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TB is a priority pathogen for the application of whole-genome sequencing (WGS) into routine public health practice. In low-incidence settings, a growing number of services have begun to incorporate routine WGS into standard practice. The increasing availability of real-time genomic information supports a variety of aspects of the public health response, including the detection of drug resistance, monitoring of laboratory and clinical practices, contact tracing investigations and active case finding. Optimal structures and approaches are needed to support the rapid translation of genomic information into practice and to evaluate outcomes and impact. In this consensus paper, we outline the elements needed to systemically incorporate routine WGS into the TB public health response, including the sustainability of services, multidisciplinary team models and monitoring and evaluation frameworks. If integrated in an efficient and thoughtful manner, routine WGS has the potential to significantly improve clinical TB care for individuals and the overall public health response., Competing Interests: Conflicts of interest: none declared., (© 2024 The Authors.)

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.

Competing Interests: All authors declare that they have no competing interests in this manuscript and its publication.

The yield of contact investigation on relapsed tuberculosis (TB) cases can guide strategies and resource allocation in the TB control programme. We conducted a retrospective cohort study to review the yield of contact investigation in relapsed TB cases and identify factors associated with TB infection (TBI) among close contacts of relapsed TB cases notified between 2018 and 2022 in Singapore. TB infection positivity was higher among contacts of relapsed cases which were culture-positive for Mycobacterium tuberculosis complex compared to those who were only polymerase chain reaction (PCR)-positive (14.8% vs. 12.3%). On multivariate analysis, after adjusting for age and gender of the index, gender, and existing comorbidities of contacts, factors independently associated with TBI were culture and smear positivity of the index (AOR 1.41, 95%CI 1.02-1.94), higher odds with every 10 years of increase in age compared to contacts below aged 30, contacts who were not Singapore residents (AOR 2.09, 95%CI 1.46-2.97), and household contacts (AOR 2.19, 95%CI 1.44-3.34). Although the yield of screening was higher for those who were culture-positive compared to only PCR-positive relapsed cases, contact tracing for only PCR-positive cases may still be important in a country with moderate TB incidence, should resources allow.

On November 26, 2021, the B.1.1.529 COVID-19 variant was classified as the Omicron variant of concern (VOC). Reports of higher transmissibility and potential immune evasion triggered flight bans and heightened health control measures across the world to stem its distribution. Wastewater-based surveillance has demonstrated to be a useful complement for clinical community-based tracking of SARS-CoV-2 variants. Using design principles of our previous assays that detect SARS-CoV-2 variants (Alpha and Delta), we developed an allele-specific RT-qPCR assay which simultaneously targets the stretch of mutations from Q493R to Q498R for quantitative detection of the Omicron variant in wastewater. We report their validation against 10-month longitudinal samples from the influent of a wastewater treatment plant in Italy. SARS-CoV-2 RNA concentrations and variant frequencies in wastewater determined using these variant assays agree with clinical cases, revealing rapid displacement of the Delta variant by the Omicron variant within three weeks. These variant trends, when mapped against vaccination rates, support clinical studies that found the rapid emergence of SARS-CoV-2 Omicron variant being associated with an infection advantage over Delta in vaccinated persons. These data reinforce the versatility, utility and accuracy of these open-sourced methods using allele-specific RT-qPCR for tracking the dynamics of variant displacement in communities through wastewater for informed public health responses., (Copyright © 2022. Published by Elsevier Ltd.)

By exposing floating gates of EEPROM memory cells with frontside sample preparation, scanning nonlinear dielectric microscopy (SNDM) succeeded in reading back the data stored in the memory cells with a 250 nm node size. At an optimized voltage bias of AC = 3 V and DC = 1 V, a clear signal contrast between programmed and erased cells is obtained. The high resolution SNDM signal reveals the details of bowling-pin shape structure of memory cells, providing high confidence in data assignment during forensic applications. Such high resolution also makes SNDM a promising technique for newer generation devices with smaller node size., (© 2021 IOP Publishing Ltd.)

Background: Descriptions of symptoms and medication use at end of life in COVID-19 are limited to small cross-sectional studies, with no Australian longitudinal data., Aims: To describe end-of-life symptoms and care needs of people dying of COVID-19., Methods: This retrospective cohort study included consecutive admitted patients who died at a Victorian tertiary referral hospital from 1 January to 30 September directly due to COVID-19. Clinical characteristics, symptoms and use of supportive therapies, including medications and non-pharmacological interventions in the last 3 days of life were extracted., Results: The cohort comprised 58 patients (median age 87 years, interquartile range (IQR) 81-90) predominantly admitted from home (n = 30), who died after a median of 11 days (IQR 6-28) in the acute medical (n = 31) or aged care (n = 27) wards of the hospital. The median Charlson Comorbidity Score was 7 (IQR 5-8). Breathlessness (n = 42), agitation (n = 36) and pain (n = 33) were the most frequent clinician-reported symptoms in the final 3 days of life, with most requiring opioids (n = 52), midazolam (n = 40), with dose escalation commonly being required. While oxygen therapy was commonly used (n = 47), few (n = 13) required an anti-secretory agent., Conclusions: This study presents one of the first and largest Australian report of the end of life and symptom experience of people dying of COVID-19. This information should help clinicians to anticipate palliative care needs of these patients, for example, recognising that higher starting doses of opioids and sedatives may help reduce prevalence and severity of breathlessness and agitation near death., (© 2021 Royal Australasian College of Physicians.)

Objective: To evaluate the use of direct to consumer Prefabricated adjustable thermoplastic mandibular advancement devices (PAT-MADs) (MyTAP™, Airway Management Inc), its effectiveness in the treatment of OSA, feasibility and short-term adherence., Methods: In sum, 50 patients with diagnosed mild-moderate OSA on formal polysomnography (PSG) were fitted with a PAT-MAD (MyTAP™, Airway Management Inc). Sleep indices included the apnea-hypopnea index (AHI), hypopnea index (HI), apnea index (AI); oxygen desaturation index (ODI), and the lowest 0 2 saturation (Lsat) were measured with a Level 3 home sleep apnea test (HSAT) pre versus post treatment. Quality of life (QOL) surveys of Epworth sleepiness scale (ESS), Pittsburg sleep quality index (PSQI), Functional outcomes of sleep quality-10 (FOSQ10) and satisfaction surveys were administered., Results: Over three months, indices showed a trend towards improvement. Results were statistically significant when stratified into groups who achieved cure and success. Moreover, there was a mean improvement in AHI: -12.7 ± 9.3, AI: -5.7 ± 8.2, HI: -6.3 ± 3.7, ODI: -11.2 ± 8.6 for responders with a success rate of 41%. Out of QOL surveys, ESS showed a decrease of -1.41 [-2.52, -0.3] (p = 0.017) when controlled for age and body mass index (BMI). Up to 68.8% of patients found that the device was useful in alleviating snore symptoms. Adherence rate was reported at 59%., Conclusion: Titratable PAT-MAD is an economical and effective option for a patient of Chinese descent. It has the potential to serve as a device for trial use and means of selection before proceeding with customized MADs. Further studies will be required to substantiate other factors which influence the recommendation of MADs for patients with this demographic., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The performance of real-time reverse transcription polymerase chain reaction (rRT-PCR) for SARS-CoV-2 varies with sampling site(s), illness stage, and infection site., Methods: Unilateral nasopharyngeal, nasal midturbinate, throat swabs, and saliva were simultaneously sampled for SARS-CoV-2 rRT-PCR from suspected or confirmed cases of COVID-19. True positives were defined as patients with at least 1 SARS-CoV-2 detected by rRT-PCR from any site on the evaluation day or at any time point thereafter, until discharge. Diagnostic performance was assessed and extrapolated for site combinations., Results: We evaluated 105 patients; 73 had active SARS-CoV-2 infection. Overall, nasopharyngeal specimens had the highest clinical sensitivity at 85%, followed by throat, 80%, midturbinate, 62%, and saliva, 38%-52%. Clinical sensitivity for nasopharyngeal, throat, midturbinate, and saliva was 95%, 88%, 72%, and 44%-56%, respectively, if taken ≤7 days from onset of illness, and 70%, 67%, 47%, 28%-44% if >7 days of illness. Comparing patients with upper respiratory tract infection (URTI) vs pneumonia, clinical sensitivity for nasopharyngeal, throat, midturbinate, and saliva was 92% vs 70%, 88% vs 61%, 70% vs 44%, 43%-54% vs 26%-45%, respectively. A combination of nasopharyngeal plus throat or midturbinate plus throat specimen afforded overall clinical sensitivities of 89%-92%; this rose to 96% for persons with URTI and 98% for persons ≤7 days from illness onset., Conclusions: Nasopharyngeal specimens, followed by throat specimens, offer the highest clinical sensitivity for COVID-19 diagnosis in early illness. Clinical sensitivity improves and is similar when either midturbinate or nasopharyngeal specimens are combined with throat specimens. Upper respiratory specimens perform poorly if taken after the first week of illness or if there is pneumonia., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Size reduction or milling of the active is often the first processing step in the design of a dosage form. The ability of a mill to convert coarse crystals into the target size and size distribution efficiently is highly desirable as the quality of the final pharmaceutical product after processing is often still dependent on the dimensional attributes of its component constituents. The F10 Fine Grind mill is a mechanical impact mill designed to produce unimodal mid-size particles by utilizing a single-pass two-stage size reduction process for fine grinding of raw materials needed in secondary processing. Box-Behnken designs were used to investigate the effects of various mill variables (impeller, blower and feeder speeds and screen aperture size) on the milling of coarse crystals. Response variables included the particle size parameters (D10, D50 and D90), span and milling rate. Milled particles in the size range of 5-200 μm, with D50 ranging from 15 to 60 μm, were produced. The impeller and feeder speeds were the most critical factors influencing the particle size and milling rate, respectively. Size distributions of milled particles were better described by their goodness-of-fit to a log-normal distribution (i.e. unimodality) rather than span. Milled particles with symmetrical unimodal distributions were obtained when the screen aperture size was close to the median diameter of coarse particles employed. The capacity for high throughput milling of particles to a mid-size range, which is intermediate between conventional mechanical impact mills and air jet mills, was demonstrated in the F10 mill. Prediction models from the Box-Behnken designs will aid in providing a better guide to the milling process and milled product characteristics., (Copyright © 2014 Elsevier B.V. All rights reserved.)

RANKL (receptor activator of nuclear factor kappaB ligand) promotes osteoclast differentiation, stimulates osteoclast activity, and prolongs osteoclast survival and adherence to bone. Abnormalities of the RANKL/RANK/osteoprotegerin system have been implicated in a range of diseases, including osteoporosis. To date, no work has been done in osteolytic lesions of the facial skeleton. In this study, specimens of ameloblastomas, dentigerous cysts, odontogenic keratocysts, and radicular cysts were subjected to immunohistochemical analysis for RANKL and tartrate-resistant acid phosphatase (TRAP). Immunofluorescence staining for TRAP was visualized under confocal microscopy. All specimens demonstrated distinct positive immunoreactivity to RANKL and TRAP. The TRAP-positive cells also stained with in situ hybridization for human calcitonin receptor, a definitive marker for osteoclasts. Mononuclear pre-osteoclasts were observed to migrate from blood to the connective tissue stroma and multinucleate toward the bone surface. It can be concluded that RANKL plays a role in bone resorption in osteolytic lesions of the facial skeleton.

A randomized clinical trial was conducted to investigate the effect of the presence of a pharyngeal pack during endotracheal anaesthesia on the incidence of postoperative sore throat. The patients were anaesthetized with fentanyl, thiopentone and atracurium. Thirty-six patients were anaesthetized without placement of pharyngeal packs while 26 patients had pharyngeal packs inserted. There were no significant differences in the incidence or severity of sore throat postoperatively in the two groups (P=0.23). These results contradict previous studies, which showed an increase in the incidence of postoperative sore throat after the use of pharyngeal packs., (Copyright 2002 The British Association of Oral and Maxillofacial Surgeons.)