Performance of the World Health Organisation suspected COVID-19 case definition in cluster-associated and sporadic SARS-CoV-2 transmission in Malaysia.

INTRODUCTION: Cluster-associated transmission has contributed to the majority of COVID-19 cases in Malaysia. Although widely used, the performance of the World Health Organization (WHO) case definition for suspected COVID19 in environments with high numbers of such cases has not been reported. MATERIALS AND METHODS: All suspected cases of COVID-19 that self-presented to hospitals or were cluster screened from 1st April to 31st May 2020 were included. Positive SARS-CoV-2 rRT-PCR was used as the diagnostic reference for COVID-19. RESULTS: 540 individuals with suspected COVID-19 were recruited. Two-third of patients were identified through contact screening, while the rest presented sporadically. Overall COVID-19 positivity rate was 59.4% (321/540) which was higher in the cluster screened group (85.6% vs. 11.6%, p<0.001). Overall, cluster-screened COVID-19 cases were significantly younger, had fewer comorbidities and were less likely to be symptomatic than those present sporadically. Mortality was significantly lower in the cluster-screened COVID-19 cases (0.3% vs. 4.5%, p<0.05). A third of all chest radiographs in confirmed COVID-19 cases were abnormal, with consolidation, ground-glass opacities or both predominating in the peripheral lower zones. The WHO suspected case definition for COVID-19 accurately classified 35.4% of all COVID-19 patients, a rate not improved by the addition of baseline radiographic data. Misclassification rate was higher among the cluster-associated cases (80.6%) compared to sporadic cases (35.3%). CONCLUSION: COVID-19 cases in Malaysia identified by active tracing of community cluster outbreaks had lower mortality rate. The WHO suspected COVID-19 performed poorly in this setting even when chest radiographic information was available, a finding that has implications for future spikes of the disease in countries with similar transmission characteristics.

Genome Sequences of Five Microbacterium foliorum Phages, GaeCeo, NeumannU, Eightball, Chivey, and Hiddenleaf.

Five siphoviruses were isolated from soil in southeastern Pennsylvania using Microbacterium foliorum. Bacteriophages NeumannU and Eightball have 25 predicted genes, Chivey and Hiddenleaf have 87 genes, and GaeCeo has 60 genes. Based on gene content similarity to sequenced actinobacteriophages, these five phages are distributed across clusters EA, EE, and EF.

Clinical and radiological outcomes of SARS-CoV-2 related organising pneumonia in COVID-19 survivors.

INTRODUCTION: COVID-19 patients frequently demonstrate radiological organising pneumonia (OP) pattern. The longterm outcome and treatment options for this group of patients remain uncertain. We aim to describe the clinical and radiological outcomes of patients with COVID-19-related OP and identify possible clinical factors associated with inferior radiological outcome. MATERIALS AND METHODS: Post-COVID-19 clinic attendees, consisting of post-COVID-19 patients discharged from major hospitals in the state of Selangor during the third pandemic wave of COVID-19 in Malaysia, were enrolled in this retrospective study for 6 months. Physician-scored Modified Medical Research Council (mMRC), patient self-reported quality of life (EQ-VAS) score and follow-up CT scan were evaluated. RESULTS: Our cohort comprised 131 patients, with a median age of 52 (IQR 39-60) years and median BMI of 29.40 (IQR 25.59-34.72). Majority (72.5%) had co-morbidities, and 97.7% had severe disease requiring supplementary oxygen support during the acute COVID-19 episode. 56.5% required intensive care; among which one-third were invasively ventilated. Median equivalent dose of methylprednisolone prescribed was 2.60 (IQR 1.29-5.18) mg/kg during admission, while the median prednisolone dose upon discharge was 0.64 (IQR 0.51-0.78) mg/kg. It was tapered over a median of 8.0 (IQR 5.8-9.0) weeks. Upon follow-up at 11 (IQR 8-15) weeks, one-third of patients remained symptomatic, with cough, fatigue and dyspnoea being the most reported symptoms. mMRC and EQ-VAS scores improved significantly (p<0.001) during follow-up. Repeat CT scans were done in 59.5% of patients, with 94.8% of them demonstrating improvement. In fact, 51.7% had complete radiological resolution. Intensive care admission and mechanical ventilation are among the factors which were associated with poorer radiological outcomes, p<0.05. CONCLUSION: Approximately one-third of patients with SARSCoV- 2-related OP remained symptomatic at 3 months of follow-up. Majority demonstrated favourable radiological outcomes at 5-month reassessment, except those who required intensive care unit admission and mechanical ventilation.

Pembrolizumab monotherapy versus chemotherapy in platinum-pretreated, recurrent or metastatic nasopharyngeal cancer (KEYNOTE-122): an open-label, randomized, phase III trial.

BACKGROUND: Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, programmed death ligand 1 (PD-L1)-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented. PATIENTS AND METHODS: KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1 : 1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary endpoint was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population. RESULTS: Between 5 May 2016 and 28 May 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cut-off (30 November 2020) was 45.1 months (interquartile range, 39.0-48.8 months). Median OS was 17.2 months [95% confidence interval (CI) 11.7-22.9 months] with pembrolizumab and 15.3 months (95% CI 10.9-18.1 months) with chemotherapy [hazard ratio, 0.90 (95% CI 0.67-1.19; P = 0.2262)]. Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage). CONCLUSION: Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events.

Methylprednisolone in severe COVID-19 with acute respiratory distress syndrome - less is more?

INTRODUCTION: Corticosteroids, particularly methylprednisolone, are part of the treatment for severe COVID-19 with acute respiratory distress syndrome (ARDS). In this study, we aimed to compare the mortalities of patients treated with higher versus lower doses of methylprednisolone. Secondary outcomes included oxygenation, need for mechanical ventilation, length of stay in intensive care unit (ICU), secondary infection, improvement of PaO2/FiO2 (PF) ratio, and inflammatory response as expressed by C-reactive protein (CRP). MATERIALS AND METHODS: A retrospective cohort study conducted at Sarawak General Hospital from 1st June to 30th September 2021. Patients who received intravenous methylprednisolone for severe COVID-19 in the ICU were identified and divided into two groups: higher dose (cumulative dose more than 10 mg per kg) and lower dose (cumulative dose less than 10 mg per kg). RESULTS: Out of a total of 165 patients, 40 (24.2%) patients received higher dose methylprednisolone. There was no significant difference in socio-demographic characteristics (age, gender, body mass index), COVID-19 vaccination status, laboratory parameters (lymphocyte count, CRP, lactate dehydrogenase, D-dimer), or usage of immunomodulator therapy between the groups. Overall mortality was 23.6%. Mortality in the higher dose group was twice as high compared to lower dose group (37.5% versus 19.2%) (OR 3.79, 95% CI 1.24-11.59, p<0.05). In addition, the higher dose cohort developed more secondary infections (87.5%) and had longer stays in ICU (median 11 days, IQR 8- 15). No significant difference was found between both cohorts in terms of CRP reduction, improvement of PF ratio, or the need for mechanical ventilation post methylprednisolone. CONCLUSION: In this study, the use of higher dose methylprednisolone in COVID-19 with ARDS was not associated with better clinical outcomes. A lower dose of methylprednisolone might be sufficient in treating severe COVID-19 with ARDS.

Diagnostic yield of medical thoracoscopy in exudative pleural effusions in a region with high tuberculosis burden.

INTRODUCTION: Pleural effusion is frequently encountered in respiratory medicine. However, despite thorough assessment including closed pleural biopsy, the cause of around 20% of pleural effusions remains undetermined. Medical thoracoscopy (MT) is the investigation of choice in these circumstances especially if malignancy is suspected. The aim of this study is to evaluate the diagnostic yield of MT in exudative pleural effusions in a single center from East Malaysia. METHODS: Retrospective chart review of all adult patients who underwent MT for undiagnosed exudative pleural effusion in a 24-month duration. RESULTS: Our cohort comprised of 209 patients with a median age of 61 years old (IQR 48.5-69.5). There were 92 (44%) patients with malignant pleural effusion (MPE) and 117 (56%) benign effusions; which included 85 tuberculous pleural effusion (TBE) and 32 cases of non-tuberculous exudative pleural effusion. Conclusive pathological diagnosis was made in 79.4% of the cases. For diagnosis of MPE, MT had a sensitivity of 89.1% (95% CI 80.4-94.3), specificity of 100% (95% CI 96.0-100.0), and positive predictive value (PPV) of 100% (95% CI 94.4-100) and negative predictive value (NPV) of 92.1% (95% CI 85.6-95.9). For TBE, MT had a sensitivity of 90.5% (95% CI 81.8-95.6), specificity of 100% (95% CI 96.3- 100.0) PPV of 100% (95% CI 94.1-100) and NPV of 93.9% (95% CI 88.0-97.2). Overall complication rate was 3.3%. CONCLUSIONS: MT showed excellent sensitivity and specificity in the diagnosis of exudative pleural effusion in this region. It reduces empirical therapy by providing histological evidence of disease when initial non-invasive investigations were inconclusive.

Radial probe endobronchial ultrasound (R-EBUS) guided transbronchial cryobiopsy in the diagnosis of peripheral solitary pulmonary nodule.

Solitary pulmonary nodule (SPN) always raises suspicion for early lung cancer, in which accurate and less invasive biopsy is needed. We report a case of transbronchial cryobiopsy of right upper lobe SPN under radial endobronchial ultrasound (R-EBUS) guidance after an inconclusive computed tomography guided transthoracic needle aspiration. A diagnosis of Stage 1B adenocarcinoma of the lung was made. Patient subsequently underwent curative right upper lobectomy after ruling out mediastinal lymph node involvement. To the best of our knowledge, this is the first report of R-EBUS guided transbronchial cryobiopsy case reported from Malaysia.

The great masquerade: Empyema thoracis as an unusual presentation of primary lung malignancy.

Primary lung malignancy presenting as empyema is rare, with a reported incidence of 0.3%. We report a case of a 60- year-old man presenting with unilateral pleural effusion; diagnostic thoracocentesis confirmed Salmonella empyema. Post-drainage, chest radiograph showed persisting right hemithorax opacity; subsequent computed tomography revealed a right lung mass with right upper lobe bronchus obliteration. Percutaneous biopsy confirmed advanced stage lung adenocarcinoma. We discuss the mechanism of post-obstructive pneumonia in lung cancerassociated empyema and the utility of bedside ultrasound in diagnosis of lung masses. Clinicians are alerted to the possibility of lung malignancy in elderly patients presenting with empyema.

Drainage of multiloculated tuberculous pleural effusion by medical thoracoscopy: When and why should it be considered?

Tuberculous pleural effusion (TBE) is a common encounter in our region. Up to 50% of patients with TBE will develop residual pleural thickening (RPT) which can lead to functional impairment. However, the need of drainage remains controversial. We report a case of end-stage renal failure patient who presented with right multiloculated tuberculous pleural effusion which was drained via a medical thoracoscope. Patient reports immediate relief of breathlessness post procedure and one month follow up shown significant improvement of RPT. We also discussed the current perspective on the rationale of TBE drainage and the role of medical thoracoscope in TBE management.

Colon carcinoma with endobronchial metastasis masquerading as bronchial asthma causing ball valve effect.

Malignant central airway obstruction (CAO) with ball valve effect (BVE) in the lung is rare. We discuss a case of metastatic colon cancer who presented with asthma like symptoms which thoracic computed tomography and bronchoscopy revealed an intraluminal tumour obstructing the left main bronchus in a ball valve manner. Airway patency was restored urgently with immediate alleviation of symptoms. This illustrates the importance of recognizing subtle features of central airway obstruction to allow expedition of appropriate investigations and therapy.

Predictors of incomplete response to therapy among Filipino patients with papillary thyroid cancer in a tertiary hospital.

BACKGROUND: Although survival rate in papillary thyroid cancer (PTC) is high, the risk of persistence and recurrence together with the dramatic rise in its incidence cannot be overemphasized. Filipinos are considered to be at greater risk for negative outcomes. A paradigm shift in the management of PTC introduces re-stratification based on response to therapy which was reported to have better correlation with long-term outcome. The study aimed to identify predictors of incomplete response after thyroidectomy and radioiodine therapy among patients with PTC. The results of the study may have important implications in our understanding of the disease process allowing more aggressive treatment and monitoring of certain subgroups of patients. METHODOLOGY: Retrospective review of 225 patients with PTC (59% ATA low risk, 30 % ATA intermediate risk and 11% ATA high risk) who underwent thyroidectomy and radioiodine therapy was performed. Thirteen variables were considered (age, gender, histopathological variant, stage, extent of disease, MACIS score, AMES score, primary tumour size, lymph node, lymphovascular invasion, bilaterality, multifocality and preoperative TSH level). Logistic regression analysis using Backward Wald algorithm was used to identify independent predictors of incomplete response to therapy after 24 months. RESULTS: Of the 225 patients, 69 (31%) had incomplete response. Biochemical and structural (predominantly thyroid bed, lung and bone) incomplete response was observed in 6 and 63 patients, respectively. Incomplete response was documented in 8, 54 and 92% of low-, intermediate- and high-risk patients based on ATA recommendation. Incomplete response was significantly dependent on gender, lymph node involvement and location, extent of malignancy and multifocality taking into account the size of concurrent tumours (p < 0.05). The model was found to have high sensitivity (71%) and specificity (96%). CONCLUSION: A significant fraction of PTC patients experienced incomplete response to therapy. Our data suggest that male gender, lateral or mediastinal lymph node involvement, class III extent of disease by De Groot and multifocality with concurrent tumour or tumours more than 1 cm are major predictors of incomplete response. Not all predictors of recurrence and mortality are consistent predictors of treatment response which may be equally important in a disease with low mortality but significant morbidity like PTC.

Specific and straightforward molecular investigation of ß-thalassemia mutations in the Malaysian Malays and Chinese using direct TaqMan genotyping assays.

Beta-thalassemia is a life-threatening inherited blood disorder. Rapid characterization of ß-globin gene mutations is necessary because of the high frequency of Malaysian ß-thalassemia carriers. A combination real-time polymerase chain reaction genotyping assay using TaqMan probes was developed to confirm ß-globin gene mutations. In this study, primers and probes were designed to specifically identify 8 common ß-thalassemia mutations in the Malaysian Malay and Chinese ethnic groups using the Primer Express software. "Blind tests" using DNA samples from healthy individuals and ß-thalassemia patients with different genotypes were performed to determine the specificity and sensitivity of this newly designed assay. Our results showed 100% sensitivity and specificity for this novel assay. In conclusion, the TaqMan genotyping assay is a straightforward assay that allows detection of ß-globin gene mutations in less than 40 min. The simplicity and reproducibility of the TaqMan genotyping assay permit its use in laboratories as a rapid and cost-effective diagnostic tool for confirmation of common ß-thalassemia mutations in Malaysia.

Early engraftment kinetics of two units cord blood transplantation.

Cord blood transplantation (CBT) is a promising alternative means of allogeneic stem cell transplantation. However, limited cell doses may compromise outcome. To enhance engraftment, CBT has been conducted using two units with promising results. However, little is known about the mechanism of engraftment. Here, we analyzed the early engraftment kinetics of eight patients given two unit umbilical CBT. Early engraftment kinetics revealed dominancy of one of two units from the day of engraftment (absolute neutrophil count > 0.5 x 10(9)/l). The median value of percentage of the predominant unit by chimerism analysis at the time of engraftment was 88% (60-100%). Two units CBT was found to be a safe, effective and promising alternative treatment option with good engraftment potential. Dominancy occurred early after CBT and is probably influenced by multiple factors.

MiniCog: a method for administering psychological tests and experiments on a handheld personal digital assistant.

Because of their minimal cost, size, and weight, handheld personal digital assistants (PDAs) are appealing as a means for administering response time tasks "in the field" or to participants in longitudinal studies who need repeated access to the testing equipment. We have developed a software package that allows investigators to author simple scripts on their desktop computers and administer the compiled tasks on PDAs. MiniCog presents instructions, practice trials with auditory feedback, and visual stimuli in random or fixed sequential orders with fixed or variable durations and intertrial intervals and records single-button responses and response times. Data from each trial are stored with a user ID, user-entered demographics and notes, and a time-and-date stamp, for later upload to a desktop computer. MiniCog performs automatic calculations of mean response time and error rate, available to users with a password and stored with the other data for upload.

Arterial balloon occlusion of the hypogastric arteries: a life-saving procedure for severe obstetric hemorrhage.

In this case report we describe two patients with life-threatening postpartum hemorrhage who were treated successfully with arterial balloon occlusion of the hypogastric arteries. Arterial balloon occlusion is easy to perform and is applicable under difficult circumstances. The technique should be available in all hospitals that provide obstetric services. Obstetricians should know about it so they can ask their radiologic colleagues to perform the procedure.

Cochlear microinjection and its effects upon auditory function in the guinea pig.

Microinjection through the round window membrane has been found to represent a method for vector delivery in intracochlear gene transfer in animal models but breaches the round window membrane, making it necessary to evaluate animals for possible postinjection hearing loss. In the present study healthy guinea pigs were evaluated for their baseline click auditory brainstem response (ABR) thresholds. Each animal was then injected with saline via the round window membrane. After 1 week auditory function was evaluated by click ABR. Animals with increased ABR thresholds were retested at 4 weeks. Animals with 1-week postoperative ABRs similar to baseline were not retested. Results showed that postoperative ABR thresholds in five animals (71%) remained unchanged from baseline, while two animals had increases of 20-25 dB in ABRs after 1 week but recovered baseline ABRs after 4 weeks. The mean baseline ABR threshold was 25.7 dB and was 27.9 dB after 1 week after injection. The difference between preoperative and 1-week postoperative averages was not significant (P = 0.707). In this preliminary study saline microinjection through the round window membrane did not cause permanent hearing loss in the guinea pigs tested, and any damage caused by microinjection appeared to be reversible.

Safety of adeno-associated virus as cochlear gene transfer vector: analysis of distant spread beyond injected cochleae.

The adeno-associated virus (AAV), inoculated into the perilymph, has been shown to be an effective vector for mediating intracochlear transgene expression. The unexpected finding of transgene expression in the contralateral cochlea in previous work raised concern about dissemination of the virus from the target tissue. The current study was undertaken to assess the extent of AAV dissemination following its introduction into the inner ear. Adult male guinea pigs were injected with recombinant AAV into their left ears and sacrificed at 2 or 4 weeks. Various organs including the cochleae were harvested to characterize the presence and expression of the viral DNA. Virus DNA was detected via polymerase chain reaction in the infused and contralateral cochlea and in the cerebellum but not in any other organs, including cortex, heart, lung, liver, spleen, and kidney. Although the viral presence was established in the cerebellum, transgene expression in this organ was undetectable with either Western blot or immunohistochemistry. Transgene expression was demonstrated via immunohistochemistry in multinucleated giant cells in the bone marrow spaces adjacent to the infused and contralateral cochleae. Collectively, these results suggest potential routes for AAV dissemination from the infused cochlea via the cochlear aqueduct or by extension through the temporal bone marrow spaces. This study reinforces the need to investigate factors that mitigate viral leakage.

Localization of integral membrane peptidylglycine alpha-amidating monooxygenase in neuroendocrine cells.

Peptidylglycine alpha-amidating monooxygenase (PAM) catalyzes the amidation of glycine-extended peptides in neuroendocrine cells. At steady state, membrane PAM is accumulated in a perinuclear compartment. We examined the distribution of membrane PAM in stably transfected AtT-20 cells and compared its localization to markers for the trans-Golgi network (TGN), endosomes, and lysosomes. At the light microscopic level, the distribution of membrane PAM does not overlap extensively with lysosomal markers but does overlap with TGN38 and with SCAMP, a component of post-Golgi membranes involved in recycling pathways. By immunoelectron microscopy, membrane PAM is present in tubulovesicular structures which constitute the TGN; some of these PAM-containing tubulovesicular structures are more distal to the Golgi stacks and do not contain TGN38. While some POMC-derived peptides are present in tubulovesicular structures like those that contain membrane PAM, the majority of the POMC-derived peptides are present in secretory granules. There is little overlap between the steady state distribution of membrane PAM and internalized FITC-transferrin in the early endosomes. Few of the perinuclear PAM-containing structures are labeled with HRP or WGA-HRP even following long incubations. Therefore, membrane PAM is localized to perinuclear tubulovesicular structures which are partially devoid of TGN38 and are not all endosomal in origin.

A phase II study of weekly high-dose cisplatin combined with oral etoposide in advanced non-small-cell lung cancer.

As a dose-response relationship has been suggested for cisplatin, it appeared attractive to explore high-dose-intensity regimens in non-small-cell lung cancer. In a phase I study of weekly administration of cisplatin combined with oral etoposide we achieved a cisplatin dose intensity of 52.5-60 mg/m2 per week in most patients. We subsequently explored this regimen in advanced non-small-cell lung cancer. Patients were treated with cisplatin infused at 70 mg/m2 on days 1, 8, 15 and 29, 36, 43 in combination with oral etoposide given at 50 mg on days 1-15 and 29-43. Patients showing stable disease or a better response were continued on treatment with oral etoposide given at 50 mg/m2 per day on days 1-21 every 28 days for a maximum of four cycles. In all, 22 patients with stage III disease and 31 patients with stage IV disease entered the study. The median number of cisplatin administration was 6 per patient; 17 patients reached the planned cisplatin dose intensity of 60 mg/m2 per week, 11 patients achieved 52.5 mg/m2 per week, and 7 patients reached 47 mg/m2 per week. Overall, 11 of 21 stage III patients had a partial response [response rate 51%, 95% confidence interval (CI) 36-81%], as did 9 of 28 patients with stage IV disease (32%; 95% CI 15-49%). Toxicity was mainly hematologic, with leukocytopenia being the most frequent cause of treatment delay. Nephrotoxicity of grade 1 was observed in seven patients. Two patients developed clinical hearing loss. With this schedule a high median cisplatin dose intensity of 52.5-60 mg/m2 per week was reached. The 51% response rate achieved in stage III disease makes this schedule attractive for further exploration; however, it is not recommended for routine use in stage IV disease.