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Background Patients with coronavirus disease 2019 (COVID-19) who have underlying malignancy have a higher mortality rate compared with those without cancer, although the magnitude of such excess risk is not clearly defined. We performed a systematic review and pooled analysis to provide precise estimates of the mortality rate among patients with both cancer and COVID-19. Methods A systematic literature search involving peer-reviewed publications, preprints and conference proceedings up to July 16, 2020, was performed. The primary end-point was the case fatality rate (CFR), defined as the rate of death among patients with cancer and COVID-19. The CFR was assessed with a random effects model, which was used to derive a pooled CFR and its 95% confidence interval (CI). Results Fifty-two studies, involving a total of 18,650 patients with both COVID-19 and cancer, were selected for the pooled analysis. A total of 4243 deaths were recorded in this population. The probability of death was 25.6% (95% CI: 22.0%–29.5%; I2 = 48.9%) in this patient population. Conclusions Patients with cancer who develop COVID-19 have high probability of mortality. Appropriate and aggressive preventive measures must be taken to reduce the risk of COVID-19 in patients with cancer and to optimally manage those who do contract the infection., Highlights • Patients with both cancer and coronavirus disease 2019 (COVID-19) have a higher mortality than reported in the overall COVID-19-positive population. • We aim to provide precise mortality estimates among patients with cancer and COVID-19. • Pooled case mortality rate was 25.6% (95% CI: 22.0%–29.5%; I2 = 48.9%). • Aggressive measures must be taken to reduce risk of infection in patients with cancer.

Introduction: At the end of the second week of June 2020, the SARS-CoV-2 responsible for COVID-19 infected above 7.5 million people and killed over 400,000 worldwide. Estimation of case fatality rate (CFR) and determining the associated factors are critical for developing targeted interventions. Methodology: The state-level adjusted case fatality rate (aCFR) was estimated by dividing the cumulative number of deaths on a given day by the cumulative number confirmed cases 8 days before, which is the average time-lag between diagnosis and death. We conducted fractional regression analysis to determine the predictors of aCFR. Results: As of 13 June 2020, India reported 225 COVID-19 cases per million population (95% CI:224-226); 6.48 deaths per million population (95% CI:6.34-6.61) and an aCFR of 3.88% (95% CI:3.81-3.97) with wide variation between states. High proportion of urban population and population above 60 years were significantly associated with increased aCFR (p=0.08, p=0.05), whereas, high literacy rate and high proportion of women were associated with reduced aCFR (p

Objectives Linezolid is one of the last resort antibiotics effectively used in the treatment of infections caused by multidrug-resistant Gram-positive bacteria. Recent outbreaks of Linezolid resistance have been the great concern worldwide, while many countries have not experienced it. In this work, we aimed to evaluate the existence of linezolid resistance and further clarify potential resistance mechanism(s) in staphylococcal isolates obtained from the hospital in Vietnam, a country in which linezolid resistance had not been previously detected. Methods Seventy staphylococcal clinical isolates including MRSA (n = 63) and methicillin-resistant coagulase-negative staphylococci (MRCNS, n = 7) were collected and analyzed for linezolid resistance. Linezolid-resistant isolates were submitted for whole genome sequencing to search for the resistance determinants. Results We identified two coagulase-negative staphylococcal isolates that were resistant to linezolid. Whole genome sequencing revealed several alterations in the 23S rRNA and L3, L17, L22, L24, L30 ribosomal proteins. Importantly, both isolates harbour the chloramphenicol/florfenicol resistance (cfr) gene on a plasmid. The plasmid was closely identical to the pLRSA417 plasmid that was originally reported in China. Conclusions To the best of our knowledge, this is the first report of cfr-mediated linezolid resistance in clinically isolated staphylococci in Vietnam. We suggest that adequate surveillance is necessary to monitor the dissemination of linezolid resistance among staphylococcal species and other important pathogens. Sin financiación 4.035 JCR (2020) Q2, 34/93 Infectious Diseases 0.917 SJR (2020) Q2, 98/197 Immunology and Allergy No data IDR 2020 UEM

Since December 2019, when the first case of coronavirus disease (COVID-19) was identified in the city of Wuhan in the Hubei Province of China, the epidemic has generated tens of thousands of cases throughout China. As of February 28, 2020, the cumulative number of reported deaths in China was 2,858. We estimated the time-delay adjusted risk for death from COVID-19 in Wuhan, as well as for China excluding Wuhan, to assess the severity of the epidemic in the country. Our estimates of the risk for death in Wuhan reached values as high as 12% in the epicenter of the epidemic and ≈1% in other, more mildly affected areas. The elevated death risk estimates are probably associated with a breakdown of the healthcare system, indicating that enhanced public health interventions, including social distancing and movement restrictions, should be implemented to bring the COVID-19 epidemic under control.

Contains fulltext : 220912.pdf (Publisher’s version ) (Closed access) Nonculprit lesions are frequently observed in patients with ST-segment elevation myocardial infarction. Results from recent randomized clinical trials suggest that complete revascularization after ST-segment elevation myocardial infarction improves outcomes. In this state-of-the-art paper, the authors review these trials and consider how best to determine which nonculprit lesions require revascularization and when this should be performed.

The emergence of the Omicron variant (and its derivatives) was a tipping point from the 2020/2021 Covid-19 pandemic to a surprisingly early endemic situation. Contrary to what is sometimes discussed, a replacement of Sars-CoV-2 Omicron by another variant that produces more clinically problematic courses is only a theoretical possibility; in practice, it will not happen. Therefore, now is the time to tailor new vaccines not only against the Sars-CoV-2 virus, but also to protect entire populations against OC43, HKU1, 229E, and NL63, which have been known for a long time. These coronaviruses are, as of February 2022, a greater public health threat than the Sars-CoV-2 virus in its Omicron variant.

Alteration of antibiotic binding sites through modification of ribosomal RNA (rRNA) is a common form of resistance to ribosome-targeting antibiotics. The rRNA-modifying enzyme Cfr methylates an adenosine nucleotide within the peptidyl transferase center, resulting in the C-8 methylation of A2503 (m8A2503). Acquisition of cfr results in resistance to eight classes of ribosome-targeting antibiotics. Despite the prevalence of this resistance mechanism, it is poorly understood whether and how bacteria modulate Cfr methylation to adapt to antibiotic pressure. Moreover, direct evidence for how m8A2503 alters antibiotic binding sites within the ribosome is lacking. In this study, we performed directed evolution of Cfr under antibiotic selection to generate Cfr variants that confer increased resistance by enhancing methylation of A2503 in cells. Increased rRNA methylation is achieved by improved expression and stability of Cfr through transcriptional and post-transcriptional mechanisms, which may be exploited by pathogens under antibiotic stress as suggested by natural isolates. Using a variant that achieves near-stoichiometric methylation of rRNA, we determined a 2.2 Å cryo-electron microscopy structure of the Cfr-modified ribosome. Our structure reveals the molecular basis for broad resistance to antibiotics and will inform the design of new antibiotics that overcome resistance mediated by Cfr., eLife digest Antibiotics treat or prevent infections by killing bacteria or slowing down their growth. A large proportion of these drugs do this by disrupting an essential piece of cellular machinery called the ribosome which the bacteria need to make proteins. However, over the course of the treatment, some bacteria may gain genetic alterations that allow them to resist the effects of the antibiotic. Antibiotic resistance is a major threat to global health, and understanding how it emerges and spreads is an important area of research. Recent studies have discovered populations of resistant bacteria carrying a gene for a protein named chloramphenicol-florfenicol resistance, or Cfr for short. Cfr inserts a small modification in to the ribosome that prevents antibiotics from inhibiting the production of proteins, making them ineffective against the infection. To date, Cfr has been found to cause resistance to eight different classes of antibiotics. Identifying which mutations enhance its activity and protect bacteria is vital for designing strategies that fight antibiotic resistance. To investigate how the gene for Cfr could mutate and make bacteria more resistant, Tsai et al. performed a laboratory technique called directed evolution, a cyclic process which mimics natural selection. Genetic changes were randomly introduced in the gene for the Cfr protein and bacteria carrying these mutations were treated with tiamulin, an antibiotic rendered ineffective by the modification Cfr introduces into the ribosome. Bacteria that survived were then selected and had more mutations inserted. By repeating this process several times, Tsai et al. identified ‘super’ variants of the Cfr protein that lead to greater resistance. The experiments showed that these variants boosted resistance by increasing the proportion of ribosomes that contained the protective modification. This process was facilitated by mutations that enabled higher levels of Cfr protein to accumulate in the cell. In addition, the current study allowed, for the first time, direct visualization of how the Cfr modification disrupts the effect antibiotics have on the ribosome. These findings will make it easier for clinics to look out for bacteria that carry these ‘super’ resistant mutations. They could also help researchers design a new generation of antibiotics that can overcome resistance caused by the Cfr protein.

Golgi apparatus protein 1 (GLG1) est une protéine transmembranaire de 160 kDa qui interagit avec l’apolipoprotéine B100 (apoB100), le récepteur des lipoprotéines de basse densité (LDLR) et la proprotein convertase subtilisin/kexin type 9 (PCSK9). Cependant, son mécanisme d’action et sa régulation post-traductionnelle sont inconnus. Des études ont montré que GLG1 subit deux clivages résultant en fragments solubles secrétés de 150 kDa et 55 kDa. Dans cette étude, notre premier objectif est d’identifier les enzymes responsables de la protéolyse de GLG1 ainsi que l’effet du clivage sur sa fonction dans le métabolisme des lipides. De plus, les résultats de nos collaborateurs montrent que les souris adultes déficientes en GLG1 ont un plus grand nombre d’adipocytes mais de taille plus petite que les souris de type sauvage. Notre deuxième objectif est de mesurer la variation de l’expression ainsi qu’identifier l’effet de GLG1 lors de la différentiation des fibroblastes en adipocytes. Pour le premier objectif, les cellules HEK293T surexprimant GLG1 ont été soit transfectées avec des convertases de proprotéines (PCSK) soit incubées avec différents inhibiteurs d’enzymes. Les milieux et les lysats cellulaires ont été analysés par immunobuvardage à la Western. Il n’y a pas eu de nouveaux fragments générés en présence des PCSK. Cependant, en présence d’inhibiteurs des sérines protéases apparentées à la trypsine soit AEBSF et Gabexate mesylate, il y a eu une réduction de la formation du fragment de 55 kDa. Pour identifier la métalloprotéase responsable du clivage de l’ectodomaine générant le fragment de 150 kDa, GLG1 a été transfectée avec les Tissue Inhibitor of Metalloproteinase (TIMP 1-4). Nos résultats ont montré que TIMP3 empêche la relâche de l’ectodomaine de GLG1 dans le milieu de culture. Finalement, nos analyses de plasma de souris par immunobuvardage à la Western ont montré la présence des fragments de 150 kDa et 55 kDa de GLG1 in vivo. Pour le deuxième objectif de l’étude, les fibroblastes préadipocytaires de souris 3T3-L1 ont été différenciés en adipocytes. Des lysats cellulaires et l’isolation d’ARN ont été effectués aux jours 0, 2, 4, 6, 8 et 10 de la différenciation. Des immunobuvardages à la Western ainsi que des RT-qPCR ont été réalisés pour analyser l’expression de GLG1 au cours de la différenciation. Nos résultats ont montré que l’expression de GLG1 augmente durant la différenciation. Bref, nos résultats démontrent que des enzymes trypsin-like clivent GLG1 et génèrent le fragment de 55 kDa. L’inhibition du clivage de l’ectodomaine de GLG1 par TIMP3 suggère que les ADAMs sont impliquées dans la relâche du fragment de 150 kDa. De plus, nous avons montré que l’expression de GLG1 augmente au cours de la différenciation adipocytaire., Golgi apparatus protein 1 (GLG1) is a 160 kDa transmembrane protein interacting with apolipoprotein B100 (apoB100), low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9). However, the protein’s posttranslational regulation and mechanism of action are poorly understood. Previous studies showed that GLG1 is cleaved resulting in two fragments of 150 kDa and 55 kDa secreted at the cell surface and in the extracellular matrix. The first objective of this study is to identify enzymes responsible for GLG1 proteolysis and the effect of cleavage on its function in lipid metabolism. Furthermore, our collaborators showed that mice with GLG1 knockout have a higher number of adipocytes, but those cells are smaller in size compared to those in wild type mice. Therefore, the second objective of the study is to measure the variation of GLG1 expression during adipocytes differentiation and to identify the effects of GLG1 knockout on adipocytes differentiation. For the first objective, HEK293T cells overexpressing GLG1 were either transfected with basic amino acid-specific proprotein convertases (PCSK) or treated with enzyme inhibitors. Media and cell lysates were analyzed by Western blot. No new fragments were detected in media of PCSK-transfected cells. Cell treatment with trypsin-like serine proteases inhibitors, AEBSF and Gabexate mesylate, reduced the secretion of the 55 kDa fragment. To identify the metalloproteinase responsible for GLG1 shedding, GLG1 was co-transfected with Tissue Inhibitors of Metalloproteinase (TIMP1-4). Our results showed that TIMP3 inhibits shedding of the 150 kDa fragment. Finally, wild-type mouse plasma was analyzed by Western blot and showed the presence of both fragments in vivo. For the second objective of the study, fibroblasts 3T3-L1 cells were differentiated into adipocytes and GLG1 mRNA and protein expression were measured at day 0, 2, 4, 6, 8 and 10 by qPCR and Western Blot. Our results showed that GLG1 expression increased during differentiation and a peak was observed at day 4. To conclude, in the first objective of our study, our results showed that trypsin-like enzymes cleave GLG1 and produce a 55 kDa fragment. Shedding of GLG1 is inhibited by TIMP3, which suggests that ADAM10 or ADAM17 are involved in the release of the 150 kDa fragment. In addition, both 55 kDa and 150 kDa fragments were found in normal mouse plasma supporting the relevance of our findings in vivo. In the second objective of our study, GLG1 expression increased during adipocyte differentiation suggesting a role in adipose tissue development and/or morphology. In conclusion, our study will help elucidate how proteolysis of GLG1 impacts its role in the regulation of apoB and PCSK9 secretion and lipid metabolism and how can GLG1 expression affect adipocytes differentiation.

1. Molecular characterization of S. aureus isolates from Afghanistan: Staphylococcus aureus (SA) is a major cause of infections in human and plethora of animals. One of the main objective of this thesis was to investigate the molecular features and the antibiotic (ATB) resistance profile of infection and colonization strains of SA/methicillin-resistant SA (MRSA) isolated from human and livestock in Kabul. All strains were identified by conventional phenotypic methods. MRSA Strains were then extensively characterized using DNA microarray. Among SA isolates from human infection in the two hospitals of Kabul, from January to June 2017, MRSA prevalence was high at 66.3%. The 98 isolates (65 MRSA and 33 MSSA) were grouped into 12 clonal complexes (CCs) and 27 distinct clones. The prevalence of nasal carriage of the SA and MRSA among healthy population in Kabul was 33.3% and 12.7% respectively. Four CCs and 7 clones were identified. Around 11.8% (2/17) of SA strains caused bovine mastitis were MRSA, belonged to two distinct clones. We found a very low prevalence (1.05%) of SA nasal carriage in sheep in Kabul. Molecular characterization of the isolates, indicates a large genetic diversity and the presence of multiple virulence and ATB resistance genes among SA/MRSA strains circulating in the health-care facilities, community and livestock in Kabul. 2. Conjugative transfer of linezolid resistance gene: Linezolid is one of the last resort for the treatment of MRSA infections. The objective of this study was to investigate the risk of conjugative transfer of linezolid resistance from S. epidermidis (SE) strains to major SA clones. Five SE strains harboring different cfr-carrying plasmids (pSA737, p12-02300, p-cfr-PBR-A, p-cfr-PBR-B), and 9 major clones of SA circulating in France were used as donors and recipients respectively. The plasmid transfer rates were highly variable. The ST8-MRSA-IV USA300 was able to receive the cfr-carrying plasmids from all the donors tested. The SE ST5 strains was more able to transfer the plasmid p-cfr-PBR-B to different recipients, compared to SE ST2. The plasmids pSA737, and p12-02300 transferred to the most of the recipients tested. Plasmid fitness cost were highly variable. Under selective pressure, the linezolid resistance mediated by cfr vectors, can be efficiently transferred to major clones of SA circulating in France.; 1. Caractérisation moléculaire des isolats de S. aureus en provenance d’Afghanistan : Staphylococcus aureus (SA) est une cause majeure d'infections chez l'Homme et de nombreux animaux. L'un des principaux objectifs de cette thèse était d'étudier les caractéristiques moléculaires et le profil de résistance aux antibiotiques des souches d'infection et de colonisation de SA / SA résistante à la méticilline (SARM) isolées chez l'Homme et le bétail à Kaboul. Toutes les souches ont été identifiées par des méthodes phénotypiques conventionnelles. Les souches de SARM ont ensuite été caractérisées à l'aide d'une puce à ADN. Parmi les isolats de SA provenant d'infections humaines dans deux hôpitaux de Kaboul entre Janvier et Juin 2017, la prévalence des SARM était élevée (66,3 %). Les 98 isolats de SASM et SARM appartenaient à 12 complexes clonaux (CC) et 27 clones distincts. La prévalence du portage nasal de SA et du SARM dans la communauté, plus précisément chez des étudiants (hors médecine) de l’Université de Kaboul, était respectivement de 33,3% et 12,7%. Les 19 isolats de SARM appartenaient à 4 Enfin, les études réalisées chez l’animal ont montré qu’environ 11,8% des souches SA responsables de mammite bovine à Kabul étaient des SARM (2/17) et que la prévalence du portage nasal de SA chez les moutons était très faible (1.05 %). La caractérisation moléculaire des isolats a mis en évidence une grande diversité génétique et la présence de multiples gènes de virulence et de résistance parmi les souches SA/SARM circulant dans les établissements de soins, la communauté et le bétail à Kaboul. 2. Transfert conjugatif de gène de résistance au linézolide : Le linézolide est l'un des derniers recours pour le traitement des infections à SARM. L'objectif de cette étude était d'étudier le risque de transfert conjugatif de la résistance au linézolide des souches de S. epidermidis (SE) vers des souches SA de fonds génétiques différents. Cinq souches de SE portant différents plasmides possédant le gène cfr (pSA737, p12-02300, p-cfr-PBR-A, p-cfr-PBR-B), et 9 clones majeurs de SA circulant en France ont été respectivement utilisés comme donneuses et receveuses. Le clone ST8-MRSA-IV USA300 a pu recevoir les plasmides contenant le gène cfr de toutes les donneuses testées. Les souches SE ST5 avaient une plus grande capacité à transférer le plasmide p-cfr-PBR-B à différentes receveuses, par rapport aux souches du ST2. Les plasmides pSA737 et p12-02300 ont été transférés à la plupart des receveuses testées. Les coûts de fitness des plasmides testés étaient très variables. Les résultats ont au final montré que la résistance au linézolide, médiée par les vecteurs cfr, peut être transférée efficacement par conjugaison de SE aux clones pathogènes majeurs de SA circulant en France.

Haemodynamic indices are widely used in clinical practice when deciding on a particular type of treatment. Low quality of the computed tomography data and tachycardia complicate interpretation of the measured or simulated values. In this work, we present a novel approach for evaluating resistances in terminal coronary arteries. Using 14 measurements from 10 patients, we show that this algorithm retains the accuracy of 1D haemodynamic simulations in less detailed (truncated) geometric models of coronary networks. We also apply the variable systole fraction model to study the effect of elevated heart rate on the values of fractional flow reserve (FFR), coronary flow reserve (CFR) and instantaneous wave-free ratio (iFR). We conclude that tachycardia may produce both overestimation or underestimation of coronary stenosis significance.

Objectives:To determine the case-fatality rate (CFR) of coronavirus disease 2019 (Covid-19) and its associated determinants in order to understand the true magnitude of the problem during the ongoing conflict in Yemen.Methods:The CFR among the confirmed Covid-19 cases in Yemen was calculated. The data was retrieved from national Covid-19 surveillance between April 10, when the first COVID-19 case reported, and May 31, 2020.Results:A total of 419 confirmed Covid-19 cases were reported. There were 14.1% and 5.7% of cases who required intensive care and mechanical ventilators, respectively. Out of the total cases, 95 deaths were reported, giving a CFR of 22.6% which is much higher compared to other countries. CFR was significantly higher among elderly people compared to young adults and varied between governorates. Mortality was associated with pre-existing hypertension (OR: 2.30; 95% CI: 1.58, 3.54) and diabetes (OR: 1.68; 95% CI: 1.08, 2.61).Conclusions:The elderly and those with comorbidities, in particular hypertension and diabetes, have higher risk for poor outcomes and therefore should receive more attention in the clinical setting. Preventive measures should also be prioritized to protect those groups in order to reduce the severe cases and deaths-associated COVID-19 in armed-conflict.

Introduction: Invasive coronary function testing (CFT) has become the recommended diagnostic tool to assess the various endotypes of coronary vasomotor dysfunction in patients with angina and no obstructive coronary artery disease (ANOCA), which has implications for therapy and prognosis. Although the expanding performance of CFT is leading to increased knowledge of coronary vasomotor dysfunction, little is known about sex-related differences in the results of comprehensive CFT.Methods: We conducted a prospective study of all consecutive patients with ANOCA that underwent clinically indicated CFT in a tertiary interventional from February 2019 to February 2021. CFT consisted of acetylcholine testing to diagnose epicardial or microvascular spasm, and adenosine testing to diagnose CMD. CMD was defined as an index of microvascular resistance (IMR) ≥ 25 and/or coronary flow reserve (CFR) < 2.0.Results: In total, 228 women and 38 men underwent CFT. No differences in traditional risk factors were seen, but women had a higher prevalence of migraine (45 vs. 14%, p = 0.001). Men more often had a history of percutaneous coronary intervention (12 vs. 49%, p = 0.001). We found no difference in clinical presentation. Coronary vasomotor dysfunction was present in 95% of men and 88% of women (p = 0.25), but males show more often epicardial spasm and less microvascular spasm than women (63 vs. 42% and 29 vs. 40% respectively, p = 0.039). Impaired CFR was more prevalent among females (6 vs 20%, p = 0.033). IMR [median of 23 (15–32) vs. 19 (13–25), p = 0.08] did not differ between the sexes.Conclusion: Men undergoing CFT show a comparable prevalence of coronary vascular dysfunction as women. However, men have a higher prevalence of epicardial spasm and a lower prevalence of microvascular spasm compared with women. An impaired CFR was more often present in women, with an equally impairment of IMR.

The purpose of this study is to investigate the effect of varying coronary flow reserve (CFR) values on the calculation of computationally-derived fractional flow reserve (FFR). CFR reflects both vessel resistance due to an epicardial stenosis, and resistance in the distal microvascular tissue. Patients may have a wide range of CFR related to the tissue substrate that is independent of epicardial stenosis levels. Most computationally based virtual FFR values such as FFRCT do not measure patient specific CFR values but use a population-average value to create hyperemic flow conditions. In this study, a coronary arterial computational geometry was constructed using magnetic resonance angiography (MRA) data acquired in a patient with moderate CAD. Coronary flow waveforms under rest and stress conditions were acquired in 13 patients with phase-contrast magnetic resonance (PCMR) to calculate CFR, and these flow waveforms and CFR values were applied as inlet flow boundary conditions to determine FFR based on computational fluid dynamics (CFD) simulations. The stress flow waveform gave a measure of the functional significance of the vessel when evaluated with the physiologically-accurate behavior with the patient-specific CFR. The resting flow waveform was then scaled by a series of CFR values determined in the 13 patients to simulate how hyperemic flow and CFR affects FFR values. We found that FFR values calculated using non–patient-specific CFR values did not accurately predict those calculated with the true hyperemic flow waveform. This indicates that both patient-specific anatomic and flow information are required to accurately non-invasively assess the functional significance of coronary lesions.

Accurate and comprehensive testing is crucial for practitioners to portray the pandemic. Without testing there is no data; yet, the exact number of infected people cannot be determined due to the lack of comprehensive testing. The number of seropositive for SARS‐CoV‐2 infection is obviously relative to the extent of testing. However, the true number of infections might be still far higher than the reported values. To compare the countries based on the number of seropositive for SARS‐CoV‐2 infection is misleading, as there may not be enough tests being carried out to properly monitor the outbreak. In this paper, we closely look through the COVID‐19 testing results. Herein, we try to draw conclusions based on the reported data: first, the presence of a possible relationship between COVID‐19 transition and patients' age will be assessed. Then, the COVID‐19 case fatality rate (CFR) is compared with the age‐demographic data for different countries. Based on the results, a method for estimating a lower bound (minimum) for the number of actual positive cases will be developed and validated. Results of this study have shown that CFR is a metric reflecting the spread of the virus, but is a factor of the extent of testing and does not necessarily show the real size of the outbreak. Moreover, no large difference in susceptibility by age has been found. The results suggest the similarity between the age distribution of COVID‐19 and the population age‐demographic is improving over the course of the pandemic. In addition, countries with lower CFRs have a more similar COVID‐19 age distribution, which is a result of more comprehensive testing. Finally, a method for estimation of the real number of infected people based on the age distributions, reported CFRs, and the extent of testing will be developed and validated.

Graphical abstract, Background The novel Coronavirus disease (COVID-19) outbreak, caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), is seeing a rapid increase in infected people worldwide and linked with various risk factors. Objective To find out the risk factors zone associated with Coronavirus disease among children under five age using malnourished status, pre-existing morbidity conditions, household environmental factors, and also with case fatality and active case rate of COVID-19 disease in India. Data sources & Methods: Data was utilized from the 4th round of the National Family Health Survey (NFHS), 2015-16, and CFR and ACR of COVID-19 related data from the Ministry of Health and Family Welfare (MoHFW) on 18th May 2020. Mean, standard deviation, and Z-score statistical methods have been employed to identify the risk factors zone and hot spot analysis (Getis-Ord Gi) has been used. Results The states and UTs which have a high composite vulnerability score of the COVID-19 among under-5 children are Meghalaya (CVS=1), Uttar Pradesh (CVS=0.93), Jharkhand (CVS=0.86), Bihar, (CVS=0.74), Madhya Pradesh (CVS=0.74), and Odisha (CVS=0.55). The states and UTs which have low composite vulnerability score of the COVID-19 among under-5 children are Sikkim (CVS= -0.90), Daman & Diu (CVS= -0.76) Lakshadweep (CVS= -0.74), Kerala (CVS= -0.72), Chandigarh (CVS= -0.71). The COVID-19 vulnerable/ risk factors zone (hot spot: 99% Confidence interval [CI]) were observed in Madhya Pradesh, Uttar Pradesh, Jharkhand, Bihar, and Meghalaya states of India, which are spatially high clustered. The low rates of (cold spot: 95% CI) less vulnerable zones were observed in Kerala, Mizoram which is spatially low clustered. Conclusions Well-built public health measures, including rapidly searching in high focus areas and testing of COVID-19, should be performed in vulnerable areas of COVID-19.

Background Coagulase-negative Staphylococci (CoNS) have emerged as a major causative agent of blood-stream infections (BSI). Linezolid (LZD) is currently used for treating glycopeptide and methicillin-resistant staphylococci. It is important to understand the resistance mechanism and probable transmission of LZD resistant (LR) CoNS within the hospital. Methods Clinically significant LRCoNS from patients with BSI were characterized using MALDI-TOF and 16S rRNA gene sequence analysis. Antimicrobial susceptibility and MIC of vancomycin and LZD were determined. LZD resistance mechanisms using PCR for the cfr gene and mutation in the V domain of the 23S rRNA gene were studied. Results The MIC of LZD ranged from 8 to 32 μg/ml. LR was observed in three different CoNS species from diverse locations within the hospital. The cfr gene was identified in all the isolates. Sequence analysis of V domain region of 23S rRNA gene confirmed mutation in single copy among 12/15 isolates with novel mutations: G2614 T and C2384T. All infections were nosocomially acquired and LZD resistance was emerging in the absence of prior LZD use. Horizontal spread of resistant isolates and cfr gene among diverse species were the probable mechanisms of transmission. Conclusion The study highlights the novel mutations associated with LRCoNS and the importance of surveillance & transmission pathway within the hospital. It also systematically discusses the published information on LRCoNS.

COVID-19 emerged as a global pandemic in the spring of 2020. Since that time, the disease has resulted in approximately 150 million cases and 3 million deaths worldwide. However, there is significant spatial variation in the rate of mortality from COVID-19. Here, we briefly explore spatial variations in COVID-19 mortality by country groupings and propose possible explanations for the differences observed. Specifically, we find that there is a statistically significant difference in COVID-19 mortality between countries grouped into categories based on (1) developed, primarily western diets and healthcare systems; (2) “Scandinavian” countries with advanced healthcare systems and generally anti-inflammatory diets, and (3) developing countries. We do not infer causality but believe that the observed associations provide hypotheses for future research investigations. Moreover, our results add further evidence to support additional exploration of vitamin D exposure/status and COVID-19 mortality.

The SARS-CoV-2 B.1.1.7 variant of concern (VOC) is increasing in prevalence across Europe. Accurate estimation of disease severity associated with this VOC is critical for pandemic planning. We found increased risk of death for VOC compared with non-VOC cases in England (hazard ratio: 1.67; 95% confidence interval: 1.34-2.09; p

In this article we present SHARP, an original approach for obtaining human activity recognition (HAR) through the use of commercial IEEE 802.11 (Wi-Fi) devices. SHARP grants the possibility to discern the activities of different persons, across different time-spans and environments. To achieve this, we devise a new technique to clean and process the channel frequency response (CFR) phase of the Wi-Fi channel, obtaining an estimate of the Doppler shift at a radio monitor device. The Doppler shift reveals the presence of moving scatterers in the environment, while not being affected by (environment-specific) static objects. SHARP is trained on data collected as a person performs seven different activities in a single environment. It is then tested on different setups, to assess its performance as the person, the day and/or the environment change with respect to those considered at training time. In the worst-case scenario, it reaches an average accuracy higher than 95%, validating the effectiveness of the extracted Doppler information, used in conjunction with a learning algorithm based on a neural network, in recognizing human activities in a subject and environment independent way. The collected CFR dataset and the code are publicly available for replicability and benchmarking purposes., This work has been published in IEEE Transactions on Mobile Computing (Open Access)

Coronary microvascular dysfunction (CMD) has been shown to contribute to cardiac hypertrophy and heart failure with preserved ejection fraction. At this point, there are no proven treatments for CMD. We have shown that histone acetylation may play a critical role in the regulation of CMD. By using a mouse model that replaces lysine with arginine at residues K98/117/161/162R of p53 (p53 4KR ), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p53 4KR could improve coronary microvascular dysfunction and prevent the progression of hypertensive cardiac hypertrophy and heart failure. Wild-type (WT) and p53 4KR mice were subjected to pressure overload (PO) by transverse aortic constriction to induce cardiac hypertrophy and heart failure (HF). Echocardiography measurements revealed improved cardiac function together with reduction of apoptosis and fibrosis in p53 4KR mice. Importantly, myocardial capillary density and coronary flow reserve (CFR) were significantly improved in p53 4KR mice. Moreover, p53 4KR upregulated the expression of cardiac glycolytic enzymes and glucose transporters, as well as the level of fructose-2,6-biphosphate; increased PFK-1 activity; and attenuated cardiac hypertrophy. These changes were accompanied by increased expression of HIF-1α and proangiogenic growth factors. Additionally, the levels of SERCA-2 were significantly upregulated in sham p53 4KR mice as well as in p53 4KR mice after TAC. In vitro , p53 4KR significantly improved endothelial cell (EC) glycolytic function and mitochondrial respiration, and enhanced EC proliferation and angiogenesis. Similarly, acetylation-deficient p53 4KR significantly improved CFR and rescued cardiac dysfunction in SIRT3 KO mice. Our data reveal the importance of p53 acetylation in coronary microvascular function, cardiac function, and remodeling, and may provide a promising approach to improve hypertension-induced coronary microvascular dysfunction (CMD) and to prevent the transition of cardiac hypertrophy to heart failure., Competing Interests: Conflict of interest The authors declare no competing interests.

This paper analyses the stochastic dynamics of the COVID-19 Case-Fatality Ratios (CFR) in three developing economies in East Asia: Indonesia, Malaysia, and the Philippines. The sample covers the daily frequency data from April 28, 2020, to June 29, 2021. For this purpose, we utilize two unit root tests, which consider one structural break and two structural breaks. The findings reveal that the CFR follows a unit root process in Indonesia and the Philippines. However, the CFR is stationary in Malaysia. This evidence indicates that the COVID-19 has a permanent effect in Indonesia and the Philippines but temporary in Malaysia. The paper also discusses the potential economic implications of these results for the post-COVID-19 era in the related developing economies.

Background: A large proportion of patients with angina and no obstructive coronary artery disease (ANOCA) has underlying coronary vasomotor dysfunction (CVDys), which can be diagnosed by a coronary function test (CFT). Coronary tortuosity is a common angiographic finding during the CFT. Yet, no data exist on the association between vasomotor dysfunction and coronary tortuosity.Aim: To investigate the association between CVDys and coronary tortuosity in patients with ANOCAMethods: All consecutive ANOCA patients who underwent clinically indicated CFT between February 2019 and November 2020 were included. CFT included acetylcholine spasm testing to diagnose epicardial or microvascular spasm, and adenosine testing to diagnose microvascular dysfunction (MVD). MVD was defined as an index of microvascular resistance (IMR) ≥ 25 and/or coronary flow reserve (CFR) Results: In total, 228 patients were included (86% female, mean age 56 ± 9 years). We found coronary artery spasm in 81% of patients and MVD in 45% of patients (15%: abnormal CFR, 30%: abnormal IMR). There were 73 patients with no tortuosity, 114 with mild tortuosity, 41 with moderate tortuosity, and no patients with severe tortuosity. No differences were found in cardiovascular risk factors or medical history, and the prevalence of CVDys did not differ between the no tortuosity, mild tortuosity and moderate tortuosity group (82, 82, and 85%, respectively).Conclusion: In this study, CVDys was not associated with coronary tortuosity. Future experimental and clinical studies on the complex interplay between coronary tortuosity, wall shear stress, endothelial dysfunction and coronary flow are warranted.