspired oxygen, depth of anaesthesia, blood transfusion, correction of bypass cannula, change of surgical plan to restore levels equal to or above baseline. The control group had standard management without NIRS. Primary outcomes were neurological impairment (early and late) and hospital length-of-stay. Secondary outcomes were ventilation times, intensive care length-of-stay, major organ dysfunction and mortality. Results: 91 patients entered each group. There was a significant improvement in self-reported six-month general functionality in the NIRS group (p = 0.016). Early neurological dysfunction and hospital length-of-stay was the same in both groups. Of the secondary outcomes only Intensive Care length-of-stay was statistically significant, being shorter in the NIRS group (p = 0.026). Conclusion: Maintaining cerebral saturations above baseline reduces time spent in Intensive Care and may improve long term functional recovery but not stroke, major organ dysfunction and mortality.

Vasoplegic Syndrome Post-cardiopulmonary Bypass in a Renal Transplant Patient: The Brain Is Not the Index Organ.

Vasoplegia syndrome (VS) is seen in cardiac surgery post-cardiopulmonary bypass (CPB) and defined by increasing requirements for more than one vasoactive agent to which the patient's response is reduced. It is also associated with normal or high cardiac output (CO). Prolonged CPB time is the second commonest precipitating factor. Here, we describe a young adult, with good right ventricular (RV) and left ventricular (LV) function, who previously was a renal transplant recipient with a functioning kidney who developed VS and shock after CPB to replace the mitral and aortic valves. During the first two hours of CPB, his mean arterial blood pressure (MAP) was never lower than 50 mmHg. His brain regional cerebral oxygen saturation (rSO2) remained above baseline, and his body temperature was kept at 33°C. Urine output was constant at 40 ml/hr. He came off CPB requiring two inotropes and two vasoconstrictors. Even so, his systolic blood pressure was low, and his pulse pressure narrows. He was then started on methylene blue which improved his MAP. On arrival to the intensive care unit (ICU), he immediately required continuous veno-veno haemodialysis (CVVHD) and developed acute liver failure. At 16 hours, he showed a clinically fair neurological recovery. Forty-eight hours post-surgery, he suffered multiorgan failure and developed an intractable arrhythmia and died. The unusual components were as follows: he was normally responsive to phenylephrine during CPB; despite normal rSO2 and a clinically neurological recovery, he suffered multiorgan failure; and his serial high-sensitivity (HS) troponin I levels never fell below 500,000 pg/ml (normal <14 pg/ml).

Safety and immunogenicity of PXVX0317, an aluminium hydroxide-adjuvanted chikungunya virus-like particle vaccine: a randomised, double-blind, parallel-group, phase 2 trial.

BACKGROUND: Chikungunya virus (CHIKV) disease is an ongoing public health threat. We aimed to evaluate the safety and immunogenicity of PXVX0317, an aluminium hydroxide-adjuvanted formulation of a CHIKV virus-like particle (VLP) vaccine. METHODS: This randomised, double-blind, parallel-group, phase 2 trial was conducted at three clinical trial centres in the USA. Eligible participants were healthy CHIKV-naïve adults aged 18-45 years. Participants were stratified by site and randomly assigned (1:1:1:1:1:1:1:1) to one of the eight vaccination groups using a block size of 16. Group 1 received two doses of unadjuvanted PXVX0317 28 days apart (2 × 20 µg; standard); all other groups received adjuvanted PXVX0317: groups 2-4 received two doses 28 days apart (2 × 6 µg [group 2], 2 × 10 µg [group 3], or 2 × 20 µg [group 4]; standard); group 4 also received a booster dose 18 months after the first active injection (40 µg; standard plus booster); groups 5-7 received two doses 14 days apart (2 × 6 µg [group 5], 2 × 10 µg [group 6], or 2 × 20 µg [group 7]; accelerated); and group 8 received one dose (1 × 40 µg; single). The primary endpoint was the geometric mean titre of anti-CHIKV neutralising antibody on day 57 (28 days after the last vaccination), assessed in the immunogenicity-evaluable population. Additionally, we assessed safety. This trial is registered at ClinicalTrials.gov, NCT03483961. FINDINGS: This trial was conducted from April 18, 2018, to Sept 21, 2020; 468 participants were assessed for eligibility. Of these, 415 participants were randomly assigned to eight groups (n=53 in groups 1, 5, and 6; n=52 in groups 2 and 8; n=51 in groups 3 and 7; and n=50 in group 4) and 373 were evaluable for immunogenicity. On day 57, serum neutralising antibody geometric mean titres were 2057·0 (95% CI 1584·8-2670·0) in group 1, 1116·2 (852·5-1461·4; p=0·0015 vs group 1 used as a reference) in group 2, 1465·3 (1119·1-1918·4; p=0·076) in group 3, 2023·8 (1550·5-2641·7; p=0·93) in group 4, 920·1 (710·9-1190·9; p<0·0001) in group 5, 1206·9 (932·4-1562·2; p=0·0045) in group 6, 1562·8 (1204·1-2028·3; p=0·14) in group 7, and 1712·5 (1330·0-2205·0; p=0·32) in group 8. In group 4, a booster dose increased serum neutralising antibody geometric mean titres from 215·7 (95% CI 160·9-289·1) on day 547 to 10 941·1 (7378·0-16 225·1) on day 575. Durability of the immune response (evaluated in groups 1, 4, and 8) was shown up to 2 years. The most common solicited adverse event was pain at the injection site, reported in 12 (23%) of 53 participants who received the unadjuvanted vaccine (group 1) and 111 (31%) of 356 who received the adjuvanted vaccine. No vaccine-related serious adverse events were reported. INTERPRETATION: PXVX0317 was well tolerated and induced a robust and durable serum neutralising antibody immune response against CHIKV up to 2 years. A single 40 µg injection of adjuvanted PXVX0317 is being further investigated in phase 3 clinical trials (NCT05072080 and NCT05349617). FUNDING: Emergent BioSolutions.

The Dilemma: Whether to Proceed or Postpone a Patient With Pyrexia at Induction of Anesthesia for Coronary Artery Bypass Graft Surgery.

Routine surgery may be postponed if a patient has high white blood cells (WBC) and/or pyrexia. However, postponement carries the risk of myocardial ischaemia or infarction in a patient having coronary artery bypass graft (CABG) surgery. Our case raises this dilemma in a high-risk patient that was further compromised by acute right ventricular (RV) dysfunction. A 51-year-old diabetic with end-stage renal failure, chest pain, and a recent non-ST elevation myocardial infarction (NSTEMI) who had previously refused surgery now presented for urgent CABG. During central line insertion, he started shivering and stated that he felt cold. His temperature was not measured pre-intubation, but he felt warm to the touch with no chest pain. Blood pressure (BP) 190/80 mmHg and HR 110 bpm. Iv glyceryl nitrate (GTN) and fentanyl controlled the BP. Cerebral oximetry was used to measure brain regional saturation (rSO2) with probes placed on the forehead pre-induction. Post-intubation his temperature was 38.1°C, end-tidal carbon dioxide (EtCO2) 9.2 kPa, heart rate (HR) 120 bpm. His recent NSTEMI and surgical referral two years previously meant that his ischaemic risk was high, and we decided to proceed with the surgery. During the internal mammary artery (IMA) harvesting and use of a retractor (IMAR), there was a steady fall in the rSO2 readings along with hypotension and an increase in central venous pressure (CVP) becoming critical after 60 minutes. At this point, the patient went onto cardiopulmonary bypass (CPB). The patient required triple vasoactive support to wean off CPB. In the intensive care unit (ICU), he required immediate support for RV failure, including nitric oxide. The next day, the patient grew Gram-negative blood cultures. In hindsight, we should have checked his temperature before induction and postponed or postponed post-induction. Regarding the IMAR or any retractor, the operating team will pay much closer attention to any haemodynamic changes resulting from their use and act accordingly.

Effect of Acute Stress Glycemic Control and Long-Term Glycemic Control on the Incidence of Post-Operative Infection in Diabetics Undergoing Cardiac Surgery.

Objective Post-operative infection after cardiac surgery causes prolonged hospital stay and increased mortality. In patients with diabetes, peri-operative and pre-operative glycemic control have been associated with increased risk of post-operative infection. Saudi Arabia is the 7th highest country in the world for the prevalence of diabetes. In our surgical population the incidence of diabetes is 77%. We were aware of a high incidence of post-operative infections in our institution. The aim of this work was to assess how peri-operative and pre-operative glycemic control was related to the six-week incidence of post-operative infection. Method We retrospectively collected data for 174 adult patients with diabetes undergoing cardiac surgery between January 2017 and June 2019. For group analysis of peri-operative glycemic control, a mean value of ≤10 mmol/l was categorized as optimal control and a mean value of >10 mmol/l as sub-optimal control. The admission glucose value, the maximum glucose value and glycosylated hemoglobin A1c (HbA1c) were separately recorded. Admission HbA1c was used for optimal long-term control group (HbA1c ≤ 7%) and sub-optimal long-term control group (HbA1c > 7%). Results Of the 174 patients 60 (34%) developed infection in the six-week post-operative period. No statistically significant difference in infections was seen in the optimal peri-operative control group (n = 24, 14%) compared to sub-optimal peri-operative control group (n = 36, 21%; p = 0.113). However, patients with infection had a significantly higher mean glucose (10.4 mmol/l versus 9.9 mmol/l, p = 0.0316) than no infection. Grouping according to their HbA1c: well controlled group (41, 24.0%) and poor control group (130, 76.0%) showed no difference in infections. However, patients with lower HbA1c had better glycemic control as measured by: initial glucose (r = 0.52, p=<0.001); mean peri-operative glucose (r = 0.45, p=<0.001); maximum recorded glucose (r = 0.41, p=<0.001). Conclusion The majority of our patients presented with sub-optimal long-term glycemic control which we linked to poor stress glycemic control perioperatively. Patients with post-operative infections had higher mean peri-operative blood glucose. With the high incidence of diabetes in Saudi Arabia we have demonstrated the importance of good pre-operative assessment which allows tighter peri-operative glycemic control to reduce post-operative morbidity.

Outcomes in Cardiac Surgery Based on Preoperative, Mean Intraoperative and Stratified Cerebral Oximetry Values.

INTRODUCTION: Cardiac surgery is associated with significant morbidity and longer length-of-stay (LOS) than most other surgeries. Regional cerebral oximetry (rSO2) using near-infrared spectroscopy (NIRS) on the patient's forehead monitors cerebral oxygenation during surgery and cardiopulmonary bypass (CPB). Its purpose is to detect and manage periods of cerebral hypoxia which may otherwise go undetected, thereby reducing morbidity. But outcomes have been inconsistent, and not all cardiac departments have adopted this non-invasive, simple-to-use technology. We aimed to study the efficacy of our use of rSO2 by recording seven outcomes for each patient according to their preoperative rSO2, the mean intraoperative rSO2, and four ischemic thresholds during surgery. METHOD: This is a retrospective audit of cardiac surgical patients in whom a protocol was used to maintain rSO2 above the preoperative value and studied seven major morbidity outcomes. Cerebral oximetry data were recorded for each patient and analyzed for six variables: preoperative baseline rSO2, mean intraoperative rSO2, and four ischemic thresholds defined as an area under the curve (AUC) in minutes% below the baseline rSO2,minus 10% below the baseline, minus 20% the below baselineand minus 50% below baseline. Outcomes examined were: delirium, stroke, postoperative rise in creatinine of 50 mmol, absolute creatinine of 200 mmol, need for new renal replacement therapy (RRT), hospital LOS and inpatient mortality. RESULTS: Complete data were available for 166 patients. Lower mean preoperative rSO2 was associated with stroke (p=0.031), mild and severe renal dysfunction (p=0.045 and p=0.036), death-in-hospital (p=0.027) and prolonged hospital LOS (p=0.005). Lower mean intraoperative rSO2 during surgery was associated with the outcomes of renal dysfunction, mild (p=0.027), moderate (p=0.003) or severe (p=0.002), death-in-hospital (p=0.003) and prolonged hospital LOS (p=0.015). Of the four ischemic thresholds defined, only new RRT occurring at minus 20% and minus 50% below baseline was significant. CONCLUSION: Lower preoperative rSO2 and mean intraoperative rSO2 were associated with poor outcomes, notably leading to a significant increase in hospital LOS. Mild degrees of cerebral ischemia below the baseline and minus 10% of the baseline during surgery were well tolerated.

Extravascular Lung Water and Effect on Oxygenation Assessed by Lung Ultrasound in Adult Cardiac Surgery.

Introduction The extravascular lung water content is determined by the use of lung ultrasound (LUS) which is represented as B-lines. The aim of this study was to investigate whether the LUS measurement of extravascular lung water was correlated to changes in oxygenation. Methods This prospective cohort study was comprised of 73 patients with an average age of 56 (range: 18 to 87 years) who underwent elective cardiac surgery using cardiopulmonary bypass. The LUS score was performed preoperatively, time zero (T0), at one hour (T1), and at 24 hours (T2) post-surgery. Additionally, arterial oxygen partial pressure and fraction of inspired oxygen (PaO2/FiO2) ratio were measured at each time and the time-to-extubation. Results A negative correlation was found between the LUS score and PaO2/FiO2 at T1 (p < 0.004). Extubation time and changes in the lung ultrasound score at T0 - T2 were positively correlated (p < 0.03). Plus, there was a positive correlation between fluid balance and lung ultrasound score at T2 (p < 0.03). Conclusion We found three significant correlations that support the use of LUS in cardiac surgery: 1) the more B-lines, the lower the oxygenation; 2) the more B-lines, the longer the period of ventilation; 3) the more B-lines, the more positive the fluid balance. LUS is a non-invasive bedside investigation that can be used to judge extravascular lung water, providing useful information in the management of patient oxygenation, fluid balance, and extubation.

Association Between Post-Operative Infection and Blood Transfusion in Cardiac Surgery.

Background Blood transfusion is a commonly used therapy in cardiac surgery, whether it is given during the surgery or in the intensive care unit. It is important to evaluate the risks and benefits of exposure to blood transfusion. The use of blood transfusions can influence patient outcome. Previous studies have implicated blood transfusion as a causative factor in post-operative infection. Objectives We aim to determine the effect of blood transfusion on post-operative infection in cardiac surgery patients at the King Faisal Cardiac Center, Jeddah, Saudia Arabia, from January 2017 to January 2019. Methods The regular six-week follow-up of cardiac surgery patients allowed us to maintain a six-week infection span. The main variables included patient characteristics, operative characteristics, pre-operative hemoglobin, six-week infection, blood transfusion, and clinical outcomes. A logistic regression model was developed to identify patient and procedure variables that were associated with blood transfusion and infection. The baseline variables were entered into the model. Variables with p-value less than 0.05 were considered significant. Results The incidence of transfusion out of 197 patients was 93.4% (n = 184). The occurrence of infection was 31.82% (n = 63). There was no difference in post-operative infection for patients who received blood transfusions compared with those who did not receive blood transfusions (p = 0.902). In comparing patients receiving 1-2 units of red blood cells (RBCs) (48%) and those receiving >2 units of RBCs (52%), there was no significance (p = 0.549). Conclusions There was no association between the incidence of infection and blood transfusion. While there are other reasons for withholding blood, it would not be recommended to do so based on the concern of infection.

Renal Outcome in Patients Undergoing Cardiac Surgery Using Cardiopulmonary Bypass.

Introduction Renal dysfunction is a significant variable in determining the outcome of surgery, such as cardiopulmonary bypass graft and valvular replacement, used to treat cardiovascular diseases. In Saudi Arabia, the incidence of renal failure and diabetes is higher than in most western populations. Our aim is to determine the renal outcome of patients who underwent cardiac surgery at King Faisal Cardiac Center from 2014 to 2017. Methods This a retrospective cohort study using a non-probability consecutive sampling technique for selection of the study population to assess the renal outcome in cardiac surgery patients using cardiopulmonary bypass from May 2014 to June 2017 in King Faisal Cardiac Center, Jeddah. Patients older than 18 years of age undergoing cardiac surgery, with available data, were included. Categorical variables were summarized by percentages and frequencies, and continuous variables by means and standard deviations, or medians and interquartile ranges if their distributions were skewed. Logistic regression was done with post-op renal impairment as the dependent variable and pre-op renal dysfunction, age, gender, smoking status, diabetes, hypertension, dyslipidemia, and cardiopulmonary bypass time as independent variables. Results Our sample size included 244 patients who underwent cardiac surgery in this study period; their mean age was 60.5 (SD =7.5) with a mean body mass index (BMI) of 28.62 (SD=5.19). Among our population, 73% (n = 179) were males and 27% (n =66) were females. Two percent (2%) of patients (n = 5) died within 30 days, 4% of patients (n = 10) with temporary dialysis, 8% of patients (n = 19) with postoperative renal dysfunction, and no patients with permanent dialysis. The data showed a significant relationship between levels of creatinine preoperatively and postoperative renal dysfunction (p-value = 0.0001, OR=1.05, 95% CI of 1.031 to 1.064). Conclusion The main predictor of poor renal outcomes for cardiac surgery is preoperative creatinine. While other factors, such as age, gender, body mass index, cardiopulmonary bypass time, diabetes, hypertension, and dyslipidemia, did not show any risk to the postoperative renal outcome.

DUX4-Induced Histone Variants H3.X and H3.Y Mark DUX4 Target Genes for Expression.

The DUX4 transcription factor is briefly expressed in the early cleavage-stage embryo, where it induces an early wave of zygotic gene transcription, whereas its mis-expression in skeletal muscle causes the muscular dystrophy facioscapulohumeral dystrophy (FSHD). Here, we show that DUX4 induces the expression of the histone variants H3.X and H3.Y. We have used a myoblast cell line with doxycycline-inducible DUX4 to show that these histone variants are incorporated throughout the body of DUX4-induced genes. Following a brief pulse of DUX4, these histones contribute to greater perdurance and to enhanced re-activation of DUX4 target gene expression. These findings provide a model for H3.X/Y as a chromatin mechanism that facilitates the expression of DUX4 target genes subsequent to a brief pulse of DUX4 expression.

Preparation for and organization during a major incident.

Major incidents during the recent past have reinforced the value that the NHS and other agencies have invested into the comprehensive Emergency, Preparedness, Resilience and Response framework. This gives a detailed structure of the role of the NHS in any type of major incident from man-made disaster to pandemic flu. This has required preparation of communication, transport, security, military and healthcare systems. Also included is how the response to the incident is handled at a local level and for different levels of response. Examples of how this has played out are described. Specialist training at the higher and advanced level for trainees is established so that victims are triaged at the scene and received by consultants with appropriate training. Hospitals, ambulance services and intensive care units across the country can use networks to ensure not only rapid access to Major Trauma Centres but also to highly sophisticated skills when advanced life support is required. The NHS response to major incidents has been shown to be effective and successful.