Hong Kong consensus recommendations on the management of pancreatic ductal adenocarcinoma.

This project was undertaken to develop the first set of consensus statements regarding the management of pancreatic ductal adenocarcinoma (PDAC) in Hong Kong, with the goal of providing guidance to local clinicians. A multidisciplinary panel of experts discussed issues surrounding current PDAC management and reviewed evidence gathered in the local context to propose treatment recommendations. The experts used the Delphi approach to finalise management recommendations. Consensus was defined as ≥80% acceptance among all expert panel members. Thirty-nine consensus statements were established. These statements cover all aspects of PDAC management, including diagnosis, resectability criteria, treatment modalities according to resectability, personalised management based on molecular profiling, palliative care, and supportive care. This project fulfils the need for guidance regarding PDAC management in Hong Kong. To assist clinicians with treatment decisions based on varying levels of evidence and clinical experience, treatment options are listed in several consensus statements.

Unequivocal Identification of Spin-Triplet and Spin-Singlet Superconductors with Upper Critical Field and Flux Quantization.

Spin-triplet superconductors play central roles in Majorana physics and quantum computing but are difficult to identify. We show the methods of kink-point upper critical field and flux quantization in superconducting rings can unequivocally identify spin-singlet, spin-triplet in centrosymmetric superconductors, and singlet-triplet admixture in noncentrosymmetric superconductors, as realized in γ-BiPd, ß-Bi_{2}Pd, and α-BiPd, respectively. Our findings are essential for identifying triplet superconductors and exploring their quantum properties.

The Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Outcomes of Patients Treated with Immune Checkpoint Inhibitors: a Retrospective Cohort Study.

AIMS: Renin-angiotensin-aldosterone system inhibitors (RAASi) are associated with improved survival outcomes in patients receiving immune checkpoint inhibitors (ICIs), but the data on the response to treatment and tumour-based endpoints across different tumour types are unknown. MATERIALS AND METHODS: We carried out a retrospective study at two tertiary referral centres in Taiwan. All adult patients treated with ICIs between January 2015 and December 2021 were included. The primary outcome was overall survival and the secondary outcomes were progression-free survival (PFS) and clinical benefit rates. RESULTS: In total, 734 patients were enrolled in our study, of which 171 were RAASi users and 563 were non-users. Compared with non-users, RAASi users had a longer median overall survival [26.8 (interquartile range 11.3-not reached) versus 15.2 (interquartile range 5.1-58.4) months, P < 0.001] and PFS [12.2 (interquartile range 3.9-34.5) versus 5.0 (interquartile range 2.2-15.2) months, P < 0.001]. In univariate Cox proportional hazard analyses, the use of RAASi was associated with a 40% reduction in the risk of mortality [hazard ratio 0.58 (95% confidence interval 0.44-0.76), P < 0.001] and disease progression [hazard ratio 0.62 (95% confidence interval 0.50-0.77), P < 0.001]. The association remained significant after adjusting for underlying comorbidities and cancer therapy in multivariate Cox analyses. A similar trend was observed for PFS. Furthermore, RAASi users experienced a greater clinical benefit rate than non-users (69% versus 57%, P = 0.006). Importantly, the use of RAASi before ICI initiation was not associated with improved overall survival and PFS. RAASi were not associated with an increased risk of adverse events. CONCLUSION: The use of RAASi is associated with improved survival outcomes, treatment response and tumour-based endpoints in patients undergoing immunotherapy.

Severe hyponatraemia with cerebral oedema after Pfizer BNT162b2 mRNA vaccination against COVID-19.

Background: Severe hyponatraemia can lead to serious neurological complications including coma, seizure and death. Hyponatraemia and the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) has been previously described in cases of COVID-19, however there have been few reports post vaccination. We describe a case of severe hyponatraemia post second Pfizer BNT162b2 mRNA vaccination against COVID-19. Case presentation: A 48-year-old previously well woman presented to the emergency department with severe headaches and confusion one day after she received her second Pfizer COVID-19 vaccination. She reported no more than 2.5 L fluid intake. Vital signs were normal. Laboratory investigation revealed serum sodium 113 mmol/L, potassium 3.4 mmol/L, urea 3.5 mmol/L and serum osmolality 266 mmol/kg. TSH, random cortisol and C-reactive protein levels were normal. She was found to be in urinary retention and developed marked polyuria post in dwelling catheter insertion. Following this she underwent spontaneous and rapid correction of serum sodium without intervention. Retrospective analysis showed an inappropriately high copeptin of 4.4 pmol/L. Conclusions: It is important to be cautioned and aware of hyponatraemia as an immediate side effect of COVID-19 vaccination. The exact mechanism is unknown and further research is required to understand the acute endocrine effects which may arise in response to COVID-19 vaccination.

Improving access to affordable quality-assured inhaled medicines in low- and middle-income countries.

BACKGROUND: Access to affordable inhaled medicines for chronic respiratory diseases (CRDs) is severely limited in low- and middle-income countries (LMICs), causing avoidable morbidity and mortality. The International Union Against Tuberculosis and Lung Disease convened a stakeholder meeting on this topic in February 2022.METHODS: Focused group discussions were informed by literature and presentations summarising experiences of obtaining inhaled medicines in LMICs. The virtual meeting was moderated using a topic guide around barriers and solutions to improve access. The thematic framework approach was used for analysis.RESULTS: A total of 58 key stakeholders, including patients, healthcare practitioners, members of national and international organisations, industry and WHO representatives attended the meeting. There were 20 pre-meeting material submissions. The main barriers identified were 1) low awareness of CRDs; 2) limited data on CRD burden and treatments in LMICs; 3) ineffective procurement and distribution networks; and 4) poor communication of the needs of people with CRDs. Solutions discussed were 1) generation of data to inform policy and practice; 2) capacity building; 3) improved procurement mechanisms; 4) strengthened advocacy practices; and 5) a World Health Assembly Resolution.CONCLUSION: There are opportunities to achieve improved access to affordable, quality-assured inhaled medicines in LMICs through coordinated, multi-stakeholder, collaborative efforts.

ECG monitoring in STREAM Stage 1: can we identify those at increased risk of QT prolongation?

BACKGROUND: STREAM (Standardised Treatment Regimen of Anti-tuberculosis Drugs for Patients with Multidrug-resistant Tuberculosis) Stage 1 was a randomised trial of a Short (9-month) regimen for rifampicin-resistant TB (RR-TB). QT or QTcF prolongation ≥500 ms occurred in 31 (11%) of 282 Short regimen participants. The frequent ECG monitoring employed might be challenging for treatment programmes. This analysis aimed to determine whether those at higher risk of severe QT prolongation could be identified early for more targeted monitoring.METHODS: Data from the first month of treatment were used to investigate whether participants were at risk of developing QT/QTcF ≥500 ms. QTcF increases from baseline at different time points were examined. Absolute QTcF measurements were categorised in 5 ms increments at each time-point. The most discriminating time points and QTcF cut-offs were combined to optimise sensitivity and specificity.RESULTS: Absolute QTcF values were more discriminating than magnitude of increase from baseline. More participants who developed QT/QTcF ≥500 ms had a QTcF of respectively ≥425 ms and ≥430 ms at 4 h and Week 3 (P < 0.05) than those who did not. By combining QTcF values ≥425 ms at 4 h and ≥430 ms at Week 3, we identified high-risk participants with 97% sensitivity and 99% negative predictive value.CONCLUSION: Reduced ECG monitoring may be possible for many Short regimen participants.

Adjudicating Mild Cognitive Impairment Due to Alzheimer's Disease as a Novel Endpoint Event in the TOMMORROW Prevention Clinical Trial.

BACKGROUND: The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer's disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. METHODS: The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant's clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages - independent review, collaborative review, and full committee review - requiring a unanimous decision and ratification by the chair. RESULTS: Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators' clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80-90% for the remainder of the study. CONCLUSIONS: The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.

Failure or relapse predictors for the STREAM Stage 1 short regimen for RR-TB.

BACKGROUND: STREAM (Standardised Treatment Regimens of Anti-tuberculosis drugs for Multidrug-Resistant Tuberculosis) Stage 1 demonstrated non-inferior efficacy of a short regimen for rifampicin-resistant TB (RR-TB) compared to a long regimen as recommended by the WHO. The present paper analyses factors associated with a definite or probable failure or relapse (FoR) event in participants receiving the Short regimen.METHODS: This analysis is restricted to 253 participants allocated to the Short regimen and is based on the protocol-defined modified intention to treat (mITT) population. Multivariable Cox regression models were built using backwards elimination with an exit probability of P = 0.157, equivalent to the Akaike Information Criterion, to identify factors independently associated with a definite or probable FoR event.RESULTS: Four baseline factors were identified as being significantly associated with the risk of definite or probable FoR (male sex, a heavily positive baseline smear grade, HIV co-infection and the presence of costophrenic obliteration). There was evidence of association of culture positivity at Week 8 and FoR in a second model and Week 16 smear positivity, presence of diabetes and of smoking in a third model.CONCLUSION: The factors associated with FoR outcomes identified in this analysis should be considered when determining the optimal shortened treatment regimen.

Global availability of susceptibility testing for second-line anti-tuberculosis agents.

BACKGROUND: The continued development of new anti-TB agents brings with it a demand for accompanying treatment regimens to prevent the development of resistance. Effectively meeting this demand requires an understanding of the pathogen´s susceptibility to various treatment options, which in turn makes access to antibiotic susceptibility testing (AST) a paramount consideration in the global treatment of TB.METHODS: A 12-question, quantitative and qualitative survey was developed to gauge global capacity and access to AST. The survey was disseminated to members of the Global Laboratory Initiative, Global Drug-resistant TB Initiative, and the TB section of the International Union Against Tuberculosis and Lung Disease to solicit responses from pertinent stakeholders.RESULTS: A total of 323 complete responses representing 84 countries and all WHO Regions were collected. AST capacity for fluoroquinolones and second-line injectables was high in all WHO Regions. AST capacity for the new and repurposed drugs is highest in the European Region, Region of the Americas and the Western Pacific Region, but quite limited in the African and Eastern Mediterranean Regions. The AST turnaround time for second-line drugs was delayed compared to that for first-line drugs as samples needed to be sent farther for analysis. Common barriers to AST for second-line drugs were lack of specimen transportation infrastructure, high costs, and lack of specialised laboratory workers and specialised laboratory facilities.CONCLUSION: Without expanding global access to AST, the growing availability of new treatment options will likely be threatened by accompanying increase in resistance. There is an earnest and pressing need to improve capacity and access to AST alongside treatment options.

Screening for osteoporosis using L1 vertebral density on abdominal CT in an Australian population.

AIM: To assess the utility of osteoporosis screening using abdominal computed tomography (CT) versus dual-energy X-ray absorptiometry (DXA) T-scores as the reference. MATERIALS AND METHODS: Patients ≥30 years undergoing abdominal CT and DXA within 12 months were assessed retrospectively. Bone mineral density (BMD) was measured using axial CT attenuation at L1, correlating with DXA T-scores. Sensitivity, specificity, area under the curve (AUC), and odds ratio (OR) were calculated. RESULTS: The study cohort comprised 407 CT-DXA pairs (58.2% women). The prevalence of osteoporosis was 11.8%. L1 density and T-score were significantly correlated in both women (r=0.35, p<0.001) and men (r=0.15, p=0.04). The AUC to distinguish osteoporosis from osteopenia and normal BMD was 0.64 (95% CI: 0.56-0.71). In women, a threshold of 190 HU detected T-scores ≤ -2.5 with a negative predictive value (NPV) of 94.4% (OR=4.4, p<0.01). In the entire cohort, a threshold of 180 HU detected T-scores ≤ -2.5 with a NPV of 96.2% (OR=4.7, p<0.01). CONCLUSIONS: CT L1 attenuation correlates with L1 DXA T-scores. Density values < 190 and 180 HU increased the probability of an osteoporosis diagnosis in Australian women and the overall cohort, respectively. Opportunistic screening for osteoporosis using abdominal CT is feasible, enabling identification of at-risk subjects for formal DXA imaging, thereby improving treatment initiation and reducing fracture risk.

QT prolongation in the STREAM Stage 1 Trial.

BACKGROUND: STREAM (Standardized Treatment Regimen of Anti-TB Drugs for Patients with MDR-TB) Stage 1 demonstrated non-inferior efficacy of a shortened regimen (the Short regimen) for rifampicin-resistant TB (RR-TB) compared to the contemporaneous WHO-recommended regimen. This regimen included moxifloxacin and clofazimine, known to cause QT prolongation, and severe prolongation was more common on the Short regimen. Here we investigate risk factors for QT prolongation with the Short regimen.METHODS: Data from patients prescribed the Short regimen (n = 282) were analysed to identify risk factors for severe QT prolongation (QT/QTcF ≥500 ms or ≥60 ms increase in QTcF from baseline).RESULTS: Of the 282 patients on the Short regimen, 94 (33.3%) developed severe QT prolongation: 31 QT/QTcF ≥500 ms; 92 experienced ≥60 ms QTcF increase from baseline. The median time to QT/QTcF ≥500 ms was 20 weeks (IQR 8-28), and the time to ≥60 ms increase from baseline was 18 weeks (IQR 8-28). Prolongation ≥500 ms was most frequent in patients from Mongolia (10/22, 45.5%) compared with 3.5-11.9% at other sites, P < 0.001. Higher baseline QTcF increased risk of prolongation to ≥500 ms (QTcF ≥400 ms: OR 5.99, 95% CI 2.04-17.62).CONCLUSION: One third of patients on the Short regimen developed severe QT prolongation. QT/QTcF ≥500 ms was more common in patients from Mongolia and in those with a higher baseline QTcF, which may have implications for implementation of treatment.

Langerhans cells and SFRP2/Wnt/beta-catenin signalling control adaptation of skin epidermis to mechanical stretching.

Skin can be mechanically stimulated to grow through a clinical procedure called tissue expansion (TE). Using a porcine TE model, we determined that expansion promptly activates transcription of SFRP2 in skin and we revealed that in the epidermis, this protein is secreted by Langerhans cells (LCs). Similar to well-known mechanosensitive genes, the increase in SFRP2 expression was proportional to the magnitude of tension, showing a spike at the apex of the expanded skin. This implies that SFRP2 might be a newly discovered effector of mechanotransduction pathways. In addition, we found that acute stretching induces accumulation of b-catenin in the nuclei of basal keratinocytes (KCs) and LCs, indicating Wnt signalling activation, followed by cell proliferation. Moreover, TE-activated LCs proliferate and migrate into the suprabasal layer of skin, suggesting that LCs rebuild their steady network within the growing epidermis. We demonstrated that in vitro hrSFRP2 treatment on KCs inhibits Wnt/b-catenin signalling and stimulates KC differentiation. In parallel, we observed an accumulation of KRT10 in vivo in the expanded skin, pointing to TE-induced, SFRP2-augmented KC maturation. Overall, our results reveal that a network of LCs delivers SFRP2 across the epidermis to fine-tune Wnt/b-catenin signalling to restore epidermal homeostasis disrupted by TE.

Cardiovascular diseases among diffuse large B-cell lymphoma long-term survivors in Asia: a multistate model study.

BACKGROUND: We modeled the clinical course of a cohort of diffuse large B-cell lymphoma (DLBCL) patients with no prior cardiovascular diseases (CVDs) using a multistate modeling framework. PATIENTS AND METHODS: Data on 2600 patients with DLBCL diagnosed between 2000 and 2018 and had received chemotherapy with or without radiotherapy were obtained from a population-wide electronic health database of Hong Kong. We used the Markov illness-death model to quantify the impact of doxorubicin and various risk factors (therapeutic exposure, demographic, comorbidities, cardiovascular risk factors, and lifestyle factors which included smoking) on the clinical course of DLBCL (transitions into incident CVD, lymphoma death, and other causes of death). RESULTS: A total of 613 (23.6%) and 230 (8.8%) of 2600 subjects died of lymphoma and developed incident CVD, respectively. Median follow-up was 7.0 years (interquartile range 3.8-10.8 years). Older ages [hazard ratio (HR) for >75 versus ≤60 years 1.88; 95% confidence interval (CI) 1.25-2.82 and HR for 61-75 versus ≤60 years 1.60; 95% CI 1.12-2.30], hypertension (HR 4.92; 95% CI 2.61-9.26), diabetes (HR 1.43; 95% CI 1.09-1.87), and baseline use of aspirin (HR 5.30; 95% CI 3.93-7.16) were associated with an increased risk of incident CVD. In a subgroup of anticipated higher-risk patients (aged 61-75 years, smoked, had diabetes, and received doxorubicin), we found that they remained on average 7.9 (95% CI 7.2-8.8) years in the DLBCL state and 0.1 (95% CI 0.0-0.4) years in the CVD state, if they could be followed up for 10 years. The brief time in the CVD state is consistent with the high chance of death in patients who developed CVD. Other causes of death have overtaken DLBCL-related death after about 5 years. CONCLUSIONS: In this Asian population-based cohort, we found that incident CVDs can occur soon after DLBCL treatment and continued to occur throughout survivorship. Clinicians are advised to balance the risks and benefits of treatment choices to minimize the risk of CVD.

Changing patterns in medication prescription for gestational diabetes during a time of guideline change in the USA: a cross-sectional study.

OBJECTIVE: To define patterns of prescription and factors associated with choice of pharmacotherapy for gestational diabetes mellitus (GDM), namely metformin, glyburide and insulin, during a period of evolving professional guidelines. DESING: Cross-sectional study. SETTING: US commercial insurance beneficiaries from Market-Scan (late 2015 to 2018). STUDY DESIGN: We included women with GDM, singleton gestations, 15-51 years of age on pharmacotherapy. The exposure was pharmacy claims for metformin, glyburide and insulin. MAIN OUTCOMES: Pharmacotherapy for GDM with either oral agent, metformin or glyburide, compared with insulin as the reference, and secondarily, consequent treatment modification (addition and/or change) to metformin, glyburide or insulin. RESULTS: Among 37 762 women with GDM, we analysed data from 10 407 (28%) with pharmacotherapy, 21% with metformin (n = 2147), 48% with glyburide (n = 4984) and 31% with insulin (n = 3276). From late 2015 to 2018, metformin use increased from 17 to 29%, as did insulin use from 26 to 44%, whereas glyburide use decreased from 58 to 27%. By 2018, insulin was the most common pharmacotherapy for GDM; metformin was more likely to be prescribed by 9% compared with late 2015/16, but glyburide was less likely by 45%. Treatment modification occurred in 20% of women prescribed metformin compared with 2% with insulin and 8% with glyburide. CONCLUSIONS: Insulin followed by metformin has replaced glyburide as the most common pharmacotherapy for GDM among a privately insured US population during a time of evolving professional guidelines. Further evaluation of the relative effectiveness and safety of metformin compared with insulin is needed. TWEETABLE ABSTRACT: Insulin followed by metformin has replaced glyburide as the most common pharmacotherapy for gestational diabetes mellitus in the USA.