Effectiveness of out-patient based acute heart failure care: a pilot randomised controlled trial.

OBJECTIVES: Acute heart failure (AHF) hospitalisation is associated with 10% mortality. Outpatient based management (OPM) of AHF appeared effective in observational studies. We conducted a pilot randomised controlled trial (RCT) comparing OPM with standard inpatient care (IPM). METHODS: We randomised patients with AHF, considered to need IV diuretic treatment for ≥2 days, to IPM or OPM. We recorded all-cause mortality, and the number of days alive and out-of-hospital (DAOH). Quality of life, mental well-being and Hope scores were assessed. Mean NHS cost savings and 95% central range (CR) were calculated from bootstrap analysis. Follow-up: 60 days. RESULTS: Eleven patients were randomised to IPM and 13 to OPM. There was no statistically significant difference in all-cause mortality during the index episode (1/11 vs 0/13) and up to 60 days follow-up (2/11 vs 2/13) [p = .86]. The OPM group accrued more DAOH {47 [36,51] vs 59 [41,60], p = .13}. Two patients randomised to IPM (vs 6 OPM) were readmitted [p = .31]. Hope scores increased more with OPM within 30 days but dropped to lower levels than IPM by 60 days. More out-patients had increased total well-being scores by 60 days (p = .04). OPM was associated with mean cost savings of £2658 (95% CR 460-4857) per patient. CONCLUSIONS: Patients with acute HF randomised to OPM accrued more days alive out of hospital (albeit not statistically significantly in this small pilot study). OPM is favoured by patients and carers and is associated with improved mental well-being and cost savings.

Bimodular continuous attractor neural networks with static and moving stimuli.

We investigated the dynamical behaviors of bimodular continuous attractor neural networks, each processing a modality of sensory input and interacting with each other. We found that when bumps coexist in both modules, the position of each bump is shifted towards the other input when the intermodular couplings are excitatory and is shifted away when inhibitory. When one intermodular coupling is excitatory while another is moderately inhibitory, temporally modulated population spikes can be generated. On further increase of the inhibitory coupling, momentary spikes will emerge. In the regime of bump coexistence, bump heights are primarily strengthened by excitatory intermodular couplings, but there is a lesser weakening effect due to a bump being displaced from the direct input. When bimodular networks serve as decoders of multisensory integration, we extend the Bayesian framework to show that excitatory and inhibitory couplings encode attractive and repulsive priors, respectively. At low disparity, the bump positions decode the posterior means in the Bayesian framework, whereas at high disparity, multiple steady states exist. In the regime of multiple steady states, the less stable state can be accessed if the input causing the more stable state arrives after a sufficiently long delay. When one input is moving, the bump in the corresponding module is pinned when the moving stimulus is weak, unpinned at intermediate stimulus strength, and tracks the input at strong stimulus strength, and the stimulus strengths for these transitions increase with the velocity of the moving stimulus. These results are important to understanding multisensory integration of static and dynamic stimuli.

Bifurcation behaviors shape how continuous physical dynamics solves discrete Ising optimization.

Simulating physical dynamics to solve hard combinatorial optimization has proven effective for medium- to large-scale problems. The dynamics of such systems is continuous, with no guarantee of finding optimal solutions of the original discrete problem. We investigate the open question of when simulated physical solvers solve discrete optimizations correctly, with a focus on coherent Ising machines (CIMs). Having established the existence of an exact mapping between CIM dynamics and discrete Ising optimization, we report two fundamentally distinct bifurcation behaviors of the Ising dynamics at the first bifurcation point: either all nodal states simultaneously deviate from zero (synchronized bifurcation) or undergo a cascade of such deviations (retarded bifurcation). For synchronized bifurcation, we prove that when the nodal states are uniformly bounded away from the origin, they contain sufficient information for exactly solving the Ising problem. When the exact mapping conditions are violated, subsequent bifurcations become necessary and often cause slow convergence. Inspired by those findings, we devise a trapping-and-correction (TAC) technique to accelerate dynamics-based Ising solvers, including CIMs and simulated bifurcation. TAC takes advantage of early bifurcated "trapped nodes" which maintain their sign throughout the Ising dynamics to reduce computation time effectively. Using problem instances from open benchmark and random Ising models, we validate the superior convergence and accuracy of TAC.

Perceived changes in symptoms and quality-of-life amongst patients with dizziness: A single-centre experience in Malaysia.

INTRODUCTION: Dizziness is a common complaint by patients, yet it always presents as a diagnostic challenge to the attending clinician. An accurate diagnosis is essential to correctly administer the precise treatment regime, alleviate the symptoms, and improve the quality-of-life of patients who present with dizziness. A specialised vestibular clinic with a holistic approach of meticulous history-taking, complete physical examination, a collection of audiovestibular test battery, and facilities for vestibular rehabilitation was set up to assist in the management of these patients. This study aims to investigate the effect of vestibular clinic intervention on the symptoms and qualityof- life of patients who were managed in the vestibular clinic. MATERIALS AND METHODS: A total of 64 new patients who were managed in the vestibular clinic were selected and the validated Malay - Vestibular Rehabilitation Benefit Questionnaire (My-VRBQ) was completed during the first and follow-up visits to measure the changes in symptoms and quality-of-life before and after receiving care at the vestibular clinic. RESULTS: Our study showed that there was a positive effect of vestibular clinic intervention on the symptoms and quality-of-life of patients who were managed by the vestibular clinic. Statistically significant improvements were seen in the total My-VRBQ scores, symptoms scores, and quality-of-life scores. The subscale scores of dizziness, anxiety, and motion-provoked dizziness also showed statistically significant improvement among the patients who received care at the vestibular clinic. CONCLUSION: This indicates that the vestibular clinic was an essential part of the work-up, diagnosis, and treatment of patients with dizziness; and a specialised vestibular clinic was able to bring about positive outcomes in the symptoms and quality-of-life of patients with balance disorders.

Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142.

BACKGROUND: In the phase II multicohort CheckMate 142 study, nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at 13.4- and 25.4-month median follow-up (Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779. Overman MJ, Lonardi S, Wong KYM, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: long-term follow-up. J Clin Oncol. 2019;37:635). Here, we present results from the 4-year follow-up of these patients. PATIENTS AND METHODS: Patients received nivolumab (3 mg/kg) plus low-dose (1 mg/kg) ipilimumab every 3 weeks (four doses) followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; as per RECIST version 1.1). RESULTS: A total of 119 patients were treated; 76% had ≥2 prior lines of therapy. Median follow-up was 50.9 months (range 46.9-62.7 months). Median duration of therapy was 24.9 months [95% confidence interval (CI) 15.8-33.2 months]. Investigator-assessed ORR increased from 55% (95% CI 45% to 64%) at 13.4 months to 65% (95% CI 55% to 73%) at 50.9 months with a disease control rate of 81% (95% CI 72% to 87%). The complete response rate increased from 3% at 13.4 months to 13% at 50.9 months. Partial responses were observed in 52% of patients; 21% had stable disease, and 12% had progressive disease. Median time to response was 2.8 months (range 1.1-37.1 months), and median duration of response was not reached (range 1.4+ to 58.0+ months). At data cut-off, 37 (48%) patients had ongoing responses. Median progression-free survival was not reached [95% CI 38.4 months-not estimable (NE)], and median overall survival was not reached (95% CI NE). Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 13% of patients had any-grade TRAEs leading to discontinuation. CONCLUSIONS: The results confirm long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC. The safety profile was manageable with no new safety signals.

Neural feedback facilitates rough-to-fine information retrieval.

Categorical relationships between objects are encoded as overlapped neural representations in the brain, where the more similar the objects are, the larger the correlations between their evoked neuronal responses. These representation correlations, however, inevitably incur interference when memories are retrieved. Here, we propose that neural feedback, which is widely observed in the brain but whose function remains largely unknown, contributes to disentangle neural correlations to improve information retrieval. We study a hierarchical neural network storing the hierarchical categorical information of objects, and information retrieval goes from rough-to-fine, aided by the push-pull neural feedback. We elucidate that the push and the pull components of the feedback suppress the interferences due to the representation correlations between objects from different and the same categories, respectively. Our model reproduces the push-pull phenomenon observed in neural data and sheds light on our understanding of the role of feedback in neural information processing.

Outcome of acute ischaemic stroke patients after intravenous alteplase in Hospital Universiti Sains Malaysia.

INTRODUCTION: Intravenous (IV) thrombolysis with recombinant tissue plasminogen activator (rt-PA) is effective in treating acute ischaemic stroke. Our primary objective is to assess the outcome of these acute ischaemic stroke (AIS) patients after IV alteplase with the modified Rankin scale (mRS). METHODS: This is a cross-sectional study in which patients receiving IV alteplase in Hospital Universiti Sains Malaysia, from January 2017 to April 2020 were recruited. Demographical data, National Institutes of Health Stroke Scale (NIHSS) scores, door-to-needle time were recorded. Modified Rankin scale (mRS) scores were evaluated at 90 days after initial therapy. Good and poor functional outcomes were defined as 0-2 and 3-6, respectively. RESULTS: A total of 30 patients were included in the study with a mean age of 59±11.47 years old. 76.7% of them were male and the rest were female. From the study, onset-toneedle time was 197.47±51.74 minutes, whereas door-toneedle time was 120.93±53.63 minutes. Seventeen (56.3%) patients achieved a favourable score of 0-2 on the mRS at 90 days after treatment. Haemorrhagic transformation occurred in eight (26.7%) of the patients with a mortality rate of 13.3%. CONCLUSION: 56.7% of our patients showed improvement in the mRS at 90 days post thrombolysis for AIS. Higher baseline NIHSS scores and diabetes mellitus were associated with poorer functional outcomes after thrombolysis.

Unusual presentation of appendicitis as soft tissue infection of the thigh.

Appendicitis remains one of the most common causes of abdominal pain across the world typically presenting with right iliac fossa pain, fever and nausea or vomiting. We describe an unusual case of appendicitis presenting as a soft tissue infection of the thigh, thereby causing a delayed diagnosis from presentation. We discuss the pathophysiological process behind soft tissue infections caused by appendicitis and highlight investigation and management strategies to ensure prompt treatment to reduce patient mortality.

Associative memory model with arbitrary Hebbian length.

Conversion of temporal to spatial correlations in the cortex is one of the most intriguing functions in the brain. The learning at synapses triggering the correlation conversion can take place in a wide integration window, whose influence on the correlation conversion remains elusive. Here we propose a generalized associative memory model of pattern sequences, in which pattern separations within an arbitrary Hebbian length are learned. The model can be analytically solved, and predicts that a small Hebbian length can already significantly enhance the correlation conversion, i.e., the stimulus-induced attractor can be highly correlated with a significant number of patterns in the stored sequence, thereby facilitating state transitions in the neural representation space. Moreover, an anti-Hebbian component is able to reshape the energy landscape of memories, akin to the memory regulation function during sleep. Our work thus establishes the fundamental connection between associative memory, Hebbian length, and correlation conversion in the brain.

Eigenvalue spectrum of neural networks with arbitrary Hebbian length.

Associative memory is a fundamental function in the brain. Here, we generalize the standard associative memory model to include long-range Hebbian interactions at the learning stage, corresponding to a large synaptic integration window. In our model, the Hebbian length can be arbitrarily large. The spectral density of the coupling matrix is derived using the replica method, which is also shown to be consistent with the results obtained by applying the free probability method. The maximal eigenvalue is then obtained by an iterative equation, related to the paramagnetic to spin glass transition in the model. Altogether, this work establishes the connection between the associative memory with arbitrary Hebbian length and the asymptotic eigen-spectrum of the neural-coupling matrix.

Immediate unilateral breast reconstruction and contralateral breast augmentation with bilateral free deep inferior epigastric perforator flaps.

A 42-year-old woman was referred for consideration of left-sided mastectomy and immediate reconstruction. She previously had a bilateral breast augmentation using silicone implants. She desired to maintain her breast size and natural appearance. Owing to the availability of sufficient abdominal tissue, the option of an immediate unilateral breast reconstruction and contralateral augmentation with a differentially split deep inferior epigastric perforator flaps was offered to the patient. The patient had a successful reconstructive and contralateral symmetrising procedure with an uneventful postoperative recovery. She was satisfied with her breast size, which was achieved without the use of implants. In selected patients the free deep inferior epigastric perforator flap provides an appropriate option for unilateral breast reconstruction and contralateral breast augmentation. It has numerous advantages including making use of available excess abdominal tissue and avoiding implant related complications.

New Service Model for Common Mental Disorders in Hong Kong: a Retrospective Outcome Study.

OBJECTIVE: To review the first 8-month outcome of the Common Mental Disorder Clinic model in Hong Kong in terms of patient exit status and improvement in depressive and anxiety symptoms. METHODS: During the first appointment, patients were interviewed by a multidisciplinary team comprising a psychiatrist, a psychiatric nurse, and an occupational therapist. A multidisciplinary case conference was conducted to discuss clinical observations, diagnosis, issues of concern, and the optimal individualised treatment plan. Low-intensity interventions by nurses and/or occupational therapists were provided, as were optional, time-limited, protocol-based interventions by clinical psychologists for those with mild to moderate depressive and anxiety symptoms. Pharmacological intervention may be used when indicated. Upon completion of the treatment plan, patients were reassessed by the treating psychiatrist. Discharge options included discharge without psychiatric follow-up, step-up to psychiatric outpatient clinics, and step-down services. The self-administered Patient Health Questionnaire-9 (PHQ-9) and Generalised Anxiety Disorder 7-item scale (GAD-7) were used to assess the past 2 weeks' depressive and anxiety symptoms, respectively, at baseline and at each session. RESULTS: From July 2015 to February 2016, 1325 Chinese patients received the new service. Of them, 170 men and 363 women (mean age, 52.6 years) completed the treatment plan. After treatment, their mean PHQ-9 score decreased from 11.06 to 7.55 (p < 0.001), and the mean GAD-7 score decreased from 9.94 to 6.54 (p < 0.001). After treatment, 42.4% and 48.2% of the patients were within the normal range of PHQ-9 and GAD-7 scores, respectively, compared with 16.9% and 20.8% before treatment. The mean time to implementation of the individualised treatment plan was 82.33 days. Of the patients, 54.4% were discharged without any need for medical or psychiatric follow-up; 28% were stepped up to psychiatric outpatient clinics; and 17.3% were stepped down. The predictors of exit status were whether psychiatric medication was prescribed during initial intake (p = 0.011), whether psychiatric medication was prescribed at last follow-up (p < 0.001), the service period (p = 0.010), and the GAD-7 final score (p = 0.005). CONCLUSIONS: The first 8-month outcome of the new service model was encouraging, with shortened waiting time, reduced severity of symptoms, and better exit status (high recovery and step-down rates).

Stress hyperglycemia: A prospective study examining the relationship between glucose, cortisol and diabetes in myocardial infarction.

AIM: We aimed to explore the relationship between stress, hyperglycemia and diabetes in myocardial infarction (MI), using serum cortisol as a surrogate marker for the severity of stress. METHODS: Subjects with acute MI were prospectively recruited upon hospital admission. Serum glucose and cortisol were measured in addition to standard testing. Subjects were defined as having stress hyperglycemia (SH) if they had an admission glucose ≥7.8 mmol/L without a history of glucose intolerance. Subjects were followed up with glucose tolerance testing post-discharge. RESULTS: Of the 200 subjects in the study, 58 had known diabetes/impaired glucose tolerance (IGT), and 45 had SH. There was a positive association between admission glucose and cortisol for the entire cohort (rs = 0.26, p < 0.01). This relationship was present in the subgroup who had SH and then normal glucose post-discharge (rs = 0.53, p = 0.03), but not in SH subjects who had diabetes/IGT on post-discharge testing. It was also evident amongst all subjects with normal glucose (rs = 0.46, p < 0.01), but not those with diabetes/IGT in general. On multivariate analysis, admission glucose was a positive predictor and cortisol a negative predictor of abnormal glucose tolerance. CONCLUSIONS: Our data suggests that SH with MI reflects either underlying glucose intolerance or more severe stress in people without glucose intolerance.

Microvascular complications in orthokeratology (Ortho-K): A real-time study on the microvasculature of the bulbar conjunctiva in Ortho-K treatment.

Orthokeratology (Ortho-K) is an over-night hard contact lens therapy, which physically reshapes the corneal curvature in order to stabilize or temporally eliminate myopia in patients. We hypothesize that the prolonged physical contact and mechanical pressure induced by the Ortho-K lenses may create lasting inadvertent effects and damages (microangiopathy), and may bring about unwanted changes in the microvasculature of the bulbar conjunctiva. Computer-assisted intravital microscopy (CAIM) was used to view, document (via videotaping) and objectively quantify (via computer-assisted image analysis) the real-time dynamic and morphometric characteristics of the conjunctival microcirculation in long-term (at least over one year) Ortho-K patients (n = 11) and matched non-user control subjects (n = 8). Ortho-K patients were instructed to wear their lenses overnight following standard protocol. During the study, the conjunctival microcirculation of the left eye of all Ortho-K lens users was viewed, frequently re-focused and videotaped, without and with the lens in place, as outlined in Methods. The matched control subjects (non-lens wearing) were videotaped and studied in like manner. The dynamic and morphometric characteristics of each user and control subject were analyzed, quantified and summated as a severity index (SI) collectively for comparison. SI of Ortho-K lens users (4.18±1.08) differed significantly from SI of control subjects (1.75±1.39, p≤0.05). In addition, changes in the conjunctival microcirculation (e.g., flow velocity, vessel diameter, shape change, etc) were viewed and videotaped immediately after the myopic patients put on the Ortho-K lenses. Eight of the 11 Ortho-K lens users displayed significant percentage changes (p≤0.05) in flow velocity and 10 of 11 displayed significant percentage changes (p≤0.05) in vessel diameter, without and with the Ortho-K lenses. The results clearly indicated that significant microvascular changes via tissue remodeling occurred, and were caused directly by the physical presence of the Ortho-K lenses.

The first pilot study of expanded newborn screening for inborn errors of metabolism and survey of related knowledge and opinions of health care professionals in Hong Kong.

INTRODUCTION: Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners' report of a 14-year-old boy who died of an undiagnosed IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM. METHODS: The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling. RESULTS: In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years. CONCLUSION: The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.