Locally Advanced Adenocarcinoma of the Esophagus: Is Esophagectomy Associated with Improved Overall Survival?

BACKGROUND: Esophagectomy in locally advanced esophageal adenocarcinoma is challenging and carries risk. The value of esophagectomy in locally advanced esophageal adenocarcinoma is not well-defined. STUDY DESIGN: The National Cancer Database was used to identify patients with cT4 esophageal adenocarcinoma from 2004 to 2020. Multivariable regression was used to identify factors associated with use of esophagectomy. Cox modeling was used to identify factors associated with all-cause mortality. Patients undergoing esophagectomy were 1:1 propensity score-matched to patients treated nonsurgically. Kaplan-Meier analysis was used to compare 5-year overall survival (OS). RESULTS: A total of 3,703 patients met inclusion criteria. Of those, 541 (15%) underwent esophagectomy, and 3,162 (85%) did not. Age 65 years or less (adjusted odds ratio [aOR] 1.69, 95% CI 1.33 to 2.14), White race (aOR 2.98, 95% CI 2.24 to 3.96), treatment in academic centers (aOR 1.64, 95% CI 1.33 to 2.02), private insurance (aOR 1.88, 95% CI 1.50 to 2.36), and tumors less than 6 cm (aOR 1.86, 95% CI 1.44 to 2.40) were associated with use of esophagectomy. Government of lack of insurance (hazard ratio [HR] 1.23, 95% CI 1.12 to 1.35), income <$46,000 (HR 1.11, 95% CI 1.03 to 1.20), treatment in nonacademic centers (HR 1.16, 95% CI 1.07 to 1.25), Charlson-Deyo Comorbidity Index 1 or more (HR 1.22, 95% CI 1.12 to 1.32), and tumors 6 cm or more (HR 1.20, 95% CI 1.09 to 1.32) were associated with risk of all-cause mortality. Esophagectomy (HR 0.50, 95% CI 0.44 to 0.56) and systemic therapy (HR 0.40, 95% CI 0.37 to 0.43) were associated with decreased risk of all-cause mortality. Patients undergoing esophagectomy had higher rates of 5-year OS (27.4% vs 13.2%, p < 0.0001) and longer median OS (24.71 vs 10.09 months, p < 0.0001). Among cT4b patients, those who underwent esophagectomy had higher rates of 5-year OS (24.5% vs 12.3%, p < 0.0001) and longer median OS (25.53 vs 11.01 months, p < 0.0001). CONCLUSIONS: In cT4 esophageal adenocarcinoma, esophagectomy is associated with improved rates of 5-year OS compared with nonsurgical treatment.

Locally advanced pancreatic cancer: Is surgical palliation associated with improved clinical outcome relative to medical palliation?

BACKGROUND: The value of palliative surgery in pancreatic cancer is not well-defined. METHODS: We queried the National Cancer Database for patients undergoing curative-intent resection, palliative surgery or medical palliation for clinical stage cT4N0-2M0 pancreatic cancer. Cohorts were 1:1:1 propensity-score-matched for comorbidities and stage. Kaplan-Meier method was used to compare overall survival for matched cohorts. RESULTS: 9,107 patients met inclusion criteria: 3,567 (39 â€‹%) underwent curative intent surgery, 1608 (18 â€‹%) surgical palliation, 3932 (43 â€‹%) medical palliation. Patients undergoing resection and surgical palliation had significant hospitalizations (11.0 â€‹± â€‹0.4 vs. 10.0 â€‹± â€‹0.3 days; p â€‹= â€‹0.821) and rates of readmission (8.1 â€‹% vs. 2.0 â€‹%; p â€‹< â€‹0.001). Patients undergoing surgical palliation demonstrated marginal increases in survival relative to those undergoing medical palliation (8.54 vs. 7.36 months; p â€‹< â€‹0.0001). CONCLUSION: In patients undergoing care for locally advanced pancreatic cancer, palliative surgery is associated with marginal improvement in survival but significant lengths of hospitalization and risk of readmission.

Fragmented care in localized pancreatic cancer: Is commission on cancer accreditation associated with improved overall survival?

BACKGROUND: Prior studies of fragmentation of care in pancreatic cancer have not adjusted for indicators of hospital quality such as Commission on Cancer accreditation. The effect of fragmentation of care has not been well defined. METHODS: We queried the National Cancer Database to identify patients undergoing pancreaticoduodenectomy and distal pancreatectomy with perioperative systemic therapy for clinical stages I-III pancreatic cancer between 2006 and 2019. Patients who received systemic therapy at a center different than the center performing surgery were categorized as having fragmentation of care. Patients having fragmentation of care were further categorized on the basis of whether (fragmentation of care Commission on Cancer) or not (fragmentation of care non-Commission on Cancer) systemic therapy was administered at a facility accredited by the Commission on Cancer. RESULTS: A total of 11,732 patients met inclusion criteria; 5,668 (48.3%) underwent fragmentation of care, and 3,426 (29.2%) fragmentation of care non-Commission on Cancer. Patients undergoing fragmentation of care non-Commission on Cancer were less likely to receive neoadjuvant systemic therapy than those undergoing fragmentation of care Commission on Cancer or non-fragmented care (27.7% vs 40.1% vs 36.8%, P < .001). On Cox analysis, advanced age, comorbid disease, node-positive disease, and facility type were associated with risk of overall survival. Fragmentation of care was not (adjusted hazard ratio = 0.99, 95% confidence interval [0.94-1.06], P = .8). On Kaplan-Meier analysis, there were no significant differences in 5-year overall survival between treatment cohorts. CONCLUSION: In patients undergoing fragmentation of care for localized pancreatic cancer, those treated with systemic therapy in Commission on Cancer accredited facilities are more likely to be given neoadjuvant therapy but demonstrate no significant improvement in survival relative to those undergoing non-fragmented care or those undergoing fragmentation of care but receiving systemic therapy in nonaccredited facilities.

Clinical stage T2N0M0 rectal adenocarcinoma: Is radical resection associated with improved overall survival in patients with low-risk histology?

BACKGROUND: Prior studies evaluating the efficacy of local excision compared to radical resection in the treatment of rectal adenocarcinoma lacked sufficient power to identify differences in outcomes for patients with cT2 disease but low-risk histopathology. We compared the outcomes of local excision and radical resection for low-risk histopathology and high-risk histology of patients with cT2N0M0 rectal adenocarcinoma to assess their outcomes. METHODS: We queried the National Cancer Database for patients presenting with cT2N0M0 rectal adenocarcinoma between 2004 and 2019 and categorized them as low-risk histopathology or high-risk histology. We used the Cox proportional hazards model to identify factors associated with the risk of all-cause mortality. We 1:1 propensity-matched patients who underwent local excision to patients who underwent radical resection and used the Kaplan-Meier method to compare overall survival for matched cohorts. RESULTS: Of the 4,446 patients selected, we classified 1,206 (27%) as high-risk histology and 3,240 (73%) as low-risk histopathology. Among the patients with high-risk histology, 121 (10%) underwent local excision and 1,085 (90%) underwent radical resection. Among the patients with low-risk histopathology, 340 (10%) underwent local excision and 2,900 (90%) radical resections. Whereas radical resection was associated with decreased risk of all-cause mortality and increased overall survival for patients with high-risk histology, it was not for patients with low-risk histopathology. CONCLUSION: The overall survival of patients with low-risk histopathology with cT2N0M0 rectal adenocarcinoma who undergo local excision is similar to those of patients with low-risk histopathology who undergo radical resection, suggesting local excision is a reasonable approach for these patients. In contrast, radical resection provides a significant survival advantage for patients with high-risk histology and should remain their treatment of choice.

Does commission on cancer (CoC) accreditation mitigate the effect of care fragmentation on clinical outcome in localized rectal cancer?

BACKGROUND: Studies of fragmented care (FC) in rectal cancer have not adjusted for indicators of hospital quality and may misrepresent the effects of FC. METHODS: We queried the National Cancer Database to identify patients undergoing care for clinical stage II and III rectal adenocarcinoma between 2006 and 2019. Those undergoing FC were sub-categorized based on whether (FC CoC) or not (FC non-CoC) they received systemic therapy at CoC accredited facilities. RESULTS: 44,339 patients met inclusion criteria; 23,921 (54 â€‹%) underwent FC, 16,929 (71 â€‹%) FC non-CoC. Differences in utilization of neoadjuvant therapy (92.3 â€‹% vs 89.7 â€‹% vs 89.5 â€‹%, p â€‹< â€‹0.01) and 5-year overall survival (76.1 vs 75.5 vs 74.1 %, p â€‹< â€‹0.01) between treatment cohorts were marginal. CONCLUSION: In patients undergoing multimodality therapy for rectal cancer, care fragmentation is not associated with long-term clinical outcome. Decisions regarding where these patients go for systemic therapy may be safely made on the basis of ease of access.

Rectal neuroendocrine tumors: Can they be observed?

BACKGROUND: Studies comparing approaches to managing rectal neuroendocrine tumors are underpowered by institutional series. The efficacy of expectant management relative to local excision and radical resection is poorly defined. METHODS: We queried the National Cancer Database to identify patients presenting with non-metastatic rectal neuroendocrine tumors between 2004 and 2019. Multivariable regression was used to identify factors associated with expectant management. Cox modeling was used to identify factors associated with all-cause mortality. Patients undergoing expectant management were 1:1:1 propensity score matched for demographics and comorbid disease to those undergoing radical resection and local excision. The Kaplan-Meier method was used to compare overall survival profiles for matched cohorts. RESULTS: A total of 6,316 patients met the inclusion criteria. Of these, 5,211 (83%) underwent local excision, 600 (9.5%) radical resection, and 505 (8%) expectant management. On multivariable regression, factors associated with expectant management included Black race, government insurance, and tumor size <2.0 centimeters. On Cox modeling, factors associated with mortality included age >65 years, male sex, government insurance, comorbidity score >0, tumor size >2 centimeters, and poorly differentiated histology. On comparison of matched cohorts: patients undergoing radical resection had longer hospitalizations and higher readmission rates than those undergoing local excision; there was no difference in overall survival between cohorts in patients with stage 1 disease; in stage 2 and 3 diseases, patients undergoing local excision and radical resection demonstrated improved rates of overall survival relative to those undergoing expectant management. CONCLUSION: Expectant management is a reasonable approach for patients with stage 1 rectal neuroendocrine tumors. Local excision should be the preferred treatment option for those presenting with stage 2/3 disease.

Virtual Multidisciplinary Rounds to Reduce Length of Stay, Decrease Variation, and Promote Accountability.

PURPOSE: Evidence suggests in-person multidisciplinary rounds can help reduce length of stay (LOS) and improve throughput, but there are limited studies about the effectiveness of virtual multidisciplinary rounds on these measures. The authors hypothesized that virtual multidisciplinary rounds could help reduce LOS, improve throughput, promote accountability, and reduce provider variation. METHODS: The research team designed and implemented virtual multidisciplinary rounds by a phone conference call with key stakeholders, including hospitalists, case managers, the clinical documentation improvement team, physical and occupational therapy, and nursing leaders. To track progress in real time, dashboards were created using data from electronic medical records. After several months, unit-based discharge huddles were also implemented to supplement the process and sustain the improvement. RESULTS: The interventions led to more than 60% of discharges below geometric mean LOS after starting the initiative, compared to approximately 52% before the initiative. Mean observation hours went from around 44 hours to 31.9 hours, and the change was sustained for more than a year. In fiscal year 2021, 3,813 excess days were reduced in 10 months, resulting in combined savings of $6.7 million. A decrease in hospitalist provider variation is noted with the initiative, which is a crucial contributor to the results. CONCLUSION: Virtual multidisciplinary rounds combined with other interventions can effectively reduce LOS and observation hours. Decreasing variation among hospitalists and improved key stakeholder engagement can be achieved with virtual multidisciplinary rounds. More studies to test the effectiveness of virtual multidisciplinary rounds in various patient care settings would provide more insights.

The interactions of SARS-CoV-2 with cocirculating pathogens: Epidemiological implications and current knowledge gaps.

Despite the availability of effective vaccines, the persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suggests that cocirculation with other pathogens and resulting multiepidemics (of, for example, COVID-19 and influenza) may become increasingly frequent. To better forecast and control the risk of such multiepidemics, it is essential to elucidate the potential interactions of SARS-CoV-2 with other pathogens; these interactions, however, remain poorly defined. Here, we aimed to review the current body of evidence about SARS-CoV-2 interactions. Our review is structured in four parts. To study pathogen interactions in a systematic and comprehensive way, we first developed a general framework to capture their major components: sign (either negative for antagonistic interactions or positive for synergistic interactions), strength (i.e., magnitude of the interaction), symmetry (describing whether the interaction depends on the order of infection of interacting pathogens), duration (describing whether the interaction is short-lived or long-lived), and mechanism (e.g., whether interaction modifies susceptibility to infection, transmissibility of infection, or severity of disease). Second, we reviewed the experimental evidence from animal models about SARS-CoV-2 interactions. Of the 14 studies identified, 11 focused on the outcomes of coinfection with nonattenuated influenza A viruses (IAVs), and 3 with other pathogens. The 11 studies on IAV used different designs and animal models (ferrets, hamsters, and mice) but generally demonstrated that coinfection increased disease severity compared with either monoinfection. By contrast, the effect of coinfection on the viral load of either virus was variable and inconsistent across studies. Third, we reviewed the epidemiological evidence about SARS-CoV-2 interactions in human populations. Although numerous studies were identified, only a few were specifically designed to infer interaction, and many were prone to multiple biases, including confounding. Nevertheless, their results suggested that influenza and pneumococcal conjugate vaccinations were associated with a reduced risk of SARS-CoV-2 infection. Finally, fourth, we formulated simple transmission models of SARS-CoV-2 cocirculation with an epidemic viral pathogen or an endemic bacterial pathogen, showing how they can naturally incorporate the proposed framework. More generally, we argue that such models, when designed with an integrative and multidisciplinary perspective, will be invaluable tools to resolve the substantial uncertainties that remain about SARS-CoV-2 interactions.

Using LASSO Regression to Estimate the Population-Level Impact of Pneumococcal Conjugate Vaccines.

Pneumococcal conjugate vaccines (PCVs) protect against diseases caused by Streptococcus pneumoniae, such as meningitis, bacteremia, and pneumonia. It is challenging to estimate their population-level impact due to the lack of a perfect control population and the subtleness of signals when the endpoint-such as all-cause pneumonia-is nonspecific. Here we present a new approach for estimating the impact of PCVs: using least absolute shrinkage and selection operator (LASSO) regression to select variables in a synthetic control model to predict the counterfactual outcome for vaccine impact inference. We first used a simulation study based on hospitalization data from Mexico (2000-2013) to test the performance of LASSO and established methods, including the synthetic control model with Bayesian variable selection (SC). We found that LASSO achieved accurate and precise estimation, even in complex simulation scenarios where the association between the outcome and all control variables was noncausal. We then applied LASSO to real-world hospitalization data from Chile (2001-2012), Ecuador (2001-2012), Mexico (2000-2013), and the United States (1996-2005), and found that it yielded estimates of vaccine impact similar to SC. The LASSO method is accurate and easily implementable and can be applied to study the impact of PCVs and other vaccines.

The Dynamic Tracheoesophageal Prosthesis Length.

OBJECTIVE: In a postlaryngectomy patient, tracheoesophageal (TE) speech is considered to be the most effective and preferred method of communication. Previous research has demonstrated that despite an appropriately sized TE prosthesis placement at the time of puncture, there are a portion of patients that require resizing postoperatively. The purpose of this study was to report on the variability of the tracheoesophageal prosthesis length. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care academic medical center. METHODS: This was a retrospective chart review of 62 patients who underwent secondary tracheoesophageal puncture (TEP) at a tertiary care academic medical center from January 2008 to November 2019. Patient demographic information, average changes in prosthesis length, number of prosthesis adjustments, and timing of prosthesis exchanges were collected. RESULTS: 62 patients met criteria for study inclusion. Mean age was 61.96 years old with 49 being male (79%) and 13 (21%) females. Overall change in prosthesis length was - 3.85 mm ± 3.58 with time to first prosthesis change at 2.29 months ± 2.73. There was an average of 4.37 changes ± 3.43 before reaching a stable length. Twenty-six patients (41.9%) had increases in their prosthesis length resulting in closure of the tracheoesophageal fistula requiring seven patients (11.3%) to return to the operating room for repuncturing. History of smoking (P = 0.02), Blom-Singer prosthesis type (P = 0.03), and larger diameter (P = 0.01) appeared to be predisposing factors for a fluctuating prosthesis length. CONCLUSION: Tracheoesophageal prosthesis length decreases over time for secondary punctures, requiring adjustments with a speech language pathologist. There are a clinically significant portion that have fluctuations in prosthesis length resulting in an increased risk for requiring re-puncturing.

Differences in life attitudes between general population and hospitalized psychosomatic patients: a comparative cross-sectional study.

To compare the extent to which value-based life attitudes measured by means of the Life Attitude Profile (LAP-R) could differ between the general population and people suffering from mental disorders hospitalized in a psychosomatic ward. Cross-sectional comparative study between a sample of general population (n = 409) and a sample of unselected patients (n = 147) at admission in a psychosomatic ward. Comparisons were carried out by means of Cronbach's alpha, correlation matrix, t-tests, robust multivariate linear regression models (MLRM), and using propensity scores. The internal consistency of LAP-R is good (alpha = 0.90). Divergent validity with BFI dimensions is widely given. In MLRM general population scored higher for the indexes 'personal meaning' and 'existential transcendence', whereas psychosomatic patients for the dimensions 'responsibleness', 'death acceptance', 'goal seeking' and especially 'existential vacuum'. Sex, partnership and schooling display few associations. Neuroticism is negatively and agreeableness positively associated with life attitudes considered as protective. Norm values and differences were stratified by age ranges. This study demonstrates that basic human attitudes like personal transcendence, personal meaning, having a biographically supported mission in life, and belief in a reason for existence are so fundamental for individuals that they are to some degree given independently of having a mental disorder or not. Neuroticism is a risk trait and agreeableness a protective trait facing life attitudes. The findings of this study indicate that people suffering from mental disorders treated in a specialized psychosomatic unit in a general hospital have important value-based resources and simultaneously higher levels of existential vacuum that have to be considered in treatment planning but should also be embedded in a therapeutic alliance. The existential vacuum deserves special consideration in the treatment of patients, especially facing risk of suicide.

A Novel Human Sex Difference: Male Sclera Are Redder and Yellower than Female Sclera.

In a seminal study, Kobayashi and Kohshima (1997) found that the human sclera-the white of the eye-is unique among primates for its whitish color, and subsequent work has supported the notion that this coloration underlies the human ability to gaze follow. Kobayashi and Kohshima also claimed that there is no significant sex difference in sclera color, though no data were presented to support the claim. We investigated sclera color in a standardized sample of faces varying in age and sex, presenting the first data comparing male and female sclera color. Our data support the claim that indeed there is a sex difference in sclera color, with male sclera being yellower and redder than female sclera. We also replicated earlier findings that female sclera vary in color across the adult lifespan, with older sclera appearing yellower, redder, and slightly darker than younger sclera, and we extended these findings to male sclera. Finally, in two experiments we found evidence that people use sclera color as a cue for making judgements of facial femininity or masculinity. When sclera were manipulated to appear redder and yellower, faces were perceived as more masculine, but were perceived as more feminine when sclera were manipulated to appear less red and yellow. Though people are typically unaware of the sex difference in sclera color, these findings suggest that people nevertheless use the difference as a visual cue when perceiving sex-related traits from the face.

Obesity-Associated Neuropathy: Recent Preclinical Studies and Proposed Mechanisms.

Significance: The prevalence of metabolic syndrome (MetS) and associated obesity has increased in recent years, affecting millions worldwide. One of the most common complications of obesity is damage to the peripheral nerve system, referred to as neuropathy. The lack of disease-modifying therapy for this complication is largely due to a poor understanding of the complex neurobiology underlying neuropathy. Recent preclinical studies suggest that in addition to glucotoxic events, other mechanisms, including lipid signaling, microbiome, or inflammation, may be viable targets to prevent nerve damage and neuropathic pain in obesity. Recent Advances: Clinical and preclinical studies using diet-induced obesity rodent models have identified novel interventions that improve neuropathy. Notably, mechanistic studies suggest that lipid, calcium signaling, and inflammation are converging pathways. Critical Issues: In this review, we focus on interventions and their mechanisms that are shown to ameliorate neuropathy in MetS obese models, including: (i) inhibition of a sensory neuron population, (ii), modification of dietary components, (iii) activation of nuclear and mitochondrial lipid pathways, (iv) exercise, and (v) modulation of gut microbiome composition and their metabolites. Future Directions: These past years, novel research increased our knowledge about neuropathy in obesity and discovered the involvement of nonglucose signaling. More studies are necessary to uncover the interplay between complex metabolic pathways in the peripheral nerve system of obese individuals. Further mechanistic studies in preclinical models and humans are crucial to create single- or multitarget interventions for this complex disease implying complex metabolic phenotyping. Antioxid. Redox Signal. 37, 597-612.

The pitfalls of inferring virus-virus interactions from co-detection prevalence data: application to influenza and SARS-CoV-2.

There is growing experimental evidence that many respiratory viruses-including influenza and SARS-CoV-2-can interact, such that their epidemiological dynamics may not be independent. To assess these interactions, standard statistical tests of independence suggest that the prevalence ratio-defined as the ratio of co-infection prevalence to the product of single-infection prevalences-should equal unity for non-interacting pathogens. As a result, earlier epidemiological studies aimed to estimate the prevalence ratio from co-detection prevalence data, under the assumption that deviations from unity implied interaction. To examine the validity of this assumption, we designed a simulation study that built on a broadly applicable epidemiological model of co-circulation of two emerging or seasonal respiratory viruses. By focusing on the pair influenza-SARS-CoV-2, we first demonstrate that the prevalence ratio systematically underestimates the strength of interaction, and can even misclassify antagonistic or synergistic interactions that persist after clearance of infection. In a global sensitivity analysis, we further identify properties of viral infection-such as a high reproduction number or a short infectious period-that blur the interaction inferred from the prevalence ratio. Altogether, our results suggest that ecological or epidemiological studies based on co-detection prevalence data provide a poor guide to assess interactions among respiratory viruses.

Divergent patterns of confrontation with death using the Anticipated Farewell to Existence Questionnaire (AFEQT): a cross-sectional comparative study of four samples with increasing proximity to death.

BACKGROUND: Based on the concept of "Daseinsverabschiedung", an anthropological theory of "Anticipated Farewell to Existence" (AFE) was suggested on the basis of six grounding dimensions: selfhood, interpersonality, temporality, corporeality, worldliness, and transcendence, which are activated in a genuine manner facing death. The purpose of the study is to quantitatively compare the extent of confrontation with death between dying people in palliative care and those in other stages of life by means of the Anticipated Farewell to Existence Questionnaire" (AFEQT), based on these dimensions. METHODS: The sample (N = 485) consists of dying individuals in palliative wards and hospices (n = 121); old people living in nursing homes not suffering from a mortal disease (n = 62); young adults (n = 152), and middle-aged adults (n = 150). The design is cross-sectional and analytical. The relevance of anticipated farewell to existence was measured by means of the AFEQT. The internal consistency of the AFEQT was assessed using Cronbach's alpha and convergent validity by means of dimensions of the Life Attitude Profile-Revised (LAP-R). Differences between groups and associations with control variables were estimated by means of multiple regression models, including propensity scores. RESULTS: Cronbach's alpha for AFEQT was > 0.80 for the whole test and all subsamples, but < 0.70 for most dimensions in dying people. Correlations between each dimension and corresponding two factors was almost overall r > 0.80, p < 0.001. Good convergent validity between dimensions of AFEQT and of Life Attitude Profile-Revised in young and middle-aged participants showed correlations for superordinate indices between -0.23 and 0.72, and an overall p < 0.001. Dying people scored significantly higher for all dimensions, especially "altruistic preoccupation" and "reconciliation with existence" than people in other life stages (p < 0.01- < 0.001). Personality traits of "openness" and "agreeableness" are positively associated with higher scoring of AFEQT dimensions. About 77% of dying participants reported a personal benefit through the interview questions. CONCLUSIONS: With proximity to death, the anthropological dimensions proposed scored significant higher than in other stages of life, reflecting a stronger awareness, confrontation and reconciliation with the end of their own life. These dimensions, especially preoccupation for related persons and coexistence of acceptance and struggle with death have to be taken into account in a sensitive way by supporting dialogues with dying people and their relatives. TRIAL REGISTRATION: Observational cross-sectional study.

Amelioration of Cognitive and Behavioral Deficits after Traumatic Brain Injury in Coagulation Factor XII Deficient Mice.

Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII-/- mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII-/- mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII-/- mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII-/- mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII-/- mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery.

Modeling influenza seasonality in the tropics and subtropics.

Climate drivers such as humidity and temperature may play a key role in influenza seasonal transmission dynamics. Such a relationship has been well defined for temperate regions. However, to date no models capable of capturing the diverse seasonal pattern in tropical and subtropical climates exist. In addition, multiple influenza viruses could cocirculate and shape epidemic dynamics. Here we construct seven mechanistic epidemic models to test the effect of two major climate drivers (humidity and temperature) and multi-strain co-circulation on influenza transmission in Hong Kong, an influenza epidemic center located in the subtropics. Based on model fit to long-term influenza surveillance data from 1998 to 2018, we found that a simple model incorporating the effect of both humidity and temperature best recreated the influenza epidemic patterns observed in Hong Kong. The model quantifies a bimodal effect of absolute humidity on influenza transmission where both low and very high humidity levels facilitate transmission quadratically; the model also quantifies the monotonic but nonlinear relationship with temperature. In addition, model results suggest that, at the population level, a shorter immunity period can approximate the co-circulation of influenza virus (sub)types. The basic reproductive number R0 estimated by the best-fit model is also consistent with laboratory influenza survival and transmission studies under various combinations of humidity and temperature levels. Overall, our study has developed a simple mechanistic model capable of quantifying the impact of climate drivers on influenza transmission in (sub)tropical regions. This model can be applied to improve influenza forecasting in the (sub)tropics in the future.

Posttraumatic learning deficits correlate with initial trauma severity and chronic cellular reactions after closed head injury in male mice.

Traumatic brain injury (TBI) is often associated with sustained attention and memory deficits. As persisting neuroinflammation and neurodegeneration may contribute to posttraumatic psychomotor dysfunction, we studied the relationship of brain cellular reactions three months after a weight-drop closed head injury in male mice with posttraumatic learning and memory using automated home-cage monitoring of socially housed mice in IntelliCages as well as tests for locomotor activity, anxiety and forepaw fine motor skills. One month after TBI, deficits in place learning and cognitive flexibility in reverse learning were clearly detectable in IntelliCages and these memory deficits correlated with the initial trauma severity on the functional neuroscore. While sucrose preference or its extinction were not influenced by TBI, traumatized mice performed significantly worse in a complex episodic memory learning task. In consecutive locomotor and forepaw skilled use tests, posttraumatic hyperactivity and impairment of contralateral paw use were evident. Analysis of cellular reactions to TBI three months after injury in selected defined regions of interest in the immediate lesion, ipsi- and contralateral frontoparietal cortex and hippocampus revealed a persistent microgliosis and astrogliosis which were accompanied by iron-containing macrophages and myelin degradation in the lesion area as well as with axonal damage in the neighboring cortical regions. Microglial and astroglial reactions in cortex showed a positive correlation with the initial trauma severity and a negative correlation with the spatial and episodic memory indicating a role of brain inflammatory reactions in posttraumatic memory deficits.

Forecasting influenza in Europe using a metapopulation model incorporating cross-border commuting and air travel.

Past work has shown that models incorporating human travel can improve the quality of influenza forecasts. Here, we develop and validate a metapopulation model of twelve European countries, in which international translocation of virus is driven by observed commuting and air travel flows, and use this model to generate influenza forecasts in conjunction with incidence data from the World Health Organization. We find that, although the metapopulation model fits the data well, it offers no improvement over isolated models in forecast quality. We discuss several potential reasons for these results. In particular, we note the need for data that are more comparable from country to country, and offer suggestions as to how surveillance systems might be improved to achieve this goal.