[A pre-conception cohort study of fertility and its related factors among couples with the intention of conception].

Objective: To describe fertility and explore factors associated with it among pre-conception couples of childbearing age. Methods: Based on the pre-conceptional offspring trajectory study of the School of Public Health of Fudan University, couples of childbearing age who participated in the pre-conception physical examination in Shanghai Jiading District from 2016 to 2021 were recruited and followed up. Couples' time to pregnancy (TTP) was analyzed and Cox proportional hazards regression model was used to explore the factors associated with TTP. Kaplan-Meier was used to calculate each menstrual cycle's cumulative pregnancy rate. Results: A total of 1 095 preconception couples were included in the analysis, the M(Q1,Q3)of TTP was 4.33 (2.41, 9.78) menstrual cycles. Age of women (FR=0.90, 95%CI: 0.85-0.95, P<0.001), women who were overweight or obese before pregnancy (FR=0.36, 95%CI: 0.24-0.55, P<0.001), women who were exposed to second-hand smoking (FR=0.63, 95%CI: 0.44-0.92, P=0.016), women whose home or office had been renovated in the past 2 years and had a particular smell (FR=0.46, 95%CI: 0.26-0.81, P=0.008) were risk factors for impaired fertility. Regular menstrual cycles (FR=1.64, 95%CI: 1.16-2.31, P=0.005), females who often drank tea/coffee (FR=1.55, 95%CI: 1.11-2.17, P=0.011) and males who took folic acid before conception (FR=2.35, 95%CI: 1.38-4.23, P=0.002) were associated with better fertility. The cumulative pregnancy rate of 3, 6, and 12 menstrual cycles was 37.6%, 64.4%, and 78.4%, respectively. Conclusion: Older couples, overweight or obesity before pregnancy, irregular menstruation, exposure to secondhand smoke and decoration pollutants in females are associated with impaired fertility. Frequent tea/coffee drinking before pregnancy in females and taking folic acid before pregnancy in males are associated with shortened conception time.

Early-stage predictors for treatment responses in patients with active lupus nephritis.

OBJECTIVE: We analyzed data of lupus nephritis (LN) patients to find parameters that can predict remission. METHODS: Sixty-four LN patients who were diagnosed with class III, IV, V or V + III/IV by renal biopsy and were followed up for more than six months in our center were enrolled retrospectively. Receiver operating characteristic curves were used to test the predictive values of urinary protein-to-creatinine ratio (UPCR), serum albumin and complement C3 at the first, second and third months as predictors for remission at the sixth month. RESULTS: The patients' renal pathologies were class III (five cases), class IV (33 cases), class V (nine cases) and class V + III/IV (17 cases). All patients received standard immunosuppressive therapy. Forty-six (71.9%) patients (grouped as the remission group) achieved remission at the end of the sixth month, including 23 complete remissions and 23 partial remissions. The other 18 patients were grouped as the no-remission group. There were no significant differences in clinical data, proportion of immunosuppressive therapy or renal pathological characteristics between the remission group and no-remission group at baseline, except the serum urea nitrogen of the remission group was lower than in the no-remission group. The UPCR were significantly lower in the remission group than in the no-remission group at months 1, 2, 3 and 6, respectively, while the serum albumin was significantly higher in the remission group than in the no-remission group at months 3 and 6, respectively. There were no significant differences in serum creatinine between the remission group and no-remission group, except at month 1. The C3 levels were higher in the remission group than in the no-remission group at months 1, 2 and 3, respectively. The areas under the curve (AUC) of the change percentage of UPCR at month 3 and the serum albumin at month 3 were the most significant (AUC 0.778, p = 0.002; AUC 0.773, p = 0.001, respectively). The cutoff value of the change percentage of UPCR at month 3 was 59%. The cutoff value of serum albumin at month 3 was 32.9g/l. CONCLUSION: The change percentage of UPCR ≥59% and the serum albumin ≥32.9 g/l at the third month were valuable for predicting remission at the sixth month in LN. Because of the small-size and retrospective nature, this study needs to be validated.

[Ikaros family zinc finger 1 mutation is a poor prognostic factor for adult Philadelphia chromosome positive acute lymphoblastic leukemia].

Objective: To analyze the prognostic impact of Ikaros family zinc finger 1(IKZF1) mutation on adult Philadelphia chromosome (Ph1) positive acute lymphoblastic leukemia (ALL) patients. Methods: IKZF1 mutation was detected in 63 adult Ph1 positive ALL patients at diagnosis using capillary electrophoresis. Recruited patients were treated in our center and other three hospitals in Ningbo from January 2014 to January 2017. Clinical data were collected and retrospectively analyzed. Results: Thirty-nine (61.9%) patients were positive IKZF1 mutation in this cohort. The white blood cell (WBC) count in IKZF1 mutation group was significantly higher than that of mutation negative group [(64.6±11.3)×10(9)/L vs. (33.7±5.6)×10(9)/L, P<0.05]. Patients with WBC count over 30×10(9)/L accounted for 56.4% in IKZF1 mutation group. Complete remission (CR) rate in the IKZF1 mutation group was also lower than that of negative group after induction chemotherapy (64.1% vs. 75.0%, P>0.05). IKZF1 was a negative prognostic factor but not independent factor for survival by univariate and multivariate analyses. Patients were divided into chemotherapy and allogeneic transplantation groups. The 3-year overall survival (OS) rate and 3-year leukemia-free survival (LFS) rate in IKZF1 mutation group were significantly lower than those of negative group in both transplantation group (42.3% vs. 59.3%; 31.2% vs. 50.0%; respectively, both P<0.05) and chemotherapy group (24.8% vs. 40.0%; 19.0% vs. 34.3%; respectively, both P<0.05). Conclusion: IKZF1 mutation is a poor prognostic factor for adult Ph1 positive ALL patients.

Dental students' ability to locate emergency equipment-lessons learned from aviation.

PURPOSE: The purpose of this study was to evaluate the dental student's ability to locate medical emergency equipment/items at the University of Michigan School of Dentistry clinic. METHODS: A total of 138 second-year dental students (traditional group) participated in this study as part of a simulation-based medical emergencies rotation course held during the winter term of 2014 and 2015. Without prior training, students were tested on their ability to locate nine predetermined items on the clinic floor using a self-reported checklist. Six months later, a convenience sample of 18 students (novel group) from the same cohort were later trained on their location and retested individually. RESULTS: Of the 138 students tested, only 10.14% students could locate seven of the nine items when compared to 100% in the novel group. Only 5.07% of students in the traditional group could locate all items initially, compared with 72.22% students in the novel group. CONCLUSION: Whilst our students have lecture-based knowledge about medical emergencies, the results of our study identified a gap of knowledge of emergency equipment/item location amongst students. Therefore, an intervention performed with a similar group of second-year dental students supported that proper training may be used to achieve retention of knowledge. Based on our "novel group" results, we have incorporated targeted training in the dental curriculum that leads to students being better prepared in locating emergency equipment/items. This study suggests that other populations, such as faculty or staff, may also benefit from hands-on training.

Epidemiology and hospital readmission associated with complications of Staphylococcus aureus bacteremia in pediatrics over a 25-year period.

We sought to comprehensively assess the prevalence and outcomes of complications associated with Staphylococcus aureus bacteremia (SAB) in children. Secondarily, prevalence of methicillin resistance and outcomes of complications from methicillin-resistant S. aureus (MRSA) vs. methicillin-susceptible S. aureus SAB were assessed. This is a single-center cross-sectional study of 376 patients ⩽18 years old with SAB in 1990-2014. Overall, 197 (52%) patients experienced complications, the most common being osteomyelitis (33%), skin and soft tissue infection (31%), and pneumonia (25%). Patients with complications were older (median 3 vs. 0·7 years, P = 0·05) and more had community-associated SAB (66% vs. 34%, P = 0·001). Fewer patients with complications had a SAB-related emergency department or hospital readmission (10% vs. 19%, P = 0·014). Prevalence of methicillin resistance increased from 1990-1999 to 2000-2009, but decreased in 2010-2014. Complicated MRSA bacteremia resulted in more intensive care unit admissions (66% vs. 47%, P = 0·03) and led to increased likelihood of having ⩾2 foci (58% vs. 26%, P < 0·001). From multivariate analysis, community-associated SAB increased risk and concurrent infections decreased risk of complications (odds ratio (OR) 1·82 (1·1-3·02), P = 0·021) and (OR 0·58 (0·34-0·97), P = 0·038), respectively. In conclusion, children with SAB should be carefully evaluated for complications. Methicillin resistance remains associated with poor outcomes but have decreased in overall prevalence.

Effects of vancomycin versus nafcillin in enhancing killing of methicillin-susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37.

Recent studies have demonstrated that anti-staphylococcal beta-lactam antibiotics, like nafcillin, render methicillin-resistant Staphylococcus aureus (MRSA) more susceptible to killing by innate host defense peptides (HDPs), such as cathelicidin LL-37. We compared the effects of growth in 1/4 minimum inhibitory concentration (MIC) of nafcillin or vancomycin on the LL-37 killing of 92 methicillin-susceptible S. aureus (MSSA) isolates. For three randomly selected strains among these, we examined the effects of nafcillin, vancomycin, daptomycin, or linezolid on LL-37 killing and autolysis. Growth in the presence of subinhibitory nafcillin significantly enhanced LL-37 killing of MSSA compared to vancomycin and antibiotic-free controls. Nafcillin also reduced MSSA production of the golden staphylococcal pigment staphyloxanthin in 39 % of pigmented strains vs. 14 % for vancomycin. Among the antibiotics tested, only nafcillin resulted in significantly increased MSSA autolysis. These studies point to additional mechanisms of anti-staphylococcal activity of nafcillin beyond direct bactericidal activity, properties that vancomycin and other antibiotic classes do not exhibit. The ability of nafcillin to enhance sensitivity to innate HDPs may contribute to its superior effectiveness against MSSA, as suggested by studies comparing clinical outcomes to vancomycin treatment.

Anxiety prevalence following spinal cord injury: a meta-analysis.

STUDY DESIGN: Meta-analysis. OBJECTIVES: Prevalence estimates indicate that anxiety following spinal cord injury (SCI) is a common problem. However, methodological differences between studies may impact the clinical interpretation of these data. METHODS: Data from 18 independent studies (Nparticipants=3158), which reported the prevalence of an anxiety disorder or associated symptoms, were identified from the Embase, PubMed and PsycInfo databases. Proportions were the primary effect size estimate. Confidence intervals, fail-safe Ns and the I(2) statistic were additionally calculated to identify the extent to which findings were robust and consistent across studies. RESULTS: Five per cent of participants met the criteria for either GAD or panic disorder, with Agoraphobia identified in 2.5%. These diagnostic data were, however, limited to two studies. Higher rates were noted for self-reported 'caseness' of anxiety, with 27% reporting clinically significant symptoms. Anxiety prevalence estimates varied across the individual self-report measures (range: 15-32%). Method of administration (range: 26-32%) did not impact significantly on these estimates nor did recruitment source, with similarly high anxiety levels reported by hospital (27%) and community (29%) samples. CONCLUSIONS: Early identification and treatment of anxiety are important in SCI rehabilitation, with a subgroup of individuals experiencing chronic symptoms. Further research is needed to establish guidelines for the interpretation of self-report data, including the use of clinical cutoffs.

Rapid hippocampal network adaptation to recurring synchronous activity--a role for calcineurin.

Neuronal networks are thought to gradually adapt to altered neuronal activity over many hours and days. For instance, when activity is increased by suppressing synaptic inhibition, excitatory synaptic transmission is reduced. The underlying compensatory cellular and molecular mechanisms are thought to contribute in important ways to maintaining normal network operations. Seizures, due to their massive and highly synchronised discharging, probably challenge the adaptive properties of neurons, especially when seizures are frequent and intense - a condition common in early childhood. In the experiments reported here, we used rat and mice hippocampal slice cultures to explore the effects that recurring seizure-like activity has on the developing hippocampus. We found that developing networks adapted rapidly to recurring synchronised activity in that the duration of seizure-like events was reduced by 42% after 4 h of activity. At the same time, the frequency of spontaneous excitatory postsynaptic currents in pyramidal cells, the expression of biochemical biomarkers for glutamatergic synapses and the branching of pyramidal cell dendrites were all dramatically reduced. Experiments also showed that the reduction in N-methyl-D-aspartate receptor subunits and postsynaptic density protein 95 expression were N-methyl-D-aspartate receptor-dependent. To explore calcium signaling mechanisms in network adaptation, we tested inhibitors of calcineurin, a protein phosphatase known to play roles in synaptic plasticity and activity-dependent dendrite remodeling. We found that FK506 was able to prevent all of the electrophysiological, biochemical, and anatomical changes produced by synchronised network activity. Our results show that hippocampal pyramidal cells and their networks adapt rapidly to intense synchronised activity and that calcineurin play an important role in the underlying processes.

High glucose inhibits the survival of HRMCs and its mechanism.

OBJECTIVE: High glucose can promote the apoptosis of glomerular mesangial cells and cause diabetic nephropathy (DN). However, the mechanism remains unclear. In the present study, we investigated the effects of high glucose on the survival of human renal mesangial cells (HRMCs). MATERIALS AND METHODS: Cells were treated with high glucose (30 mM) or normal glucose (5 mM) for 48 hours. Cell proliferation was determined by trypan blue assay. The relative expression of metalloproteinase-3 (TIMP3) and inflammatory factors detected by real-time polymerase chain reaction (PCR). Protein expression of Smad2/3, p-Smad2/3 and Smad7 in HRMCs were analyzed by Western blot. RESULTS: Compared with normal glucose, we found that high glucose significantly inhibited cell survival, accompanied by the decrease of tissue metalloproteinase-3 (TIMP3) mRNA expression. Western blot results showed that the expression of p-Smad2/3 was significantly up-regulated, the expression of Smad7 was significantly downregulated, and inflammatory factors IL-6/IL-8 mRNA expression were increased in the HRMCs cultured with the high glucose. We also found that, compared with the normal glucose, the level of MDA was significantly increased (p<0.01), and the level of SOD was significantly lower (p<0.05) in the HRMCs cultured with the high glucose. CONCLUSIONS: These findings suggested that high glucose inhibited the survival of HRMCs and may be associated with the downregulation of TIMP3 expression, Smad signaling pathway, inflammation and oxidative stress.

[Research advances in transmission dynamic models on hand, foot, and mouth disease].

Hand, foot, and mouth disease (HFMD) is a common childhood infectious disease caused by various enteroviruses. China has the most significant number of reported cases and deaths of HFMD over the globe. Understanding the epidemic laws of HFMD can provide a scientific basis for designing prevention and control measures. The dynamic transmission models focus on the transmission mechanism of infectious diseases. They can simulate the actual situation to study the epidemic rules of diseases by adding, deleting, and subdividing compartments. More researchers have paid attention to dynamic models because of their high flexibility. To carry out the dynamic model of the HFMD research more effectively, a comprehensive understanding of related research progress in this field is deeply needed. In this paper, based on various researchers' different research purposes of dynamic models, the research progress was classified and summarized, providing meaningful guidance for model construction methods and future research directions and references for dynamic modeling of other models of infectious diseases. It was found that most studies used the SIR dynamic model or its extended model (such as the SEIR model), and few studies contained a complex factor compartment. Some important epidemiological parameters (such as R0) were obtained by studying the HFMD cases in a specific region, simulating different intervention scenarios to evaluate the effect of measures, or revealing the future trend by model prediction. However, there is no dynamic model simultaneously considering age structure, population moving, seasonality and periodicity, and vaccination.

Prolactin activation of the long form of its cognate receptor causes increased visceral fat and obesity in males as shown in transgenic mice expressing only this receptor subtype.

To date the best defined function of prolactin (PRL) is its action on the ovary and mammary gland, although it has also been shown to have an effect on lipid metabolism. Using mice engineered to express only the long form of the prolactin receptor (PRL-RL), we demonstrate that PRL acting through PRL-RL alone causes severe adipose accumulation in visceral fat of males at 6 months of age. The increase in visceral fat accumulation is attributed to loss of adipose-derived leptin, which results in diminished lipolysis. The reduction in leptin also corresponds to decreased activation of AMP-activated protein kinase (AMPK), which further results in diminished fatty acid oxidation and increased fatty acid synthesis. Interestingly, the blunted AMPK response was only observed in adipose tissue and not in liver suggesting that this PRL mediated effect is tissue specific. A glucose tolerance study inferred that PRL-RL mice may suffer from insulin resistance or a reduction in insulin production that is not due to aberrant expression of glucose transporter 4 (Glut4). Collectively, our findings demonstrate that PRL signaling through the long form receptor causes reduced fatty acid oxidation, increased lipid storage, glucose intolerance, and obesity. These findings are of great importance towards understanding the etiology of obesity associated with hyperprolactinemia in humans as well as the role of PRL as a metabolic regulator in adipose tissue.

Ultrastructure and molecular characterization of a microsporidium, Tubulinosema hippodamiae, from the convergent lady beetle, Hippodamia convergens Guérin-Méneville.

Hippodamia convergens, the convergent lady beetle, is available for aphid control in home gardens and in commercial food production systems throughout the United States and Canada. Beetles received from commercial insectaries for biological control are occasionally infected with a microsporidium. The objective of this study was to describe the pathogen by means of ultrastructure, molecular characterization and tissue pathology. All stages of the microsporidium were in direct contact with the host cell cytoplasm. Early developmental stages were proximal to mature spores and both were observed throughout the tissue sections that were examined. Merogony resulted from binary fission. Early-stage sporoblasts were surrounded by a highly convoluted plasma membrane and contained an electron-dense cytoplasm and diplokaryon. Ovoid to elongated late-stage sporoblasts were surrounded by a relatively complete spore wall. The polar filament, polaroplast, and anchoring disk were readily observed within the cell cytoplasm. Mature spores were typical of terrestrial microsporidia, with a thickened endospore surrounded by a thin exospore. Spores contained well-defined internal structures, including a diplokaryon, lamellar polaroplast and a slightly anisofilar polar filament with 10-14 coils arranged in a single or double row. A prominent indentation was evident at the apical end of the spore wall proximal to the anchoring disk. Aberrant spores were also observed. These had a fully developed endospore and exospore but lacked any discernable internal spore structures, and were, instead, filled with lamellar or vesicular structures. Typical and aberrant spores measured 3.58 ± 0.2 × 2.06 ± 0.2 µm (n=10) and 3.38 ± 0.8 × 2.13 ± 0.2 µm (n=10), respectively. Spores were observed in longitudinal muscle surrounding the midgut and within the fat body, Malpighian tubules, pyloric valve epithelium, ventral nerve cord ganglia, muscles and ovaries. The hindgut epithelium was often infected but the connective tissues were rarely invaded. The life cycle and pathology of the microsporidium bears some resemblance to Nosema hippodamiae, the only microsporidium reported from H. convergens by Lipa and Steinhaus in 1959. Molecular characterization of the pathogen genomic DNA revealed that it is 99% similar to Tubulinosema acridophagus and T. ratisbonensis, two pathogens that infect Drosophila melanogaster and 98% similar to T. kingi from D. willistoni. Based on similarities in pathogen ultrastructure and the molecular information gained during this study, we propose that the microsporidium in H. convergens be given the name Tubulinosema hippodamiae.

[Establishment of an auxiliary diagnosis system of newborn screening for inherited metabolic diseases based on artificial intelligence technology and a clinical trial].

Objective: To establish a disease risk prediction model for the newborn screening system of inherited metabolic diseases by artificial intelligence technology. Methods: This was a retrospectively study. Newborn screening data (n=5 907 547) from February 2010 to May 2019 from 31 hospitals in China and verified data (n=3 028) from 34 hospitals of the same period were collected to establish the artificial intelligence model for the prediction of inherited metabolic diseases in neonates. The validity of the artificial intelligence disease risk prediction model was verified by 360 814 newborns' screening data from January 2018 to September 2018 through a single-blind experiment. The effectiveness of the artificial intelligence disease risk prediction model was verified by comparing the detection rate of clinically confirmed cases, the positive rate of initial screening and the positive predictive value between the clinicians and the artificial intelligence prediction model of inherited metabolic diseases. Results: A total of 3 665 697 newborns' screening data were collected including 3 019 cases' positive data to establish the 16 artificial intelligence models for 32 inherited metabolic diseases. The single-blind experiment (n=360 814) showed that 45 clinically diagnosed infants were detected by both artificial intelligence model and clinicians. A total of 2 684 cases were positive in tandem mass spectrometry screening and 1 694 cases were with high risk in artificial intelligence prediction model of inherited metabolic diseases, with the positive rates of tandem 0.74% (2 684/360 814)and 0.46% (1 694/360 814), respectively. Compared to clinicians, the positive rate of newborns was reduced by 36.89% (990/2 684) after the application of the artificial intelligence model, and the positive predictive values of clinicians and artificial intelligence prediction model of inherited metabolic diseases were 1.68% (45/2 684) and 2.66% (45/1 694) respectively. Conclusion: An accurate, fast, and the lower false positive rate auxiliary diagnosis system for neonatal inherited metabolic diseases by artificial intelligence technology has been established, which may have an important clinical value.

Mice that lack the interferon-gamma receptor have profoundly altered responses to infection with Bacillus Calmette-Guérin and subsequent challenge with lipopolysaccharide.

Mice with a targeted disruption of the interferon gamma receptor gene (IFN-gamma R0/0 mice) and control wild-type mice were inoculated with the Bacillus Calmette-Guérin (BCG) strain of Mycobacterium bovis. BCG infection was not lethal for wild-type mice whereas all IFN-gamma R0/0 mice died approximately 7-9 wk after inoculation. Histological examination at 2 and 6 wk after BCG inoculation showed that livers of IFN-gamma R0/0 mice had higher numbers of acid-fast bacteria than wild-type mice, especially at 6 wk. In parallel, the livers of IFN-gamma R0/0 mice showed a reduction in the formation of characteristic granulomas at 2 wk after inoculation. Injection of lipopolysaccharide (LPS) 2 wk after BCG inoculation was significantly less lethal for IFN-gamma R0/0 mice than for wild-type mice. Reduced lethality of LPS correlated with a drastically reduced production of tumor necrosis factor alpha (TNF-alpha) in the IFN-gamma R0/0 mice. Interleukin 1 alpha (IL-1 alpha) and IL-6 levels in the serum were also significantly reduced in the IFN-gamma R0/0 mice after BCG infection and LPS challenge. The greatly reduced capacity of BCG-infected IFN-gamma R0/0 mice to produce TNF-alpha may be an important factor in their inability to resist BCG infection. These results show that the presence of a functional IFN-gamma receptor is essential for the recovery of mice from BCG infection, and that IFN-gamma is a key element in the complex process whereby BCG infection leads to the sensitization to endotoxin.

Interrelationships of human interferon-gamma with lymphotoxin and monocyte cytotoxin.

Crude preparations of interferon (IFN)-gamma derived from human peripheral blood leukocyte (PBL) cultures induced with 12-O-tetra-decanoylphorbol-13-acetate (TPA) and phytohemagglutinin (PHA) were more cytotoxic to HeLa cells than partially purified nautral or highly purified recombinant human IFN-gamma preparations. Conditioned media from PBL cultures contained, in addition to IFN-gamma, a mixture of cytotoxins, including classic lymphocyte-derived lymphotoxin (LT), and a TPA-induced cytotoxic activity produced by the adherent cell population (presumably monocytes). These two types of cytotoxins, indistinguishable in the mouse L929 cell LT assay, could be differentiated by an antiserum prepared against LT derived from the B lymphoblastoid cell line RPMI 1788. This antiserum neutralized lymphocyte-derived classic LT but failed to neutralize the activity of the monocyte-derived cytotoxin. Processing of conditioned media by sequential chromatography on silicic acid, Con A-Sepharose, and DEAE-Sephacel failed to separate IFN-gamma from the LT activity. However, this procedure did remove the monocyte-derived cytotoxic activity present in the original starting material, leaving predominantly classic LT. This LT showed a slightly basic isoelectric point (pI 7.6) which partially overlapped the more basic pI range of IFN-gamma. The two lymphokine activities also could not be completely separated by fast protein liquid chromatography or molecular sieve chromatography. LT in these partially purified preparations was associated with a protein having an apparent molecular weight of 58,000 on gel filtration. This form dissociated partially into a 20,000 mol wt species after denaturation with 0.1% NaDodSO4. IFN-gamma could be selectively removed from preparations containing both IFN-gamma and LT with the aid of monoclonal antibody to IFN-gamma. The addition of purified LT to purified E. coli-derived recombinant human IFN-gamma resulted in a marked synergistic enhancement of cytotoxicity for HeLa cells.

Outcomes in patients with severe COVID-19 disease treated with tocilizumab: a case-controlled study.

BACKGROUND: COVID-19 is an ongoing threat to society. Patients who develop the most severe forms of the disease have high mortality. The interleukin-6 inhibitor tocilizumab has the potential to improve outcomes in these patients by preventing the development of cytokine release storm. AIMS: To evaluate the outcomes of patients with severe COVID-19 disease treated with the interleukin-6 inhibitor tocilizumab. METHODS: We conducted a retrospective, case-control, single-center study in patients with severe to critical COVID-19 disease treated with tocilizumab. Disease severity was defined based on the amount of oxygen supplementation required. The primary endpoint was the overall mortality. Secondary endpoints were mortality in non-intubated patients and mortality in intubated patients. RESULTS: A total of 193 patients were included in the study. Ninety-six patients received tocilizumab, while 97 served as the control group. The mean age was 60 years. Patients over 65 years represented 43% of the population. More patients in the tocilizumab group reported fever, cough and shortness of breath (83%, 80% and 96% vs. 73%, 69% and 71%, respectively). There was a non-statistically significant lower mortality in the treatment group (52% vs. 62.1%, P = 0.09). When excluding intubated patients, there was statistically significant lower mortality in patients treated with tocilizumab (6% vs. 27%, P = 0.024). Bacteremia was more common in the control group (24% vs. 13%, P = 0.43), while fungemia was similar for both (3% vs. 4%, P = 0.72). CONCLUSION: Our study showed a non-statistically significant lower mortality in patients with severe to critical COVID-19 disease who received tocilizumab. When intubated patients were excluded, the use of tocilizumab was associated with lower mortality.

Requirement for transcription factor IRF-1 in NO synthase induction in macrophages.

Production of nitric oxide (NO) by macrophages is important for the killing of intracellular infectious agents. Interferon (IFN)-gamma and lipopolysaccharide stimulate NO production by transcriptionally up-regulating the inducible NO synthase (iNOS). Macrophages from mice with a targeted disruption of the IFN regulatory factor-1 (IRF-1) gene (IRF-1-/- mice) produced little or no NO and synthesized barely detectable iNOS messenger RNA in response to stimulation. Two adjacent IRF-1 response elements were identified in the iNOS promoter. Infection with Mycobacterium bovis (BCG) was more severe in IRF-1-/- mice than in wild-type mice. Thus, IRF-1 is essential for iNOS activation in murine macrophages.

Adenocarcinoma of the lower esophagus with Barrett's esophagus or without Barrett's esophagus: differences in patients' survival after preoperative chemoradiation.

It remains unclear whether the overall survival (OS) of patients with localized esophageal adenocarcinoma (LEA) with Barrett's esophagus (BE) (Barrett's-positive) and those with LEA without BE (Barrett's-negative) following preoperative chemoradiation is different. Based on the published differences in the molecular biology of the two entities, we hypothesized that the two groups will have a different clinical biology (and OS). In this retrospective analysis, all patients with LEA had surgery following preoperative chemoradiation. Apart from age, gender, baseline clinical stage, location, class of cytotoxics, post-therapy stage, and OS, LEAs were divided up into Barrett's-positive and Barrett's-negative groups based on histologic documentation of BE. The Kaplan-Meier and Cox regression analytic methods were used. We analyzed 362 patients with LEA (137 Barrett's-positive and 225 Barrett's-negative). A higher proportion of Barrett's-positive patients had (EUS)T2 cancers (27%) than those with Barrett's-negative cancer (17%). More Barrett's-negative LEAs involved gastroesophageal junction than Barrett's-positive ones (P = 0.001). The OS was significantly shorter for Barrett's-positive patients than that for Barrett's-negative patients (32 months vs. 51 months; P = 0.04). In a multivariate analysis for OS, Barrett's-positive LEA (P = 0.006), old age (P = 0.016), baseline positive nodes (P = 0.005), more than 2 positive (yp)N (P = 0.0001), higher (yp)T (P = 0.003), and the use of a taxane (0.04) were the independent prognosticators. Our data demonstrate that the clinical biology (reflected in OS) is less favorable for patients with Barrett's-positive LEA than for patients with Barrett's-negative LEA. Our intriguing findings need confirmation followed by in-depth molecular study to explain these differences.