Repurposing the FDA-approved anthelmintic pyrvinium pamoate for pancreatic cancer treatment: study protocol for a phase I clinical trial in early-stage pancreatic ductal adenocarcinoma.

BACKGROUND: Recent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical models. Here, we report about an ongoing phase I open-label, single-arm, dose escalation clinical trial to determine the safety and tolerability of PP in PDAC surgical candidates. METHODS AND ANALYSIS: In a 3+3 dose design, PP is initiated 3 days prior to surgery. The first three patients will be treated with the initial dose of PP at 5 mg/kg orally for 3 days prior to surgery. Dose doubling will be continued to a reach a maximum of 20 mg/kg orally for 3 days, if the previous two dosages (5 mg/kg and 10 mg/kg) were tolerated. Dose-limiting toxicity grade≥3 is used as the primary endpoint. The pharmacokinetic and pharmacodynamic (PK/PD) profile of PP and bioavailability in humans will be used as the secondary objective. Each participant will be monitored weekly for a total of 30 days from the final dose of PP for any side effects. The purpose of this clinical trial is to examine whether PP is safe and tolerable in patients with pancreatic cancer, as well as assess the drug's PK/PD profile in plasma and fatty tissue. Potential implications include the utilisation of PP in a synergistic manner with chemotherapeutics for the treatment of pancreatic cancer. ETHICS AND DISSEMINATION: This study was approved by the Thomas Jefferson Institutional Review Board. The protocol number for this study is 20F.041 (Version 3.1 as of 27 October 2021). The data collected and analysed from this study will be used to present at local and national conferences, as well as, written into peer-reviewed manuscript publications. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05055323.

Simultaneous cardio-cerebral infarction: a meta-analysis.

BACKGROUND/INTRODUCTION: Cardio-cerebral infarction (CCI), which involves the simultaneous occurrence of acute ischaemic stroke and acute myocardial infarction, has a reported incidence of 0.0009%. Treatment of CCI presents a dilemma to physicians as both conditions are time critical. Despite the need for standardized treatment protocols, published data are sparse. AIM: We aimed to summarize the reported cardio-cerebral infarction cases in the literature. DESIGN: Meta-analysis. METHODS: Four databases, Pubmed, Embase, Scopus and Google Scholar were searched until 25 August 2020. A title and abstract sieve, full-text review and extraction of data were conducted independently by three authors. RESULTS: A total of 44 cases of CCI were identified from 37 case reports and series; 15 patients (34.1%) were treated using percutaneous coronary intervention (PCI) with stent, 8 patients (18.2%) were treated with a PCI without stent, 10 patients (22.7%) were treated via a cerebral vessel thrombectomy and 8 patients (18.2%) were treated via a thrombectomy of a coronary vessel. For medications, 20 patients (45.5%) were treated with thrombolytics, 10 patients (22.7%) were treated with anticoagulants, 8 patients (18.2%) were treated with antiplatelets and 11 patients (25.0%) were treated with anticoagulants and antiplatelets. Of 44 patients, 10 patients died, and 9 of those were due to cardiac causes. Among the 44 patients, days to death was observed to be a median of 2.0 days (interquartile range (IQR): 1.5, 4.0). The modified Rankin Score was measured in nine patients, with a median score of 2.0 (IQR: 1.0, 2.5) being reported. DISCUSSION/CONCLUSION: The condition of CCI has substantial morbidity and mortality, and further studies are needed to examine the optimal diagnostic and treatment strategies of these patients.

Incinerator bottom ash derived from municipal solid waste as a potential catalytic support for biomass tar reforming.

Environment-friendly and sustainable routes for municipal solid waste (MSW) incineration bottom ash (IBA) recycling and utilization is one of the major concerns for the urbanized countries like Singapore. In this research paper, the possibility of bulk utilization of MSW-IBA as a catalyst support material has been explored for sustainable syn-gas production. The change in the texture of the IBA with simple hydrothermal treatment using NaOH has also been investigated. Furthermore, with hydrothermal treatment for 24 h at 180 °C, the texture of raw IBA with respect to basicity, surface area, total pore volume and reducibility was greatly improved. These textural properties are highly significant for a material to be utilized as a catalyst or catalytic supports for reforming applications. Ni supported on hydrothermally treated IBA was tested for steam reforming of biomass tar reforming reaction between 700 °C and 800 °C at relatively low steam-to-carbon ratio of 2. Among all the catalysts, Ni supported on IBA hydrothermally treated for 24 h gave stable toluene conversion (of 40%) at 700 °C with reduced coke formation (of 7.5 mgC/g·h) than other catalysts. The superior catalytic performance of this catalyst is mainly due to the presence of high amounts of surface Ni° species and improved reducibility and basicity properties among all. The Raman, DT/TGA and XRD analyses on spent catalysts revealed the deposited carbon during steam reforming of tar reaction is majorly amorphous. Due to this, the deposition of carbon did not show any kind of deactivation within the catalyst testing period.

Detection of LGI1 and CASPR2 antibodies with a commercial cell-based assay in patients with very high VGKC-complex antibody levels.

BACKGROUND: The presence of VGKC-complex antibodies, without LGI1/CASPR2 antibodies, as a standalone marker for neurological autoimmunity remains controversial. Additionally, the lack of an unequivocal VGKC-complex antibody cut-off level defining neurological autoimmunity makes it important to test for monospecific antibodies. We aim to determine the performance characteristics of a commercial assay (Euroimmun, Lübeck, Germany) for LGI1/CASPR2 antibody detection in patients with very high VGKC-complex antibody levels and report their clinico-serological associations. METHODS: We identified 8 patients in our cohort with the highest VGKC-complex antibody levels (median 2663.5pM, range 933-6730pM) with VGKC-complex antibody related syndromes (Group A). Two other groups were identified; 1 group with suspected neuronal surface antibody syndromes and negative for VGKC-complex antibodies (Group B, n=8), and another group with cerebellar ataxia and negative for onconeuronal antibodies (Group C, n=8). RESULTS: Seven out of 8 patients (87.5%) in Group A had LGI1 and/or CASPR2 antibodies. One Group B patient had LGI1 antibodies but was negative on re-testing with a live cell assay. No Group C patients had monospecific antibodies. Inter-rater reliability was high; combining Groups A and B patients, the kappa statistic was 0.87 and 1.0 for LGI1 and CASPR2 antibodies respectively. CONCLUSION: We demonstrated that a high proportion of patients with very high VGKC-complex antibody levels and relevant clinical syndromes have LGI1 and/or CASPR2 antibodies detected by the commercial assay. Our findings lend support to the use of the assay for rapid and reliable detection of LGI1 and CASPR2 antibodies.

Potential Use of Multiplex PCR in Diagnosis of Tuberculous Meningitis.

Accurate and rapid diagnosis of tuberculous meningitis (TBM) is important for early administration of treatment. In this study, we have evaluated the diagnostic value of smear, culture, multiplex PCR and GeneXpert MTB/RIF to detect M. tuberculosis in cerebrospinal fluid (CSF) samples from patients with suspected TBM registered in Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia. Of the 55 CSF samples collected, 12 (21.8%) samples were positive by multiplex PCR, 3 (5.4%) by GeneXpert MTB/RIF and only 1 (1.8%) by smear and culture. Multiplex PCR showed higher sensitivity to detect M. tuberculosis in patients with suspected TBM and has the potential to be used as a diagnostic method.

Primary spinal oligoastrocytoma mimicking longitudinally extensive transverse myelitis.

Longitudinally extensive transverse myelitis (LETM) is most commonly associated with neuromyelitis optica spectrum disorders (NMOSD). However, a wide range of etiologies may produce longitudinally extensive spinal cord lesions (LESCLs) on imaging. We highlight the case of a patient with a spinal cord tumor whose imaging showed LESCL and was diagnosed with LETM. He did not respond to immunosuppression and subsequently developed a progressive and protracted clinical course. Thoracic cord biopsy performed 6 years after symptom onset showed primary spinal oligoastrocytoma. We discuss the features that should raise suspicion of a neoplasm in the context of LESCL and serve a reminder that not all LESCLs are inflammatory.

Cerebellar strokes: a clinical outcome review of 79 cases.

INTRODUCTION: Cerebellar infarcts and haemorrhages are relatively uncommon, accounting for less than 10% of all strokes. The objective of the present study was to quantify and compare the outcomes of patients with cerebellar infarct and those of patients with cerebellar haemorrhage, as well as to identify the risk factors that predict poor outcome in patients with cerebellar stroke. METHODS: We retrospectively reviewed the medical records of consecutive patients admitted to National University Hospital, Singapore, between 2004 and 2006, within one week of cerebellar stroke onset. Baseline data included demographics, concomitant comorbidities, and the presence or absence of brainstem compression and hydrocephalus (on computed tomography or magnetic resonance imaging). The Glasgow Outcome Scale and modified Rankin Score were used to assess outcome at discharge and at six months after discharge. RESULTS: A total of 79 patients with cerebellar stroke were admitted during the study period. Of these 79 patients, 17.7% died and 31.6% had poor outcomes at six months after discharge. Patients with cerebellar haemorrhage were found to be more likely to have poor outcomes as compared to patients with cerebellar infarct, both at discharge (odds ratio [OR] 4.3, 95% confidence interval [CI] 1.3-14.1) and at six months after discharge (OR 5.2, 95% CI 1.6-17.2). When compared to small lesions (< 5 cm(3)), lesions > 20 cm(3) were significantly associated with poorer outcomes and the development of hydrocephalus and brainstem compression. CONCLUSION: Cerebellar strokes are a significant cause of morbidity and mortality. The outcomes of patients with cerebellar haemorrhage are more likely to be worse than those of patients with cerebellar infarct.

Factors that are associated with the risk of acquiring Plasmodium knowlesi malaria in Sabah, Malaysia: a case-control study protocol.

INTRODUCTION: Plasmodium knowlesi has long been present in Malaysia, and is now an emerging cause of zoonotic human malaria. Cases have been confirmed throughout South-East Asia where the ranges of its natural macaque hosts and Anopheles leucosphyrus group vectors overlap. The majority of cases are from Eastern Malaysia, with increasing total public health notifications despite a concurrent reduction in Plasmodium falciparum and P. vivax malaria. The public health implications are concerning given P. knowlesi has the highest risk of severe and fatal disease of all Plasmodium spp in Malaysia. Current patterns of risk and disease vary based on vector type and competence, with individual exposure risks related to forest and forest-edge activities still poorly defined. Clustering of cases has not yet been systematically evaluated despite reports of peri-domestic transmission and known vector competence for human-to-human transmission. METHODS AND ANALYSIS: A population-based case-control study will be conducted over a 2-year period at two adjacent districts in north-west Sabah, Malaysia. Confirmed malaria cases presenting to the district hospital sites meeting relevant inclusion criteria will be requested to enrol. Three community controls matched to the same village as the case will be selected randomly. Study procedures will include blood sampling and administration of household and individual questionnaires to evaluate potential exposure risks associated with acquisition of P. knowlesi malaria. Secondary outcomes will include differences in exposure variables between P. knowlesi and other Plasmodium spp, risk of severe P. knowlesi malaria, and evaluation of P. knowlesi case clustering. Primary analysis will be per protocol, with adjusted ORs for exposure risks between cases and controls calculated using conditional multiple logistic regression models. ETHICS: This study has been approved by the human research ethics committees of Malaysia, the Menzies School of Health Research, Australia, and the London School of Hygiene and Tropical Medicine, UK.

A study protocol for a randomised open-label clinical trial of artesunate-mefloquine versus chloroquine in patients with non-severe Plasmodium knowlesi malaria in Sabah, Malaysia (ACT KNOW trial).

INTRODUCTION: Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species. METHODS AND ANALYSIS: ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (α 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis. ETHICS AND DISSEMINATION: This study has been approved by relevant institutional ethics committees in Malaysia and Australia. Results will be disseminated to inform knowlesi malaria treatment policy in this region through peer-reviewed publications and academic presentations. TRIAL REGISTRATION NUMBER: NCT01708876.

Enhancing a search for traditional medicinal plants with anthelmintic action by using wild type and stress reporter Caenorhabditis elegans strains as screening tools.

Traditional healers in Sarawak, Malaysia, use plants such as Picria fel-terrae, Linariantha bicolor and Lansium domesticum to treat gastrointestinal infections. This study aimed to test whether their nematocidal activities could be confirmed in vitro using highly standardised Caenorhabditis elegans models. We applied eight different ethanol solubilised plant extracts and two commercial anthelmintic drugs to larval and adult stages of C. elegans in vitro. Seven C. elegans strains were evaluated, one wild type and six strains with GFP-tagged stress response pathways to help characterise and compare the pathways affected by plant extracts. Our in vitro screen confirmed that both of the commercial anthelmintic drugs and five of the eight traditionally used plant extracts had significant nematocidal activity against both larval and adult C. elegans. The most effective extracts were from P. fel-terrae. The plant extracts triggered different stress response pathways from the commercial anthelmintic drugs. This study showed that using traditional knowledge of plant medicinal properties in combination with a C. elegans in vitro screen provided a rapid and economical test with a high hit rate compared with the random screening of plants for nematocidal activities. The use of transgenic C. elegans strains may allow this approach to be refined further to investigate the mode of action of active extracts.

Intracranial pial arteriovenous fistula in infancy: a case report and literature review.

Intracranial pial arteriovenous fistulas (AVF) are rare vascular malformation especially in the first 2 years of life. The pathology in this age group is associated with greater morbidity and mortality. We report a rare case of 36-day-old male infant with a pial AVF associated with an arterial aneurysm, who presented with intraventricular hemorrhage and hydrocephalus. In addition, an online review of the literatures on pediatric pial AVF was performed using PubMed on published case reports and articles from 1980 to April 2013.

Management of ruptured intracranial aneurysms in the post-ISAT era: outcome of surgical clipping versus endovascular coiling in a Singapore tertiary institution.

INTRODUCTION: The results of the International Subarachnoid Aneurysm Trial (ISAT) in 2002 have significantly influenced the management of ruptured intracranial aneurysms. There is now an established shift worldwide toward endovascular coiling as the initial treatment of choice. We assessed the outcomes of patients admitted to our institution for aneurysmal subarachnoid haemorrhage (SAH), comparing the outcomes of patients (World Federation of Neurosurgical Societies [WFNS] grades 1-3) who underwent surgical clipping versus those who underwent endovascular coiling. METHODS: We retrospectively reviewed patients admitted to the National University Hospital for SAH secondary to ruptured intracranial aneurysm in 2005-2009. Patients were divided into two groups - clipping and coiling. Data on individual demographics, comorbidities, Fisher grading and Glasgow Outcome Scale scores were collected for the two groups and subjected to relevant statistical analyses. RESULTS: Of the 133 patients admitted for nontraumatic SAH, 89 had ruptured aneurysms. Among the 56 patients classified as WFNS grades 1-3, 23 underwent coiling while the remaining 33 underwent clipping. A significant association was found between Fisher grade and the likelihood of developing hydrocephalus in these patients. CONCLUSION: Although we acknowledge the presence of management bias in our institution, our findings were similar to those of the ISAT trial. Upon correlation between our results and current evidence-based findings, our findings show that clipping provides similar long-term outcomes as endovascular coiling. In the event that an aneurysm is deemed unsuitable for coiling, clipping remains an effective option.

Lethal intratumoral haemorrhages of brain metastases during radiosurgery: case reports and literature review.

Gamma Knife surgery (GKS) is an effective and important treatment modality in the management of brain metastases. The short-term complication rate is low and the tumour control rate high. Complications caused by acute radiation-induced oedema are rare and usually benign. In this article, two cases of lethal haemorrhagic event immediately following GKS are described from two centres, which had prompted us to review the literature.

Variations of atrioventricular block.

Atrioventricular (AV) block comprises a spectrum of cardiac conduction delays with varying clinical presentations. It is commonly encountered in both hospital as well as ambulatory settings, and recognition of the type of AV conduction delay is essential for appropriate subsequent management. The electrocardiogram is a key tool for identification of patients with AV conduction delays. Contrasting management strategies should be employed for differing levels of conduction block.

Ministry of Health clinical practice guidelines: Chronic Hepatitis B Infection.

The Ministry of Health (MOH) publishes clinical practice guidelines on Chronic Hepatitis B Infection to provide doctors and patients in Singapore with evidence-based guidance on managing important medical conditions. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on Chronic Hepatitis B Infection, for the information of readers of the Singapore Medical Journal. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website (http://www.moh.gov.sg/mohcorp/publications.aspx?id=26108). The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.