Origin of Antimicrobial Therapy.

Medical historians typically situate the origins of the antimicrobial era during the early germ period at the turn of the 20th century. They have regarded the development of chemical compounds designed to treat infectious diseases by killing their causative germ as the beginning of the antimicrobial era. Scholars, however, had been speculating about the causal relationship between germs and diseases for centuries beforehand. One of them also addressed the practical applications of this theory. The Italian physician Fracastoro proposed in 1546 that infectious diseases could be treated by administering substances to antagonize disease causing germs. He claimed that health could be restored to people who became ill with infections by nullifying the responsible germs at a time when investigators could not see germs or investigate their ability to cause disease. The long genealogy of antimicrobial therapy from its conception to its fruition took place over the span of several centuries.

Impact of Vietnam-era G.I. Bill eligibility on later-life blood pressure distribution: evidence from the Vietnam draft lottery natural experiment.

We quantified the impact of Vietnam-era G.I Bill eligibility, which subsidized college education for eligible Veterans, on the later-life blood pressure distribution by exploiting the Vietnam draft lottery natural experiment. We restricted Health and Retirement Study data (2006-2018) to men born between 1947-1953 (N=1,970). We estimated intention-to-treat effects at the mean and 1st-99th quantiles of blood pressure using linear and quantile regressions. Our outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP), hypertension, and self-reported stroke. We proxied G.I. Bill eligibility using lottery-defined draft eligibility. We also conducted analyses stratified by childhood socioeconomic status (cSES) defined based on a previously validated measure. Draft eligibility reduced mean blood pressure outcomes (e.g., effect on SBP: -1.33 [95% confidence interval (CI) -2.85, 0.19]). Draft eligibility also had larger protective effects at higher quantiles of the SBP and DBP distributions relative to lower quantiles (effects on SBP at the 10th and 90th quantiles: -0.33mmHg [95% CI -2.35,1.68]; -3.00mmHg [95% CI -5.68,-0.32]). Draft eligibility had protective effects on blood pressure among low and medium cSES men but opposite effects among high cSES men. G.I. Bill eligibility reshaped the blood pressure distribution to one of lower morbidity risk, particularly among low and medium cSES men.

Rolling the DICEP on lymphoma salvage treatments? Choose wisely.

Although immunotherapy is rapidly changing the treatment approach to r/r diffuse large B cell lymphoma, there is still a place for autologous stem cell transplantation in some patients. The report by Stewart et al. focuses on induction therapy and the importance of the pretransplantation phase. Commentary on: Stewart et al. Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-Outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19555.

Anti-Spike IgG antibodies as correlates of protection against SARS-CoV-2 infection in the pre-Omicron and Omicron era.

Anti-Spike IgG antibodies against SARS-CoV-2, which are elicited by vaccination and infection, are correlates of protection against infection with pre-Omicron variants. Whether this association can be generalized to infections with Omicron variants is unclear. We conducted a retrospective cohort study with 8457 blood donors in Tyrol, Austria, analyzing 15,340 anti-Spike IgG antibody measurements from March 2021 to December 2022 assessed by Abbott SARS-CoV-2 IgG II chemiluminescent microparticle immunoassay. Using a Bayesian joint model, we estimated antibody trajectories and adjusted hazard ratios for incident SARS-CoV-2 infection ascertained by self-report or seroconversion of anti-Nucleocapsid antibodies. At the time of their earliest available anti-Spike IgG antibody measurement (median November 23, 2021), participants had a median age of 46.0 years (IQR 32.8-55.2), with 45.3% being female, 41.3% having a prior SARS-CoV-2 infection, and 75.5% having received at least one dose of a COVID-19 vaccine. Among 6159 participants with endpoint data, 3700 incident SARS-CoV-2 infections with predominantly Omicron sublineages were recorded over a median of 8.8 months (IQR 5.7-12.4). The age- and sex-adjusted hazard ratio for SARS-CoV-2 associated with having twice the anti-Spike IgG antibody titer was 0.875 (95% credible interval 0.868-0.881) overall, 0.842 (0.827-0.856) during 2021, and 0.884 (0.877-0.891) during 2022 (all p < 0.001). The associations were similar in females and males (Pinteraction = 0.673) and across age (Pinteraction = 0.590). Higher anti-Spike IgG antibody titers were associated with reduced risk of incident SARS-CoV-2 infection across the entire observation period. While the magnitude of association was slightly weakened in the Omicron era, anti-Spike IgG antibody continues to be a suitable correlate of protection against newer SARS-CoV-2 variants.

Treatment strategies and survival of patients with connective tissue disease and pulmonary arterial hypertension: a COMPERA analysis.

OBJECTIVES: Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH. METHODS: We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes. RESULTS: This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n = 390) were 85%, 59% and 42%; for SLE-PAH (n = 34) they were 97%, 77% and 61%; for MCTD-PAH (n = 33) they were 97%, 70% and 59%; for UCTD-PAH (n = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P = 0.001). In these patients, the survival estimates were significantly better with initial ERA-PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P = 0.016 and P = 0.012, respectively). CONCLUSIONS: Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA-PDE5i combination therapy compared with initial monotherapy.

Artificial intelligence-based prognostic model accurately predicts the survival of patients with diffuse large B-cell lymphomas: analysis of a large cohort in China.

BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) display high molecular heterogeneity, but the International Prognostic Index (IPI) considers only clinical indicators and has not been updated to include molecular data. Therefore, we developed a widely applicable novel scoring system with molecular indicators screened by artificial intelligence (AI) that achieves accurate prognostic stratification and promotes individualized treatments. METHODS: We retrospectively enrolled a cohort of 401 patients with DLBCL from our hospital, covering the period from January 2015 to January 2019. We included 22 variables in our analysis and assigned them weights using the random survival forest method to establish a new predictive model combining bidirectional long-short term memory (Bi-LSTM) and logistic hazard techniques. We compared the predictive performance of our "molecular-contained prognostic model" (McPM) and the IPI. In addition, we developed a simplified version of the McPM (sMcPM) to enhance its practical applicability in clinical settings. We also demonstrated the improved risk stratification capabilities of the sMcPM. RESULTS: Our McPM showed superior predictive accuracy, as indicated by its high C-index and low integrated Brier score (IBS), for both overall survival (OS) and progression-free survival (PFS). The overall performance of the McPM was also better than that of the IPI based on receiver operating characteristic (ROC) curve fitting. We selected five key indicators, including extranodal involvement sites, lactate dehydrogenase (LDH), MYC gene status, absolute monocyte count (AMC), and platelet count (PLT) to establish the sMcPM, which is more suitable for clinical applications. The sMcPM showed similar OS results (P < 0.0001 for both) to the IPI and significantly better PFS stratification results (P < 0.0001 for sMcPM vs. P = 0.44 for IPI). CONCLUSIONS: Our new McPM, including both clinical and molecular variables, showed superior overall stratification performance to the IPI, rendering it more suitable for the molecular era. Moreover, our sMcPM may become a widely used and effective stratification tool to guide individual precision treatments and drive new drug development.

Genome analysis of Streptococcus spp. isolates from animals in pre-antibiotic era with respect to antibiotic susceptibility and virulence gene profiles.

Lyophilized Streptococcus spp. isolates (n = 50) from animal samples submitted to the diagnostic laboratory at the University of Connecticut in the 1940s were revivified to investigate the genetic characteristics using whole-genome sequencing (WGS). The Streptococcus spp. isolates were identified as follows; S. agalactiae (n = 14), S. dysgalactiae subsp. dysgalactiae (n = 10), S. dysgalactiae subsp. equisimils (n = 5), S. uberis (n = 8), S. pyogenes (n = 7), S. equi subsp. zooepidemicus (n = 4), S. oralis (n = 1), and S. pseudoporcinus (n = 1). We identified sequence types (ST) of S. agalactiae, S. dysgalactiae, S. uberis, S. pyogenes, and S. equi subsp. zooepidemicus and reported ten novel sequence types of those species. WGS analysis revealed that none of Streptococcus spp. carried antibiotic resistance genes. However, tetracycline resistance was observed in four out of 15 S. dysgalactiae isolates and in one out of four S. equi subsp. zooepidemicus isolate. This data highlights that antimicrobial resistance is pre-existed in nature before the use of antibiotics. The draft genome sequences of isolates from this study and 426 complete genome sequences of Streptococcus spp. downloaded from BV-BRC and NCBI GenBank database were analyzed for virulence gene profiles and phylogenetic relationships. Different Streptococcus species demonstrated distinct virulence gene profiles, with no time-related variations observed. Phylogenetic analysis revealed high genetic diversity of Streptococcus spp. isolates from the 1940s, and no clear spatio-temporal clustering patterns were observed among Streptococcus spp. analyzed in this study. This study provides an invaluable resource for studying the evolutionary aspects of antibiotic resistance acquisition and virulence in Streptococcus spp.

Comparison of characteristics of children hospitalized for respiratory syncytial virus infection during the pre- and post-COVID-19 eras: a multicenter retrospective study.

BACKGROUND: Respiratory syncytial virus (RSV), a leading cause of lower respiratory tract infection (LRTI) among children, has resurged in the form of endemic or even pandemic in many countries and areas after the easing of COVID-19 containment measures. This study aimed to investigate the differences in epidemiological and clinical characteristics of children hospitalized for RSV infection during pre- and post-COVID-19 eras in Yunnan, China. METHODS: A total of 2553 pediatric RSV inpatients from eight hospitals in Yunnan were retrospectively enrolled in this study, including 1451 patients admitted in 2018-2019 (pre-COVID-19 group) and 1102 patients admitted in 2023 (post-COVID-19 group). According to the presence or absence of severe LRTI (SLRTI), patients in the pre- and post-COVID-19 groups were further divided into the respective severe or non-severe subgroups, thus analyzing the risk factors for RSV-associated SLRTI in the two eras. Demographic, epidemiological, clinical, and laboratory data of the patients were collected for the final analysis. RESULTS: A shift in the seasonal pattern of RSV activity was observed between the pre-and post-COVID-19 groups. The peak period of RSV hospitalizations in the pre-COVID-19 group was during January-April and October-December in both 2018 and 2019, whereas that in the post-COVID-19 group was from April to September in 2023. Older age, more frequent clinical manifestations (fever, acute otitis media, seizures), and elevated laboratory indicators [neutrophil-to-lymphocyte ratio (NLR), c-reactive protein (CRP), interleukin 6 (IL-6), co-infection rate] were identified in the post-COVID-19 group than those in the pre-COVID-19 group (all P < 0.05). Furthermore, compared to the pre-COVID-19 group, the post-COVID-19 group displayed higher rates of SLRTI and mechanical ventilation, with a longer length of hospital stay (all P < 0.05). Age, low birthweight, preterm birth, personal history of atopy, underlying condition, NLR, IL-6 were the shared independent risk factors for RSV-related SLRTI in both pre- and post-COVID-19 groups, whereas seizures and co-infection were independently associated with SLRTI only in the post-COVID-19 group. CONCLUSIONS: An off-season RSV endemic was observed in Yunnan during the post-COVID-19 era, with changed clinical features and increased severity. Age, low birthweight, preterm birth, personal history of atopy, underlying condition, NLR, IL-6, seizures, and co-infection were the risk factors for RSV-related SLRTI in the post-COVID-19 era.

The impact of perceived life stress and online social support on university students' mental health during the post-COVID era in Northwestern China: gender-specific analysis.

BACKGROUND: Before the pandemic, research had already established the potential impact of perceived life stress and social support on the mental health status of Chinese students. However, in the Post-COVID Era, the specific mechanisms linking these variables and the distinct role of online social support remain relatively unexplored. METHODS: After the cessation of China's dynamic zeroing policy, a total of 1180 university students from Northwestern China participated in this study by completing a demographic questionnaire, as well as self-report measures assessing mental health, perceived life stress, and online social support. RESULTS: Approximately 25% of students exhibited psychological symptoms. When examining different categories of perceived life stress, males reported experiencing a significantly greater impact in terms of punishment and interpersonal relationships compared to females. Females experienced significantly higher levels of learning pressure compared to males. Specific types of perceived life stress were found to be significant predictors of students' mental health status. Moreover, online social support was identified as a significant moderator in the relationship between all types of perceived life stress and mental health, irrespective of gender. CONCLUSION: Our study findings unveiled two significant aspects: Firstly, the impact of perceived life stress on the mental health of students was identified as a risk factor. Secondly, the role of online social support emerged as a protective factor, particularly in the post-pandemic context. Additionally, gender-specific patterns were observed in these relationships.

Dose-response relationship between 15 weeks of running and aerobic fitness: a retrospective analysis based on the fun running program.

BACKGROUND: Students' physical fitness, particularly aerobic fitness, has seriously declined during the COVID-19 epidemic. However, in the post-epidemic era, there are few studies on the methods of improving aerobic fitness. Understanding the dose-response relationship between physical activity and aerobic fitness is crucial for developing effective exercise prescriptions. METHOD: This retrospective study reviewed the Fun Running program at Wannan Medical College in China. We conducted a pre-post study design to analyze the impact of 15 weeks of Fun Running training on aerobic fitness. Middle and long-distance running pace (MLDR-P) was used as the primary indicator of aerobic fitness. A paired sample T-test was used to analyze the differences between the two MLDR-Ps. Pearson's correlation was used to examine the correlation between variables. Multiple linear regression was used to determine the extent to which Fun Running components explain the variance in MLDR-P. RESULTS: A total of 3244 college students participated in this study. 15 weeks of Fun Running training can significantly improve the MLDR-P in both females (P < 0.001, ES = 0.68) and males (P < 0.001, ES = 0.72). The MLDR-P was significantly correlated with Fun Running (R2 = 0.95, p < 0.05, for females; R2 = 0.96, p < 0.05, for males). The component that had the greatest impact on MLDR-P was pace (ß = 1.39, for females; ß = 1.09, for males), followed by distance (ß = 0.49, for females; ß = 0.15, for males), and last frequency (ß = -0.03, for all). CONCLUSION: This study fills the gap in research on the dose-response relationship between running and aerobic fitness among college students in the post-epidemic era. The results show that 15 weeks of Fun Running training can significantly improve aerobic fitness. Examination of the dose-response relationship between Fun Running and MLDR-P provides practitioners with valuable insights into prescribing aerobic fitness training, allowing them to develop more effective training programs. Future research should focus on how to implement a hierarchical Fun Running program effectively.

Evaluation of disease severity and prediction of severe cases in children hospitalized with influenza A (H1N1) infection during the post-COVID-19 era: a multicenter retrospective study.

BACKGROUND: The rebound of influenza A (H1N1) infection in post-COVID-19 era recently attracted enormous attention due the rapidly increased number of pediatric hospitalizations and the changed characteristics compared to classical H1N1 infection in pre-COVID-19 era. This study aimed to evaluate the clinical characteristics and severity of children hospitalized with H1N1 infection during post-COVID-19 period, and to construct a novel prediction model for severe H1N1 infection. METHODS: A total of 757 pediatric H1N1 inpatients from nine tertiary public hospitals in Yunnan and Shanghai, China, were retrospectively included, of which 431 patients diagnosed between February 2023 and July 2023 were divided into post-COVID-19 group, while the remaining 326 patients diagnosed between November 2018 and April 2019 were divided into pre-COVID-19 group. A 1:1 propensity-score matching (PSM) was adopted to balance demographic differences between pre- and post-COVID-19 groups, and then compared the severity across these two groups based on clinical and laboratory indicators. Additionally, a subgroup analysis in the original post-COVID-19 group (without PSM) was performed to investigate the independent risk factors for severe H1N1 infection in post-COIVD-19 era. Specifically, Least Absolute Shrinkage and Selection Operator (LASSO) regression was applied to select candidate predictors, and logistic regression was used to further identify independent risk factors, thus establishing a prediction model. Receiver operating characteristic (ROC) curve and calibration curve were utilized to assess discriminative capability and accuracy of the model, while decision curve analysis (DCA) was used to determine the clinical usefulness of the model. RESULTS: After PSM, the post-COVID-19 group showed longer fever duration, higher fever peak, more frequent cough and seizures, as well as higher levels of C-reactive protein (CRP), interleukin 6 (IL-6), IL-10, creatine kinase-MB (CK-MB) and fibrinogen, higher mechanical ventilation rate, longer length of hospital stay (LOS), as well as higher proportion of severe H1N1 infection (all P < 0.05), compared to the pre-COVID-19 group. Moreover, age, BMI, fever duration, leucocyte count, lymphocyte proportion, proportion of CD3+ T cells, tumor necrosis factor α (TNF-α), and IL-10 were confirmed to be independently associated with severe H1N1 infection in post-COVID-19 era. A prediction model integrating these above eight variables was established, and this model had good discrimination, accuracy, and clinical practicability. CONCLUSIONS: Pediatric H1N1 infection during post-COVID-19 era showed a higher overall disease severity than the classical H1N1 infection in pre-COVID-19 period. Meanwhile, cough and seizures were more prominent in children with H1N1 infection during post-COVID-19 era. Clinicians should be aware of these changes in such patients in clinical work. Furthermore, a simple and practical prediction model was constructed and internally validated here, which showed a good performance for predicting severe H1N1 infection in post-COVID-19 era.

Evaluation of the EMA log kow trigger for fish BCF testing based on data for several human pharmaceuticals.

In the European Medicines Agency (EMA) "Guideline for Environmental Risk Assessment of Medicinal Products for Human Use," a fish bioconcentration factor (BCF) study is triggered in Phase I for pharmaceuticals having log Kow >4.5, to support Persistence, Bioaccumulation and Toxicity (PBT) screening, and in Phase II to assess secondary poisoning and bioaccumulation ('B') potential when log Kow ≥3. The standard sampling schedule outlined in OECD Test Guideline 305 (TG305) may require assessment of approximately 200 fish following exposure to low- and high-test concentrations and a negative control. We report experimental log Kow and BCF values for 64 human pharmaceuticals that were used to evaluate the current BCF testing trigger of log Kow ≥3, and whether a single BCF exposure concentration allows accurate classification of bioaccumulation potential. Our data support raising the BCF testing trigger to log Kow ≥4, and use of a single test concentration. The resulting reduction in the use of fish is consistent with the 3 R s principle and did not adversely affect classification accuracy. An assessment of potential risk of secondary poisoning was also conducted for three drugs classified as either B or vB, and no risks were identified.

The natural history of hypertension in older adults: a study of two Finnish generational cohorts born 20 years apart.

BACKGROUND: We conducted a comparative analysis of hypertension prevalence, progression, and treatment in two Finnish population-based cohorts comprising older adults born 20 years apart. The study covered data from pre- and post-HYVET Study eras and spanned the onset of the COVID-19 pandemic. METHODS: All 70-year-old home-dwelling citizens of Turku, in Southwest Finland, were invited to participate in the survey in 1990 (1920-born TUVA cohort) and in 2010 (1940-born UTUVA cohort) with a 25-year follow-up plan. The analyses included those with available data for systolic and diastolic blood pressure (BP), yielding 1015 TUVA and 888 UTUVA participants at baseline. Biomarkers associated with BP were analysed with t- and chi-square tests. RESULTS: At baseline, 83.4% of TUVA and 74.3% of UTUVA participants had uncontrolled BP, with respective antihypertensive medication usage at 36.0% and 55.9% (p < .001 for both between-cohort differences). Systolic BP exhibited an inverted U-shaped trajectory, with TUVA initially 7.8 mmHg higher at 155.4 mmHg than UTUVA (p < .001). However, by the ages 80-82, the difference in systolic BP trajectories between the cohorts was attenuated to 4.0 mmHg (p = .03). Diastolic BP differences were less clinically significant. UTUVA demonstrated higher use of all five conventional antihypertensive categories than TUVA (p ≤ .02 for all categories). CONCLUSIONS: In the early years of older adulthood, the 1940-born cohort showed a positive trend in hypertension management, yet maintained a 74.3% baseline rate of uncontrolled BP. Furthermore, by the ages 81-82, the benefits observed over the 1920-born cohort had lessened, influenced by the COVID-19 pandemic or other lasting factors. Heightened efforts to improve hypertension treatment in older adults remain crucial in the post-HYVET era.

We studied two generational cohorts of older adults from Finland, born 20 years apart, to examine changes in blood pressure readings over time, the prevalence of high blood pressure, and its treatment. Our investigation spanned periods both before and after the HYVET Study, a significant research effort demonstrating the benefits of treating hypertension in older adult patients, reducing the risk of stroke and other causes of mortality. Additionally, we considered the potential impact of the COVID-19 pandemic on blood pressure control.We invited all 70-year-olds living at home in Turku, Southwest Finland, to participate in our survey in 1990 (the 1920-born cohort) and in 2010 (the 1940-born cohort), with plans to follow them for 25 years. We collected data on their blood pressure readings and the medications they were prescribed.At the outset of our study, when participants were 70 years old, a higher proportion of individuals in the 1920-born cohort had uncontrolled high blood pressure compared to those in the 1940-born group. In addition, the participants born in 1940 showed increased usage and a wider selection of antihypertensive medications compared to the 1920-born cohort. Despite this, over 70% of the 70-year-olds even in the 1940-born cohort still had uncontrolled blood pressure. Furthermore, by the time these individuals reached their early 80s, the initial improvements in blood pressure control over the 1920-born cohort had somewhat diminished.Our findings underscore the ongoing need for improvements in managing high blood pressure among older adults. This remains crucial as individuals age, emphasising the importance of continued research to develop better treatment approaches, even after landmark studies like HYVET.

Preventing Fluid Retention After Subarachnoid Haemorrhage During Administration of Endothelin Receptor Antagonist.

Prevention of delayed cerebral infarction (DCI) due to cerebral vasospasm after subarachnoid haemorrhage (SAH) has been done with intravenous Rho kinase inhibitors (ROCKI), ozagrel sodium (TXA2I), selective ROCKI infusion (ROCKI i.a.), and cerebrospinal fluid (CSF) drainage. The endothelin receptor antagonist (ERA, clazosentan) became available in 2022 and is said to be highly recommended for DCI prevention, while fluid retention such as pleural effusion and pulmonary oedema accumulation is often experienced. We investigated the relationship between patient background, fluid retention, and ERA. Ten consecutive SAH patients treated with ERA from July to December 2022 were included. We examined the results of blood sampling on admission, echocardiography, chest computed tomography (CT), with postoperative DCI, and hydrocephalus requiring cerebrospinal fluid shunt (hydro), and symptomatic fluid retention requiring albumin and furosemide (third fluid space). Two males and eight females, mean age 63 years, mean preoperative World Federation Neurosurgical Surgeons (WFNS) grade 3.5, mean creatinine 0.94, mean brain natriuretic peptide (NT-proBNP). In 1883, two patients with Takotsubo cardiomyopathy and four patients with neurogenic pulmonary oedema are present. All patients underwent coil embolisation, and postoperative CSF drainage, ROCKI, TXA2I systemic administration, and ROCKI i.a. There were one DCI, three hydro, and five third fluid cases. Concerning the third fluid, the only significant difference was found in the age. An improvement in fluid retention after ERA discontinuation in old patients was shown. Our experience suggests that age may be the most influential factor. Based on these results, we have also found that by avoiding the use of ERA in patients older than 80 years, strictly limiting the infusion volume when using ERA, and actively using the drugs for heart failure early on, the frequency of suffering from third fluid space is reduced.

Beyond the hockey stick: Climate lessons from the Common Era.

More than two decades ago, my coauthors, Raymond Bradley and Malcolm Hughes, and I published the now iconic "hockey stick" curve. It was a simple graph, derived from large-scale networks of diverse climate proxy ("multiproxy") data such as tree rings, ice cores, corals, and lake sediments, that captured the unprecedented nature of the warming taking place today. It became a focal point in the debate over human-caused climate change and what to do about it. Yet, the apparent simplicity of the hockey stick curve betrays the dynamicism and complexity of the climate history of past centuries and how it can inform our understanding of human-caused climate change and its impacts. In this article, I discuss the lessons we can learn from studying paleoclimate records and climate model simulations of the "Common Era," the period of the past two millennia during which the "signal" of human-caused warming has risen dramatically from the background of natural variability.

Self-study and online interactive case-based discussion to improve knowledge of medical students in the COVID-19 era.

BACKGROUND: We aimed to determine whether a new online interactive learning method for fifth-year medical students could improve their knowledge of pre- and postoperative care during the COVID-19 era. METHODS: A retrospective cohort study was conducted from June 2020 to May 2022 during the pre- and postoperative care course for fifth-year medical students in a university hospital in southern Thailand. Students in the 2020 cohort received only a 60-minute lecture on spinal anesthesia via Zoom while a 3-step online interactive learning method was used for the 2021 cohort. Step 1: students performed self-study comprised of video lectures and case-based discussion one week before the online class with a pre-test submitted via Google forms. Step 2: an online interactive case-based discussion class was performed via Zoom by two experienced anesthesia staff and a post-test was submitted by the students via Google forms. Step 3: a small group discussion of course evaluation between 13 representatives of students and anesthesia staff was performed via Zoom. A comparison of the post-test and pre-test scores containing 20 multiple choice questions as well as the final exam scores before (2020) and after (2021) the new interactive learning was performed using a t-test. RESULTS: There were 136 and 117 students in the 2020 and 2021 academic years, respectively. The final mean (SD) exam scores for the 2020 and 2021 academic years were 70.3 (8.4) and 72.5 (9.0), respectively with a mean (95% confidence interval (CI)) difference of 2.2 (4.3, -0.02). In 2021, the mean (95% CI) difference between the post-test and pre-test scores was 5.8 (5.1, 6.5). The student representatives were satisfied with the new learning method and gave insightful comments, which were subsequently implemented in the 2022 academic year course. CONCLUSION: The new interactive learning method improved the knowledge of fifth-year medical students attending pre- and postoperative care course during the COVID-19 era. The final exam scores may not be suitable to represent the overall outcomes of the new interactive learning method. Using an online two-way communication method can improve the overall satisfaction and course adaptation during the COVID-19 era.

The Role of the Endometrium in Implantation: A Modern View.

According to the current data, the endometrium acts as a "sensor" of embryo quality, which promotes the implantation of euploid embryos and prevents the implantation and/or subsequent development of genetically abnormal embryos. The present review addresses the nature of the "sensory function" of the endometrium and highlights the necessity for assessing its functional status. The first section examines the evolutionary origin of the "sensory" ability of the endometrium as a consequence of spontaneous decidualization that occurred in placental animals. The second section details the mechanisms for implementing this function at the cellular level. In particular, the recent findings of the appearance of different cell subpopulations during decidualization are described, and their role in implantation is discussed. The pathological consequences of an imbalance among these subpopulations are also discussed. Finally, the third section summarizes information on currently available clinical tools to assess endometrial functional status. The advantages and disadvantages of the approaches are emphasized, and possible options for developing more advanced technologies for assessing the "sensory" function of the endometrium are proposed.

The Anti-Atherosclerotic Effects of Endothelin Receptor Antagonist, Bosentan, in Combination with Atorvastatin-An Experimental Study.

Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male ApoE-/- mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, p < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG (p < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG (p < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG (p < 0.05). Bosentan treatment in diabetic, atherosclerotic ApoE-/- mice delayed the atherosclerosis progression and enhanced plaques' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.

A global comparative study on the impact of COVID-19 policy on atmospheric nitrogen dioxide (NO2): Evidence from remote sensing data in 2019-2022.

A significant body of research has documented the profound changes in global atmospheric conditions during the COVID-19 pandemic. However, there is still an inadequate comprehensive comparison and assessment of countries before, during, and after the pandemic. Variations in restriction policies, human behaviors, and national traits lead to significant differences in how restriction policies affect atmospheric pollution. This study focuses on NO2, a pollutant with high temporal sensitivity, and utilizes the Oxford COVID-19 policy stringency index along with demographic information. Through spatial-temporal mapping, we analyzed NO2 emission fluctuations and calculated the emission changes in each country. Drawing from this analysis, we explored the relationships among these factors and found that over the span of 2019-2022, across 193 countries, global NO2 emissions displayed a distinct trajectory: initially decreasing, subsequently rebounding, and eventually fluctuating. Most countries exhibited seasonal variations in NO2 emissions. Additionally, the study uncovered a correlation between the stringency of COVID-19 policies and the reduction in NO2 emissions: as policies became stricter, emissions significantly decreased in most countries. In contrast, in countries with lower population densities, stricter policies paradoxically led to an increase in emissions. These findings underscore the importance of considering demographic factors and geographical context in the formulation and implementation of environmental policies.

Working Vacations and Adventure: American Women Physician Volunteers to the Labrador Mission of Wilfred Grenfell Before 1914.

Many accounts, autobiographical and scholarly, emphasize how volunteers portrayed their work in the mission established for fishers by British physician Wilfred Grenfell in Newfoundland and Labrador: as escapist adventure. Scholars have not studied women physicians or their motivations to volunteer, however. This oversight derives from their small number combined with lack of knowledge about this mission's distinction from the foreign medical missions and domestic frontier missions that drew many women physicians to permanent positions. This study therefore discusses two American physicians, Alfreda B. Withington (1860-1951) and Emma E. Musson (1862-1913), who volunteered for summer service with this mission in 1907 and 1909, respectively. Through their publications, biographical sources, and clinical accounts, it reveals the appeal to them of such temporary, accessible volunteer service as a working vacation that rejuvenated. Importantly, it counters the skewed perspective of contemporary accounts in which the connection of Withington and Musson to an international celebrity, Wilfred Grenfell, overrode fuller considerations of their own lives, careers, and experiences. Finally, this examination suggests possible differences in their volunteerism between women physicians and their male counterparts: along with other women professionals, medical women often incorporated volunteer vacation experience into a continuum of similar endeavors in their careers.