Contributions of GeneXpert® to TB diagnosis in Myanmar.

BACKGROUND: Xpert® MTB/RIF, a rapid, molecular TB diagnostic assay, can detect Mycobacterium tuberculosis and rifampin resistance directly from clinical sputum samples in <2 h with high sensitivity and specificity. The added diagnostic value of Xpert over smear microscopy at a national level in Myanmar has not been previously reported.METHODS: We evaluated 339,358 Xpert and demographic records captured from January 2015 to December 2018 as part of the Myanmar National TB Program Data Utilization and Connectivity Project to examine the additional diagnostic yield of Xpert relative to smear for the detection of M. tuberculosis for TB diagnosis in Myanmar, with a focus on people living with HIV (PLHIV) and sample type.RESULTS: Use of Xpert increased TB case detection by 40% compared to smear microscopy results. Among PLHIV, use of Xpert increased TB case detection by almost 100% compared to smear microscopy results.CONCLUSION: Xpert testing identified more patients with TB than smear microscopy alone, particularly in cohorts with significant proportions of PLHIV. The use of Xpert as a screening tool in countries with a high burden of TB could lead to significantly increased diagnosis of TB at a regional and national level.

Anti-CRISPR prediction using deep learning reveals an inhibitor of Cas13b nucleases.

As part of the ongoing bacterial-phage arms race, CRISPR-Cas systems in bacteria clear invading phages whereas anti-CRISPR proteins (Acrs) in phages inhibit CRISPR defenses. Known Acrs have proven extremely diverse, complicating their identification. Here, we report a deep learning algorithm for Acr identification that revealed an Acr against type VI-B CRISPR-Cas systems. The algorithm predicted numerous putative Acrs spanning almost all CRISPR-Cas types and subtypes, including over 7,000 putative type IV and VI Acrs not predicted by other algorithms. By performing a cell-free screen for Acr hits against type VI-B systems, we identified a potent inhibitor of Cas13b nucleases we named AcrVIB1. AcrVIB1 blocks Cas13b-mediated defense against a targeted plasmid and lytic phage, and its inhibitory function principally occurs upstream of ribonucleoprotein complex formation. Overall, our work helps expand the known Acr universe, aiding our understanding of the bacteria-phage arms race and the use of Acrs to control CRISPR technologies.

Mapping Local Failure Following Bladder Radiotherapy According to Dose.

AIMS: To determine the relationship between local relapse following radical radiotherapy for muscle-invasive bladder cancer (MIBC) and radiation dose. MATERIALS AND METHODS: Patients with T2-4N0-3M0 MIBC were recruited to a phase II study assessing the feasibility of intensity-modulated radiotherapy to the bladder and pelvic lymph nodes. Patients were planned to receive 64 Gy/32 fractions to the bladder tumour, 60 Gy/32 fractions to the involved pelvic nodes and 52 Gy/32 fractions to the uninvolved bladder and pelvic nodes. Pre-treatment set-up was informed by cone-beam CT. For patients who experienced local relapse, cystoscopy and imaging (CT/MRI) was used to reconstruct the relapse gross tumour volume (GTVrelapse) on the original planning CT . GTVrelapse D98% and D95% was determined by co-registering the relapse image to the planning CT utilising deformable image registration (DIR) and rigid image registration (RIR). Failure was classified into five types based on spatial and dosimetric criteria as follows: A (central high-dose failure), B (peripheral high-dose failure), C (central elective dose failure), D (peripheral elective dose failure) and E (extraneous dose failure). RESULTS: Between June 2009 and November 2012, 38 patients were recruited. Following treatment, 18/38 (47%) patients experienced local relapse within the bladder. The median time to local relapse was 9.0 months (95% confidence interval 6.3-11.7). Seventeen of 18 patients were evaluable based on the availability of cross-sectional relapse imaging. A significant difference between DIR and RIR methods was seen. With the DIR approach, the median GTVrelapse D98% and D95% was 97% and 98% of prescribed dose, respectively. Eleven of 17 (65%) patients experienced type A failure and 6/17 (35%) patients type B failure. No patients had type C, D or E failure. MIBC failure occurred in 10/17 (59%) relapsed patients; of those, 7/11 (64%) had type A failure and 3/6 (50%) had type B failure. Non-MIBC failure occurred in 7/17 (41%) patients; 4/11 (36%) with type A failure and 3/6 (50%) with type B failure. CONCLUSION: Relapse following radiotherapy occurred within close proximity to the original bladder tumour volume and within the planned high-dose region, suggesting possible biological causes for failure. We advise caution when considering margin reduction for future reduced high-dose radiation volume or partial bladder radiotherapy protocols.

COVID-19 outbreak in Greece has passed its rising inflection point and stepping into its peak

Since the beginning of 2020, COVID-19 is the most urgent and challenging task for the international scientific community, in order to identify its behaviour, track its progress and plan effective mitigation policies. In this study, Greece is the main focus for assessing the national outbreak and estimating the general trends and outlook of it. Multiple data analytics procedures, spectral decomposition and curve-fitting formulations are developed based on the data available at hand. Standard SIEQRDP epidemic modelling is applied for Greece and for the general region around it, providing hints for the outbreak progression in the mid- and long-term, for various infections under-reporting rates. The overall short-term outlook for Greece seems to be towards positive, with a downward trend in infections rate daily increase (i.e., now beyond the exponential growth rate), a possible peak within a few days beyond April 14th, as well as the high availability level of ICU w.r.t. expected demand at peak. On the negative side, the fade-out period seems to be in the order of several months, with high probability of recurrent surges of the outbreak. The mitigation policies for the next day should be focused on close tracking of the epidemic via large-scale tests, strict border checking in international travelling and an adaptive plan for selective activation of mitigation measures when deemed necessary. Significance StatementThis study focuses on the COVID-19 outbreak in Greece and provides data-driven epidemic modelling and experimental results regarding the current state. Based on these results, the overall short-term outlook for Greece seems to be towards positive, having recently passed the rising inflection point and approaching the peak of the infections, and most probably capable of covering the projected ICU demand peak by a large margin. On the downside, the fade-out period seems to be in the order of several months, with high probability of recurrent surges of the outbreak. The next day mitigation policies need to be carefully planned, highly adaptive and based on close tracking of the outbreak via large-scale testing in the general population.

The Intensity-Modulated Pelvic Node and Bladder Radiotherapy (IMPART) Trial: A Phase II Single-Centre Prospective Study.

AIMS: Node-positive bladder cancer (NPBC) carries a poor prognosis and has traditionally been treated palliatively. However, surgical series suggest that a subset of NPBC patients can achieve long-term control after cystectomy and lymph node dissection. There is little published data regarding the use of radiotherapy to treat NPBC patients. This is in part due to concerns regarding the toxicity of whole-pelvis radiotherapy using conventional techniques. We hypothesised that, using intensity-modulated radiotherapy (IMRT), the pelvic nodes and bladder could be treated within a radical treatment volume with acceptable toxicity profiles. MATERIALS AND METHODS: The Intensity-modulated Pelvic Node and Bladder Radiotherapy (IMPART) trial was a phase II single-centre prospective study designed to assess the feasibility of delivering IMRT to treat the bladder and pelvic nodes in patients with node-positive or high-risk node-negative bladder cancer (NNBC). The primary end point was meeting predetermined dose constraints. Secondary end points included acute and late toxicity, pelvic relapse-free survival and overall survival. RESULTS: In total, 38 patients were recruited and treated between June 2009 and November 2012; 22/38 (58%) had NPBC; 31/38 (81.6%) received neoadjuvant chemotherapy; 18/38 (47%) received concurrent chemotherapy; 37/38 (97%) patients had radiotherapy planned as per protocol. Grade 3 gastrointestinal and genitourinary acute toxicity rates were 5.4 and 20.6%, respectively. At 1 year, the grade 3 late toxicity rate was 5%; 1-, 2- and 5-year pelvic relapse-free survival rates were 55, 37 and 26%, respectively. The median overall survival was 1.9 years (95% confidence interval 1.1-3.8) with 1-, 2- and 5-year overall survival rates of 68, 50 and 34%, respectively. CONCLUSION: Delivering IMRT to the bladder and pelvic nodes in NPBC and high-risk NNBC is feasible, with low toxicity and low pelvic nodal recurrence rates. Long-term control seems to be achievable in a subset of patients. However, relapse patterns suggest that strategies targeting both local recurrence and the development of distant metastases are required to improve patient outcomes.

What the public think about participation in medical research during an influenza pandemic: an international cross-sectional survey.

OBJECTIVES: The public and patients are primary contributors and beneficiaries of pandemic-relevant clinical research. However, their views on research participation during a pandemic have not been systematically studied. We aimed to understand public views regarding participation in clinical research during a hypothetical influenza pandemic. STUDY DESIGN: This is an international cross-sectional survey. METHODS: We surveyed the views of nationally representative samples of people in Belgium, Poland, Spain, Ireland, the United Kingdom, Canada, Australia and New Zealand, using a scenario-based instrument during the 2017 regional influenza season. Descriptive and regression analyses were conducted. RESULTS: Of the 6804 respondents, 5572 (81.8%) thought pandemic-relevant research was important, and 5089 (74.8%) thought 'special rules' should be applied to make this research feasible. The respondents indicated willingness to take part in lower risk (4715, 69.3%) and higher risk (3585, 52.7%) primary care and lower risk (4780, 70.3%) and higher risk (4113, 60.4%) intensive care unit (ICU) study scenarios. For primary care studies, most (3972, 58.4%) participants preferred standard enrolment procedures such as prospective written informed consent, but 2327 (34.2%) thought simplified procedures would be acceptable. For ICU studies, 2800 (41.2%) preferred deferred consent, and 2623 (38.6%) preferred prospective third-party consent. Greater knowledge about pandemics, trust in a health professional, trust in the government, therapeutic misconception and having had ICU experience as a patient or carer predicted increased willingness to participate in pandemic-relevant research. CONCLUSIONS: Our study indicates current public support for pandemic-relevant clinical research. Tailored information and initiatives to advance research literacy and maintain trust are required to support pandemic-relevant research participation and engagement.

Childhood abuse and psychotic experiences - evidence for mediation by adulthood adverse life events.

AIMS: We have previously reported an association between childhood abuse and psychotic experiences (PEs) in survey data from South East London. Childhood abuse is related to subsequent adulthood adversity, which could form one pathway to PEs. We aimed to investigate evidence of mediation of the association between childhood abuse and PEs by adverse life events. METHODS: Data were analysed from the South East London Community Health Study (SELCoH, n = 1698). Estimates of the total effects on PEs of any physical or sexual abuse while growing up were partitioned into direct (i.e. unmediated) and indirect (total and specific) effects, mediated via violent and non-violent life events. RESULTS: There was strong statistical evidence for direct (OR 1.58, 95% CI: 1.19-2.1) and indirect (OR 1.51, 95% CI: 1.32-1.72) effects of childhood abuse on PEs after adjustment for potential confounders, indicating partial mediation of this effect via violent and non-violent life events. An estimated 47% of the total effect of abuse on PEs was mediated via adulthood adverse life events, of which violent life events made up 33% and non-violent life events the remaining 14%. CONCLUSIONS: The association between childhood abuse and PEs is partly mediated through the experience of adverse life events in adulthood. There is some evidence that a larger proportion of this effect was mediated through violent life events than non-violent life events.

Management and Outcomes of HIV-Associated Primary Effusion Lymphoma: A Single Center Experience.

BACKGROUND: Primary effusion lymphoma (PEL) is a rare malignancy usually associated with HIV infection. Management and outcomes are poorly understood. METHODS: The medical records of all patients diagnosed with HIV-associated PEL at our institution between 1999 and 2014 were reviewed. Patients were followed till death, treatment failure or loss of follow-up. RESULTS: Twelve patients with PEL were identified during the 15 year study period; 9 had HIV infection. All 9 were male; median age was 45 years. All presented with local symptoms and were diagnosed with PEL a median of 11 years after HIV diagnosis. Location was pleural (3), pericardial (3), peritoneal (1) and extracavitatory (2). By definition, all had Ann Arbor stage 4 at diagnosis. Median follow-up was 34 months. Two patients had poor performance status and were unable to get chemotherapy. Seven patients had a complete remission (CR) and two died within 1 month of diagnosis. The median CD4 levels at PEL diagnosis in patients with poor versus good outcomes were 54 cells/mm3 (range, 26-82 cells/mm3) and 211 cells/mm3 (range, 73-800 cells/mm3). In contrast, the median lactate dehydrogenase (LDH) levels at PEL diagnosis with poor versus good prognosis were 1074 U/L (range, 703-1445 U/L) and 283 U/L (range, 156-760 U/L). CONCLUSIONS: Given its rarity, our knowledge of PEL relies solely on case reports and case series. Prompt HAART and chemotherapy may be effective in HIV- associated PEL and good outcomes are possible. LDH and CD4 may be possible prognostic factors in PEL.

Bilateral Facial Nerve Palsy in Acute B Cell Lymphoblastic Leukemia: A Case Report and Review of the Literature.

Acute lymphoblastic leukemia (ALL) is a haematological malignancy that can involve the central nervous system (CNS). Less than 10 % of patients with ALL have CNS involvement at presentation. The cranial nerve most commonly affected is cranial nerve VII although bilateral involvement is rare. Management and outcomes of these patients are not well understood. Moreover bilateral Bells palsy as a presenting symptom of ALL is extremely uncommon. We report a very unusual presentation of ALL with bilateral facial nerve palsy, and discuss the management strategies and outcomes for patients with ALL that present with cranial nerve palsies.

Hyaline-Vascular Type Castleman's Disease, Sarcoidosis, and Crohns Disease.

Sarcoidosis and Crohns disease have been associated with increased long term risk of lymphoproliferative disorders, including lymphomas. Newly developed lymphadenopathy in a patient with these disorders should prompt pathological evaluation. Castleman's disease is a lymphoproliferative disorder characterized by enlarged hyperplastic lymph nodes with regressed follicles surrounded by expanded mantle zones of small lymphocytes, and interfollicular vascular proliferation in the hyaline-vascular type. Similar to sarcoidosis and Crohns disease, its etiology is incompletely understood, although immune dysregulation, genetic factors and infectious and environmental factors are thought to play a role in all three diseases. Interleukin-6 is a possible pathological common factor between these three disease processed. Unicentric, hyaline-vascular type Castleman's disease can be treated successfully with complete surgical resection. We report a patient with long history of sarcoidosis and Crohns disease with newly developed lymphadenopathy which was found to be due to Castleman's disease.

Parasaccharibacter apium, gen. nov., sp. nov., Improves Honey Bee (Hymenoptera: Apidae) Resistance to Nosema.

The honey bee, Apis mellifera L., is host to a variety of microorganisms. The bacterial community that occupies the adult worker gut contains a core group of approximately seven taxa, while the hive environment contains its own distribution of bacteria that is in many ways distinct from the gut. Parasaccharibacter apium, gen. nov., sp. nov., is a hive bacterium found in food stores and in larvae, worker jelly, worker hypopharyngeal glands, and queens. Parasaccharibacter apium increases larval survival under laboratory conditions. To determine if this benefit is extended to colonies in the field, we tested if P. apium 1) survives and reproduces in supplemental pollen patty, 2) is distributed throughout the hive when added to pollen patty, 3) benefits colony health, and 4) increases the ability of bees to resist Nosema. Parasaccharibacter apium survived in supplemental diet and was readily consumed by bees. It was distributed throughout the hive under field conditions, moving from the pollen patty to hive larvae. While P. apium did not significantly increase colony brood production, food stores, or foraging rates, it did increase resistance to Nosema infection. Our data suggest that P. apium may positively impact honey bee health.

Anxiety and anxious-depression in Parkinson's disease over a 4-year period: a latent transition analysis.

BACKGROUND: Depression and anxiety in Parkinson's disease are common and frequently co-morbid, with significant impact on health outcome. Nevertheless, management is complex and often suboptimal. The existence of clinical subtypes would support stratified approaches in both research and treatment. METHOD: Five hundred and thirteen patients with Parkinson's disease were assessed annually for up to 4 years. Latent transition analysis (LTA) was used to identify classes that may conform to clinically meaningful subgroups, transitions between those classes over time, and baseline clinical and demographic features that predict common trajectories. RESULTS: In total, 64.1% of the sample remained in the study at year 4. LTA identified four classes, a 'Psychologically healthy' class (approximately 50%), and three classes associated with psychological distress: one with moderate anxiety alone (approximately 20%), and two with moderate levels of depression plus moderate or severe anxiety. Class membership tended to be stable across years, with only about 15% of individuals transitioning between the healthy class and one of the distress classes. Stable distress was predicted by higher baseline depression and psychiatric history and younger age of onset of Parkinson's disease. Those with younger age of onset were also more likely to become distressed over the course of the study. CONCLUSIONS: Psychopathology was characterized by relatively stable anxiety or anxious-depression over the 4-year period. Anxiety, with or without depression, appears to be the prominent psychopathological phenotype in Parkinson's disease suggesting a pressing need to understanding its mechanisms and improve management.