Improved Survival for Patients with Systemic Sclerosis-associated Pulmonary Arterial Hypertension: The Johns Hopkins Registry.

Rationale: To date, it remains unclear whether recent changes in the management of patients with systemic sclerosis-associated pulmonary hypertension (SSc-PH) have improved survival. Objectives: To describe a cohort of patients with SSc-PH and compare their characteristics and survival between the last two decades. Methods: Patients with SSc-PH prospectively enrolled in the Johns Hopkins Pulmonary Hypertension Center Registry were grouped into two cohorts based on the date of diagnostic right heart catheterization: cohort A included patients whose disease was diagnosed between 1999 and 2010, and cohort B included those whose disease was diagnosed between 2010 and 2021. Patients' characteristics were compared between the two cohorts. Measurements and Main Results: Of 504 patients with SSc-PH distributed almost equally between the two cohorts, 308 (61%) had World Symposium on Pulmonary Hypertension group 1, 43 (9%) had group 2, and 151 (30%) had group 3 disease. Patients with group 1 disease in cohort B had significantly better clinical and hemodynamic characteristics at diagnosis, were more likely to receive upfront combination pulmonary arterial hypertension therapy, and had a nearly 4-year increase in median transplant-free survival in univariable analysis than those in cohort A (P < 0.01). Improved transplant-free survival was still observed after adjusting for patients' baseline characteristics. In contrast, for group 2 or 3 patients with SSc-PH, there were no differences in baseline clinical, hemodynamic, or survival characteristics between the two cohorts. Conclusions: This is the largest single-center study that compares clinical characteristics of patients with SSc-PH between the last two decades. Transplant-free survival has improved significantly for those with group 1 disease over the last decade, possibly secondary to earlier detection and better therapeutic management. Conversely, those with group 2 or 3 disease continue to have dismal prognosis.

Development of the FAST-M maternal sepsis bundle for use in low-resource settings: a modified Delphi process.

OBJECTIVE: To develop a sepsis care bundle for the initial management of maternal sepsis in low resource settings. DESIGN: Modified Delphi process. SETTING: Participants from 34 countries. POPULATION: Healthcare practitioners working in low resource settings (n = 143; 34 countries), members of an expert panel (n = 11) and consultation with the World Health Organization Global Maternal and Neonatal Sepsis Initiative technical working group. METHODS: We reviewed the literature to identify all potential interventions and practices around the initial management of sepsis that could be bundled together. A modified Delphi process, using an online questionnaire and in-person meetings, was then undertaken to gain consensus on bundle items. Participants ranked potential bundle items in terms of perceived importance and feasibility, considering their use in both hospitals and health centres. Findings from the healthcare practitioners were then triangulated with those of the experts. MAIN OUTCOME MEASURE: Consensus on bundle items. RESULTS: Consensus was reached after three consultation rounds, with the same items deemed most important and feasible by both the healthcare practitioners and expert panel. Final bundle items selected were: (1) Fluids, (2) Antibiotics, (3) Source identification and control, (4) Transfer (to appropriate higher-level care) and (5) Monitoring (of both mother and neonate as appropriate). The bundle was given the acronym 'FAST-M'. CONCLUSION: A clinically relevant maternal sepsis bundle for low resource settings has been developed by international consensus. TWEETABLE ABSTRACT: A maternal sepsis bundle for low resource settings has been developed by international consensus.

Iraqi regulatory authority current system and experience with biosimilars.

Biological medicines have significantly altered treatment for many patients with chronic diseases such as cancers, autoimmune diseases, and diabetes. However, the high cost of biological medicines has limited patients' access to them. Iraq is one of the countries that have decided to increase access to these medicines through biosimilars, which are copies of originator biological medicines. Prior to 2019, the Iraqi National Regulatory Authority (NRA) had no clear guidelines in place for biosimilars uptake. Therefore, approvals of many biosimilars were delayed. As a response to that, a new pivotal committee was found within this authority, and the first version of Iraqi basis and guidelines for the approval of biosimilars was enacted. With the implementation of the Iraqi biosimilars guidelines and escalating the cooperation within the Iraqi NRA, many benefits have been attained in a short time including the approval of many essential biosimilar products which has resulted in a total cost savings estimated to exceed 50 million USD in just the year 2020. However, there are still some barriers towards making the utmost benefit from biosimilars in Iraq, such as lack of familiarity of these products among the Iraqi health care providers which requires appropriate biosimilars-awareness enhancement strategies.

Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV).

BACKGROUND: Since the identification of the first case of infection with the Middle East respiratory syndrome corona virus (MERS-CoV) in Saudi Arabia in June 2012, the number of laboratory-confirmed cases has exceeded 941 cases globally, of which 347 died. The disease presents as severe respiratory infection often with shock, acute kidney injury, and coagulopathy. Recently, we observed three cases who presented with neurologic symptoms. These are so far the first reported cases of neurologic injury associated with MERS-CoV infection. METHODS: Data was retrospectively collected from three patients admitted with MERS-CoV infection to Intensive Care unit (ICU) at King Abdulaziz Medical City, Riyadh. They were managed separately in three different wards prior to their admission to ICU. FINDING: The three patients presented with severe neurologic syndrome which included altered level of consciousness ranging from confusion to coma, ataxia, and focal motor deficit. Brain MRI revealed striking changes characterized by widespread, bilateral hyperintense lesions on T2-weighted imaging within the white matter and subcortical areas of the frontal, temporal, and parietal lobes, the basal ganglia, and corpus callosum. None of the lesions showed gadolinium enhancement. INTERPRETATION: CNS involvement should be considered in patients with MERS-CoV and progressive neurological disease, and further elucidation of the pathophysiology of this virus is needed.

Review of development survey of phase change material models in building applications.

The application of phase change materials (PCMs) in green buildings has been increasing rapidly. PCM applications in green buildings include several development models. This paper briefly surveys the recent research and development activities of PCM technology in building applications. Firstly, a basic description of phase change and their principles is provided; the classification and applications of PCMs are also included. Secondly, PCM models in buildings are reviewed and discussed according to the wall, roof, floor, and cooling systems. Finally, conclusions are presented based on the collected data.

Diversity of endophytic fungi from medicinal plant Oxalis latifolia and their antimicrobial potential against selected human pathogens.

Endophytic fungi that inhabit medicinal plants are microbial resources renowned for having compounds analogous to those produced by their host plants. This study aimed to describe the diversity of endophytic fungi found in Oxalis latifolia Kunth. To better understand the diversity of foliar endophytic fungi found in the leaves of the medicinal plant Oxalis latifolia, we isolated and characterized endophytic by using both morphological and molecular methods employing ITS markers. The antimicrobial activity of endophytic fungi against common human pathogens Escherichia coli, Staphylococcus aureus, and Bacillus subtilis was also investigated. A Total of 16 endophytic fungi were successfully isolated from leaves and classified into five orders of Pezizomycotina based on the phylogenic analyses; Xylariales (56%), Diaporthales (19%) Sordariales (6%), Glomerellales (13%) and Botryosphaeriales (6%). The antimicrobial activity of crude extracts from fungal endophyte against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis revealed that three isolates; N. aurantiaca, Phyllosticta capitalensis N. oryzae were the most potent, while Colletotrichum karstii and N. sphaerica displayed no growth inhibition property against the tested organism. The diversity indices were calculated by using the Shannon-Wiener, Margalef, and Simpson indices. The diversity indices analysis revealed an abundance of species diversity, where the dominant species were Nigrospora oryzae, N. sphaerica, and Colletotrichum karstii. This study describes the diversity of endophytic fungi found in O. latifolia and emphasizes their potential as a source of novel bioactive compounds. More research on phytochemical composition and antimicrobial activity is ongoing to correlate the traditional uses and scientific findings.

Anxiolytic and Sedative Properties of Melatonin Premedication in Pediatrics Undergoing Elective Cardiac Catheterization: A Randomized Placebo Study.

BACKGROUND: Preoperative anxiety in children has been linked to various postoperative consequences, such as postoperative regressive behavioral issues, extended distress during the recovery period, eating disorders, and bedwetting. The current study aimed to investigate the efficacy of low-dose oral melatonin in alleviating preoperative anxiety among children in the Iraqi population. STUDY DESIGN: A randomized, double-blinded comparative study was undertaken, involving children aged four to 14 years scheduled for elective cardiac catheterization under general anesthesia. The study comprised a total of 80 children. The involved individuals were randomly assigned to two groups, each with 40 subjects. Group A received 0.5 mg/kg melatonin as premedication, while Group B received a placebo. RESULTS: The two groups demonstrated similarity in mean age, weight, cardiac disease, and gender distribution. Statistically significant reductions in anxiety scores were observed in the melatonin group compared to the placebo group. Particularly, children administered 0.5 mg/kg melatonin exhibited the most substantial anxiolysis and venipuncture compliance (P < 0.05). Additionally, children who were premedicated with melatonin experienced decreased cognition, maximum sedation, successful parental separation, and psychomotor impairment (P < 0.05). CONCLUSIONS: Melatonin demonstrated an effective sedation level without significant side effects, making it a preferred choice due to its efficacy, safety, current availability, and cost-effectiveness compared to other anesthetic agents used in premedication procedures.

Assessing the Premedication Properties of Sublingual Melatonin in Young Women Undergoing Cesarean Section With Spinal Anesthesia: A Double-Blind Randomized Study.

INTRODUCTION: Preoperative anxiety can negatively impact patient outcomes by influencing the intraoperative requirements for anesthetics and analgesics, increasing postoperative pain intensity, and augmenting the need for analgesia. Moreover, it may contribute to higher rates of postoperative morbidity and mortality following certain types of surgery. This study investigates the anxiolytic and sedative properties of sublingual melatonin as a premedication agent in young females undergoing cesarean section under spinal anesthesia. METHODS: A double-blind, randomized, placebo-controlled trial was conducted in Nasiriyah, Iraq. Eighty females were included, 40 in each group, based on specific inclusion and exclusion criteria. Premedication was administered in the morning, 60 minutes before the procedure. In the melatonin group (M), patients received 10 mg of sublingual melatonin, while the placebo group (P) received placebo premedication. Anxiety and sedation levels were evaluated three times: before taking premedication, five minutes before the insertion of the spinal needle, and one hour postoperatively, using the visual analog scale and Richmond Sedation Scale. RESULTS: The results show a highly significant P-value regarding anxiety levels between the M Group and P Group (p-value < 0.001). There was a significant difference in the median sedation scores between the studied groups at pre-spinal insertion and postoperatively (p-value < 0.001). The mean heart rate in the M Group was significantly lower than in the P Group (p-value = 0.0019). Significant differences were noted in systolic and diastolic blood pressures between the two groups, measured five minutes before and after spinal needle insertion (p-value < 0.001). CONCLUSION: These findings contribute to understanding the impact of sublingual melatonin as an anxiolytic and sedative premedication agent on patients undergoing elective cesarean sections under spinal anesthesia. Further research is warranted to fully elucidate the benefits and implications of melatonin administration in such procedures.

The Comparison of Irisin, Subfatin, and Adropin in Normal-Weight and Obese Polycystic Ovary Syndrome Patients.

Background: A combination of genetic and environmental factors contribute to the highly common, complex, and varied endocrine condition known as polycystic ovary syndrome (PCOS) in women. PCOS primarily affects women between the ages of 15 and 35 who are in the early to late stages of pregnancy. Thus, this study aimed to evaluate the serum levels of irisin, subfatin, and adropin in PCOS with and without obesity compared to the control group. Methods: The present cross-sectional study was conducted in 2022 at Al-Nahrain University/Department of Chemistry (Baghdad, Iraq). The serum levels of irisin, subfatin, and adropin were measured with the enzyme-linked immunosorbent assay (ELISA) method. Body mass index, lipid profile, insulin, fasting glucose, follicle-stimulating hormone, and luteinizing hormone levels were also evaluated. The data were analyzed using one-way analysis of variance (ANOVA) by GraphPad Prism software version 8.0.2. A P<0.05 was considered statistically significant. Results: The study population comprised PCOS patients (n=90, divided into 45 obese and 45 normal weight) and healthy women (n=30). According to the results, the serum levels of irisin were significantly higher (P<0.001) in obese and normal-weight PCOS patients than controls. While adropin and subfatin were significantly lower in PCOS than controls (P<0.001). Moreover, there are higher levels of serum insulin, fasting glucose, and luteinizing hormone in PCOS women than in healthy women. Conclusion: According to the findings, PCOS patients had a higher level of irisin than the controls. In addition, decreased subfatin and adropin levels were observed in PCOS patients compared with healthy women. Further research is required to confirm these results in the future.

CALCINOSIS CUTIS - A SERIES OF 59 CONSECUTIVE CASES CONFINED AMONG WOMEN.

BACKGROUND: Calcinosis cutis is the cutaneous deposition of calcium salts. Tumoral Calcinosis is a condition consisting of massive subcutaneous deposits of calcium salts often overlying large joints in otherwise healthy patients. OBJECTIVE: To describe the characteristics of a series of patients with Tumoral Calcinosis in the Gurage Zone of Central Ethiopia. METHODOLOGY: Data was collected from 59 patients who presented with clinical diagnosis of calcinosis cutis around hip region between January 2005 and January 2009. RESULTS: All cases were females, with a mean (standard deviation) age at diagnosis of 50.7(10.8). The duration of illness ranged from one to eighteen years. The cases were distributed in the different villages of Gurage Zone without any sign of clustering of cases. The lesions were localized around hip region on both sides. The patients did not have any related co-morbidity or any history of similar illness among close family members. None of the patients gave history of evident trauma to the site of the lesions. Significant proportion of the patients (53.4%) confirmed to carry water container and/or other goods on their side. Serum Phosphate and Calcium levels in selected patients were with in normal limit. Histo-pathological examinations of five cases revealed Calcium deposits in collagenous connective tissue. CONCLUSION: The lesion was found to be relatively common in the study area and specifically confined to females. The probable factor associated with the cases is carrying objects on their side (hip area). Further research with in-depth clinical and laboratory evaluation is of paramount importance.

Electrokinetic remediation of estuarine sediments using a large reactor: spatial variation of physicochemical, mineral, and chemical properties.

The treatment and beneficial use of polluted or contaminated environmental matrices have become major issues, especially as the world strives toward a zero-waste policy. In this regard, dredged sediments need to be treated before they can be used in an environmentally safe and sustainable manner. Therefore, this work aims to treat estuarine sediments and, more importantly, use physicochemical, mineral, organic, and chemical information to understand the reactions that occur upon treatment. Dredged estuarine sediments were collected from Tancarville (Seine River estuary, France) and subjected to electrokinetic (EK) remediation using a 128-L laboratory-scale reactor. The sediments were treated 8 h per day for 21 days. The electric (voltage and current) and physicochemical (pH and electric conductivity) parameters were monitored during treatment. Sediments were collected from various sections in the reactor at the end of the experiment (lengthwise, widthwise, and depthwise). The spatial variation was investigated in terms of organic, mineral, and metal contents. Statistical analyses proved that the variation occurred only in the lengthwise direction. Furthermore, three main phases described the treatment, which were mainly linked to carbonate dissolution and pH variation. The results also showed that the trace elements Ni and Zn were reduced by 21% and 19%, respectively, without a direct link to pH, while Ca and Mg were only redistributed. The buffering capacity of the anodic sediment was reduced due to carbonate dissolution. The treated sediments showed reduced contents in trace metals without affecting major elements that can be useful in agriculture (i.e., Ca and Mg).

Studies on the effects of aspartame on memory and oxidative stress in brain of mice.

OBJECTIVE: The dipeptide aspartame (N-L-alpha-aspartyl-Lphenylalanine, 1-methyl ester; alpha-APM) is one of the most widely used artificial sweeteners. The present study aimed to investigate the effect of repeated administration of aspartame in the working memory version of Morris water maze test, on oxidative stress and brain monoamines in brain of mice. MATERIALS AND METHODS: Aspartame (0.625, 1.875 or 5.625 mg/kg) was administered once daily subcutaneously for 2 weeks and mice were examined four times a week for their ability to locate a submerged plate. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide levels (the concentrations of nitrite/nitrate) and glucose were determined in brain. RESULTS: Only at the highest dose of 5.625 mg/kg, did aspartame significantly impaired water maze performance. The mean time taken to find the escape platform (latency) over 2 weeks was significantly delayed by aspartame 5.625 mg/kg, compared with the saline-treated control group. Significant differences occurred only on the first trial to find the escape platform. Significant increase in brain MDA by 16.5% and nitric oxide by 16.2% and a decrease in GSH by 25.1% and glucose by 22.5% occurred after treatment with aspartame at 1.875 mg/kg. Aspartame administered at 5.625 mg/kg significantly increased brain MDA by 43.8%, nitric oxide by 18.6% and decreased GSH by 32.7% and glucose by 25.8%. Aspartame caused dose-dependent inhibition of brain serotonin, noradrenaline and dopamine. CONCLUSIONS: These findings suggest impaired memory performance and increased brain oxidative stress by repeated aspartame administration. The impaired memory performance is likely to involve increased oxidative stress as well as decreased brain glucose availability.

Knowledge and Attitude of Sudanese Emergency Registrars Towards the Use of Tissue Plasminogen Activator in the Management of Acute Ischemic Stroke.

BACKGROUND: Recent guidelines report that the administration of tissue plasminogen activator (tPA) within 4.5 hours enhances the clinical outcome of ischemic stroke. We assessed the knowledge and attitude of Sudanese emergency medicine registrars towards the use of tissue plasminogen activators in the management of acute ischemic stroke (AIS). METHODS: This is a descriptive, cross-sectional, hospital-based study. The study was conducted in emergency departments at Khartoum State Hospitals in Sudan during the period from May to July 2021. The study sample was 150 emergency medicine registrars who fulfilled the inclusion criteria of the study. Data was collected by using a self-administered questionnaire as a Google form that was sent to the study participants by email. RESULTS: Knowledge about tPA in the management of AIS at the emergency department was poor, average, and good in 54 (36%), 55 (36.7%), and 41 (27.3%) individuals, respectively. However, there was no significant difference in overall knowledge based on age; nevertheless, good and average knowledge levels were considerably higher among females, level 3 and level 4 of training, and years of experience 5-10 years (p-value = 0.05). The overall attitude of the participants was positive 62 (41.3%), neutral 45 (30%), and negative 43 (28.7%). The positive attitude regarding tPAs for patients with AIS was significantly associated with age 30-40 years, females, levels 3 and 4 of training, and experience 5-10 years (p-value < 0.05). CONCLUSION: The overall knowledge and attitude of emergency medicine registrars were average to good, with a significant proportion of participants reporting low knowledge. The issues encountered by participants in the use of tPAs were the absence of a stroke team in hospitals, the absence of a protocol for the care pathway of AIS management in hospitals, and the absence of tPAs.

Risk Stratification of Patients with Pulmonary Arterial Hypertension: The Role of Echocardiography.

Background: Given the morbidity and mortality associated with pulmonary arterial hypertension (PAH), risk stratification approaches that guide therapeutic management have been previously employed. However, most patients remain in the intermediate-risk category despite initial therapy. Herein, we sought to determine whether echocardiographic parameters could improve the risk stratification of intermediate-risk patients. Methods: Prevalent PAH patients previously enrolled in observational studies at 3 pulmonary hypertension centers were included in this study. A validated PAH risk stratification approach was used to stratify patients into low-, intermediate-, and high-risk groups. Right ventricular echocardiographic parameters were used to further stratify intermediate-risk patients into intermediate-low- and intermediate-high-risk groups based on transplant-free survival. Results: From a total of 146 patients included in our study, 38 patients died over a median follow-up of 2.5 years. Patients with intermediate-/high-risk had worse echocardiographic parameters. Tricuspid annular plane systolic excursion (TAPSE) and the degree of tricuspid regurgitation (TR) were highly associated with survival (p < 0.01, p = 0.04, respectively) and were subsequently used to further stratify intermediate-risk patients. Among intermediate-risk patients, survival was worse for patients with TAPSE < 19 mm compared to those with TAPSE ≥ 19 mm (estimated one-year survival 74% vs. 96%, p < 0.01) and for patients with moderate/severe TR compared to those with no/trace/mild TR (estimated one-year survival 70% vs. 93%, p < 0.01). Furthermore, among intermediate-risk patients, those with both TAPSE < 19 mm and moderate/severe TR had an estimated one-year survival (56%) similar to that of high-risk patients (56%), and those with both TAPSE ≥ 19 mm and no/trace/mild TR had an estimated one-year survival (97%) similar to that of low-risk patients (95%). Conclusions: Echocardiography, a routinely performed, non-invasive imaging modality, plays a pivotal role in discriminating distinct survival phenotypes among prevalent intermediate-risk PAH patients using TAPSE and degree of TR. This can potentially help guide subsequent therapy.

Blast-Induced Traumatic Brain Injuries: Experience from the Deadliest Double Suicide Bombing Attack in Iraq.

INTRODUCTION: Blast-induced traumatic brain injuries (bTBIs) are increasingly frequent in civilian settings. We present the first study of individuals with bTBI in Iraq. The study focuses on one of the deadliest suicide car bomb attacks in Iraq and uses it to show the devastating nature of bTBIs. METHODS: This study was conducted at the Neurosurgery Teaching Hospital in Baghdad, Iraq. A retrospective chart analysis of patients with bTBI admitted to the Neurosurgery Teaching Hospital was performed. Measured parameters included patients' demographics, initial presentation, injury patterns, hospital course, surgical management, and outcomes. RESULTS: A total of 75 patients with bTBI were included in this study, 19 of whom died in the emergency room. The remaining 56 patients were admitted to the hospital. Of those patients, 68.6% (n = 39) underwent surgery, and 30.4% were managed conservatively. A modified, tailored triaging system was implemented. All surgery was guided by the principles of damage control neurosurgery. In addition, 76.9% and 46.2% of patients underwent corticectomy and decompressive craniectomy, respectively. Dural venous sinus repair was performed in 17.9% of patients, and 30.7% of the operations entailed additional steps to control major (arterial) cerebrovascular bleeding. The net bTBI-related complication rate was 76%. The total mortality was 48%. Of survivors, 10.7% (n = 8) were discharged with a severe disability. Overall, good outcomes were achieved in 41.3% of the patients. CONCLUSIONS: This study sheds light on the devastating nature of bTBIs. Neurosurgeons worldwide need to be mindful of the unique triaging, diagnostic, and management requirements of these injuries.

A novel approach to perioperative risk assessment for patients with pulmonary hypertension.

RATIONALE: Pulmonary hypertension (PH) is associated with significant perioperative morbidity and mortality. We hypothesised that pulmonary arterial hypertension (PAH) composite risk assessment scores could estimate perioperative risk for PH patients when adjusted for inherent procedural risk. METHODS: We identified patients in the Johns Hopkins PH Center Registry that had noncardiac surgery (including endoscopies) between September 2015 and January 2020. We collected information on preoperative patient-level and procedural variables and used logistic regression to evaluate associations with a composite outcome of death within 30 days or serious postoperative complication. We generated composite patient-level risk assessment scores for each subject and used logistic regression to estimate the association with adverse surgical outcomes. We adjusted multivariable models for inherent procedural risk of major cardiovascular events and used these models to generate a numerical PH perioperative risk (PHPR) score. RESULTS: Among 150 subjects, 19 (12.7%) reached the primary outcome, including 7 deaths (4.7%). Individual patient-level and procedural variables were associated with the primary outcome (all p<0.05). A composite patient-level risk assessment score built on three noninvasive parameters was strongly associated with reduced risk for poor outcomes (OR=0.4, p=0.03). This association was strengthened after adjusting the model for procedural risk. A PHPR score derived from the multivariable model stratified patients into low (0%), intermediate (≤10%), or high (>10%) risk of reaching the primary outcome. CONCLUSION: Composite PAH risk assessment scores can predict perioperative risk for PH patients after accounting for inherent procedural risk. Validation of the PHPR score in a multicentre, prospective cohort is warranted.

Identifying practices and ideas to improve the implementation of maternal mortality reduction programmes: findings from five South Asian countries.

OBJECTIVE: The successful implementation of programmes to reduce maternal mortality is constrained by a 'know-do' gap: the disparity between what is known and the application of that knowledge in policy and practice. This study identified innovations, practices and ideas aimed to improve project and programme implementation. DESIGN: Cross-sectional. SETTING: Five South Asian countries: Afghanistan, Bangladesh, India, Nepal and Pakistan. SAMPLE: Sixteen projects and programmes, and 100 key informants. METHODS: In-depth review of documents, key informant interviews and focus-group discussions. MAIN OUTCOME MEASURES: Innovations and ideas to improve programme implementation, and their perceived effects. RESULTS: Delegation of duties to intermediate-level health workers, incentivisation of health workers, providing the means to overcome financial barriers for accessing care, quality improvements and knowledge transfer were examples of ideas put into practice to improve programme implementation. There was a perception that these improved service use and availability, but objective evidence was lacking. CONCLUSIONS: Some innovations, practices and ideas are supported by evidence of effect, and could be replicated, whereas others have not been formally evaluated. Testing of these innovations is required before more widespread adoption can be recommended, although experiences should be shared to narrow the 'know-do' gap, even though the evidence on beneficial effects remains unclear.

Post-Translational Modifications in NETosis and NETs-Mediated Diseases.

: Neutrophils undergo a unique form of cell death that generates neutrophil extracellular traps (NETs) that may help to neutralize invading pathogens and restore homeostasis. However, uncontrolled NET formation (NETosis) can result in numerous diseases that adversely affect health. Recent studies further elucidate the mechanistic details of the different forms of NETosis and their common end structure, as NETs were constantly found to contain DNA, modified histones and cytotoxic enzymes. In fact, emerging evidence reveal that the post translational modifications (PTMs) of histones in neutrophils have a critical role in regulating neutrophil death. Histone citrullination is shown to promote a rapid form of NET formation independent of NADPH oxidase (NOX), which relies on calcium influx. Interestingly, few studies suggest an association between histone citrullination and other types of PTMs to control cell survival and death, such as histone methylation. Even more exciting is the finding that histone acetylation has a biphasic effect upon NETosis, where histone deacetylase (HDAC) inhibitors promote baseline, NOX-dependent and -independent NETosis. However, increasing levels of histone acetylation suppresses NETosis, and to switch neutrophil death to apoptosis. Interestingly, in the presence of NETosis-promoting stimuli, high levels of HDACis limit both NETosis and apoptosis, and promote neutrophil survival. Recent studies also reveal the importance of the PTMs of neutrophils in influencing numerous pathologies. Histone modifications in NETs can act as a double-edged sword, as they are capable of altering multiple types of neutrophil death, and influencing numerous NET-mediated diseases, such as acute lung injury (ALI), thrombosis, sepsis, systemic lupus erythematosus, and cancer progression. A clear understanding of the role of different PTMs in neutrophils would be important for an understanding of the molecular mechanisms of NETosis, and to appropriately treat NETs-mediated diseases.

Histone Deacetylase Inhibitors Dose-Dependently Switch Neutrophil Death from NETosis to Apoptosis.

Acetylation is an important post translational modification of histone that plays a role in regulation of physiological and pathological process in the body. We have recently shown that the inhibition of histone deacetylases (HDAC) by low concentrations of HDAC inhibitors (HDACis), belinostat (up to 0.25 µM) and panobinostat (up to 0.04 µM) promote histone acetylation (e.g., AcH4) and neutrophil extracellular trap formation (NETosis). Clinical use of belinostat and panobinostat often leads to neutropenia and the in vivo concentrations vary with time and tissue locations. However, the effects of different concentrations of these HDACis on neutrophil death are not fully understood. We considered that increasing concentrations of belinostat and panobinostat could alter the type of neutrophil death. To test this hypothesis, we treated human neutrophils with belinostat and panobinostat in the presence or absence of agonists that promote NOX-dependent NETosis (phorbol myristate acetate or lipopolysaccharide from Escherichia coli 0128) and NOX-independent NETosis (calcium ionophores A23187 or ionomycin from Streptomyces conglobatus). Increasing concentrations of HDACis induced histone acetylation in a dose-dependent manner. ROS analyses showed that increasing concentrations of HDACis, increased the degree of NOX-derived ROS production. Higher levels (>1 µM belinostat and >0.2 µM panobinostat) of AcH4 resulted in a significant inhibition of spontaneous as well as the NOX-dependent and -independent NETosis. By contrast, the degree of neutrophil apoptosis significantly increased, particularly in non-activated cells. Collectively, this study establishes that increasing concentrations of belinostat and panobinostat initially increases NETosis but subsequently reduces NETosis or switches the form of cell death to apoptosis. This new information indicates that belinostat and panobinostat can induce different types of neutrophil death and may induce neutropenia and regulate inflammation at different concentrations.