Neural Correlates of Gain Control in Drosophila and Humans

Previous research has shown that visual sensitivity in human epilepsy patients is abnormal – characterized by increased responses at high contrast levels. These abnormalities have been linked to changes in neuronal gain control. Using animal models to study these changes is a useful approach. In this thesis, we used a steady-state visually evoked potential (SSVEP) technique similar to that used in humans to study photoreceptor-level and neuronal gain control in wild type (w-) Drosophila across a range of ages. We then compared these responses to those obtained from Drosophila carrying the kcc potassium channel mutation that renders young flies susceptible to light and shock-induced seizures. By taking into account the age and temperature dependence of the mutant (kccDHS1) flies, we were able to identify increased neural activity that recovers to the normal profile as they get older. We also found that these kccDHS1 flies are hypersensitive to light, particularly when young. These two findings are consistent with the fact that the level of the KCC protein increases with age. In addition, we found that kccDHS1 flies generate high frequency oscillations in their ERGs in response (50 – 100 Hz) to abrupt light onsets and offsets – a phenomenon that might be linked to abnormal changes in the gain control of neuronal feedback circuits. Studying visual abnormalities in Drosophila can reveal important information but eventually we need to link any visual abnormalities observed in animal models to humans. We therefore, attempted to measure subtle changes in gain control in humans due to adaptation, and at the same time make use of the human mental ability to measure another measure of gain control, attention, using an fMRI technique. Although our data did not show any interaction between adaptation and attention, it suggests that attention in early visual pathways largely affects the level of suppression in non-stimulated regions around the adaptor rather than responses to the probe itself. This is a manipulation that links to our work on adaptation in Drosophila in Chapter 6. Overall, the results presented in this thesis showed that fly models of epilepsy can be useful for studying changes in visual gain control, and showed that this work might be extended to humans

Thyroid disorders, epidemiology and outcome among patients in South Western region: Southern Saudi Arabia

Background: Thyroid gland may have a group of a medical condition that affects its main function. The thyroid gland is located at the front of the neck and produces thyroid hormones. The released hormones go through the blood to many body organs for regulating their function, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development. The study aimed to assess the epidemiology of thyroid disorders among cases in the south-western region, Saudi Arabia, and to assess the reporting quality for these cases data.Methods: A retrospective record based descriptive approach was used through reviewing medical records of all cases that were admitted and diagnosed as thyroid related disorders for different indications in the main hospital (king Khalid Hospital) during the period from January 2018 to January 2020. Data extracted throng pre-structured questionnaire including patient's bio-clinical data, preoperative radiological and laboratory investigations. Also, laryngoscope pre and post operatively was reviewed to record findings.Results: The study included 405 cases with thyroid disorders whose ages ranged from 15 to 71 years old with a mean age of 30.5±10.6 years. Females were 82.7% of the included cases, and 83.8% were Saudi. Thyroid related symptoms were recorded for 1-2 years among 58.1% of the cases and for more than 5 years among 15.8%. Thyroid enlargement was recorded for 73.1% of the cases. The multinodular enlargement was recorded for 53.5% of the cases followed with diffuse thyroid enlargement (27.3%). Regarding the type of surgery undergone, total thyroidectomy was the most recorded followed with lobectomy.Conclusions: The study revealed that the majority of the cases were females at middle age presented with benign lesions with Euthyroid status. The most important conclusion was the significant remarkable underreporting of the different clinical data for the cases with many missing items

Oral semaglutide adequate glycaemia control with safe cardiovascular ‎profile

BackgroundType 2 diabetes is a chronic and progressive disease that ‎associated with series complication such as major adverse ‎cardiovascular events. Adequate glycaemic control proven ‎to reduce this risk. Orally administered semaglutide ‎promising medication in managing patient with type 2 ‎diabetes.‎AimsTo assess the cardiovascular safety and efficacy of semaglutide, a recently approved glucagon-like peptide 1 receptor agonist (GLP-1 RA) for type 2 diabetes.Methods Pub Med, ‎Google Scholar, and EBSCO ‎ databases were ‎systematically search for relevant articles. The terms‎ diabetes‎, Glucagon-like peptide, semaglutide‎ were used. Out of hundred twenty-two records, only ‎four fulfilled ‎the inclusion criteria.Results Four placebo-controlled studies with oral semaglutide ‎were included. Single study concern about the cardiovascular safety of oral semaglutide ‎and showed that, ‎compared with placebo, semaglutide ‎ was not associated ‎with increased in the cardiovascular events. On the other ‎hand, the remaining trials shown that, semaglutide ‎ can ‎effectively control the blood glucose as evident by ‎reduction in HA1c.ConclusionOral semaglutide can effectively and safely lower blood glucose without increase in the major adverse ‎cardiovascular events‎‎ (MACE).

Utility of Initial Arterial Blood Gas in Neuromuscular versus Non-Neuromuscular Acute Respiratory Failure in Intensive Care Unit Patients

Background: The arterial blood gas (ABG) parameters of patients admitted to intensive care units (ICUs) with acute neuromuscular respiratory failure (NMRF) and non-NMRF have not been defined or compared in the literature. Methods: We retrospectively collected the initial ABG parameters (pH, PaCO2, PaO2, and HCO3) of patients admitted to ICUs with acute respiratory failure. We compared ABG parameter ranges and the prevalence of abnormalities in NMRF versus non-NMRF and its categories, including primary pulmonary disease (PPD) (chronic obstructive pulmonary disease, asthma, and bronchiectasis), pneumonia, and pulmonary edema. Results: We included 287 patients (NMRF, n = 69; non-NMRF, n = 218). The difference between NMRF and non-NMRF included the median (interquartile range (IQR)) of pH (7.39 (7.32–7.43), 7.33 (7.22–7.39), p < 0.001), PaO2 (86.9 (71.4–123), 79.6 (64.6–99.1) mmHg, p = 0.02), and HCO3 (24.85 (22.9–27.8), 23.4 (19.4–26.8) mmol/L, p = 0.006). We found differences in the median of PaCO2 in NMRF (41.5 mmHg) versus PPD (63.3 mmHg), PaO2 in NMRF (86.9 mmHg) versus pneumonia (74.3 mmHg), and HCO3 in NMRF (24.8 mmol/L) versus pulmonary edema (20.9 mmol/L) (all p < 0.01). NMRF compared to non-NMRF patients had a lower frequency of hypercarbia (24.6% versus 39.9%) and hypoxia (33.8% versus 50.5%) (all p < 0.05). NMRF compared to PPD patients had lower frequency of combined hypoxia and hypercarbia (13.2% versus 37.8%) but more frequently isolated high bicarbonate (33.8% versus 8.9%) (all p < 0.001). Conclusions: The ranges of ABG changes in NMRF patients differed from those of non-NMRF patients, with a greater reduction in PaO2 in non-NMRF than in NMRF patients. Combined hypoxemia and hypercarbia were most frequent in PPD patients, whereas isolated high bicarbonate was most frequent in NMRF patients

SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population

International Nosocomial Infection Control Consortium report, data summary of 50 countries for 2010-2015: Device-associated module

•We report INICC device-associated module data of 50 countries from 2010-2015.•We collected prospective data from 861,284 patients in 703 ICUs for 3,506,562 days.•DA-HAI rates and bacterial resistance were higher in the INICC ICUs than in CDC-NHSN's.•Device utilization ratio in the INICC ICUs was similar to CDC-NHSN's. Background: We report the results of International Nosocomial Infection Control Consortium (INICC) surveillance study from January 2010-December 2015 in 703 intensive care units (ICUs) in Latin America, Europe, Eastern Mediterranean, Southeast Asia, and Western Pacific. Methods: During the 6-year study period, using Centers for Disease Control and Prevention National Healthcare Safety Network (CDC-NHSN) definitions for device-associated health care-associated infection (DA-HAI), we collected prospective data from 861,284 patients hospitalized in INICC hospital ICUs for an aggregate of 3,506,562 days. Results: Although device use in INICC ICUs was similar to that reported from CDC-NHSN ICUs, DA-HAI rates were higher in the INICC ICUs: in the INICC medical-surgical ICUs, the pooled rate of central line-associated bloodstream infection, 4.1 per 1,000 central line-days, was nearly 5-fold higher than the 0.8 per 1,000 central line-days reported from comparable US ICUs, the overall rate of ventilator-associated pneumonia was also higher, 13.1 versus 0.9 per 1,000 ventilator-days, as was the rate of catheter-associated urinary tract infection, 5.07 versus 1.7 per 1,000 catheter-days. From blood cultures samples, frequencies of resistance of Pseudomonas isolates to amikacin (29.87% vs 10%) and to imipenem (44.3% vs 26.1%), and of Klebsiella pneumoniae isolates to ceftazidime (73.2% vs 28.8%) and to imipenem (43.27% vs 12.8%) were also higher in the INICC ICUs compared with CDC-NHSN ICUs. Conclusions: Although DA-HAIs in INICC ICU patients continue to be higher than the rates reported in CDC-NSHN ICUs representing the developed world, we have observed a significant trend toward the reduction of DA-HAI rates in INICC ICUs as shown in each international report. It is INICC's main goal to continue facilitating education, training, and basic and cost-effective tools and resources, such as standardized forms and an online platform, to tackle this problem effectively and systematically

Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): a multicentre, prospective, observational cohort study

Background Current management practices and outcomes in weaning from invasive mechanical ventilation are poorly understood. We aimed to describe the epidemiology, management, timings, risk for failure, and outcomes of weaning in patients requiring at least 2 days of invasive mechanical ventilation. Methods WEAN SAFE was an international, multicentre, prospective, observational cohort study done in 481 intensive care units in 50 countries. Eligible participants were older than 16 years, admitted to a participating intensive care unit, and receiving mechanical ventilation for 2 calendar days or longer. We defined weaning initiation as the first attempt to separate a patient from the ventilator, successful weaning as no reintubation or death within 7 days of extubation, and weaning eligibility criteria based on positive end-expiratory pressure, fractional concentration of oxygen in inspired air, and vasopressors. The primary outcome was the proportion of patients successfully weaned at 90 days. Key secondary outcomes included weaning duration, timing of weaning events, factors associated with weaning delay and weaning failure, and hospital outcomes. This study is registered with ClinicalTrials.gov, NCT03255109. Findings Between Oct 4, 2017, and June 25, 2018, 10 232 patients were screened for eligibility, of whom 5869 were enrolled. 4523 (77·1%) patients underwent at least one separation attempt and 3817 (65·0%) patients were successfully weaned from ventilation at day 90. 237 (4·0%) patients were transferred before any separation attempt, 153 (2·6%) were transferred after at least one separation attempt and not successfully weaned, and 1662 (28·3%) died while invasively ventilated. The median time from fulfilling weaning eligibility criteria to first separation attempt was 1 day (IQR 0–4), and 1013 (22·4%) patients had a delay in initiating first separation of 5 or more days. Of the 4523 (77·1%) patients with separation attempts, 2927 (64·7%) had a short wean (≤1 day), 457 (10·1%) had intermediate weaning (2–6 days), 433 (9·6%) required prolonged weaning (≥7 days), and 706 (15·6%) had weaning failure. Higher sedation scores were independently associated with delayed initiation of weaning. Delayed initiation of weaning and higher sedation scores were independently associated with weaning failure. 1742 (31·8%) of 5479 patients died in the intensive care unit and 2095 (38·3%) of 5465 patients died in hospital. Interpretation In critically ill patients receiving at least 2 days of invasive mechanical ventilation, only 65% were weaned at 90 days. A better understanding of factors that delay the weaning process, such as delays in weaning initiation or excessive sedation levels, might improve weaning success rates

Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): a multicentre, prospective, observational cohort study

Background: Current management practices and outcomes in weaning from invasive mechanical ventilation are poorly understood. We aimed to describe the epidemiology, management, timings, risk for failure, and outcomes of weaning in patients requiring at least 2 days of invasive mechanical ventilation. Methods: WEAN SAFE was an international, multicentre, prospective, observational cohort study done in 481 intensive care units in 50 countries. Eligible participants were older than 16 years, admitted to a participating intensive care unit, and receiving mechanical ventilation for 2 calendar days or longer. We defined weaning initiation as the first attempt to separate a patient from the ventilator, successful weaning as no reintubation or death within 7 days of extubation, and weaning eligibility criteria based on positive end-expiratory pressure, fractional concentration of oxygen in inspired air, and vasopressors. The primary outcome was the proportion of patients successfully weaned at 90 days. Key secondary outcomes included weaning duration, timing of weaning events, factors associated with weaning delay and weaning failure, and hospital outcomes. This study is registered with ClinicalTrials.gov, NCT03255109. Findings: Between Oct 4, 2017, and June 25, 2018, 10 232 patients were screened for eligibility, of whom 5869 were enrolled. 4523 (77·1%) patients underwent at least one separation attempt and 3817 (65·0%) patients were successfully weaned from ventilation at day 90. 237 (4·0%) patients were transferred before any separation attempt, 153 (2·6%) were transferred after at least one separation attempt and not successfully weaned, and 1662 (28·3%) died while invasively ventilated. The median time from fulfilling weaning eligibility criteria to first separation attempt was 1 day (IQR 0-4), and 1013 (22·4%) patients had a delay in initiating first separation of 5 or more days. Of the 4523 (77·1%) patients with separation attempts, 2927 (64·7%) had a short wean (≤1 day), 457 (10·1%) had intermediate weaning (2-6 days), 433 (9·6%) required prolonged weaning (≥7 days), and 706 (15·6%) had weaning failure. Higher sedation scores were independently associated with delayed initiation of weaning. Delayed initiation of weaning and higher sedation scores were independently associated with weaning failure. 1742 (31·8%) of 5479 patients died in the intensive care unit and 2095 (38·3%) of 5465 patients died in hospital. Interpretation: In critically ill patients receiving at least 2 days of invasive mechanical ventilation, only 65% were weaned at 90 days. A better understanding of factors that delay the weaning process, such as delays in weaning initiation or excessive sedation levels, might improve weaning success rates. Funding: European Society of Intensive Care Medicine, European Respiratory Society