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Vaccination has successfully controlled several infectious diseases although better vaccines remain desirable. Host response to vaccination studies have identified correlates of vaccine immunogenicity that could be useful to guide development and selection of future vaccines. However, it remains unclear whether these findings represent mere statistical correlations or reflect functional associations with vaccine immunogenicity. Functional associations, rather than statistical correlates, would offer mechanistic insights into vaccine-induced adaptive immunity. Through a human experimental study to test the immunomodulatory properties of metformin, an anti-diabetic drug, we chanced upon a functional determinant of neutralizing antibodies. Although vaccine viremia is a known correlate of antibody response, we found that in healthy volunteers with no detectable or low yellow fever 17D viremia, metformin-treated volunteers elicited higher neutralizing antibody titers than placebo-treated volunteers. Transcriptional and metabolomic analyses collectively showed that a brief course of metformin, started 3 days prior to YF17D vaccination and stopped at 3 days after vaccination, expanded oxidative phosphorylation and protein translation capacities. These increased capacities directly correlated with YF17D neutralizing antibody titers, with reduced reactive oxygen species response compared to placebo-treated volunteers. Our findings thus demonstrate a functional association between cellular respiration and vaccine-induced humoral immunity and suggest potential approaches to enhancing vaccine immunogenicity., (© 2024. The Author(s).)

Introduction: Hypoxic ischemic encephalopathy (HIE) is a clinically defined syndrome of disturbed neurologic function in the newborn with evidence of perinatal asphyxia. Stages of HIE are categorised into mild, moderate or severe based on the Sarnat classification. Neurological dysfunction constitutes a part of the wide spectrum of hypoxic ischemic insult as affected infants can have co-existing multi-organ dysfunction which further contributes to morbidities and mortality. This study aims to determine the relationship between the severity of HIE with multi-organ complications and early clinical outcomes., Materials and Methods: All neonates who were admitted to the NICU at Hospital Sultan Abdul Halim between January 2018 to December 2022, who fulfilled the inclusion criteria were included. Demographic data, clinical course and investigation results were retrospectively obtained from the medical records., Results: From a total of 90 infants (n = 90) who fulfilled our inclusion criteria, 31 (34%) were mild, 31 (34%) were moderate and 28 (31%) were severe HIE. The mean maternal age was 27 years. Common antenatal issues include diabetes mellitus (37.8%) and anaemia (22.2%). The Apgar scores at 1 and 5 minutes, initial resuscitation requiring intubation, chest compression and adrenaline were associated with higher severity of HIE (p < 0.05). Coagulation dysfunction was the most common complication (79.7%), followed by respiratory dysfunction (33.3%), cardiac dysfunction (28.9%), renal dysfunction (16.1%), haematological dysfunction (15.6%) and hepatic dysfunction (12%). Respiratory and haematological dysfunctions were significantly associated with higher mortality (p < 0.05). There was a significant longer hospital stay (p = 0.023), longer duration of ventilation (p < 0.001) and increase in frequency of seizures (p < 0.001) when comparing moderate and severe HIE patients to mild HIE patients. With increasing severity of HIE, there was also statistically significant higher mortality (p < 0.001)., Conclusions: There is a significant relationship between multiorgan dysfunction, the severity of HIE and mortality. Early anticipation of multi-organ injury is crucial for optimal early management which would reduce the mortality and improve the neurological outcome of the patients.

Introduction: Endoscopic sphincterotomy (EST) plus endoscopic papillary large balloon dilatation (EPLBD) has been reported as a valid alternative to EST alone in removing common bile duct (CBD) stone. The aim of this study is to compare efficacy, and safety of these two groups of patients in removing CBD stone in Hospital Universiti Sains Malaysia (HUSM)., Materials and Methods: This is a prospective single centre randomised single blinded comparative study conducted in HUSM. The primary endpoints for this study are the overall complete stone clearance rate and complication rate, while the secondary outcome for this study are duration of procedure and rate of usage of adjunct methods. Objective data analysis is conducted using independent sample t-test and chi-squared test., Results: A total of 66 patients underwent endoscopic retrograde cholangiopancreatography (ERCP) for choledocholithiasis which is CBD stone. 34 patients were allocated to EST plus EPLBD arm (n=34), and 32 patients were in EST alone arm (n=32) using randomisation method. For intention to treat, patients from EST alone arm that unable to achieve complete stone clearance will be switched to EST plus EPLBD arm. The overall complete stone removal rate for both groups were comparable (EST plus EPLDB: 100% versus EST alone: 93.8%; p= 0.139). The two patients from EST alone group (6.2%) that unable to achieve complete stone clearance were converted to EST plus EPLBD group for intention to treat and able to achieve complete stone clearance by EST plus EPLBD. For procedural time, both arms are comparable as well (EST plus EPLDB: 15.8 minutes vs EST alone: 15.5 minutes; p= 0.860). Complications such as pancreatitis occurred in one patient in EST plus EPLBD arm (EST plus EPLDB: 2.9 % vs EST alone: 0 %; p= 0.328), and bleeding occurred in one patient in EST alone arm (EST plus EPLDB: 0 % vs EST alone: 3.1 %; p= 0.299) , but it is not statistically significant. No perforation or cholangitis complication occurred in both groups. No adjunct usage was observed in both groups., Conclusion: In this study with limited sample size, both EST plus EPLBD and EST alone are effective and has comparable procedural time in removing CBD stone. Even though both methods are equally effective, EPLBD plus EST is an alternative solution if complete stone clearance is unable to achieve via EST alone.

Background: This prospective, randomized controlled study compared the changes in acid-base balance and serum electrolytes with the use of intravenous balanced and non-balanced crystalloid solutions intraoperatively during elective neurosurgery., Methods: Thirty consented adult patients who underwent craniotomy were randomly allocated into two groups of 15 patients each. The non-balanced group received 0.9% normal saline while the balanced group received Sterofundin®ISO as the intraoperative fluid for maintenance. Biochemical indices for acid-base balance and serum electrolytes were analyzed periodically., Results: In the non-balanced group, significant changes were noted in the pH, base excess and bicarbonate values over time compared to its respective baseline values (P<0.01). Four patients (27.7%) also developed a pH<7.35 and 5 patients (33.3%) developed marked acidosis with base excess <-4.0 at the end of surgery. Both mean sodium and chloride levels were also significantly higher compared to its baseline values respectively (142.6±2.4 versus 138±2.7 mmol/L, P<0.01 and 105.7±4.1 versus 113.2±3.0 mmol/L (P<0.01)., Conclusions: A balanced solution (Sterofundin®ISO) provided significantly better control over acid-base balance, sodium and chloride levels when used as intraoperative fluid maintenance and replacement during elective neurosurgery.

Context: Selecting an appropriate size double-lumen tube (DLT) for one-lung ventilation has always been a challenge as most choose it based on experience or using the existing guidelines based on gender and height., Aims: The aim of this study was to determine if the appropriate choice of this tube could be based on the patients' height, weight, tracheal diameter (TD), or the left main stem bronchus diameter (LMBD) and also to determine the relationship between height and depth of insertion among Asians., Subjects and Methods: This was a retrospective review of 179 patients who were intubated with a left-sided DLT and also had a posterior-anterior view of a digital chest radiograph for tracheal and left main bronchus diameter measurements. Additional data collected included patients' demographics and DLT size used., Results: There were 123 (68.7%) males and 56 (31.3%) females with an overall mean age of 33.3 ± 16.3 years. Majority of the males (48.8%) used a size 39 Fr while females (46.4%) used a 35 Fr. There were weak correlations between DLT size with height (male: R2 = 0.222; female: R2 = 0.193), DLT size with weight (male: R2 = 0.109; female: R2 = 0.211), DLT size with TD (male: R2 = 0.027); female: R2 = 0.016), and DLT size with LMBD (male: R2 = 0.222; female: R2 = 0.193). There was a good correlation between depth of DLT inserted with patient's height for both genders., Conclusion: The appropriate size of the left-sided DLT could not be predicted based on patients' height, weight, tracheal or left main bronchus diameter alone in Asians; however, the depth of insertion of the tube was dependent on the height in both genders., Competing Interests: There are no conflicts of interest.

Zika virus (ZIKV), formerly a neglected pathogen, has recently been associated with microcephaly in fetuses, and with Guillian-Barré syndrome in adults. Here we present the 3.7 Å resolution cryo-electron microscopy structure of ZIKV, and show that the overall architecture of the virus is similar to that of other flaviviruses. Sequence and structural comparisons of the ZIKV envelope (E) protein with other flaviviruses show that parts of the E protein closely resemble the neurovirulent West Nile and Japanese encephalitis viruses, while others are similar to dengue virus (DENV). However, the contribution of the E protein to flavivirus pathobiology is currently not understood. The virus particle was observed to be structurally stable even when incubated at 40 °C, in sharp contrast to the less thermally stable DENV. This is also reflected in the infectivity of ZIKV compared to DENV serotypes 2 and 4 (DENV2 and DENV4) at different temperatures. The cryo-electron microscopy structure shows a virus with a more compact surface. This structural stability of the virus may help it to survive in the harsh conditions of semen, saliva and urine. Antibodies or drugs that destabilize the structure may help to reduce the disease outcome or limit the spread of the virus.

Cystine knot α-amylase inhibitors are cysteine-rich, proline-rich peptides found in the Amaranthaceae and Apocynaceae plant species. They are characterized by a pseudocyclic backbone with two to four prolines and three disulfides arranged in a knotted motif. Similar to other knottins, cystine knot α-amylase inhibitors are highly resistant to degradation by heat and protease treatments. Thus far, only the α-amylase inhibition activity has been described for members of this family. Here, we show that cystine knot α-amylase inhibitors named alstotides discovered from the Alstonia scholaris plant of the Apocynaceae family display antiviral activity. The alstotides (As1-As4) were characterized by both proteomic and genomic methods. All four alsotides are novel, heat-stable and enzyme-stable and contain 30 residues. NMR determination of As1 and As4 structures reveals their conserved structural fold and the presence of one or more cis-proline bonds, characteristics shared by other cystine knot α-amylase inhibitors. Genomic analysis showed that they contain a three-domain precursor, an arrangement common to other knottins. We also showed that alstotides are antiviral and cell-permeable to inhibit the early phase of infectious bronchitis virus and Dengue infection, in addition to their ability to inhibit α-amylase. Taken together, our results expand membership of cystine knot α-amylase inhibitors in the Apocynaceae family and their bioactivity, functional promiscuity that could be exploited as leads in developing therapeutics., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

There are four closely-related dengue virus (DENV) serotypes. Infection with one serotype generates antibodies that may cross-react and enhance infection with other serotypes in a secondary infection. We demonstrated that DENV serotype 2 (DENV2)-specific human monoclonal antibody (HMAb) 2D22 is therapeutic in a mouse model of antibody-enhanced severe dengue disease. We determined the cryo-electron microscopy (cryo-EM) structures of HMAb 2D22 complexed with two different DENV2 strains. HMAb 2D22 binds across viral envelope (E) proteins in the dimeric structure, which probably blocks the E protein reorganization required for virus fusion. HMAb 2D22 "locks" two-thirds of or all dimers on the virus surface, depending on the strain, but neutralizes these DENV2 strains with equal potency. The epitope defined by HMAb 2D22 is a potential target for vaccines and therapeutics., (Copyright © 2015, American Association for the Advancement of Science.)

Background: Video-laryngoscopes have gained popularity in the recent years and have shown definite advantages over the conventional Macintosh direct laryngoscopes. However, there is still insufficient evidence comparing the C-MAC with the Macintosh for patients during manual inline stabilization (MILS)., Methods: This prospective, randomized, single blind study was carried out to compare tracheal intubation using the C-MAC video-laryngoscope and Macintosh laryngoscope in patients during MILS. Ninety consented patients, without features of difficult airway, who required general anesthesia and tracheal intubation were recruited. Intubation was performed with either the C-MAC video-laryngoscope or the Macintosh laryngoscope by one single investigator experienced with both devices. Various parameters which included Cormack and Lehane score, time to intubate, intubation attempts, optimization maneuvers, complications and hemodynamic changes were recorded over the initial period of 5 minutes., Results: C-MAC video-laryngoscope performed significantly better with lower Cormack and Lehane grades, shorter time to intubate of 32.7 ± 6.8 vs. 38.8 ± 8.9 seconds (p = 0.001) and needed less optimization maneuvers. There were no significant differences seen in the intubation attempts, complications or hemodynamic status of the patients with either device., Conclusion: The C-MAC video-laryngoscope was superior to the Macintosh laryngoscope for patients requiring intubation when manual inline neck stabilization was applied.

Background: The LMA-Classic laryngeal mask airway (Classic LMA) is an autoclavable and reusable laryngeal mask airway with strong evidence supporting its efficacy and safety. Due to the concern of infection risk particularly of prion disease, various single-use laryngeal mask devices were developed. The Ambu AuraOnce LMA (Ambu LMA) is a single use disposable laryngeal mask airway with special design that conforms better to the anatomy of the airway., Objectives: The Ambu LMA was compared to the LMA-Classic Classic LMA in respect to ease of insertion, adequacy of seal intraoperatively and postoperative complications in patients undergoing elective general anaesthesia with positive pressure ventilation., Methods: One hundred and eighteen ASA I and II patients undergoing elective general anaesthesia were randomly allocated into receiving either the Ambu LMA or the Classic LMA. The time taken and number of attempts taken to insert the laryngeal mask was recorded. Intra-operative adequacy of seal was assessed via the amount of nitrous oxide leak using a nitrous oxide analyser. Readings were charted at 0, 20, 40 and 60 minutes of operation. Complications postoperatively (blood stains on the device and occurrence of sore throat) were also recorded., Results: The success of first attempt insertion was comparable between the two groups (Classic LMA 87% versus Ambu LMA 83%). However the time of insertion was significantly shorter in the Ambu LMA group (p = 0.008). Nitrous oxide level was comparable between the two groups up to 20 minutes of operation. At 40 and 60 minutes, the Ambu LMA showed a significant lower nitrous oxide leak compared to the Classic LMA. Postoperatively, incidence of blood stains was comparable between the two groups, however the incidence of sore throat was lower in the Ambu LMA group (p = 0.025)., Conclusions: This study demonstrated that the Ambu LMA was comparable to the Classic LMA in terms of the ease of insertion, but provided better seal during positive pressure ventilation with less postoperative sore throat.

The aim of this study was to compare 6% hydroxyethyl starch 130/0.4 with 4% succinylated gelatin for priming the cardiopulmonary bypass circuit and as volume replacement in patients undergoing coronary artery bypass, in terms of postoperative bleeding, blood transfusion requirements, renal function, and outcome after surgery. Forty-five patients received 6% hydroxyethyl starch 130/0.4 (Voluven) and another 45 were given 4% succinylated gelatin (Gelofusine) as the priming solution for the cardiopulmonary bypass circuit as well as for volume replacement. Postoperative bleeding was quantified from the hourly chest drainage in the first 4 h and at 24 h postoperatively. The baseline characteristics of both groups were similar. In the hydroxyethyl starch group, the total amount of colloid used was 1.9 +/- 1.0 L, while the gelatin group had 2.0 +/- 0.7 L. There was no significant difference in hourly chest drainage between groups. Blood transfusion requirements, estimated glomerular filtration rate, extubation time, intensive care unit and hospital stay were similar in both groups. It was concluded that 6% hydroxyethyl starch 130/0.4 is a safe alternative colloid for priming the cardiopulmonary bypass circuit and volume replacement in patients undergoing coronary artery bypass surgery.

A prospective study was carried out to compare the outcomes of patients with preexisting non-dialysis-dependent renal dysfunction who underwent coronary artery bypass grafting with or without cardiopulmonary bypass. Elective off-pump coronary artery bypass was performed in 29 patients with renal dysfunction. Their results were compared with those of a similar group of 35 patients who underwent the conventional on-pump coronary artery grafting. There was a significant deterioration in creatinine clearance in the on-pump group on days 1, 2, and 4 after surgery, while creatinine clearance in the off-pump group remained close to the baseline level. Both groups had improved to the preoperative creatinine clearance values on follow-up at 4 weeks. It was concluded that off-pump surgery provided better renal protection than the conventional on-pump technique in patients with preexisting non-dialysis-dependent renal dysfunction.