High-dose pulse methylprednisolone vs. dexamethasone standard therapy for severe and critical COVID-19 pneumonia: Efficacy assessment in a retrospective single-centre experience from Malaysia.

INTRODUCTION: The use of dexamethasone (DXM) has been associated with decreased mortality in the patients with hypoxemia during the coronavirus disease-2019 (COVID-19) pandemic, while the outcomes with methylprednisolone (MTP) have been mixed. This real-life study aimed to evaluate the outcomes of patients with severe respiratory failure due to COVID-19 who were treated with high doses of MTP. MATERIALS AND METHODS: This retrospective cohort study enrolled hospitalised patients between May 2021 and August 2021, aged 18 years and above, with severe respiratory failure defined by a ratio of oxygen saturation to fraction of inspired oxygen (SF ratio) of less than 235. The treatment protocol involved administering high-dose MTP for 3 days, followed by DXM, and the outcomes were compared with those of patients who received DXM alone (total treatment duration of 10 days for both groups). RESULTS: A total of 99 patients were enrolled, with 79 (79.8%) receiving pulse MTP therapy and 20 (20.2%) being treated with DXM only. The SF ratio significantly improved from a mean of 144.49 (±45.16) at baseline to 208 (±85.19) at 72 hours (p < 0.05), with a mean difference of 63.51 (p < 0.001) in patients who received ≤750 mg of MTP. Additionally, in patients who received >750 mg of MTP, the SF ratio improved from a baseline mean of 130.39 (±34.53) to 208.44 (±86.61) at 72 hours (p < 0.05), with a mean difference of 78.05 (p = 0.001). In contrast, patients who received DXM only demonstrated an SF ratio of 132.85 (±44.1) at baseline, which changed minimally to 133.35 (±44.4) at 72 hours (p = 0.33), with a mean difference of 0.50 (p = 0.972). The incidence of nosocomial infection was higher in the MTP group compared with the DXM group (40.5% vs. 35%, p = 0.653), with a relative risk of 1.16 (95% CI: 0.60-2.23). CONCLUSION: MTP did not demonstrate a significant reduction in intubation or intensive care unit admissions. Although a high dose of MTP improved gas exchange in patients with severe and critical COVID-19, it did not provide an overall mortality benefit compared to standard treatment.

Decision rule to predict pneumonia in children presented with acute febrile respiratory illness.

BACKGROUND: It is a frequent challenge for physicians to identify pneumonia in patients with acute febrile respiratory symptoms, particularly in stable pediatric patients without respiratory distress. A decision rule is required to assist judgement on the need of ordering a chest radiograph. METHOD: This was a multicenter prospective study in 3 emergency departments. Children younger than 6 years old with an acute onset of fever and respiratory symptoms were recruited. Split sample method was adopted for derivation and validation of the Pediatric Acute Febrile Respiratory Illness rule (PAFRI Rule). PAFRI was derived from logistic regression with weighting based on adjusted odds ratios. RESULTS: Out of 967 children evaluated, 530 had taken chest radiograph examination, with 91 demonstrated evidence of pneumonia on radiograph. PAFRI Rule was derived from logistic regression with 5 weighed predictors: duration of fever <3 days (0 points), 3-4 days (2 points), 5-6 days (4 points), ≥7 days (5 points), chills (2 points), nasal symptoms (-2 points), abnormal chest examination (3 points), SpO2 ≤96% or tachypnea (3 points). The Area under ROC curve of the PAFRI Rule, the Bilkis Decision Rule and Bilkis Simpler Rule were 0.733, 0.600 and 0.579 respectively. A PAFRI score of ≥0 gives a sensitivity of 91.7% and negative predictive value of 97.7%. CONCLUSION: PAFRI rule can be used as a reference tool for guiding the need for taking Chest radiograph examination for pediatric patients. While promising, the PAFRI rule requires further validation. WHAT'S KNOWN ON THIS SUBJECT: It is often a challenge for physicians to identify pneumonia in children acutely febrile with respiratory symptoms, particularly in those who are stable without respiratory distress. The decision to order chest radiograph was based on clinical assessment with heterogenous practice. A valid and verified clinical prediction rule for ordering chest radiograph examination for stable febrile children without signs of respiratory distress would therefore assist in management of this group of patients. WHAT THIS STUDY ADDS: The PAFRI rule, based on parameters from clinical bedside assessment, can be used as a reference tool for guiding the need for referral to emergency department or taking use of chest radiograph for pediatric patients, and triaging for higher priority of clinical care.

The first pilot study of expanded newborn screening for inborn errors of metabolism and survey of related knowledge and opinions of health care professionals in Hong Kong.

INTRODUCTION: Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners' report of a 14-year-old boy who died of an undiagnosed IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM. METHODS: The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling. RESULTS: In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years. CONCLUSION: The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.

Comparison of green pit viper and Agkistrodon halys antivenom in inhibition of coagulopathy due to Trimeresurus albolabris venom: an in-vitro study using human plasma.

INTRODUCTION: There are two antivenoms that may be administered in Hong Kong following a bite by Trimeresurus albolabris: the green pit viper antivenom from the Thai Red Cross Society in Thailand and the Agkistrodon halys antivenom from the Shanghai Institute of Biological Products in China. Both are recommended by the Central Coordinating Committee of Accident and Emergency Services of the Hospital Authority for treating patients with a bite by Trimeresurus albolabris. The choice of which antivenom to use is based on physician preference. This study aimed to compare the relative efficacy of the two antivenoms. METHODS: This in-vitro experimental study was carried out by a wildlife conservation organisation and a regional hospital in Hong Kong. Human plasma from 40 adult health care worker volunteers was collected. The Trimeresurus albolabris venom was added to human plasma and the mixture was assayed after incubation with each antivenom (green pit viper and Agkistrodon halys) using saline as a control. Fibrinogen level and clotting time in both antivenom groups were studied. RESULTS: The mean fibrinogen level was elevated from 0 g/L to 2.86 g/L and 1.11 g/L after the addition of green pit viper antivenom and Agkistrodon halys antivenom, respectively. When mean clotting time was measured, the value was 6.70 minutes in the control, prolonged to more than 360 minutes by green pit viper antivenom and to 19.06 minutes by Agkistrodon halys antivenom. CONCLUSIONS: Green pit viper antivenom was superior to Agkistrodon halys antivenom in neutralisation of the thrombin-like and hypofibrinogenaemic activities of Trimeresurus albolabris venom.

Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody-drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer.

BACKGROUND: MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody-drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). PATIENTS AND METHODS: This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3-3.2 mg/kg) or weekly (Q1W, 0.8-1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken. RESULTS: Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC. CONCLUSIONS: DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required. CLINICAL TRIAL NUMBER: NCT01335958.

Clinical Performance Scores Are Independently Associated with the American Board of Anesthesiology Certification Examination Scores.

BACKGROUND: It is unknown whether clinical performance during residency is related to the American Board of Anesthesiology (ABA) oral examination scores. We hypothesized that resident clinical performance would be independently associated with oral examination performance because the oral examination is designed to test for clinical judgment. METHOD: We determined clinical performance scores (Zrel) during the final year of residency for all 124 Massachusetts General Hospital (MGH) anesthesia residents who graduated from 2009 to 2013. One hundred eleven graduates subsequently took the ABA written and oral examinations. We standardized each graduate's written examination score (ZPart 1) and oral examination score (ZPart 2) to the national average. Multiple linear regression analysis was used to determine the partial effects of MGH clinical performance scores and ABA written examination scores on ABA oral examination scores. RESULTS: MGH clinical performance scores (Zrel) correlated with both ABA written examination scores (ZPart 1) (r = 0.27; P = 0.0047) and with ABA oral examination scores (ZPart 2) (r = 0.33; P = 0.0005). ABA written examination scores (ZPart 1) correlated with oral examination scores (ZPart 2) (r = 0.46; P = 0.0001). Clinical performance scores (Zrel) and ABA written examination scores (ZPart 1) independently accounted for 4.5% (95% confidence interval [CI], 0.5%-12.4%; P = 0.012) and 20.8% (95% CI, 8.0%-37.2%; P < 0.0001), respectively, of the variance in ABA oral examination scores (ZPart 2). CONCLUSIONS: Clinical performance scores and ABA written examination scores independently accounted for variance in ABA oral examination scores. Clinical performance scores are independently associated with the ABA oral examination scores.

Outcomes of transcatheter aortic valve implantation in high surgical risk and inoperable patients with aortic stenosis: a single Australian Centre experience.

BACKGROUND: Degenerative aortic stenosis is the most common valvular heart disease in the elderly, and many patients are not suitable for aortic valve replacement surgery. Transcatheter aortic valve implantation (TAVI) is a new therapeutic option for selected patients at high risk for surgery. AIM: To evaluate the safety and efficacy of TAVI in Australian patients. METHODS: This is a prospective study of patients undergoing TAVI for severe symptomatic aortic stenosis at The Prince Charles Hospital, Brisbane, Australia between August 2008 and July 2013. Patients were at high risk of surgical aortic valve replacement, or inoperable, as deemed by a multidisciplinary 'heart team'. Outcomes include procedural success and complications, 30-day and 1-year mortality and stroke, combined end-points as outlined by the Valve Academic Research Consortium 2 consensus document. RESULTS: Two hundred and nine patients underwent TAVI during the study period. The mean age was 83.7 ± 6.7 years, and 101 (48%) were men. The valve systems utilised were as follows: Edwards-SAPIEN valve in 104 (49.5%), Medtronic CoreValve in 86 (41.2%) and Boston Scientific Lotus valve in 19 (9.3%) patients. Thirty-day and 1-year mortality rates were 5.7% and 11.5% respectively. Thirty-day and 1-year stroke rates were 4.3% and 6.2% respectively. The composite end-points of device success, early safety and clinical efficacy occurred in 80.4%, 27.3% and 68.4%. CONCLUSIONS: TAVI with various valve systems, delivered through several approaches, is feasible in high surgical risk and inoperable patients with severe aortic stenosis, with acceptable outcomes at short-term and intermediate-term follow up.

Confirmatory factor analysis of the Strengths and Difficulties Questionnaire in Singaporean kindergartners.

BACKGROUND: The Strengths and Difficulties Questionnaire (SDQ) assesses behavioural adjustment in children aged 3 to 16 years. To ascertain the appropriateness of the scale for a specific population, it is important to examine whether the distinctiveness of the scale dimensions can be verified empirically. AIMS: Confirmatory factor analysis was used to test explicitly which of three models better explain our data, and whether model fit was improved by the addition of method factors. METHODS: Parents of 411 Singaporean kindergartners completed the SDQ. RESULTS: A four-factor multi-trait multi-method model (Prosocial, Conduct, Hyperactivity, Internalizing and two method factors) provided the best fit to the data. There was strong evidence for convergent and discriminant validity. However, differences in configural loading pattern indicated gender-related differences in the mapping of the SDQ items. DISCUSSION: Differences in factor structure across countries and gender may reflect differing conceptions of the underlying dimensions, as well as differences in normative expectations. However, our findings may allow its use as a screening tool to identify Singaporean children at risk of emotional and behavioural difficulties.

Streptococcal co-infection augments Candida pathogenicity by amplifying the mucosal inflammatory response.

Mitis-group streptococci are ubiquitous oral commensals that can promote polybacterial biofilm virulence. Using a novel murine oral mucosal co-infection model we sought to determine for the first time whether these organisms promote the virulence of C. albicans mucosal biofilms in oropharyngeal infection and explored mechanisms of pathogenic synergy. We found that Streptococcus oralis colonization of the oral and gastrointestinal tract was augmented in the presence of C. albicans. S. oralis and C. albicans co-infection significantly augmented the frequency and size of oral thrush lesions. Importantly, S. oralis promoted deep organ dissemination of C. albicans. Whole mouse genome tongue microarray analysis showed that when compared with animals infected with one organism, the doubly infected animals had genes in the major categories of neutrophilic response/chemotaxis/inflammation significantly upregulated, indicative of an exaggerated inflammatory response. This response was dependent on TLR2 signalling since oral lesions, transcription of pro-inflammatory genes and neutrophil infiltration, were attenuated in TLR2(-/-) animals. Furthermore, S. oralis activated neutrophils in a TLR2-dependent manner in vitro. In summary, this study identifies a previously unrecognized pathogenic synergy between oral commensal bacteriaand C. albicans. This is the first report of the ability of mucosal commensal bacteria to modify the virulence of an opportunistic fungal pathogen.

The Impact of a Shortage of Pharmacy-Prepared Ephedrine Syringes on Intraoperative Medication Use.

BACKGROUND: Anesthesia-related medication shortages have become increasingly common in the United States. We tested whether a local shortage of pharmacy-prepared ephedrine syringes, replaced by provider-prepared ephedrine, was associated with provider-level changes in ephedrine and phenylephrine use and patient-level changes in intraoperative hemodynamics. METHODS: Consecutive patients undergoing general and orthopedic surgery at a tertiary care center were included 1 month before and 1 month after the start of the pharmacy-prepared ephedrine syringe shortage. Lowest mean arterial blood pressure and slowest heart rate were obtained as measures of hemodynamics. Adjusted associations were tested using mixed-effects regression with repeated measures. RESULTS: Three hundred four patients before the shortage and 298 patients after the shortage began were included. The administration of at least 1 bolus of ephedrine was significantly more common before versus during the shortage (148/304 [48.7]% vs 117/298 [39.3]%; P = 0.0199). After adjusting for age, sex, ASA physical status, surgery type, anesthesia provider, and operative duration, patients were significantly less likely to receive ephedrine during the shortage (relative risk [RR] = 0.78 [95% confidence interval {CI}, 0.61-0.96]; P = 0.0198) and more likely to receive a phenylephrine bolus (RR = 1.27 [95% CI, 1.02-1.51]; P = 0.0357). Patient hemodynamics assessed by slowest heart rate or lowest mean arterial blood pressure did not differ significantly during the shortage. CONCLUSIONS: There was an alteration in medication administration patterns during a shortage of pharmacy-prepared syringes. Changes in ephedrine and phenylephrine use were noted; however, patient hemodynamics remained comparable. Provider use patterns were sensitive even to a relative and not absolute medication shortage as observed in this study.

Cannabinoid receptor type 1 antagonist, AM251, attenuates mechanical allodynia and thermal hyperalgesia after burn injury.

BACKGROUND: Burn injury causes nociceptive behaviors, and inflammation-related pathologic pain can lead to glial cell activation. This study tested the hypothesis that burn injury activates glial cells, and cannabinoid receptor 1 (CB1R) antagonist, AM251, will decrease burn pain. METHODS: Anesthetized rats received 0.75-cm third-degree burn on dorsal hind paw. Vehicle or AM251 30 µg intrathecally (older rats, n=6 per group) or, either vehicle, 0.1 or 1.0 mg/kg intraperitoneally (younger rats, n=6 per group), started immediate postburn, was administered for 7 days. Mechanical allodynia and thermal hyperalgesia were tested on ventral paw for 14 days. Microglial and astroglial activity was assessed by immunocytochemistry. RESULTS: Allodynia, observed on burn side from day 1 to 14, was significantly (P<0.05) attenuated by intrathecal and intraperitoneal AM251 (1 mg/kg) starting from 3 to 14 days. Hyperalgesia, observed from day 3 to 12, was completely (P<0.05) reversed by intrathecal and intraperitoneal AM251 (1 mg/kg). AM251 0.1 mg/kg had no effect. Microglial activity (n=3 per time point) increased (P<0.05) 18.5±7.5 and 12.3±1.6 (mean±SD) fold at 7 and 14 days, respectively. Astroglial activity (n=4 per time point) increased 2.9±0.3 fold at day 7 only. Glial activities were unaltered by AM251. CONCLUSIONS: AM251 inhibited nociceptive behaviors after burn even beyond 7-day period of administration. Although many studies have documented the utility of CB1R agonists, this study indicates that endogenous cannabinoids may have an unexpected pronociceptive effect during development of burn pain, explaining why CB1R antagonist, AM251, improves nociceptive behaviors. The decreased nociception with AM251 without altering glial activity indicates that AM251 acts further downstream of activated glial cells.

Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome: a treatable genetic liver disease warranting urgent diagnosis.

Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is an autosomal recessive disorder caused by a defect in ornithine translocase. This condition leads to variable clinical presentations, including episodic hyperammonaemia, hepatic derangement, and chronic neurological manifestations. Fewer than 100 affected patients have been reported worldwide. Here we report the first two cases in Hong Kong Chinese, who were compound heterozygous siblings for c.535C>T (p.Arg179*) and c.815C>T (p.Thr272Ile) in the SLC25A15 gene. When the mother refused prenatal diagnosis for the second pregnancy, urgent genetic testing provided the definitive diagnosis within 24 hours to enable specific treatment. Optimal management of these two patients relied on the concerted efforts of a multidisciplinary team and illustrates the importance of an expanded newborn screening service for early detection and treatment of inherited metabolic diseases.

Fever as a predictor of doctor shopping in the paediatric population.

OBJECTIVES: To estimate prevalence and assess factors associated with doctor shopping among caregivers of children acutely admitted to a hospital in Hong Kong, and examine the reasons for such behaviour and caregivers' awareness of its possible dangers. DESIGN: Cross-sectional study with face-to-face surveys. SETTING: A paediatric unit in a teaching hospital in Hong Kong. PARTICIPANTS: Caregivers of children admitted to acute paediatric wards between April and July 2011. MAIN OUTCOME MEASURES; Socio-demographic characteristics of the interviewee, personal history and clinical data of the patient, presence of doctor shopping (consulting more than one doctor for medical advice without referral) for each episode, the reasons behind such behaviour, and awareness of potential dangers. Data retrieved were analysed to estimate the prevalence and logistic regression was used to assess factors associated with doctor shopping. RESULTS: In all, 649 such patients were admitted into hospital during the study period, of which 336 were recruited, with about a half being absent or given home leave. Thirty-four patients were excluded due to absent caregivers or refusal, and 302 were included in the study. More than half (79.5%) were female and the caregivers' monthly household incomes were between HK$10 001 and HK$15 000 (21.2%), similar to the median household income in Hong Kong. The prevalence of doctor shopping was 53%. The only significant clinical parameter associated with doctor shopping was presence of fever (odds ratio=2.4; 95% confidence interval, 1.4-3.9). Persistence of symptoms was the commonest reason given by interviewees for doctor shopping, and the majority (75.5%) were unaware of the possible dangers of this behaviour. CONCLUSION: Doctor shopping is highly prevalent among caregivers of children with acute paediatric conditions. Most caregivers do not know the potential complications of this behaviour. Further measures should be taken to educate subjects on the associated dangers of this behaviour and the natural course of acute illnesses with fever.

Development of anti-influenza A compounds: a pilot study.

1. There is no effective anti-H5N1 avian influenza agent. 2. A chemical compound­ BFDBSC­can inhibit H5N1 virus infection in cell cultures, and such inhibition might be attributable to its halogenated benzoyl residues. 3. This pilot study assessed anti- H5N1 activity and toxicity of four chemical compounds with halogenated benzoyl residues in cell culture system. 4. Two compounds­FPBFDBSC and BFB-gallate­ showed higher antiviral effectsthan BFDBSC, whearas the other two­BFB-borneol and BFB-menthol­showed lower antiviral effects. These compounds did not show toxicity. 5. The halogenated benzoyl residues may play a key role in anti-H5N1 effects. However, all these compounds showed poor solubility, which may limit their utility

Simultaneous bilateral patellar tendon avulsion in an adolescent.

A 13-year-old boy sustained an injury to both knees upon landing after a forceful jump in a soccer game. Plain radiography and magnetic resonance imaging demonstrated bilateral distal patellar tendon avulsions without fracture of the tibial tuberosities and the physes. To our knowledge, this particular injury has not been previously described in the literature. Open surgeries and internal fixation were performed with excellent functional outcome. This type of injury was similar to the well-recognised acute tibial tuberosity avulsion fracture in terms of the pathogenesis and treatment. We propose a further subtype of this injury pattern.