Quantum circuits with many photons on a programmable nanophotonic chip.

Growing interest in quantum computing for practical applications has led to a surge in the availability of programmable machines for executing quantum algorithms1,2. Present-day photonic quantum computers3-7 have been limited either to non-deterministic operation, low photon numbers and rates, or fixed random gate sequences. Here we introduce a full-stack hardware-software system for executing many-photon quantum circuit operations using integrated nanophotonics: a programmable chip, operating at room temperature and interfaced with a fully automated control system. The system enables remote users to execute quantum algorithms that require up to eight modes of strongly squeezed vacuum initialized as two-mode squeezed states in single temporal modes, a fully general and programmable four-mode interferometer, and photon number-resolving readout on all outputs. Detection of multi-photon events with photon numbers and rates exceeding any previous programmable quantum optical demonstration is made possible by strong squeezing and high sampling rates. We verify the non-classicality of the device output, and use the platform to carry out proof-of-principle demonstrations of three quantum algorithms: Gaussian boson sampling, molecular vibronic spectra and graph similarity8. These demonstrations validate the platform as a launchpad for scaling photonic technologies for quantum information processing.

Bolometer operating at the threshold for circuit quantum electrodynamics.

Radiation sensors based on the heating effect of absorbed radiation are typically simple to operate and flexible in terms of input frequency, so they are widely used in gas detection1, security2, terahertz imaging3, astrophysical observations4 and medical applications5. Several important applications are currently emerging from quantum technology and especially from electrical circuits that behave quantum mechanically, that is, circuit quantum electrodynamics6. This field has given rise to single-photon microwave detectors7-9 and a quantum computer that is superior to classical supercomputers for certain tasks10. Thermal sensors hold potential for enhancing such devices because they do not add quantum noise and they are smaller, simpler and consume about six orders of magnitude less power than the frequently used travelling-wave parametric amplifiers11. However, despite great progress in the speed12 and noise levels13 of thermal sensors, no bolometer has previously met the threshold for circuit quantum electrodynamics, which lies at a time constant of a few hundred nanoseconds and a simultaneous energy resolution of the order of 10h gigahertz (where h is the Planck constant). Here we experimentally demonstrate a bolometer that operates at this threshold, with a noise-equivalent power of 30 zeptowatts per square-root hertz, comparable to the lowest value reported so far13, at a thermal time constant two orders of magnitude shorter, at 500 nanoseconds. Both of these values are measured directly on the same device, giving an accurate estimation of 30h gigahertz for the calorimetric energy resolution. These improvements stem from the use of a graphene monolayer with extremely low specific heat14 as the active material. The minimum observed time constant of 200 nanoseconds is well below the dephasing times of roughly 100 microseconds reported for superconducting qubits15 and matches the timescales of currently used readout schemes16,17, thus enabling circuit quantum electrodynamics applications for bolometers.

Operation of a silicon quantum processor unit cell above one kelvin.

Quantum computers are expected to outperform conventional computers in several important applications, from molecular simulation to search algorithms, once they can be scaled up to large numbers-typically millions-of quantum bits (qubits)1-3. For most solid-state qubit technologies-for example, those using superconducting circuits or semiconductor spins-scaling poses a considerable challenge because every additional qubit increases the heat generated, whereas the cooling power of dilution refrigerators is severely limited at their operating temperature (less than 100 millikelvin)4-6. Here we demonstrate the operation of a scalable silicon quantum processor unit cell comprising two qubits confined to quantum dots at about 1.5 kelvin. We achieve this by isolating the quantum dots from the electron reservoir, and then initializing and reading the qubits solely via tunnelling of electrons between the two quantum dots7-9. We coherently control the qubits using electrically driven spin resonance10,11 in isotopically enriched silicon12 28Si, attaining single-qubit gate fidelities of 98.6 per cent and a coherence time of 2 microseconds during 'hot' operation, comparable to those of spin qubits in natural silicon at millikelvin temperatures13-16. Furthermore, we show that the unit cell can be operated at magnetic fields as low as 0.1 tesla, corresponding to a qubit control frequency of 3.5 gigahertz, where the qubit energy is well below the thermal energy. The unit cell constitutes the core building block of a full-scale silicon quantum computer and satisfies layout constraints required by error-correction architectures8,17. Our work indicates that a spin-based quantum computer could be operated at increased temperatures in a simple pumped 4He system (which provides cooling power orders of magnitude higher than that of dilution refrigerators), thus potentially enabling the integration of classical control electronics with the qubit array18,19.

Identification of genomic regions associated with differences in fleece type in Huacaya and Suri alpacas (Vicugna pacos).

The difference in fleece type is the distinguishing trait between the two types of alpacas (Vicugna pacos), Huacaya and Suri. The Suri fleece type has been found to be inherited dominantly over the Huacaya type, resulting in offspring with the Suri phenotype. The aim of our study was to map genomic regions associated with the two different fleece types. In this study, 91 alpacas (54 Huacayas and 37 Suris) from Germany and Switzerland were genotyped using the 76k alpaca SNP array. Only 59k chromosome-localised markers map to the alpaca reference assembly VicPac3.1, and after quality control 49 866 SNPs, were retained for population structure assessment and to conduct a genome-wide association study. Both principal component and neighbour-joining tree analysis showed that the two fleece-type cohorts overlapped rather than forming two distinct clusters. Genome-wide significantly associated markers were observed in the scaffold region of chromosome 16 (NW_021964192.1), which contains a cluster of keratin genes. A haplotype predominantly found in Suri alpacas has been identified which supports dominant inheritance. Variant filtering of nine whole-genome sequenced alpacas from both fleece types in the critical interval of 0.4 Mb did not reveal perfect segregation of either fleece type for specific variants. To our knowledge, this is the first study to use the recently developed species-specific SNP array to identify genomic regions associated with differences in fleece type in alpacas. There are still some limitations, such as the preliminary status of the reference assembly and the incomplete annotation of the alpaca genome.

Access to COVID-19 vaccination by socio-economic status in older Singaporean adults: a population-based cohort study.

OBJECTIVES: Socio-economic status (SES) disparities exist in the uptake of COVID-19 vaccination; however, most studies were conducted during the initial pandemic wave when vaccination was less discretionary, limiting generalizability. We aimed to determine whether differences in vaccination uptake across SES strata widened after the removal of vaccination-differentiated measures prior to the rollout of the second boosters, in a nationwide cohort of older Singaporeans at higher risk of severe-COVID-19. STUDY DESIGN: Retrospective population-based cohort study. METHODS: Retrospective population-based cohort study of all Singaporeans aged ≥60 years from 22nd February 2021-14th February 2023. Cox regression models controlling for demographics and comorbidities were used to estimate hazard-ratios (HRs) for the uptake of primary vaccination as well as first/second boosters, as recorded in the national vaccination registry, according to SES (housing type). RESULTS: 836,170 individuals were included for completion of a primary vaccine series; 784,938 individuals for completion of the first booster and 734,206 individuals for the completion of the second booster. Differences in vaccination uptake by SES strata were observed (e.g. vaccination uptake in lowest-SES [1-2 room public-housing] versus highest-SES [private housing]: second booster, 47.6% vs. 58.1%; first booster, 93.9% vs. 98.0%). However, relative differences did not markedly widen during second booster rollout when vaccination was more discretionary (e.g. amongst those aged 60-69 years: 0.75 [95% CI = 0.73-0.76] for the first booster; 0.81 [95% CI = 0.79-0.84] for the second booster). CONCLUSION: While differences in vaccination uptake across SES strata by housing type persisted during the rollout of primary vaccination and subsequent boosters in a nationwide cohort of older Singaporeans, differences did not widen substantially when vaccination was made more discretionary.

Management of chronic kidney disease: a Hong Kong consensus recommendation.

Chronic kidney disease (CKD) imposes a significant burden on healthcare systems worldwide, and diabetes is a major risk factor for CKD. There is currently no consensus in Hong Kong regarding the prioritisation of early identification and intervention for CKD. A comprehensive and Hong Kong-specific diabetes and CKD treatment guideline is also lacking. A multidisciplinary group of experts discussed issues surrounding the current management of CKD and reviewed evidence in the context of local experience to support recommendations. The experts used a modified Delphi approach to finalise recommendations. Consensus was regarded as ≥75% acceptability among all expert panel members. The panel members finalised 14 CKD-focused consensus statements addressing disease definition, screening, disease monitoring, lifestyle management, and treatment strategies. The recommendations provided are relevant to the Hong Kong healthcare setting and can be used as a guide by physicians across various specialties to facilitate the appropriate management of CKD.

Comorbidities in newly diagnosed epilepsy: Pre-existing health conditions are common and complex across age groups.

OBJECTIVES: People with epilepsy have a higher prevalence of medical and psychiatric comorbidities compared to the general population. Comorbidities are associated with poor epilepsy outcomes, and there have been recommendations for screening and early identification to improve clinical management. Data from 'First Seizure Clinics' (FSCs) with expert epileptological review can inform about disorders already present at the point of diagnosis of epilepsy or unprovoked seizures. Here, we aimed to describe pre-existing conditions with a focus on psychiatric, substance use, cardiac, neurological, and cancer health domains. METHODS: We included 1383 adults who received a new diagnosis of epilepsy or unprovoked seizures at Austin Hospital (AH) or Royal Melbourne Hospital (RMH) (Australia) FSCs from 2000 to 2010. Data were audited from FSC records, primarily detailed interviews undertaken by epileptologists. Logistic regression examined age distribution and other risk factors. RESULTS: The median age at FSC presentation was 37 years (IQR 26-53, range 18-94). Pre-existing conditions were reported by 40 %; from 32 % in the youngest group (18-30 years) to 53 % in the oldest (65+ years). Psychiatric (18 %) and substance use (16 %) disorders were most common, with higher prevalence among patients 18 to 65 years of age compared to those older than 65 years (p < 0.001). Cardiac, neurological, or cancer conditions were reported by 3-6 %, most often amongst those older than 65 years (p < 0.01). Eight percent (n = 112) reported disorders in >1 health domain. The commonest combination was a psychiatric condition with substance use disorder. Of the sixty-two patients reporting this combination, 61 were ≤65 years of age. CONCLUSIONS: Pre-existing health conditions are present in a substantial proportion of patients diagnosed with epilepsy or unprovoked seizures. Disorders are highest amongst elders, but one-third of younger adults also reported positive histories. These are predominantly psychiatric and/or substance use disorders, conditions strongly associated with poor outcomes in the general population. These findings inform post-diagnosis planning and management, as well as research examining post-diagnostic outcomes and associations between comorbidities and epilepsy.

Structures of riboswitch RNA reaction states by mix-and-inject XFEL serial crystallography.

Riboswitches are structural RNA elements that are generally located in the 5' untranslated region of messenger RNA. During regulation of gene expression, ligand binding to the aptamer domain of a riboswitch triggers a signal to the downstream expression platform. A complete understanding of the structural basis of this mechanism requires the ability to study structural changes over time. Here we use femtosecond X-ray free electron laser (XFEL) pulses to obtain structural measurements from crystals so small that diffusion of a ligand can be timed to initiate a reaction before diffraction. We demonstrate this approach by determining four structures of the adenine riboswitch aptamer domain during the course of a reaction, involving two unbound apo structures, one ligand-bound intermediate, and the final ligand-bound conformation. These structures support a reaction mechanism model with at least four states and illustrate the structural basis of signal transmission. The three-way junction and the P1 switch helix of the two apo conformers are notably different from those in the ligand-bound conformation. Our time-resolved crystallographic measurements with a 10-second delay captured the structure of an intermediate with changes in the binding pocket that accommodate the ligand. With at least a 10-minute delay, the RNA molecules were fully converted to the ligand-bound state, in which the substantial conformational changes resulted in conversion of the space group. Such notable changes in crystallo highlight the important opportunities that micro- and nanocrystals may offer in these and similar time-resolved diffraction studies. Together, these results demonstrate the potential of 'mix-and-inject' time-resolved serial crystallography to study biochemically important interactions between biomacromolecules and ligands, including those that involve large conformational changes.

Fibreglass dermatitis: diagnostic challenges and occupational interventions.

Fibreglass dermatitis is a common occupationally acquired irritant contact dermatitis, where small spicules of fibreglass lodging in the stratum corneum result in mechanical irritation. We present two patients, an air-conditioning ducting worker and an injection moulding machine operator, who both presented with generalized pruritus. In the first case, polarized microscopy of a skin biopsy specimen demonstrated rare small spicules, with a diameter of 1 µm, lodged in the stratum corneum. In the second case, skin tape stripping demonstrated fibreglass particles, not found on skin biopsy. Proper work practices, personal hygiene and use of impervious barrier materials were recommended. The first patient did not return for follow-up, and the second patient's dermatitis resolved after handling of fibreglass-containing material was eliminated from his job scope. In conclusion, we present two cases of fibreglass dermatitis to illustrate the challenges in diagnosis and highlight strategies for prevention.

Development of an online animated sexting prevention module based on the prototype willingness model to reduce intention and willingness to sexting among diploma students.

INTRODUCTION: Sexting refers to the act of sending and receiving sexually explicit content in the form of in the form of texts, photos, or videos via the Internet and mobile phones. This behaviour is associated with many negative health consequences among young people. However, there is a lack of intervention studies to curb this behaviour. We have developed a new sexting prevention module and tested it using a randomised controlled field trial. This paper reported the phase one of the study i.e., the development of an animated sexting prevention module using the prototype willingness model (PWM) to reduce the intention and willingness to sext amongst diploma students in Malaysia. MATERIALS AND METHOD: The initial phase involved a review of previous interventions, validation from field experts, and the process of developing video. Then the module pilot was tested among 30 diploma students from a public university. They were given access to the newly developed videos posted on a private YouTube channel and asked to evaluate the videos quantitatively and qualitatively by using the acceptability of the intervention module (AIM), intervention appropriateness measure (IAM) and feasibility of the intervention measure (FIM). The minimum and maximum scores of each measure were 12 and 24 respectively whereby a higher score indicated greater acceptability, appropriateness and feasibility. RESULTS: The intervention consisted of five sections addressing the constructs of PWM, namely attitude, perceived norm, prototype perception, as well as intention and willingness of sexting. The contents were then converted into five videos with a total duration of 23 minutes. Based on the pilot test, the scores of AIM, IAM and FIM were not normally distributed and their median and the interquartile range values were 20 (4), 21 (4) and 22 (4) respectively. Most of the respondents gave favourable opinions on the intervention besides providing some input for improvement. CONCLUSION: This animated sexting intervention module based on PWM to reduce the intention and willingness was novel. The module was acceptable, appropriate and feasible to be implemented among undergraduate students. Further evaluation of this intervention module can be performed to provide more comprehensive evidence of its effectiveness.

Development of a prediction score (ThyroCOVID) for identifying abnormal thyroid function in COVID-19 patients.

PURPOSE: Thyroid dysfunction in COVID-19 carries clinical and prognostic implications. In this study, we developed a prediction score (ThyroCOVID) for abnormal thyroid function (TFT) on admission amongst COVID-19 patients. METHODS: Consecutive COVID-19 patients admitted to Queen Mary Hospital were prospectively recruited during July 2020-May 2021. Thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) were measured on admission. Multivariable logistic regression analysis was performed to identify independent determinants of abnormal TFTs. ThyroCOVID was developed based on a clinical model with the lowest Akaike information criteria. RESULTS: Five hundred and forty six COVID-19 patients were recruited (median age 50 years, 45.4% men, 72.9% mild disease on admission). 84 patients (15.4%) had abnormal TFTs on admission. Patients with abnormal TFTs were more likely to be older, have more comorbidities, symptomatic, have worse COVID-19 severity, higher SARS-CoV-2 viral loads and more adverse profile of acute-phase reactants, haematological and biochemical parameters. ThyroCOVID consisted of five parameters: symptoms (malaise), comorbidities (ischaemic heart disease/congestive heart failure) and laboratory parameters (lymphocyte count, C-reactive protein, and SARS-CoV-2 cycle threshold values). It was able to identify abnormal TFT on admission with an AUROC of 0.73 (95% CI 0.67-0.79). The optimal cut-off of 0.15 had a sensitivity of 75.0%, specificity of 65.2%, negative predictive value of 93.5% and positive predictive value of 28.1% in identifying abnormal TFTs on admission amongst COVID-19 patients. CONCLUSION: ThyroCOVID, a prediction score to identify COVID-19 patients at risk of having abnormal TFT on admission, was developed based on a cohort of predominantly non-severe COVID-19 patients.

Ordering of computed tomography scans for head and cervical spine: a qualitative study exploring influences on doctors' decision-making.

BACKGROUND: Ordering of computed tomography (CT) scans needs to consideration of diagnostic utility as well as resource utilisation and radiation exposure. Several factors influence ordering decisions, including evidence-based clinical decision support tools to rule out serious disease. The aim of this qualitative study was to explore factors influencing Emergency Department (ED) doctors' decisions to order CT of the head or cervical spine. METHODS: In-depth semi-structured interviews were conducted with purposively selected ED doctors from two affiliated public hospitals. An interview tool with 10 questions, including three hypothetical scenarios, was developed and validated to guide discussions. Interviews were audio recorded, transcribed verbatim, and compared with field notes. Transcribed data were imported into NVivo Release 1.3 to facilitate coding and thematic analysis. RESULTS: In total 21 doctors participated in semi-structured interviews between February and December 2020; mean interview duration was 35 min. Data saturation was reached. Participants ranged from first-year interns to experienced consultants. Five overarching emerging themes were: 1) health system and local context, 2) work structure and support, 3) professional practices and responsibility, 4) reliable patient information, and 5) holistic patient-centred care. Mapping of themes and sub-themes against a behaviour change model provided a basis for future interventions. CONCLUSIONS: CT ordering is complex and multifaceted. Multiple factors are considered by ED doctors during decisions to order CT scans for head or c-spine injuries. Increased education on the use of clinical decision support tools and an overall strategy to improve awareness of low-value care is needed. Strategies to reduce low-yield CT ordering will need to be sustainable, sophisticated and supportive to achieve lasting change.

A quality improvement project: Reducing bloodstream infection by improving adherence to the care bundle of peripheral vascular catheters at the COVID-19 treatment centre.

INTRODUCTION: During the COVID-19 pandemic, bloodstream infection (BSI) rates were substantially rising in Sungai Buloh Hospital (HSB). It is believed that the COVID-19 pandemic has had an adverse impact on BSI incidence caused by contaminated periphery vascular catheters (PVCs). The study's objective is to reduce the BSI rates in HSB by improving adherence to the PVC care bundle via the Plan-Do-Study-Act (PDSA) approach. MATERIALS AND METHODS: A quality improvement (QI) project was employed over four months, from June to September 2021, during the COVID-19 pandemic in HSB. All adults hospitalised for COVID-19 with intravenous lines were subjected to data collection. A baseline audit was conducted to study BSI incidence from April to May 2021. Implementation was carried out by PDSA cycles and data on BSI rates per 100 admissions was described using a monthly run chart. RESULTS: At baseline, the BSI rate per 100 admissions was 5.44 before implementing our QI project. Initial changes via PDSA cycles did not bring significant improvements to BSI rates and a rising trend in BSI rates was observed after two PDSA cycles. Further audits identified the problem of noncompliance with the practice of aseptic non-touch technique (ANTT) and a lack of effective leadership in implementing the PVC care bundle. The third PDSA cycle focused on adopting practical leadership skills among senior clinicians to ensure compliance with the prevention bundle and to encourage the use of ultrasound guidance for difficult line insertion. After the third PDSA cycle, the BSI rate per 100 admissions was reduced from 6.41 to 4.34 (p < 0.05). The BSI rates continued to decline down the line for another five months. CONCLUSION: Through QI initiatives, the risk of BSI can be significantly reduced.

Clinical severity of COVID-19 with omicron variant predominance in relation to vaccination status, age, comorbidities- a single center in Selangor, Malaysia.

INTRODUCTION: Recently, the rapid surge of reported COVID-19 cases attributed to the Omicron variant of severe acute respiratory syndrome coronavirus (SARS-CoV-2) created an immediate concern across nations. Local information pertaining to the new variant of concern (VOC) is lacking. We aimed to determine the clinical characteristics of COVID-19 during a period of Omicron prevalence among patients hospitalised from February 1 to 21, 2022 at Sungai Buloh Hospital and to estimate the risks of disease progression presumably caused by this variant in association with gender, age, comorbidity, and vaccination status. MATERIALS AND METHODS: In this retrospective, singlecentered, retrospective cohort study, all hospitalised adults with laboratory-confirmed COVID-19, aged 18 and above, were recruited from February 1 to 21, 2022. Clinical characteristics, investigations, and outcomes were assessed. RESULTS: A total of 2279 patients aged 18 years and above with laboratory-proven COVID-19 were recruited and analysed, excluding 32 patients owing to incomplete data. Majority of the study population had a mean age of 41.8 ± 17.7, was female-predominant (1329/2279, 58.6%), had completed a primary series of vaccination with a booster (1103/2279, 48.4%), and had no underlying medical conditions (1529/2279, 67.4%). The risk of COVID-19-related disease progression was significantly lower in hospitalised patients under the age of 50 who were female, had no comorbidity, and had completed two doses of the primary series with or without a booster. [respectively, OR 7.94 (95% CI 6.16, 10.23); 1.68 (1.34, 2,12); 2.44 (1.85, 3.22); 2.56 (1.65, 3.97), p< 0.001]. CONCLUSION: During the period of Omicron prevalence, a favourable outcome of COVID-19 was strongly associated with female gender, age below 50, a comorbidity-free condition, and having completed immunization. With this new observation, it could help improve public health planning and clinical management in response to the emergence of the latest VOC.

Prognosis after neoadjuvant chemoradiation or chemotherapy for locally advanced gastro-oesophageal junctional adenocarcinoma.

BACKGROUND: Trials typically group cancers of the gastro-oesophageal junction (GOJ) with oesophageal or gastric cancer when studying neoadjuvant chemoradiation and perioperative chemotherapy, so the results may not be fully applicable to GOJ cancer. Because optimal neoadjuvant treatment for GOJ cancer remains controversial, outcomes with neoadjuvant chemoradiation versus chemotherapy for locally advanced GOJ adenocarcinoma were compared retrospectively. METHODS: Data were collected from all patients who underwent neoadjuvant treatment followed by surgery for adenocarcinoma located at the GOJ at a single high-volume institution between 2002 and 2017. Postoperative major complications and mortality were compared between groups using Fisher's exact test. Overall survival (OS) and disease-free survival (DFS) were assessed by log rank test and multivariable Cox regression analyses. Cumulative incidence functions were used to estimate recurrence, and groups were compared using Gray's test. RESULTS: Of 775 patients, 650 had neoadjuvant chemoradiation and 125 had chemotherapy. These groups were comparable in terms of clinical tumour and lymph node categories, although the chemoradiation group had greater proportions of white men, complete pathological response to chemotherapy, and smaller proportions of diffuse cancer, poor differentiation, and neurovascular invasion. Postoperative major complications (20.0 versus 17.6 per cent) and 30-day mortality (1.7 versus 1.6 per cent) were not significantly different between the chemoradiation and chemotherapy groups. After adjustment, type of therapy (chemoradiation versus chemotherapy) was not significantly associated with OS (hazard ratio (HR) 1.26, 95 per cent c.i. 0.96 to 1.67) or DFS (HR 1.27, 0.98 to 1.64). Type of recurrence (local, regional, or distant) did not differ after neoadjuvant chemoradiation versus chemotherapy. CONCLUSION: In patients undergoing surgical resection for locally advanced adenocarcinoma of the GOJ, OS and DFS did not differ significantly between patients who had neoadjuvant chemoradiation compared with chemotherapy.

Treating advanced cancer of the gastro-oesophageal junction (GOJ) poses a challenge given its location in the distal oesophagus and proximal stomach, and whether it should be treated as oesophageal or gastric cancer. Given the indistinct location, it is unclear whether GOJ cancer should be treated with neoadjuvant chemoradiation, which is the treatment of choice for advanced oesophageal cancers, or perioperative chemotherapy, which is the treatment of choice for advanced gastric cancers. Few studies have addressed treatment options specifically for GOJ cancers. This study investigated whether there was a difference in survival between patients with GOJ cancer who were treated with chemoradiation versus chemotherapy.

Cost-effectiveness of FRAX®-based intervention thresholds for management of osteoporosis in Singaporean women.

Cost-effectiveness analysis of FRAX® intervention thresholds (ITs) in Singaporean women > 50 years of age showed that generic alendronate was cost-effective at age-dependent major osteoporotic fracture (MOF) IT from the ages of 65 years for both full and real-world adherence whilst hip fracture (HF) ITs were cost-effective from the ages of 60 and 65 years. Alendronate was cost-effective irrespective of age only at fixed MOF IT of 14% and HF IT of 3.5%. INTRODUCTION: FRAX®-based intervention thresholds (ITs) were recently identified for osteoporosis management in Singapore. This study aimed to assess the cost-effectiveness of ITs in Singaporean women over the age of 50 years. METHODS: A validated Markov microsimulation model was used to estimate the lifetime healthcare costs (SGD2019) per quality-adjusted life-years (QALY) of generic alendronate compared with no treatment. Cost-effectiveness of age-dependent FRAX® major osteoporotic fracture (MOF) and hip fracture (HF) ITs was explored. In addition, ITs that would lead to cost-effectiveness were computed. Fracture incidence and cost data were obtained from the Ministry of Health and a previously published Singaporean study. A cost-effectiveness threshold of SGD 62,500/QALY gained was used, based conservatively on 0.7 times the Singapore GDP per capita. RESULTS: Generic alendronate was shown to be cost-effective at MOF ITs from the ages of 65 years, while HF ITs were cost-effective from the ages of 60 and 65 years, assuming full and real-world adherence, respectively. A 14% MOF and a 3.5% HF ITs were required for alendronate to be cost-effective above 50 years. CONCLUSION: This study suggests that the treatment of Singaporean women with alendronate is cost-effective at age-dependant FRAX® intervention thresholds at 65 years and older. Furthermore, identifying women at any age above 50 years with a 10-year risk of MOF or HF of 14% or 3.5% would lead to efficient use of resources. Cost-effective access to therapy for patients at high fracture probability based on FRAX® could contribute to reduce the growing burden of osteoporotic fractures in Singapore.

Excess mortality after hip fracture: fracture or pre-fall comorbidity?

Comorbidity and hip fracture independently increased mortality risk for 9 years in both sexes, with a significant additive interaction in the first year among women and through 6 years among men. INTRODUCTION: Hip fracture is associated with a persistently elevated mortality risk, but it is unknown whether the elevated risk is due to the fracture or to pre-fracture comorbidity. METHODS: In a population-based study in Singapore with 9 years of follow-up, patients age > 50 with first hip fracture from 2008 to 2017 were pair-matched to a cohort without hip fracture by age, sex, ethnicity, and pre-fracture Charlson Comorbidity Index (CCI). We investigated additive interaction using the relative excess risk due to interaction (RERI) and multiplicative interaction using the ratio of relative risks. RESULTS: Twenty-two thousand five hundred ninety of 22,826 patients with a first hip fracture in 2008-2017 were successfully matched. Hip fracture and comorbidity independently increased mortality risk for 9 years in both sexes. After adjustment for comorbidity, excess mortality risk continued to persist for 9 years post-fracture in both men and women. Women with a hip fracture and pre-fracture CCI > 4 had a higher relative risk (RR) of mortality at 9 years of 3.29 [95% confidence interval (CI) 3.01, 3.59] than those without comorbidity (RR 1.51, 95%CI 1.36, 1.68) compared to the referent without hip fracture or comorbidity. An additive interaction between hip fracture and pre-fracture CCI > 4 was observed in the first post-fracture year` [relative excess risk due to interaction (RERI) 1.99, 95%CI 0.97, 3.01]. For men with CCI ≥ 4, the positive additive interaction was observed through 6 years. CONCLUSIONS: Excess mortality risks post-fracture are attributable to both the fracture and pre-fracture comorbidity. Early interventions in hip fracture patients with high comorbidity could reduce their excess mortality.

Differential heterologous neutralisation profile against strains within DENV-3 genotype II.

The dengue virus type 3 (DENV-3) homotypic outbreak cycles reported in Klang Valley, Malaysia in 1992-1995 and 2002 demonstrated different epidemic magnitude and duration. These outbreak cycles were caused by two closely related strains of viruses within the DENV-3 genotype II (DENV-3/II). The role of viral genotypic diversity and factors that could have influenced this phenomenon were investigated. The serum neutralisation sensitivity of DEN3/II strains responsible for the DENV-3 outbreak cycles in 1992-1995 and 2002 were examined. Representative virus isolates from the respective outbreaks were subjected to virus neutralisation assay using identified sera of patients with homotypic (DENV-3) or heterotypic dengue infections (DENV-1 and DENV-2). Results from the study suggested that isolates representing DENV-3/II group E (DENV-3/II-E) from the 1992-1995 outbreak and DENV-3/II group F (DENV-3/II-F) from the 2002 outbreak were neutralised at similar capacity (intergenotypic differences <2-fold) by sera of patients infected with DENV-3, DENV-1 and DENV-2/Asian genotypes. Sera of the DENV-2/Cosmopolitan infection efficiently neutralised DENV-3/II-F (FRNT50 = 508.0) at a similar neutralisation capacity against its own homotypic serotype, DENV-2 (FRNT50 = 452.5), but not against DENV-3/II-E (FRNT50 = 100.8). The different neutralisation sensitivities of DENV-3/II strains towards the cross-reacting DENV-2 heterotypic immunity could play a role in shaping the DENV-3 recurring outbreaks pattern in Malaysia. Two genetic variations, E-132 (H/Y) and E-479 (A/V) were identified on the envelope protein of DENV-3/II-E and DENV-3/II-F, respectively. The E-132 variation was predicted to affect the protein stability. A more extensive study, however, on the implication of the naturally occurring genetic variations within closely related DENV genotypes on the neutralisation profile and protective immunity would be needed for a better understanding of the DENV spread pattern in a hyperendemic setting.

Poor sleep is associated with higher blood pressure and uterine artery pulsatility index in pregnancy: a prospective cohort study.

OBJECTIVE: To elucidate the association between sleep disturbances and blood pressure as well as uterine artery Doppler during pregnancy in women with no pre-existing hypertension. DESIGN: Prospective cohort study. SETTING: Outpatient specialist clinics at KK Women's and Children's Hospital, Singapore. POPULATION: Women with viable singleton pregnancies confirmed by ultrasonography at less than 14 weeks of amenorrhoea at first visit. METHODS: In all, 926 subjects were recruited for this study in the outpatient specialist clinics at KK Women's and Children's Hospital, Singapore, between 1 September 2010 and 31 August 2014. They were followed up throughout pregnancy with sleep quality, blood pressure and uterine artery Doppler assessed at each visit. MAIN OUTCOME MEASURES: Sleep quality, blood pressure and uterine artery Doppler. RESULTS: Sleep progressively worsened as pregnancy advanced. Shorter sleep duration and poorer sleep efficiency were associated with higher blood pressure, especially in the first trimester. Mixed model analysis demonstrated an overall positive association between sleep quality represented by Pittsburgh Sleep Quality Index (PSQI) score and diastolic blood pressure (DBP) (P < 0.001) and mean arterial pressure (MAP) (P = 0.005) during pregnancy after considering all trimesters. Sleep duration was found to be negatively associated with both systolic blood pressure (SBP) (P = 0.029) and DBP (P = 0.002), whereas sleep efficiency was negatively correlated with DBP (P = 0.002) only. Overall poor sleep during pregnancy was also found to be associated with a higher uterine artery pulsatility index. CONCLUSION: Our prospective study demonstrated that poor sleep quality is significantly associated with higher blood pressure and uterine artery pulsatility index during pregnancy. TWEETABLE ABSTRACT: Poor sleep quality is significantly associated with higher blood pressure and higher uterine artery pulsatility index during pregnancy.