Singapore tuberculosis (TB) clinical management guidelines 2024: A modified Delphi adaptation of international guidelines for drug-susceptible TB infection and pulmonary disease.

Introduction: Tuberculosis (TB) remains endemic in Singapore. Singapore's clinical practice guidelines for the management of tuberculosis were first published in 2016. Since then, there have been major new advances in the clinical management of TB, ranging from diagnostics to new drugs and treatment regimens. The National TB Programme convened a multidisciplinary panel to update guidelines for the clinical management of drug-susceptible TB infection and disease in Singapore, contextualising current evidence for local practice. Method: Following the ADAPTE framework, the panel systematically reviewed, scored and synthesised English-language national and international TB clinical guidelines published from 2016, adapting recommendations for a prioritised list of clinical decisions. For questions related to more recent advances, an additional primary literature review was conducted via a targeted search approach. A 2-round modified Delphi process was implemented to achieve consensus for each recommendation, with a final round of edits after consultation with external stakeholders. Results: Recommendations for 25 clinical questions spanning screening, diagnosis, selection of drug regimen, monitoring and follow-up of TB infection and disease were formulated. The availability of results from recent clinical trials led to the inclusion of shorter treatment regimens for TB infection and disease, as well as consensus positions on the role of newer technologies, such as computer-aided detection-artificial intelligence products for radiological screening of TB disease, next-generation sequencing for drug-susceptibility testing, and video observation of treatment. Conclusion: The panel updated recommendations on the management of drug-susceptible TB infection and disease in Singapore.

Prevalence and healthcare utilization in managing herpes zoster in primary care: a retrospective study in an Asian urban population.

Herpes zoster (HZ) causes significant morbidity, particularly in older adults. With the advent of a recombinant zoster vaccine, HZ is potentially preventable. However, data on HZ burden and healthcare utilization in primary care populations remains scarce. This study described the prevalence and healthcare utilization in managing HZ in a developed community. A retrospective database review was conducted across a cluster of 8 public primary care clinics in urban Singapore. Data of multi-ethnic Asian patients with a diagnosis code of "herpes zoster" from 2018 to 2020 was extracted from their electronic medical records. Socio-demographic, clinical, visitation, medical leave, prescription, and referral data were analyzed. A total of 2,987 out of 737,868 individuals were diagnosed with HZ over 3 years. The mean age was 59.9 (SD + 15.5) years; 49.2% were male; 78.5% Chinese, 12.2% Malay, and 4.1% Indian. The prevalence was 221, 224, 203 per 100,000 persons in 2018, 2019, and 2020, respectively. The 70 to 79-year age group had the highest prevalence (829/100,000) across 3 years. Oral acyclovir (median daily dose 4,000 mg; median duration 7 days) and topical acyclovir were prescribed in 71.6 and 47.6%, respectively. Analgesia prescribed were gabapentin (41.0%), paracetamol combinations (30.1%), oral NSAIDs (23.7%), opioids (6.0%), and tricyclic antidepressants (1.9%). Most individuals consulted only once (84.3%); 32.7% of them required medical leave and 5.6% had more than 7 days of absenteeism. HZ-related referrals to the hospital were required in 8.9% (4.9% emergency, 2.8% ophthalmology). The findings of this study suggest a need for HZ vaccination among older age groups. Visitation and referral rates were low. The use of topical acyclovir was uncovered, and further research should evaluate the underlying reasons, benefits, and harms of such practice. The use of analgesia combinations may be explored further.

Worth the risk? Contemporary indications, yield and complications of lumbar punctures in a metropolitan Australian health service.

BACKGROUND: Performing lumbar punctures carries a risk of harm to the patient, but the information cerebrospinal fluid provides often makes this procedure necessary. Clinicians in the Australian setting would benefit from having more information on these procedures, in order to help them in a risk versus benefit analysis. AIMS: To describe the contemporary indications, cerebrospinal fluid findings and complications of lumbar punctures in a metropolitan Australian health service. METHODS: Retrospective electronic medical records audit of lumbar punctures performed on 525 adults within three acute hospitals between 1 July 2018 and 30 June 2019. Main outcome measures include frequency of indication for lumbar puncture by category, normal versus abnormal cerebrospinal fluid for each category, and frequency, severity and type of complications of lumbar punctures. RESULTS: Of 525 adult lumbar punctures that were assessed in this study, 466 were performed for a diagnostic indication. The most common diagnostic indications were acute severe headache (156 procedures; 33.5%) and encephalopathy (128 procedures; 27.5%). The yield of abnormal results varied by indication category, with the above indications yielding abnormal results in 85 (54.5%) and 72 (56.3%) cases respectively. A complication was recorded in 54 (10.3% of total) procedures. The majority (45; 8.6%) of complications were minor in severity and most frequently consisted of post-dural puncture headache (PDPH). CONCLUSIONS: In the era of an increased reliance on high quality neuroimaging, lumbar puncture has a high diagnostic yield with a low rate of major complications. The most common complication is PDPH, which is mild and self-limiting in most cases.

Body mass index is inversely associated with capillary ketones at the time of colonoscopy: Implications for SGLT2i use.

OBJECTIVE: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been associated with diabetic ketoacidosis at the time of colonoscopy. This study aimed to identify factors associated with ketone concentrations in SGLT2i-treated type 2 diabetes compared with non-SGLT2i-treated diabetes, and those with impaired fasting glycaemia (IFG) and normoglycaemia. DESIGN: Cross-sectional, multicentre, observational study June-December 2020 in four Australian tertiary hospitals. PARTICIPANTS: Capillary glucose and ketones were measured in people undergoing colonoscopy: 37 SGLT2i-treated and 105 non-SGLT2i-treated type 2 diabetes, 65 IFG and 151 normoglycaemia. MEASUREMENTS: Body mass index (BMI), age, glucose, fasting duration and where relevant, HbA1c and time since last SGLT2i dose. RESULTS: In SGLT2i-treated diabetes, BMI (ρ = -0.43 [95% confidence interval: -0.67, -0.11]) and duration since last SGLT2i dose (ρ = -0.33 [-0.60, 0.00]) correlated negatively with increasing ketones, but there was no correlation with fasting duration. In non-SGLT2i-treated diabetes, BMI correlated negatively (ρ = -0.24 [-0.42, -0.05]) and fasting duration positively (ρ = 0.26 [0.07, 0.43]) with ketones. In IFG participants, only fasting duration correlated with ketones (ρ = 0.28 [0.03, 0.49]). In normoglycaemic participants, there were negative correlations with BMI (ρ = -0.20 [-0.35, -0.04]) and fasting glucose (ρ = -0.31 [-0.45, -0.15]) and positive correlations with fasting duration (ρ = 0.20 [0.04, 0.35]) and age (ρ = 0.19 [0.03, 0.34]). Multiple regression analysis of the entire cohort showed BMI, age and fasting glucose remained independently associated with ketones, but in SGLT2i-treated participants only BMI remained independently associated. CONCLUSIONS: In SGLT2i-treated diabetes, lower BMI was a novel risk factor for higher ketones precolonoscopy. Pending larger confirmatory studies, extra vigilance for ketoacidosis is warranted in these people.

Allelic variation in class I HLA determines CD8+ T cell repertoire shape and cross-reactive memory responses to SARS-CoV-2.

Effective presentation of antigens by human leukocyte antigen (HLA) class I molecules to CD8+ T cells is required for viral elimination and generation of long-term immunological memory. In this study, we applied a single-cell, multiomic technology to generate a unified ex vivo characterization of the CD8+ T cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across four major HLA class I alleles. We found that HLA genotype conditions key features of epitope specificity, TCRα/ß sequence diversity, and the utilization of pre-existing SARS-CoV-2-reactive memory T cell pools. Single-cell transcriptomics revealed functionally diverse T cell phenotypes of SARS-CoV-2-reactive T cells, associated with both disease stage and epitope specificity. Our results show that HLA variations notably influence the CD8+ T cell repertoire shape and utilization of immune recall upon SARS-CoV-2 infection.

Airway management in the adult patient with COVID-19: High flow nasal oxygen or not? A summary of evidence and local expert opinion.

The use of high flow nasal oxygen in the care of COVID-19-positive adult patients remains an area of contention. Early guidelines have discouraged the use of high flow nasal oxygen therapy in this setting due to the risk of viral spread to healthcare workers. However, there is the need to balance the relative risks of increased aerosol generation and virus transmission to healthcare workers against the role high flow nasal oxygen has in reducing hypoxaemia when managing the airway in high-risk patients during intubation or sedation procedures. The authors of this article undertook a narrative review to present results from several recent papers. Surrogate outcome studies suggest that the risk of high flow nasal oxygen in dispersing aerosol-sized particles is probably not as great as first perceived. Smoke laser-visualisation experiments and particle counter studies suggest that the generation and dispersion of bio-aerosols via high flow nasal oxygen with flow rates up to 60 l/min is similar to standard oxygen therapies. The risk appears to be similar to oxygen supplementation via a Hudson mask at 15 l/min and significantly less than low flow nasal prong oxygen 1-5 l/min, nasal continuous positive airway pressure with ill-fitting masks, bilevel positive airway pressure, or from a coughing patient. However, given the limited safety data, we recommend a cautious approach. For intubation in the COVID-positive or suspected COVID-positive patient we support the use of high flow nasal oxygen to extend time to desaturation in the at-risk groups, which include the morbidly obese, those with predicted difficult airways and patients with significant hypoxaemia, ensuring well-fitted high flow nasal oxygen prongs with staff wearing full personal protective equipment. For sedation cases, we support the use of high flow nasal oxygen when there is an elevated risk of hypoxaemia (e.g. bariatric endoscopy or prone-positioned procedures), but recommend securing the airway with a cuffed endotracheal tube for the longer duration procedures when theatre staff remain in close proximity to the upper airway, or considering the use of a surgical mask to reduce the risk of exhaled particle dispersion.

What are the measures taken to prevent COVID-19 infection among healthcare workers? A retrospective study in a cluster of primary care clinics in Singapore.

OBJECTIVE: To examine factors contributing to the low COVID-19 infectivity rate among healthcare workers in SingHealth Polyclinics (SHP), Singapore, from February to July 2020. DESIGN: Retrospective description, analysis and discussion of the factors and their contribution. SETTING: Single-institution study. METHODS: We describe and discuss the healthcare policies, infrastructure, people and processes contributing to the low COVID-19 infectivity rate in SHP.There were 1212 full-time and 198 contract staff. Of these, 171 SHP employees also supported the work in dormitories, isolation and community care facilities. During the review period, healthcare workers (HCWs) in SHP managed about 867 076 patient attendances, including 63 503 for upper respiratory tract infections, across its cluster of eight polyclinics. 29 642 swabs for COVID-19 were performed in SHP, with 126 positive results. 395 swabs were carried out in the dormitories and 59 were positive. Despite the high exposure, only two SHP staff were infected with COVID-19. Both have recovered well. RESULTS: Provision of adequate personal protection equipment, zonal segregation of high-risk patients, reduction in physical patient visits, effective staff communication, implementation of self-declared temperature monitoring and the maintenance of sustainable workload and work hours of HCWs contributed to the mitigation of COVID-19 infection risk among our staff. CONCLUSIONS: Until the widespread uptake of safe and effective vaccines against COVID-19, these measures are important in protecting HCWs. They are also important when managing future pandemics of similar nature to COVID-19.

Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies.

Aberrant activation of Wnt/ß-catenin signaling occurs frequently in cancer. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics. Crystal structures revealed a common binding site for these monoclonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. However, these mAbs displayed gastrointestinal toxicity or poor plasma exposure in vivo. Structure-guided engineering was used to refine the binding of each mAb for FZD receptors, resulting in antibody variants with improved in vivo tolerability and developability. Importantly, the lead variant mAb significantly inhibited tumor growth in the HPAF-II pancreatic tumor xenograft model. Taken together, our data demonstrate that anti-FZD cancer therapeutic antibodies with broad specificity can be fine-tuned to navigate in vivo exposure and tolerability while driving therapeutic efficacy.

Recombinant BCG Overexpressing phoP-phoR Confers Enhanced Protection against Tuberculosis.

The live tuberculosis vaccine Mycobacterium bovis BCG (Bacille Calmette-Guérin) comprises a number of genetically distinct substrains. In BCG-Prague, phoP of the PhoP-PhoR two-component system is a pseudogene due to a single insertion mutation. We hypothesized that this mutation partially accounts for the low immunogenicity of BCG-Prague observed in the 1970s. In this study, we showed that complementation with the M. bovis allele of phoP restored BCG-Prague's immunogenicity. Furthermore, we showed that overexpression of the M. bovis allele of phoP-phoR in BCG-Japan, a strain already containing a copy of phoP-phoR, further enhanced immunogenicity and protective efficacy. Vaccination of C57BL/6 mice with the recombinant strain rBCG-Japan/PhoPR induced higher levels of interferon-γ (IFN-γ) production by CD4+ T cells than that with the parental BCG. Guinea pigs vaccinated with rBCG-Japan/PhoPR were better protected against challenge with Mycobacterium tuberculosis than those immunized with the parental BCG, showing significantly longer survival time, reduced bacterial burdens, and less severe pathology. Taken together, our study has identified a genetic modification that could be generally applied to generate new recombinant BCG vaccines.

Transcription factors Rv0081 and Rv3334 connect the early and the enduring hypoxic response of Mycobacterium tuberculosis.

The ability of Mycobacterium tuberculosis (M. tb) to survive and persist in the host for decades in an asymptomatic state is an important aspect of tuberculosis pathogenesis. Although adaptation to hypoxia is thought to play a prominent role underlying M. tb persistence, how the bacteria achieve this goal is largely unknown. Rv0081, a member of the DosR regulon, is induced at the early stage of hypoxia while Rv3334 is one of the enduring hypoxic response genes. In this study, we uncovered genetic interactions between these two transcription factors. RNA-seq analysis of ΔRv0081 and ΔRv3334 revealed that the gene expression profiles of these two mutants were highly similar. We also found that under hypoxia, Rv0081 positively regulated the expression of Rv3334 while Rv3334 repressed transcription of Rv0081. In addition, we demonstrated that Rv0081 formed dimer and bound to the promoter region of Rv3334. Taken together, these data suggest that Rv0081 and Rv3334 work in the same regulatory pathway and that Rv3334 functions immediately downstream of Rv0081. We also found that Rv3334 is a bona fide regulator of the enduring hypoxic response genes. Our study has uncovered a regulatory pathway that connects the early and the enduring hypoxic response, revealing a transcriptional cascade that coordinates the temporal response of M. tb to hypoxia.

Loss of Lipid Virulence Factors Reduces the Efficacy of the BCG Vaccine.

Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is the only vaccine available for tuberculosis (TB) control. BCG comprises a number of substrains that exhibit genetic and biochemical differences. Whether and how these differences affect BCG efficacy remain unknown. Compared to other BCG strains, BCG-Japan, -Moreau, and -Glaxo are defective in the production of phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs), two lipid virulence factors. To determine if the loss of PDIMs/PGLs affects BCG efficacy, we constructed a PDIM/PGL-deficient strain of BCG-Pasteur by deleting fadD28, and compared virulence, immunogenicity, and protective efficacy in animal models. SCID mouse infection experiments showed that ∆fadD28 was more attenuated than wild type (WT). The ∆fadD28 and WT strains induced equivalent levels of antigen specific IFN-γ by CD4(+) and CD8(+) T cells; however, ∆fadD28 was less effective against Mycobacterium tuberculosis challenge in both BALB/c mice and guinea pigs. These results indicate that the loss of PIDMs/PGLs reduces the virulence and protective efficacy of BCG. Since the loss of PDIMs/PGLs occurs naturally in a subset of BCG strains, it also suggests that these strains may have been over-attenuated, which compromises their effectiveness. Our finding has important implications for current BCG programs and future vaccine development.

Vaccination in the primary care setting: when is it safe to proceed?

Primary care practitioners play an important role in administering and advocating vaccinations against vaccine-preventable infectious diseases and ensuring herd immunity in our population. This is a follow-up article to an earlier one which dealt with the principles of vaccine scheduling and administration. This article describes several false contraindications to vaccination that a primary care practitioner may encounter, including pregnancy, current breastfeeding, history of febrile seizures, and having immunosuppressed or pregnant household contacts. We aimed to provide a guide for safe and timely vaccine administration in the primary care setting.

When babies turn yellow.

Neonatal jaundice is a common condition seen in the primary care setting. Most afflicted babies have physiological jaundice and their prognosis is good. However, others have pathological jaundice, which must be detected early. High levels of serum bilirubin can also result in bilirubin encephalopathy. This article describes consultation tasks in the primary care setting with the aim of providing a guide for the safe management of neonatal jaundice. They include clinical assessment of the baby's well-being; looking out for features that suggest pathological jaundice; assessment for the presence of high-risk features; utilising appropriate laboratory tests for monitoring; assessing the degree of jaundice to decide if the child can be safely followed up in primary care; and providing advice on primary prevention measures and allaying parental concerns. The importance of stool colour examination and its role in early detection of cholestatic jaundice is emphasised.

Recurrent wheeze and cough in young children: is it asthma?

A clinical diagnosis of asthma is often considered when a child presents with recurrent cough, wheeze and breathlessness. However, there are many other causes of wheeze in a young child. These range from recurrent viral infections to chronic suppurative lung disease, gastro-oesophageal reflux disease and rare structural abnormalities. Arriving at a diagnosis includes taking into consideration the symptomatology, triggers, atopic features, family history, absence of red flags and therapeutic trial, where indicated.

Childhood immunisation.

Primary care practitioners play an important role in administering and advocating childhood vaccination to protect our children against infectious diseases and to ensure herd immunity in our population. Primary care practitioners may encounter children who present out-of-schedule, as well as children who come for vaccination with intercurrent illnesses, egg or other allergies, or are on long-term medications. This article describes the approach to these issues and present useful resources and references that primary care practitioners can access.

PILL series. Prescribing health: exercise.

The healthcare challenges in developed countries centre around the rise of chronic conditions and obesity. There is a call to shift the focus toward the primary prevention of these conditions. Clinicians will need to move beyond the comfort of prescribing pharmaceuticals and expand the scope to prescribing health, i.e. exercise. We discuss an easy-to-follow exercise prescription to highlight some essential principles and useful tools that can help busy family practices achieve this.