Study protocol: infectious diseases consortium (I3D) for study on integrated and innovative approaches for management of respiratory infections: respiratory infections research and outcome study (RESPIRO).

BACKGROUND: Community-acquired respiratory infections are a leading cause of illness and death globally. The aetiologies of community-acquired pneumonia remain poorly defined. The RESPIRO study is an ongoing prospective observational cohort study aimed at developing pragmatic logistical and analytic platforms to accurately identify the causes of moderate-to-severe community-acquired pneumonia in adults and understand the factors influencing disease caused by individual pathogens. The study is currently underway in Singapore and has plans for expansion into the broader region. METHODS: RESPIRO is being conducted at three major tertiary hospitals in Singapore. Adults hospitalised with acute community-acquired pneumonia or lower respiratory tract infections, based on established clinical, laboratory and radiological criteria, will be recruited. Over the course of the illness, clinical data and biological samples will be collected longitudinally and stored in a biorepository for future analysis. DISCUSSION: The RESPIRO study is designed to be hypothesis generating, complementary to and easily integrated with other research projects and clinical trials. The detailed clinical database and biorepository will yield insights into the epidemiology and outcomes of community-acquired lower respiratory tract infections in Singapore and the surrounding region and offers the opportunity to deeply characterise the microbiology and immunopathology of community-acquired pneumonia.

Infectious disease for the rhinologist.

PURPOSE OF REVIEW: The purpose of this review is to summarize the recent literature relating to viral, fungal and bacterial infections and their interactions within the sinonasal tract in the past 18 months. RECENT FINDINGS: Coronavirus disease 2019 (COVID-19)-associated olfactory dysfunction (OD) is variant dependent. Magnetic resonance imaging studies have found greater olfactory cleft opacification and higher olfactory bulb volume in post-COVID-19 OD. Olfactory training remains the mainstay of treatment, while platelet-rich plasma injections and ultramicronized palmitoylethanolamide and luteolin combination oral supplementation have shown early promise.Consensus statements on paranasal sinus fungal balls and acute invasive fungal sinusitis have been released.Studies on the nasal microbiome have reported Staphylococcus and Corynebacterium as the most abundant genera, with higher levels of Staphylococcus and Corynebacterium being found in patients with chronic rhinosinusitis (CRS) and healthy individuals respectively. However, there is conflicting evidence on the significance of biodiversity of the nasal microbiome found in CRS versus healthy patients. SUMMARY: While the peak of the COVID-19 pandemic is behind us, its sequelae continue to pose treatment challenges. Further studies in OD have implications in managing the condition, beyond those afflicted post-COVID-19 infection. Similarly, more research is needed in studying the nasal microbiome and its implications in the development and treatment of CRS.

Early peripheral blood MCEMP1 and HLA-DRA expression predicts COVID-19 prognosis.

BACKGROUND: Mass vaccination has dramatically reduced the incidence of severe COVID-19, with most cases now presenting as self-limiting upper respiratory tract infections. However, those with co-morbidities, the elderly and immunocompromised, as well as the unvaccinated, remain disproportionately vulnerable to severe COVID-19 and its sequelae. Furthermore, as the effectiveness of vaccination wanes with time, immune escape SARS-CoV-2 variants could emerge to cause severe COVID-19. Reliable prognostic biomarkers for severe disease could be used as early indicator of re-emergence of severe COVID-19 as well as for triaging of patients for antiviral therapy. METHODS: We performed a systematic review and re-analysis of 7 publicly available datasets, analysing a total of 140 severe and 181 mild COVID-19 patients, to determine the most consistent differentially regulated genes in peripheral blood of severe COVID-19 patients. In addition, we included an independent cohort where blood transcriptomics of COVID-19 patients were prospectively and longitudinally monitored previously, to track the time in which these gene expression changes occur before nadir of respiratory function. Single cell RNA-sequencing of peripheral blood mononuclear cells from publicly available datasets was then used to determine the immune cell subsets involved. FINDINGS: The most consistent differentially regulated genes in peripheral blood of severe COVID-19 patients were MCEMP1, HLA-DRA and ETS1 across the 7 transcriptomics datasets. Moreover, we found significantly heightened MCEMP1 and reduced HLA-DRA expression as early as four days before the nadir of respiratory function, and the differential expression of MCEMP1 and HLA-DRA occurred predominantly in CD14+ cells. The online platform which we developed is publicly available at https://kuanrongchan-covid19-severity-app-t7l38g.streamlitapp.com/, for users to query gene expression differences between severe and mild COVID-19 patients in these datasets. INTERPRETATION: Elevated MCEMP1 and reduced HLA-DRA gene expression in CD14+ cells during the early phase of disease are prognostic of severe COVID-19. FUNDING: K.R.C is funded by the National Medical Research Council (NMRC) of Singapore under the Open Fund Individual Research Grant (MOH-000610). E.E.O. is funded by the NMRC Senior Clinician-Scientist Award (MOH-000135-00). J.G.H.L. is funded by the NMRC under the Clinician-Scientist Award (NMRC/CSAINV/013/2016-01). S.K. is funded by the NMRC under the Transition Award. This study was sponsored in part by a generous gift from The Hour Glass.

Adverse effects following anti-COVID-19 vaccination with mRNA-based BNT162b2 are alleviated by altering the route of administration and correlate with baseline enrichment of T and NK cell genes.

Ensuring high vaccination and even booster vaccination coverage is critical in preventing severe Coronavirus Disease 2019 (COVID-19). Among the various COVID-19 vaccines currently in use, the mRNA vaccines have shown remarkable effectiveness. However, systemic adverse events (AEs), such as postvaccination fatigue, are prevalent following mRNA vaccination, and the underpinnings of which are not understood. Herein, we found that higher baseline expression of genes related to T and NK cell exhaustion and suppression were positively correlated with the development of moderately severe fatigue after Pfizer-BioNTech BNT162b2 vaccination; increased expression of genes associated with T and NK cell exhaustion and suppression reacted to vaccination were associated with greater levels of innate immune activation at 1 day postvaccination. We further found, in a mouse model, that altering the route of vaccination from intramuscular (i.m.) to subcutaneous (s.c.) could lessen the pro-inflammatory response and correspondingly the extent of systemic AEs; the humoral immune response to BNT162b2 vaccination was not compromised. Instead, it is possible that the s.c. route could improve cytotoxic CD8 T-cell responses to BNT162b2 vaccination. Our findings thus provide a glimpse of the molecular basis of postvaccination fatigue from mRNA vaccination and suggest a readily translatable solution to minimize systemic AEs.

A randomized controlled study of acupuncture for pain relief during first trimester surgical termination of pregnancy performed under local analgesia.

BACKGROUND: Acupuncture reduces pain levels in many painful conditions. This study compared pain levels during surgical termination of first trimester pregnancy by suction evacuation (SE) under local analgesia with and without the use of acupuncture. METHODS: In all, 60 nulliparous women undergoing SE before 10 weeks of gestation were randomly assigned into one of the following three groups in a 1:1:1 ratio according to a computer-generated randomization list. In the control group, women received oral diazepam 5 mg and intramuscular (i.m.) injection of pethidine 30 and 15 min, respectively, prior to SE. In the acupuncture group, women received acupuncture 10 min before SE until the end of SE while oral diazepam 5 mg and i.m. injection of normal saline were given. In the combined group, women received acupuncture in addition to the drugs in the control group. Data from 52 participants were analysed. Pain scores during and after SE, post-operative side-effects and satisfaction levels were compared. RESULTS: The three groups had similar baseline characteristics. The median pain levels during SE differed significantly between the control, acupuncture, and combined groups (80, 50 and 66 mm, respectively, p = 0.03). Pain levels during SE in the acupuncture and combined groups were significantly lower than that of the control group. However, the anxiety scores did not differ between the three groups after SE (p = 0.86). CONCLUSION: Acupuncture can provide additional benefit in terms of pain relief in women undergoing first trimester termination of pregnancy by SE under local analgesia.

Feasibility and utility of facemask sampling in the detection of SARS-CoV-2 during an ongoing pandemic.

Easy access to screening for timely identification and isolation of infectious COVID-19 patients remains crucial in sustaining the international efforts to control COVID-19 spread. A major barrier limiting broad-based screening is the lack of a simple, rapid, and cost-effective COVID-19 testing method. We evaluated the feasibility and utility of facemask sampling in a cohort of 42 COVID-19-positive and 36 COVID-19-negative patients. We used a prototype of Steri-Strips™ (3 M) applied to the inner surface of looped surgical facemasks (Assure), which was worn by patients for a minimum wear time of 3 h, then removed and sent for SARS-CoV-2 PCR testing. Baseline demographics and symptomatology were also collected. Facemask sampling positivity was highest within the first 5 days of symptomatic presentation. Patients with nasopharyngeal and/or oropharyngeal swab SARS-CoV-2 PCR Ct values < 25.09 had SARS-CoV-2 detected on facemask sampling, while patients with Ct values ≥ 25.2 had no SARS-CoV-2 detected on facemask sampling. Facemask sampling can identify patients with COVID-19 during the early symptomatic phase or those with high viral loads, hence allowing timely identification and isolation of those with the highest transmission risk. Given the widespread use of facemasks, this method can potentially be easily applied to achieve broad-based, or even continuous, population screening.

Use of music in reducing pain during outpatient hysteroscopy: Prospective randomized trial.

AIM: To evaluate the effect of music in reducing pain during outpatient hysteroscopy under no anesthesia. METHODS: We conducted a prospective randomized controlled trial From June 2019 to December 2019 in Pamela Youde Nethersole Eastern Hospital in Hong Kong. A total of 107 patients were randomized to music group (n = 54) or non-music group (n = 53). Music was played during outpatient hysteroscopy in the music group. Patients in the non-music group had the procedure done in the same setting without music. Primary outcome was the level of pain measured using the visual analog scale (VAS) score before and during the procedure. Secondary outcomes were vital parameters that reflect the level of pain including blood pressure and heart rate. RESULTS: Patients in the music group experienced significantly less pain during outpatient hysteroscopy (VAS score 4.54 ± 2.89 vs 5.88 ± 2.90; P = 0.02). The anticipated pain level was similar in both groups (VAS score 5.59 ± 2.27 vs 6.11 ± 2.43; P = 0.27). There was no statistically significant difference between the two groups in all the vital parameters. CONCLUSION: Listening to music during outpatient hysteroscopy under no anesthesia significantly reduces pain in a well-matched Chinese population. Music is easy to provide with low-cost equipment and manpower. We recommend the routine use of music during outpatient hysteroscopy to improve patient care.

Use of oral progestogen in women with threatened miscarriage in the first trimester: a randomized double-blind controlled trial.

STUDY QUESTION: Will use of oral progestogen in women with threatened miscarriage in the first trimester reduce the miscarriage rate when compared with placebo? SUMMARY ANSWER: Use of oral progestogen in women with threatened miscarriage in the first trimester did not reduce miscarriage before 20 weeks when compared with placebo. WHAT IS KNOWN ALREADY: Miscarriage is a common complication of pregnancy and occurs in 15-20% of clinically recognized pregnancies. Use of vaginal progestogens is not effective in reducing miscarriage but there is still no good evidence to support use of oral progestogen for the treatment of threatened miscarriage. STUDY DESIGN, SIZE, DURATION: This was a randomized double-blind controlled trial. A total of 406 women presenting with threatened miscarriage in the first trimester were recruited from 30 March 2016 to May 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women attending Early Pregnancy Assessment Clinics because of vaginal bleeding during the first trimester were recruited and randomly assigned to use dydrogesterone 40 mg orally, followed by 10 mg orally three times a day or placebo until 12 completed weeks of gestation or 1 week after the bleeding stopped, whichever was later. The primary outcome was the miscarriage rate before 20 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: The two groups of women had comparable age, BMI, number of previous miscarriages, gestation and ultrasound findings at presentation. The miscarriage rate before 20 weeks of gestation was similar in both groups, being 12.8% (26/203) in the progestogen group and 14.3% (29/203) in the placebo group (relative risk 0.897, 95% CI 0.548-1.467; P = 0.772). The live birth rate was 81.3% in the progestogen group versus 83.3% in the placebo group (P = 0.697). No significant differences were found between the two groups in terms of obstetric outcomes and side effects. LIMITATIONS, REASONS FOR CAUTION: The primary outcome was the miscarriage rate, rather than the live birth rate. Women were recruited from Early Pregnancy Assessment Clinics and those with heavy vaginal bleeding might be admitted into wards directly instead of attending Early Pregnancy Assessment Clinic. The severity of vaginal bleeding was subjectively graded by women themselves. The sample size was not adequate to demonstrate a smaller difference in the miscarriage rate between the progestogen and placebo groups. We did not exclude women with multiple pregnancy, which increased the risk of miscarriage although there was only one set of twin pregnancy in the placebo group. WIDER IMPLICATIONS OF THE FINDINGS: Use of oral progestogen is not recommended in women with threatened miscarriage in the first trimester. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Health and Medical Research Fund, HKSAR (reference number 12132341). All authors declared no conflict of interest. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov with an identifier NCT02128685. TRIAL REGISTRATION DATE: 1 May 2014. DATE OF FIRST PATIENT'S ENROLMENT: 30 March 2016.

Efficacy of commercial mouth-rinses on SARS-CoV-2 viral load in saliva: randomized control trial in Singapore.

PURPOSE: One of the key approaches to minimize the risk of COVID-19 transmission would be to reduce the titres of SARS-CoV-2 in the saliva of infected COVID-19 patients. This is particularly important in high-risk procedures like dental treatment. The present randomized control trial evaluated the efficacy of three commercial mouth-rinse viz. povidone-iodine (PI), chlorhexidine gluconate (CHX) and cetylpyridinium chloride (CPC), in reducing the salivary SARS-CoV-2 viral load in COVID-19 patients compared with water. METHODS: A total of 36 SARS-CoV-2-positive patients were recruited, of which 16 patients were randomly assigned to four groups-PI group (n = 4), CHX group (n = 6), CPC group (n = 4) and water as control group (n = 2). Saliva samples were collected from all patients at baseline and at 5 min, 3 h and 6 h post-application of mouth-rinses/water. The samples were subjected to SARS-CoV-2 RT-PCR analysis. RESULTS: Comparison of salivary Ct values of patients within each group of PI, CHX, CPC and water at 5 min, 3 h and 6 h time points did not show any significant differences. However, when the Ct value fold change of each of the mouth-rinse group patients were compared with the fold change of water group patients at the respective time points, a significant increase was observed in the CPC group patients at 5 min and 6 h and in the PI group patients at 6 h. CONCLUSION: The effect of decreasing salivary load with CPC and PI mouth-rinsing was observed to be sustained at 6 h time point. Within the limitation of the current study, as number of the samples analyzed, the use of CPC and PI formulated that commercial mouth-rinses may be useful as a pre-procedural rinse to help reduce the transmission of COVID-19. ISRCTN (ISRCTN95933274), 09/09/20, retrospectively registered.

Performance of ovarian response prediction index (ORPI) in predicting ovarian response and livebirth in the in-vitro fertilisation cycle using a standard stimulation with corifollitropin alpha in a GnRH antagonist protocol.

The objective of this study was to evaluate the performance of ovarian response prediction index (ORPI) in predicting ovarian response and livebirth of women undergoing their first in-vitro fertilisation (IVF) cycle. This is a retrospective analysis of 285 women from 2013 to 2016. The outcome measures were area (AUC) under the receiver-operator characteristic (ROC) curves for prediction of excessive and poor response, livebirth in the fresh cycle and cumulative livebirth. The ORPI was significantly correlated with the oocyte number. For prediction of excessive response, AUC for ORPI was comparable to AMH and significantly higher than AFC and female age. At a cut-off of 0.42, ORPI has a sensitivity and specificity of 84% and 77% respectively for prediction of excessive response. For prediction of poor response, AUC for ORPI was significantly higher than AFC, AMH and female age. At a cut-off of 0.12, ORPI has a sensitivity of 69% and specificity of 89% respectively for prediction of poor response. For prediction of livebirth, AUCs of ORPI were not significantly different from AFC and female age. Therefore, ORPI is not a good predictor of livebirth. Its prediction of excessive and poor ovarian response is comparable to that of serum AMH.

The Pandemic Academy: Reflections of Infectious Diseases Fellows During COVID-19.

The COVID-19 pandemic has taken over the world at an unprecedented scale. As Infectious Diseases fellows, this has come straight into the heart of our specialty and created a unique impact on our training progress and perspective. Here, we reflect on our early experiences during the first three months of battling COVID-19 in Singapore and glean some lessons for this pandemic and beyond.

Phase 1 Trial of a Therapeutic Anti-Yellow Fever Virus Human Antibody.

BACKGROUND: Insufficient vaccine doses and the lack of therapeutic agents for yellow fever put global health at risk, should this virus emerge from sub-Saharan Africa and South America. METHODS: In phase 1a of this clinical trial, we assessed the safety, side-effect profile, and pharmacokinetics of TY014, a fully human IgG1 anti-yellow fever virus monoclonal antibody. In a double-blind, phase 1b clinical trial, we assessed the efficacy of TY014, as compared with placebo, in abrogating viremia related to the administration of live yellow fever vaccine (YF17D-204; Stamaril). The primary safety outcomes were adverse events reported 1 hour after the infusion and throughout the trial. The primary efficacy outcome was the dose of TY014 at which 100% of the participants tested negative for viremia within 48 hours after infusion. RESULTS: A total of 27 healthy participants were enrolled in phase 1a, and 10 participants in phase 1b. During phase 1a, TY014 dose escalation to a maximum of 20 mg per kilogram of body weight occurred in 22 participants. During phases 1a and 1b, adverse events within 1 hour after infusion occurred in 1 of 27 participants who received TY014 and in none of the 10 participants who received placebo. At least one adverse event occurred during the trial in 22 participants who received TY014 and in 8 who received placebo. The mean half-life of TY014 was approximately 12.8 days. At 48 hours after the infusion, none of the 5 participants who received the starting dose of TY014 of 2 mg per kilogram had detectable YF17D-204 viremia; these participants remained aviremic throughout the trial. Viremia was observed at 48 hours after the infusion in 2 of 5 participants who received placebo and at 72 hours in 2 more placebo recipients. Symptoms associated with yellow fever vaccine were less frequent in the TY014 group than in the placebo group. CONCLUSIONS: This phase 1 trial of TY014 did not identify worrisome safety signals and suggested potential clinical benefit, which requires further assessment in a phase 2 trial. (Funded by Tysana; ClinicalTrials.gov number, NCT03776786.).

A Non-structural 1 Protein G53D Substitution Attenuates a Clinically Tested Live Dengue Vaccine.

The molecular basis of dengue virus (DENV) attenuation remains ambiguous and hampers a targeted approach to derive safe but nonetheless immunogenic live vaccine candidates. Here, we take advantage of DENV serotype 2 PDK53 vaccine strain, which recently and successfully completed a phase-3 clinical trial, to identify how this virus is attenuated compared to its wild-type parent, DENV2 16681. Site-directed mutagenesis on a 16681 infectious clone identifies a single G53D substitution in the non-structural 1 (NS1) protein that reduces 16681 infection and dissemination in both Aedes aegypti, as well as in mammalian cells to produce the characteristic phenotypes of PDK53. Mechanistically, NS1 G53D impairs the function of a known host factor, the endoplasmic reticulum (ER)-resident ribophorin 1 protein, to properly glycosylate NS1 and thus induce a host antiviral gene through ER stress responses. Our findings provide molecular insights on DENV attenuation on a clinically tested strain.

Quantifying the economic cost of antibiotic resistance and the impact of related interventions: rapid methodological review, conceptual framework and recommendations for future studies.

BACKGROUND: Antibiotic resistance (ABR) poses a major threat to health and economic wellbeing worldwide. Reducing ABR will require government interventions to incentivise antibiotic development, prudent antibiotic use, infection control and deployment of partial substitutes such as rapid diagnostics and vaccines. The scale of such interventions needs to be calibrated to accurate and comprehensive estimates of the economic cost of ABR. METHODS: A conceptual framework for estimating costs attributable to ABR was developed based on previous literature highlighting methodological shortcomings in the field and additional deductive epidemiological and economic reasoning. The framework was supplemented by a rapid methodological review. RESULTS: The review identified 110 articles quantifying ABR costs. Most were based in high-income countries only (91/110), set in hospitals (95/110), used a healthcare provider or payer perspective (97/110), and used matched cohort approaches to compare costs of patients with antibiotic-resistant infections and antibiotic-susceptible infections (or no infection) (87/110). Better use of methods to correct biases and confounding when making this comparison is needed. Findings also need to be extended beyond their limitations in (1) time (projecting present costs into the future), (2) perspective (from the healthcare sector to entire societies and economies), (3) scope (from individuals to communities and ecosystems), and (4) space (from single sites to countries and the world). Analyses of the impact of interventions need to be extended to examine the impact of the intervention on ABR, rather than considering ABR as an exogeneous factor. CONCLUSIONS: Quantifying the economic cost of resistance will require greater rigour and innovation in the use of existing methods to design studies that accurately collect relevant outcomes and further research into new techniques for capturing broader economic outcomes.

A Human Bite on the Scrotum: Case Report and Review of Management in the Emergency Department.

BACKGROUND: Human bites involving the genitalia rarely present to the emergency department (ED). They have the potential to cause life-threatening secondary infections as well as serious physical and functional damage. CASE REPORT: We report a case of an adult male who sustained a human bite to the scrotum, resulting in a ragged laceration on the anterior scrotum, with a devascularized flap and necrotic edges overlying the wound. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Human bites to the scrotum are rare and, hence, the experience of emergency physicians treating patients presenting with these injuries may be minimal. This puts patients at risk of underevaluation or suboptimal treatment. The rapid initiation of antibiotics in the ED and thorough wound debridement will prevent infections, aid healing, and lead to improved outcomes by preserving organ function and integrity. We therefore present a systematic approach to the management of patients with human bite to the scrotum in the ED.

Mini-review: Can non-human leucocyte antigen genes determine susceptibility to severe dengue syndromes?

Dengue viral infections are endemic or epidemic in virtually all tropical countries. Among individuals infected with the dengue virus, severe dengue syndromes (i.e., dengue haemorrhagic fever and dengue shock syndromes) tend to affect only some and this may be due to a combination of host genetic susceptibility and viral factors. In this review article we analyse and discuss the present knowledge of non-human leucocyte antigen host genetic susceptibility to severe dengue syndromes. The relevance of genetic polymorphisms in the pathways of antigen recognition, uptake, processing and presentation, activation of interferon α responses, mast cell and complement activation and T cell activation and dengue disease severity has been reviewed and analysed.

Unusual complication of bronchoscopy.

In the last twenty years, the field of bronchoscopy has become increasingly more complex and invasive. It is now widely used in the management of pulmonary diseases and has the benefit of low mortality and complication rates. Overall incidence of complications and mortality reported ranges around 1% and 0.02% respectively. Common complications of bronchoscopy include pulmonary haemorrhage, desaturation, pneumothorax, and pulmonary oedema. However, facial and neck petechiae associated with subcutaneous hemorrhage post-bronchoscopy has not been reported before in the literature. We hereby report two novel cases of facial/neck petechiae post-bronchoscopy as a complication to be recognized by bronchoscopists. It is essential that bronchoscopists recognise such phenomenon as the clinical presentation is visually alarming to both the patient and clinician. It is usually self-resolving. However such presentation after bronchoscopy may trigger extensive and unnecessary investigations from the physician.