iBlock: An Intelligent Decentralised Blockchain-based Pandemic Detection and Assisting System.

The recent COVID-19 outbreak highlighted the requirement for a more sophisticated healthcare system and real-time data analytics in the pandemic mitigation process. Moreover, real-time data plays a crucial role in the detection and alerting process. Combining smart healthcare systems with accurate real-time information about medical service availability, vaccination, and how the pandemic is spreading can directly affect the quality of life and economy. The existing architecture models are become inadequate in handling the pandemic mitigation process using real-time data. The present models are server-centric and controlled by a single party, where the management of confidentiality, integrity, and availability (CIA) of data is doubtful. Therefore, a decentralised user-centric model is necessary, where the CIA of user data is assured. In this paper, we have suggested a decentralized blockchain-based pandemic detection and assistance system (iBlock). The iBlock uses robust technologies like hybrid computing and IPFS to support system functionality. A pseudo-anonymous personal identity is introduced using H-PCS and cryptography for anonymous data sharing. The distributed data management module guarantees data CIA, security, and privacy using cryptography mechanisms. Furthermore, it delivers useful intelligent information in the form of suggestions and alerts to assist the users. Finally, the iBlock reduces stress on healthcare infrastructure and workers by providing accurate predictions and early warnings using AI/ML.

HDAC1,2 inhibition and doxorubicin impair Mre11-dependent DNA repair and DISC to override BCR-ABL1-driven DSB repair in Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia.

Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL) expressing BCR-ABL1 oncoprotein is a major subclass of ALL with poor prognosis. BCR-ABL1-expressing leukemic cells are highly dependent on double-strand break (DSB) repair signals for their survival. Here we report that a first-in-class HDAC1,2 selective inhibitor and doxorubicin (a hyper-CVAD chemotherapy regimen component) impair DSB repair networks in Ph+ B-cell precursor ALL cells using common as well as distinct mechanisms. The HDAC1,2 inhibitor but not doxorubicin alters nucleosomal occupancy to impact chromatin structure, as revealed by MNase-Seq. Quantitative mass spectrometry of the chromatin proteome along with functional assays showed that the HDAC1,2 inhibitor and doxorubicin either alone or in combination impair the central hub of DNA repair, the Mre11-Rad51-DNA ligase 1 axis, involved in BCR-ABL1-specific DSB repair signaling in Ph+ B-cell precursor ALL cells. HDAC1,2 inhibitor and doxorubicin interfere with DISC (DNA damage-induced transcriptional silencing in cis)) or transcriptional silencing program in cis around DSB sites via chromatin remodeler-dependent and -independent mechanisms, respectively, to further impair DSB repair. HDAC1,2 inhibitor either alone or when combined with doxorubicin decreases leukemia burden in vivo in refractory Ph+ B-cell precursor ALL patient-derived xenograft mouse models. Overall, our novel mechanistic and preclinical studies together demonstrate that HDAC1,2 selective inhibition can overcome DSB repair 'addiction' and provide an effective therapeutic option for Ph+ B-cell precursor ALL.

Saccharomyces boulardii and bismuth subsalicylate as low-cost interventions to reduce the duration and severity of cholera.

We conducted a randomised single-blinded clinical trial of 100 cholera patients in Port-au-Prince, Haiti to determine if the probiotic Saccharomyces cerevisiae var. boulardii and the anti-diarrhoeal drug bismuth subsalicylate (BS) were able to reduce the duration and severity of cholera. Subjects received either: S. boulardii 250 mg, S. boulardii 250 mg capsule plus BS 524 mg tablet, BS 524 mg, or two placebo capsules every 6 hours alongside standard treatment for cholera. The length of hospitalisation plus the number and volume of emesis, stool and urine were recorded every 6 hours until the study subject was discharged (n = 83), left against medical advice (n = 11), or requested removal from the study (n = 6). There were no reported deaths or adverse study-related events. There were no statistically significant differences between the study arms and the outcomes of interest.

Role for the endometrial epithelial protein MFG-E8 and its receptor integrin αvß3 in human implantation: results of an in vitro trophoblast attachment study using established human cell lines.

OBJECTIVE: To investigate the role of MFG-E8 and its receptor integrin αvß3 in the attachment of trophoblast cells to the endometrial epithelium. DESIGN: Experimental in vitro study. SETTING: Academic center. PATIENT(S): None. INTERVENTION(S): By using a well-differentiated endometrial adenocarcinoma cell line (Ishikawa cells) and choriocarcinoma human trophoblast cells (Jar cells), an in vitro assay mimicking human implantation was established. To investigate the impact of blocking MFG-E8 and integrin αvß3, we pretreated the cell lines with antibodies against those proteins at different concentrations before the attachment assay. MAIN OUTCOME MEASURE(S): Attachment rate of Jar spheroids to the epithelial cell monolayer. RESULT(S): Pretreatment of Ishikawa cells with anti-MFG-E8 antibody caused a dose-dependent and significant inhibition of attachment. On the other hand, pretreatment of Jar spheroids did not result in a significant effect on the attachment rate. Pretreatment of Ishikawa cells as well as Jar spheroids with anti-integrin αvß3 antibodies resulted in a dose-dependent, significant inhibition of attachment. CONCLUSION(S): This study showed that blocking MFG-E8 and its receptor integrin αvß3 in Ishikawa cells diminishes Jar spheroid attachment. Moreover, blocking integrin αvß3 in the trophoblastic cells also diminished their attachment to the Ishikawa monolayer.

Ivermectin causes Cimex lectularius (bedbug) morbidity and mortality.

BACKGROUND: Bedbug infestations are increasing across North America and Europe, with more people presenting to Emergency Departments for treatment. Physicians cannot provide substantive treatment for people affected by bedbugs. STUDY OBJECTIVE: To determine if ivermectin, a relatively inexpensive and safe, long-acting oral anti-parasitic drug is able to cause bedbug morbidity and mortality. METHODS: We evaluated the effects of ivermectin on bedbugs using an artificial feeding membrane and mice and humans. Bedbug morbidity, mortality, and nymph molting was recorded. RESULTS: Using an artificial feeding membrane, bedbug mortality was 98% (n = 81) for 260 ng/mL ivermectin and 0% for 0 ng/mL ivermectin (control; n = 90) after 13 days. Mortality for bedbugs fed on mice injected with the human equivalent of 200 µg/kg ivermectin was 86% (n = 22), vs. 0% in the 0 µg/kg ivermectin (control; n = 21). Of the surviving nymphs, 0% exposed to ivermectin molted by day 75, vs. 80% in the control group by day 8. Bedbugs that fed once on human study subjects 3 h after consuming 200 µg/kg of oral ivermectin had a 63% (n = 24) 20-day mortality rate, vs. 8% (n = 24) in the control group. Of the surviving nymphs, 0% (n = 5) in the 3-h ivermectin group molted, vs. 80% (n = 10) of the control group. CONCLUSIONS: It may be possible that ivermectin could help eradicate, suppress, or prevent a bedbug infestation.

Sex steroids regulate epithelial-stromal cell cross talk and trophoblast attachment invasion in a three-dimensional human endometrial culture system.

Human embryo implantation involves a complex network of molecular signaling that is modulated by endocrine and paracrine pathways. Here, we performed studies using a unique and recently developed three-dimensional (3D) implantation model, characterized by an endometrium-like 3D culture system and Jar cell-derived spheroids mimicking the embryo/trophoblast. The aims were to investigate the effects of 17ß estradiol (E2) and medroxyprogesterone acetate (MPA) on (1) the interaction between epithelial and stromal cells, and (2) the attachment and invasion of trophoblast cells. We observed that epithelial and stromal cells in the 3D culture were ERα⁺, ERß⁺, and PR⁺. Decidualization was confirmed by enhanced prolactin gene expression on day 7 of E2 plus MPA treatment. An effect of epithelial cells on the decidualization of stromal cells was indicated by significantly higher levels of prolactin mRNA expression in the 3D culture compared to stromal cells grown within the fibrin-agarose gel matrix. On the other hand, the relative gene expressions of E-cadherin and IL-1ß in epithelial cells of the 3D culture under decidualization conditions significantly differed from those in epithelial cells grown over the fibrin-agarose gel matrix without stromal cells, pointing to regulation of epithelial cells by the stroma. The attachment rate of Jar spheroids to the 3D was significantly increased by E2 plus MPA treatment. Analyses of Z-stack confocal and stained optic microscopic images demonstrated that Jar spheroids breached the epithelial cell monolayer, invaded, and were embedded into the 3D matrix in response to decidualization signals. In summary, the newly bioengineered system provides a unique model for studying interactions between the different endometrial cell compartments, via soluble-paracrine signals as well as cell-to-cell interactions, and is a useful tool to study early embryonic implantation events.

Epithelial cell protein milk fat globule-epidermal growth factor 8 and human chorionic gonadotropin regulate stromal cell apoptosis in the human endometrium.

OBJECTIVE: To study the regulation of apoptosis in human endometrial cells. The specific aims were to determine whether milk fat globule-epidermal growth factor 8 (MFG-E8), a novel endometrial epithelial protein, modulates caspase activation and DNA fragmentation; and to examine whether hCG, an early embryonic product, regulates Bax and Bcl-2 equilibrium, as well as MFG-E8 expression. DESIGN: Primary cultures of human endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs). SETTING: Academic center. PATIENT(S): Ovulatory women aged 21-30 years. INTERVENTION(S): Treatment with MFG-E8 and hCG. MAIN OUTCOME MEASURE(S): Apoptotic activity was quantified using a luciferase assay. Deoxyribonucleic acid fragmentation was detected by TUNEL assay. Bax, Bcl-2, and MFG-E8 messenger RNA expression levels were determined by quantitative reverse transcription-polymerase chain reaction. Immunocytochemistry was used to establish cell purity and presence of MFG-E8 and hCG-R (receptor) proteins. RESULT(S): Endometrial epithelial cells were cytokeratin(+), vimentin(-), MFG-E8(+), and hCG-R(+), whereas ESC were vimentin(+), cytokeratin(-), MFG-E8(-), and hCG-R(+). Treatment of ESC with MFG-E8 resulted in a 13-fold increase in caspase activity and a 30-fold increase in TUNEL. On the other hand, hCG decreased messenger RNA expression of Bax in ESC. CONCLUSION(S): Milk fat globule-epidermal growth factor 8 has proapoptotic activity, suggesting participation in endometrial remodeling via an epithelial-stromal cell paracrine effect. Conversely, pregnancy levels of hCG has opposite effects on stromal cells.

Setting benchmarks and determining psychiatric workloads in community mental health programs.

Administrators and clinicians must find ways to effectively and efficiently use psychiatric resources without compromising the quality of care. The author outlines a model for setting benchmarks for allocating psychiatrists' time in a community mental health service setting. After the percentage of time for direct-care activities is agreed on (for example, 60 percent), the amounts of time necessary for three direct-care clinical activities-assessment of new patients, follow-up of stable patients, and follow-up of unstable patients and emergencies--are established. Time for documentation should be included in each task. At the end of six months, workloads are evaluated, and benchmarks are reset as appropriate.

A woman with recurrent acute confusion: a case of cycloid psychosis.

A woman 46 years old presented with recurrent, brief, sudden-onset episodes of confusion, aimless motor overactivity and lability of mood, from which she recovered completely. She was admitted on each occasion to a medical unit with a provisional diagnosis of organic mental disorder and thoroughly examined. No organic etiology was identified. This patient meets the criteria for cycloid psychosis. The implications for diagnosis, investigations and management are discussed.