WHO Global Situational Alert System: a mixed methods multistage approach to identify country-level COVID-19 alerts.

BACKGROUND: Globally, since 1 January 2020 and as of 24 January 2023, there have been over 664 million cases of COVID-19 and over 6.7 million deaths reported to WHO. WHO developed an evidence-based alert system, assessing public health risk on a weekly basis in 237 countries, territories and areas from May 2021 to June 2022. This aimed to facilitate the early identification of situations where healthcare capacity may become overstretched. METHODS: The process involved a three-stage mixed methods approach. In the first stage, future deaths were predicted from the time series of reported cases and deaths to produce an initial alert level. In the second stage, this alert level was adjusted by incorporating a range of contextual indicators and accounting for the quality of information available using a Bayes classifier. In the third stage, countries with an alert level of 'High' or above were added to an operational watchlist and assistance was deployed as needed. RESULTS: Since June 2021, the system has supported the release of more than US$27 million from WHO emergency funding, over 450 000 rapid antigen diagnostic testing kits and over 6000 oxygen concentrators. Retrospective evaluation indicated that the first two stages were needed to maximise sensitivity, where 44% (IQR 29%-67%) of weekly watchlist alerts would not have been identified using only reported cases and deaths. The alerts were timely and valid in most cases; however, this could only be assessed on a non-representative sample of countries with hospitalisation data available. CONCLUSIONS: The system provided a standardised approach to monitor the pandemic at the country level by incorporating all available data on epidemiological analytics and contextual assessments. While this system was developed for COVID-19, a similar system could be used for future outbreaks and emergencies, with necessary adjustments to parameters and indicators.

A tissue-bioengineering strategy for modeling rare human kidney diseases in vivo.

The lack of animal models for some human diseases precludes our understanding of disease mechanisms and our ability to test prospective therapies in vivo. Generation of kidney organoids from Tuberous Sclerosis Complex (TSC) patient-derived-hiPSCs allows us to recapitulate a rare kidney tumor called angiomyolipoma (AML). Organoids derived from TSC2-/- hiPSCs but not from isogenic TSC2+/- or TSC2+/+ hiPSCs share a common transcriptional signature and a myomelanocytic cell phenotype with kidney AMLs, and develop epithelial cysts, replicating two major TSC-associated kidney lesions driven by genetic mechanisms that cannot be consistently recapitulated with transgenic mice. Transplantation of multiple TSC2-/- renal organoids into the kidneys of immunodeficient rats allows us to model AML in vivo for the study of tumor mechanisms, and to test the efficacy of rapamycin-loaded nanoparticles as an approach to rapidly ablate AMLs. Collectively, our experimental approaches represent an innovative and scalable tissue-bioengineering strategy for modeling rare kidney disease in vivo.

Immunological responses and evaluation of the protection in dairy cows vaccinated with staphylococcal surface proteins.

Bovine mastitis is a significant cause of economic losses in the dairy industry. Staphylococcus aureus is one of the most common contagious mastitis pathogens, whereas Staphylococcus chromogenes increasingly became a significant cause of subclinical mastitis in dairy cows. Current mastitis control measures are not effective on all mastitis pathogens. There is no effective vaccine to control Staphylococcal mastitis in dairy cows. The objective of this study was to evaluate the immune responses and protection in dairy cows vaccinated with S. aureus surface proteins (SASP) or S. chromogenes surface proteins (SCSP). We divided eighteen Holstein dairy cows randomly into three groups of 6 animals each. We vaccinated group 1 and 2 animals with SASP and SCSP with Emulsigen-D adjuvant, respectively. We injected control (group 3) animals with PBS (pH 7.2) in Emulsigen®-D. We vaccinated animals three times at 28 and 14 days before drying off, and at dry off. Two weeks after the third vaccination, we challenged each animal by dipping all teats in S. aureus culture suspension once daily for 14 consecutive days. We evaluated milk or mammary secretion and serum antibody titers during vaccination and challenge periods. We evaluated milk samples for the number of bacteria shedding and somatic cell counts (SCC). Out of six cows vaccinated with SASP, one cow was removed from the study due to injury, two were infected clinically, another two were infected subclinically, and the remaining cow was not infected. No SCSP vaccinated cows developed clinical or subclinical mastitis. Out of six control cows, two developed clinical mastitis whereas four were infected subclinically. The SCSP vaccine cross-protected against S. aureus mastitis and reduced number of S. aureus shedding in milk. We concluded that the SCSP is a promising vaccine to control Staphylococcal mastitis in dairy cows.

Voriconazole associated mucormycosis in a patient with relapsed acute lymphoblastic leukemia and hematopoietic stem cell transplant failure: A case report.

The patients with hematologic malignancies and hematopoietic stem cell transplantation (HSCT) recipients are at high risk for invasive fungal diseases (IFDs) mainly due to the severe and prolonged neutropenia related to high-dose chemotherapy. Voriconazole prophylaxis is recommended for possible IFDs. Mucormycosis is a fulminant infection, which may occur after voriconazole prophylaxis for invasive aspergillosis in immunocompromised hosts. Here, we report mucormycosis after 4 months of voriconazole prophylaxis in a young patient with relapsed acute lymphoblastic leukemia and hematopoietic stem cell transplant failure and discuss the clinical manifestation, imaging, laboratory findings and therapeutic regimens. Clinician's awareness of this entity and timely diagnosis using conventional and molecular methods are the promising approach for the management of this devastating infection.

Bovine intramammary infection associated immunogenic surface proteins of Streptococcus uberis.

In spite of the increasing prevalence of Streptococcus uberis mastitis, its pathogenesis and associated virulence factors are not clearly defined. The aim of this study was to identify virulence associated genes and their products that can be used to develop effective vaccine to control bovine S. uberis mastitis. S. uberis was co-cultured with primary bovine mammary epithelial cells (PBMEC) or infused into mammary gland of dairy cows. The messenger RNA (mRNA) from S. uberis associated with PBMEC after 2 h or 4 h of co-culture was purified and sequenced. Results showed that virulence-associated genes such as surface lipoprotein (slp), infection induced histidine kinase (iihK), infection induced response regulator (iirR) and extracellular sugar binding protein 1 and 2 (exsbP1 and exsbP2) were among the top-up-regulated genes. To verify this observation in vivo, quantitative real time PCR (qRT - PCR) was conducted on mRNA of S. uberis recovered from milk of infected mammary glands 24 h post infection. Results revealed that in vitro up-regulated virulence-associated genes were also significantly up regulated under in vivo conditions. The iihK and iirR are flanked by exsbP1 and exsbP2 genes and this entire operon seems to be involved in adaptation to glands micro-environment, survival and colonization of the bovine mammary glands. Based on immunogenic epitope prediction of proteins encoded by these up-regulated genes during early stages of host-bacterial interactions slp, exsbP1 and exsbP2 genes were selected, cloned and expressed in E. coli. The purified recombinant proteins (rSlP, rExsbP1 & rExsbP2) reacted strongly with convalescent serum from cows experimentally infected with S. uberis confirming that they are immunogenic. These proteins may serve as potential targets to develop an effective vaccine against S. uberis mastitis.

Novel Application of Localized Nanodelivery of Anti-Interleukin-6 Protects Organ Transplant From Ischemia-Reperfusion Injuries.

Ischemia-reperfusion injury (IRI) evokes intragraft inflammatory responses, which markedly augment alloimmune responses against the graft. Understanding the mechanisms underlying these responses is fundamental to develop therapeutic regimens to prevent/ameliorate organ IRI. Here, we demonstrate that IRI results in a marked increase in mitochondrial damage and autophagy in dendritic cells (DCs). While autophagy is a survival mechanism for ischemic DCs, it also augments their production of interleukin (IL)-6. Allograft-derived dendritic cells (ADDCs) lacking autophagy-related gene 5 (Atg5) showed higher death rates posttransplantation. Transplanted ischemic hearts from CD11cCre/Atg5 conditional knockout mice showed marked reduction in intragraft expression of IL-6 compared with controls. To antagonize the effect of IL-6 locally in the heart, we synthesized novel anti-IL-6 nanoparticles with capacity for controlled release of anti-IL-6 over time. Compared with systemic delivery of anti-IL-6, localized delivery of anti-IL-6 significantly reduced chronic rejection with a markedly lower amount administered. Despite improved allograft histology, there were no changes to splenic T cell populations, illustrating the importance of local IL-6 in driving chronic rejection after IRI. These data carry potential clinical significance by identifying an innovative, targeted strategy to manipulate organs before transplantation to diminish inflammation, leading to improved long-term outcomes.

Small ruminant pasteurellosis in Tigray region, Ethiopia: marked serotype diversity may affect vaccine efficacy.

The aim of this study was to investigate the prevalent Bibersteinia, Mannheimia and Pasteurella serotypes, risk factors and degree of serotype co-infections in sheep and goats in the Tigray region of Ethiopia. Serum was collected from 384 sheep and goats from the Tanqua-Abergelle district of Tigray region using cross-sectional random sampling. An indirect haemagglutination test was used for serotyping. Risk factors for infections were evaluated by logistic regression. Potential clustering of multiple serotypes within individual animals due to common risk factors was evaluated by redundancy analysis. Eight serotypes were identified: all studied animals were serologically positive for at least one serotype. Overall, 355 (92·45%) of the animals were infected by four or more serotypes. Of the five risk factors studied, peasant association (PA), animal species, age (serotype A1), and bodyweight (serotype T15) were significantly associated with infection, but sex was not significant. Only PA explained a significant proportion of the variation (adjusted R 2 = 0·16) in the serological responses. After the effect of PA was accounted for, T3 and T4; A7 and Pasteurella multocida A; and A7 and T10 were positively correlated for co-infection, while T4 and T10 were less likely to be found within the same animal. Diverse serotypes were circulating in the Tigray region and could be a challenge in selecting serotypes for vaccine.

Testing the Efficacy of Contrast-Enhanced Ultrasound in Detecting Transplant Rejection Using a Murine Model of Heart Transplantation.

One of the key unmet needs to improve long-term outcomes of heart transplantation is to develop accurate, noninvasive, and practical diagnostic tools to detect transplant rejection. Early intragraft inflammation and endothelial cell injuries occur prior to advanced transplant rejection. We developed a novel diagnostic imaging platform to detect early declines in microvascular perfusion (MP) of cardiac transplants using contrast-enhanced ultrasonography (CEUS). The efficacy of CEUS in detecting transplant rejection was tested in a murine model of heart transplants, a standard preclinical model of solid organ transplant. As compared to the syngeneic groups, a progressive decline in MP was demonstrated in the allografts undergoing acute transplant rejection (40%, 64%, and 92% on days 4, 6, and 8 posttransplantation, respectively) and chronic rejection (33%, 33%, and 92% on days 5, 14, and 30 posttransplantation, respectively). Our perfusion studies showed restoration of MP following antirejection therapy, highlighting its potential to help monitor efficacy of antirejection therapy. Our data suggest that early endothelial cell injury and platelet aggregation contributed to the early MP decline observed in the allografts. High-resolution MP mapping may allow for noninvasive detection of heart transplant rejection. The data presented have the potential to help in the development of next-generation imaging approaches to diagnose transplant rejection.

Local-Reference Patient Dose Evaluation in Conventional Radiography Examinations in Mazandaran, Iran.

BACKGROUND: The most efficient application of ionizing radiation is serving medical purposes and using this radiation has caused people to learn that artificial sources of radiation exposure among these resources can be of highest exposure rate. OBIECTIVE: The present study is aimed at initially establishing a baseline for local-reference dose level in Mazandaran, Iran in 12 projections of the most conventional x-ray examination. METHODS: In this study, 13 public hospitals in Mazandaran province were selected for review and required data collected for ten adult patients with mean weight of 70±10kg in each projection. Then, information of each center was separately analyzed. Next, in order to measure x-ray output tube, the dosimeter RTI model Barracuda calibrated has been applied for measuring air karma within energy rage of 40-150kvp. ESAK and ESD parameters, usually used for monitoring DRL in conventional radiography, were calculated. RESULTS: Mean ESDs in this study has been obtained to 1.47±0.98 for skull (PA/AP), 1.01±0.79 for skull (LAT), 0.67±0.38 for cervical spine (AP), 0.79±0.37 for cervical (LAT), 0.49±0.38 for chest (PA/AP), 1.06±0.44 for chest (LAT), 2.15±0.73 for thoracic spine (AP), 3±0.87 for thoracic spine (LAT), 2.81 ±0.82 for lumbar spine (AP), 4.28±0.78 for lumbar (LAT), 2.07±1.17 for abdomen and 1.90±0.99 for pelvis, respectively. The ESDs calculated for chest examination in both projections, PA and LAT are more than values recommended by the UK (2000), Brazil and Slovenia. CONCLUSION: The present study has determined wide variations in radiation dose of x-ray examinations among hospitals in Mazandaran, Iran. In order to reduce skin dose, an optimization procedure should be considered. Application of a reference dose (DRL) could be a practical method for this purpose. The role of optimization of radiography parameters for reducing patient dose is a significant issue. Through optimizing parameters, it would be possible to preserve image quality while reduction of patient dose.

Post-bone marrow transplant thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) is a systemic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ failure. Post-bone marrow transplant TMA (post-BMT TMA) is a life-threatening condition that has been reported to afflict between 0.5 and 63.6% of BMT patients. The incidence of post-BMT TMA is affected by evolving therapies such as conditioning regimens. The etiology of post-BMT TMA is thought to be multifactorial, including the effects of immunosuppressive agents, viral infections, TBI and GvHD. A growing body of evidence highlights the importance of complement system activation and endothelial damage in post-BMT TMA. Although plasmapheresis has commonly been used, its therapeutic rationale for the majority of post-BMT TMA cases is unclear in the absence of circulatory inhibitors. It has become possible to target complement activation with eculizumab, a drug that blocks the terminal complement pathway. Early studies have highlighted the importance of anti-complement therapies in treating post-BMT TMA. Moreover, finding complement gene mutations may identify patients at risk, but whether such patients benefit from prophylactic anti-complement therapies before BMT remains to be studied. This review focuses on diagnostic criteria, pathophysiology, treatment and renal outcomes of post-BMT TMA.

Dose Assessment in Computed Tomography Examination and Establishment of Local Diagnostic Reference Levels in Mazandaran, Iran.

BACKGROUND: Medical X-rays are the largest man-made source of public exposure to ionizing radiation. While the benefits of Computed Tomography (CT) are well known in accurate diagnosis, those benefits are not risk-free. CT is a device with higher patient dose in comparison with other conventional radiation procedures. OBJECTIVE: This study is aimed at evaluating radiation dose to patients from Computed Tomography (CT) examination in Mazandaran hospitals and defining diagnostic reference level (DRL). METHODS: Patient-related data on CT protocol for four common CT examinations including brain, sinus, chest and abdomen & pelvic were collected. In each center, Computed Tomography Dose Index (CTDI) measurements were performed using pencil ionization chamber and CT dosimetry phantom according to AAPM report No. 96 for those techniques. Then, Weighted Computed Tomography Dose Index (CTDIW), Volume Computed Tomography Dose Index (CTDI vol) and Dose Length Product (DLP) were calculated. RESULTS: The CTDIw for brain, sinus, chest and abdomen & pelvic ranged (15.6-73), (3.8-25. 8), (4.5-16.3) and (7-16.3), respectively. Values of DLP had a range of (197.4-981), (41.8-184), (131-342.3) and (283.6-486) for brain, sinus, chest and abdomen & pelvic, respectively. The 3rd quartile of CTDIW, derived from dose distribution for each examination is the proposed quantity for DRL. The DRLs of brain, sinus, chest and abdomen & pelvic are measured 59.5, 17, 7.8 and 11 mGy, respectively. CONCLUSION: Results of this study demonstrated large scales of dose for the same examination among different centers. For all examinations, our values were lower than international reference doses.

Emerging therapies targeting intra-organ inflammation in transplantation.

Over the past several years, the field of transplantation has witnessed significant progress on several fronts; in particular, achievements have been made in devising novel immunosuppressive strategies. An under-explored area that may hold great potential to improve transplantation outcomes is the design of novel strategies to apply specifically to organs to reduce intra-graft inflammation. A growing body of evidence indicates a key role of intra-graft inflammatory cascade in potently instigating the alloimmune response. Indeed, controlling the activation of innate immunity/inflammatory responses has been shown to be a promising strategy to increase the graft acceptance and survival. In this minireview, we provide an overview of emerging targeted strategies, which can be directly applied to grafts to down-regulate intra-graft inflammation prior to transplantation.

Serine protease inhibitor-6 differentially affects the survival of effector and memory alloreactive CD8-T cells.

The clonal expansion of effector T cells and subsequent generation of memory T cells are critical in determining the outcome of transplantation. While cytotoxic T lymphocytes induce direct cytolysis of target cells through secretion of Granzyme-B (GrB), they also express cytoplasmic serine protease inhibitor-6 (Spi6) to protect themselves from GrB that has leaked from granules. Here, we studied the role of GrB/Spi6 axis in determining clonal expansion of alloreactive CD8-T cells and subsequent generation of memory CD8-T cells in transplantation. CD8-T cells from Spi6(-/-) mice underwent more GrB mediated apoptosis upon alloantigen stimulation in vitro and in vivo following adoptive transfer into an allogeneic host. Interestingly, while OT1.Spi6(-/-) CD8 T cells showed significantly lower clonal expansion following skin transplants from OVA mice, there was no difference in the size of the effector memory CD8-T cells long after transplantation. Furthermore, lack of Spi6 resulted in a decrease of short-lived-effector-CD8-cells but did not impact the pool of memory-precursor-effector-CD8-cells. Similar results were found in heart transplant models. Our findings suggest that the final alloreactive CD8-memory-pool-size is independent from the initial clonal-proliferation as memory precursors express low levels of GrB and therefore are independent of Spi6 for survival. These data advance our understanding of memory T cells generation in transplantation and provide basis for Spi6 based strategies to target effector T cells.

An investigation of duration of untreated psychosis and the affecting factors.

One of the main goals in treatment planning of psychiatric disorders is early diagnosis of patients in the early psychosis period so that duration of untreated psychosis (DUP) is decreased and the treatment response and outcome is improved. The aim of this study was to investigate the DUP of psychosis and factors affecting it. In this cross-sectional study, 80 patients from the psychiatric clinic of Fatemi hospital in Ardabil and Razi hospital in Tabriz who were in the first episode of psychosis completed a questionnaire. The data were analysed by SPSS statistical software. In this study, the mean DUP measured from the appearance of the first symptoms of psychosis were 261.3 ± 110.8 and 212.5 ± 143.5 days for patients referring to Razi and Fatemi hospital, respectively. About 65% of the patients in Fatemi hospital and 32.5% of them in Razi hospital considered visiting a psychiatrist as hard and very hard. The DUP mean here was found to be higher as compared with that of the developed countries. The following factors were found to be playing a role in making DUP longer: lower education, implausible beliefs and culturally rooted social stigma status of visiting a psychiatrist.

Genomic studies of GVHD-lessons learned thus far.

GVHD remains the most significant complication of hematopoietic SCT, despite advances in HLA matching and the identification of risk various factors. To account for the variation in the incidence and severity of this disease, many genetic association studies have been performed in order to explore the role of immunoregulatory gene polymorphisms. These genes include those that encode cytokines, chemokines, and costimulatory molecules. Polymorphisms in other classes of genes such as those involved in drug metabolism, protein folding, and DNA replication have also been studied. In this review, we address the current knowledge of the role of genetic polymorphisms in GVHD. We also discuss the potential pitfalls inherent in genetic association testing and alternative strategies to address these problems.

The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival.

Apolipoprotein L-1 (APOL1) gene variants are associated with end-stage renal disease in African Americans (AAs). Here we investigate the impact of recipient APOL1 gene distributions on kidney allograft outcomes. We conducted a retrospective analysis of 119 AA kidney transplant recipients, and found that 58 (48.7%) carried two APOL1 kidney disease risk variants. Contrary to the association seen in native kidney disease, there is no difference in allograft survival at 5-year posttransplant for recipients with high-risk APOL1 genotypes. Thus, we were able to conclude that APOL1 genotypes do not increase risk of allograft loss after kidney transplantations, and carrying 2 APOL1 risk alleles should not be an impediment to transplantation.

Brain hemodynamics in patients with end-stage renal disease between hemodialysis sessions.

INTRODUCTION: End-stage renal disease has been associated with premature atherosclerosis of the cerebral circulation. The risk of stroke, a frequent complication of uremia as a result of cerebral blood flow reduction, is high in dialysis patients. This study aimed to assess brain hemodynamics between hemodialysis interval periods by transcranial Doppler ultrasonography. MATERIALS AND METHODS: In a case-control study, to evaluate cerebral circulation homodynamics, 20 hemodialysis patients and 20 age- gender-matched healthy control subjects underwent transcranial Doppler ultrasonography. Blood parameters were also measured simultaneously. Among hemodialysis patients, these studies were performed 48 hours after a dialysis session. RESULTS: The mean blood flow velocity (MV) values were significantly higher in the middle cerebral artery (P = .007), anterior cerebral artery (P = .003), posterior cerebral artery-segment 2 (P = .03), basilar artery (P = .05) in hemodialysis patients compared to the controls. The MV had a negative meaningful correlation with hemoglobin and hematocrit in most intracranial arteries of the patients, but no significant correlation was observed between these variables and MV of the arteries in the control group. CONCLUSIONS: The MV of the cerebral arteries significantly increases in hemodialysis patients, which could be due to the decrease in hemoglobin levels in these patients.

Human peripheral blood CD4 T cell-engrafted non-obese diabetic-scid IL2rγ(null) H2-Ab1 (tm1Gru) Tg (human leucocyte antigen D-related 4) mice: a mouse model of human allogeneic graft-versus-host disease.

Graft-versus-host disease (GVHD) is a life-threatening complication of human allogeneic haematopoietic stem cell transplantation. Non-obese diabetic (NOD)-scid IL2rγ(null) (NSG) mice injected with human peripheral blood mononuclear cells (PBMC) engraft at high levels and develop a robust xenogeneic (xeno)-GVHD, which reproduces many aspects of the clinical disease. Here we show that enriched and purified human CD4 T cells engraft readily in NSG mice and mediate xeno-GVHD, although with slower kinetics compared to injection of whole PBMC. Moreover, purified human CD4 T cells engraft but do not induce a GVHD in NSG mice that lack murine MHC class II (NSG-H2-Ab1(tm1Gru), NSG-Ab°), demonstrating the importance of murine major histocompatibility complex (MHC) class II in the CD4-mediated xeno-response. Injection of purified human CD4 T cells from a DR4-negative donor into a newly developed NSG mouse strain that expresses human leucocyte antigen D-related 4 (HLA-DR4) but not murine class II (NSG-Ab° DR4) induces an allogeneic GVHD characterized by weight loss, fur loss, infiltration of human cells in skin, lung and liver and a high level of mortality. The ability of human CD4 T cells to mediate an allo-GVHD in NSG-Ab° DR4 mice suggests that this model will be useful to investigate acute allo-GVHD pathogenesis and to evaluate human specific therapies.