Influence of Neoadjuvant Immunotherapy-Chemotherapy on Perioperative Outcomes in Locally Advanced Esophageal Adenocarcinoma.

BACKGROUND: This study evaluated the perioperative outcomes for patients who had locally advanced esophageal adenocarcinoma (EAC) treated with neoadjuvant immunotherapy (IO) and chemotherapy versus a matched cohort of patients who received neoadjuvant chemotherapy (NAC) alone. METHODS: A single-center non-randomized phase 2 trial was undertaken with locally advanced (cT3-4 and/or N+) EAC, and 49 patients completed neoadjuvant avelumab + docetaxel, cisplatin, 5FU (DCF) and esophagectomy between February 2018 and February 2020. These patients were matched with contemporary patients (January 2018 to June 2020) who met the inclusion criteria but received neoadjuvant chemotherapy alone (NAC) with a comparable docetaxel-based therapy. The postoperative outcomes then were compared between the two groups. RESULTS: For this study, 99 patients with locally advanced EAC underwent esophagectomy and met the enrolment criteria. Of these patients, 50 received NAC alone and 49 received IO + NAC. Baseline characteristics such as age, gender, and clinical stage were comparable between the two groups. Operative approach and rate of minimally invasive esophagectomy (~ 60%) were similar in the two groups. For the NAC-alone and IO + NAC groups, the respective overall and major complication rates were similar between the two groups (50% vs. 51% [p = 0.91] and 20% vs. 26% [p = 0.44], respectively), with concordant rates for anastomotic leak (6 [12%] vs. 6 [12%]; p = 0.86) and respiratory complications (13 [26%] vs. 11 [22%]; p = 0.68). The two groups did not differ significantly in terms of hospital length of stay or 30- and 90-day mortality rates. CONCLUSION: The addition of immunotherapy to neoadjuvant chemotherapy for locally advanced esophageal adenocarcinoma does not appear to alter perioperative short-term outcomes significantly after esophagectomy.

Transition from mild cognitive impairment to normal cognition: Determining the predictors of reversion with multi-state Markov models.

INTRODUCTION: The theoretical framework of the Alzheimer's disease continuum considers transition between stages in a unidirectional manner. Here we examine the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) and explore a set of potential variables associated with this phenomenon. METHODS: A total of 985 Spanish community-dwelling individuals aged 70 years and over at baseline were monitored for 5 years. During this time, 173 MCI and 36 dementia cases were identified. Multi-state Markov models were performed to characterize transitions between states through the dementia continuum. RESULTS: The rate of reversion from MCI to NC was 11%. There were significant non-modifiable (age, socioeconomic status, or apolipoprotein E) and modifiable factors (cognitive training or absence of affective symptoms) associated with reversion. DISCUSSION: Overall, our results highlight that the likelihood of progression from MCI to dementia is very similar to that of reversion from MCI to NC.

Refractive Error of Students (15- to 18-year-olds) in Northwest Mexico.

SIGNIFICANCE: We assessed the prevalence of refractive error in a sample of children of Northern Mexico using the Refractive Error Study in Children protocol of the World Health Organization, which allows for the comparison with other global studies. PURPOSE: Uncorrected refractive error is the main cause of visual impairment in children. The purpose of this study was to assess the refractive error and visual dysfunctions of students (15 to 18 years old) in the upper-middle school system of Sinaloa, Mexico. METHODS: A total of 3468 students in Sinaloa's high school system participated in the study from 2017 to 2019. Optometrists and student clinicians from the Optometry Program of the Autonomous University of Sinaloa conducted the testing. Tests included visual acuities and static retinoscopy. We did not use a cycloplegic agent. RESULTS: The results showed a high prevalence of uncorrected refractive errors. Myopia, defined as a refractive error ≤-0.50 D, had a prevalence of 36.11% (95% confidence interval, 33.47 to 38.83%); hyperopia, defined as a refractive error ≥+2.00 D, had a prevalence of 1.49% (95% confidence interval, 0.09 to 2.33%); and astigmatism, defined as a refractive error with a cylinder ≥0.75 D, had a prevalence of 29.17% (95% confidence interval, 26.60 to 31.76%). We found a significant effect of sex on visual acuity. CONCLUSIONS: Our results are consistent with a high prevalence of myopia reported in adolescents worldwide and in Mexico's northern regions. The results suggest that students attending high school and entering universities should be required to have an optometric eye examination. Additional studies are needed to investigate the prevalence of refractive errors in children in Mexico.

Impact of individual and neighborhood dimensions of socioeconomic status on the prevalence of mild cognitive impairment over seven-year follow-up.

Objectives: There is strong evidence about the association between low socioeconomic status (SES) and higher risk of dementia. However, it has not been conveniently addressed so far the role of SES on the incidence of mild cognitive impairment (MCI). This study examines the impact of individual and neighbourhood dimensions of SES, as well as their interaction, on the risk of developing MCI in a sample of older adults.Method: Data from the Vallecas Project cohort, an ongoing community-based longitudinal study for early detection of cognitive impairment and dementia, were used to build two indices of SES namely individual and neighbourhood, as well as a global SES as a combination of both, and to investigate their effects on MCI conversion by means of a multivariate-adjusted Cox proportional hazard model.Results: A total of 1180 participants aged 70 years and older were enrolled in this study. Of these, 199 cases of MCI (16.9%) were diagnosed at any point of the follow-up. The individual and neighbourhood dimensions of SES played different roles in the dynamics of the MCI occurrence through aging. Most importantly, the risk of developing MCI was almost double for lower SES quartiles when compared to the highest one.Conclusion: The incidence of MCI in older adults was related to both individual characteristics and socioeconomic context. Public health strategies should be holistic and focus not only on promoting the classical individual preventive measures, but also on reducing social inequalities to foster healthy aging and reduce dementia burden.

'I feel like a person has a right to use a product to protect themselves ': a qualitative study of the risk-benefit calculus on women's contraceptive use and choice.

Background Reducing pregnancy risk requires a multidimensional approach to sexual and reproductive health product development. The purpose of this analysis is to identify, compare, and contrast women's pre-use beliefs and attitudes about three different forms of contraceptives: intravaginal rings; spermicide in conjunction with condoms; and oral contraceptive pills - and explore how those attitudes and beliefs, along with actual method-use experience, may affect potential choices in contraceptive method moving forward. The relationship of beliefs and attitudes to their risk-benefit calculations when using these methods was also considered.? METHODS: Women used one or more contraceptive methods, each for 3-6 months. Qualitative data from individual in-depth interviews completed after each 3-month use period were analysed using a summary matrix framework. Data were extracted and summarised into themes. Each woman's experiences were compared among the methods she used; comparisons were also made across participants. RESULTS: The data consist of 33 90-120 min in-depth qualitative interviews from 16 women aged 20-34 years, in which they discussed various elements of their method use experience. One prominent theme was identified: the influence of attitudes and beliefs on the risk-benefit calculus. There were six key elements within the theme: pregnancy prevention; dosing and the potential for user error; side-effects; familiarity; disclosure; and sexual partnerships. CONCLUSIONS: Women weighed perceived risks and benefits in their decision-making and, ultimately, their contraception choices. Understanding women's beliefs and attitudes that contribute to a calculation of risk-benefit can inform the development of sexual and reproductive health products.

Developing Online Recruitment and Retention Methods for HIV Prevention Research Among Adolescent Males Who Are Interested in Sex with Males: Interviews with Adolescent Males.

BACKGROUND: Adolescent males interested in sex with males (AMSM) are an important audience for HIV prevention interventions, but they are difficult to reach due to their age and social stigma. OBJECTIVE: We aim to identify efficient methods to recruit and retain AMSM in online research. METHODS: Interviews with 14-to-18-year-old AMSM (N=16) were conducted at 2017 Pride events in Boston, MA and Providence, RI. RESULTS: Participants reported that (1) social media platforms are viable recruitment venues; (2) recruitment advertisements should describe the study using colorful/bright pictures, familiar words, and information about compensation; (3) surveys should be <20 minutes in length; (4) modest compensation (eg, email gift card, US $10 to $20) was preferred; and (5) communications that remind participants about the length and content of surveys, and compensation, should be sent between study activities to increase retention. CONCLUSIONS: Soliciting input from AMSM provides critical guidance regarding recruitment and retention procedures to increase the efficiency of HIV prevention research for this at-risk group.

Urban-rural disparities in COVID-19 hospitalisations and mortality: A population-based study on national surveillance data from Germany and Italy.

PURPOSE: Recent literature has highlighted the overlapping contribution of demographic characteristics and spatial factors to urban-rural disparities in SARS-CoV-2 transmission and outcomes. Yet the interplay between individual characteristics, hospitalisation, and spatial factors for urban-rural disparities in COVID-19 mortality have received limited attention. METHODS: To fill this gap, we use national surveillance data collected by the European Centre for Disease Prevention and Control and we fit a generalized linear model to estimate the association between COVID-19 mortality and the individuals' age, sex, hospitalisation status, population density, share of the population over the age of 60, and pandemic wave across urban, intermediate and rural territories. FINDINGS: We find that in what type of territory individuals live (urban-intermediate-rural) accounts for a significant difference in their probability of dying given SARS-COV-2 infection. Hospitalisation has a large and positive effect on the probability of dying given SARS-CoV-2 infection, but with a gradient across urban, intermediate and rural territories. For those living in rural areas, the risk of dying is lower than in urban areas but only if hospitalisation was not needed; while for those who were hospitalised in rural areas the risk of dying was higher than in urban areas. CONCLUSIONS: Together with individuals' demographic characteristics (notably age), hospitalisation has the largest effect on urban-rural disparities in COVID-19 mortality net of other individual and regional characteristics, including population density and the share of the population over 60.

Clinical predictors for mechanical ventilation assistance in Guillain-Barré syndrome.

Background: Guillain-Barré syndrome (GBS) frequently leads to respiratory failure and autonomic dysfunction, resulting in approximately one-third of patients requiring mechanical ventilation. Objective: This study aimed to identify clinical predictors for mechanical ventilation in patients with GBS. Methods: This research was conducted from 2010 to 2021 using registries from a tertiary hospital in an upper middle-income Latin American country. Participants were categorized into two groups based on their ventilation status. Demographic data were collected, and independent predictors of the need for mechanical ventilation were determined through multivariate logistic regression analysis. Results: Dysautonomic events occurred in 36% of the patients, with 17% requiring mechanical ventilation; the average duration of intubation was 1.16 ± 3.18 days. The multivariate analysis indicated that bulbar dysfunction significantly increased the likelihood of requiring mechanical ventilation by 19-fold (OR 18.67, 95% CI 5.85-59.42), followed by ophthalmoplegia, which increased the likelihood by sixfold (OR 5.68, 95% CI 1.28-25.19). Conclusion: Bulbar dysfunction, dysautonomia, and lower Medical Research Council (MRC) scores were significant predictors of the need for mechanical ventilation in hospitalized GBS patients. These findings support the need for close monitoring and early admission to the intensive care unit (ICU) admission for at-risk patients.

The development and implementation of a low-cost mechanical ventilator in a low-middle-income country during the COVID-19 pandemic: The Unisabana-HERONS.

Background: The COVID-19 pandemic in Latin America generated the need to develop low-cost, fast-manufacturing mechanical ventilators. The Universidad de La Sabana and the Fundacion Neumologica Colombiana designed and manufactured the Unisabana-HERONS (USH) ventilator. Here, we present the preclinical and clinical study results to evaluate its effectiveness and safety characteristics in an animal model (Yorkshire Sow) and five patients with acute respiratory failure receiving mechanical ventilatory support for 24 h. Methods: The effectiveness and safety outcomes included maintaining arterial blood gases and pulse oximetry saturation (SpO2), respiratory pressures and volumes (during continuous monitoring) in the range of ARDS and lung-protective strategy goals, and the occurrence of barotrauma. A significance level of 0.05 was used for statistical tests. This clinical trial was registered on Clinicaltrials.gov (NCT04497623) and approved by the ethics committee. Results: Among patients treated with the Unisabana-HERONS, the most frequent causes of acute respiratory failure were pneumonia in 3/5 (60 %) and ARDS in 2/5 (40 %). During the treatment, the ventilatory parameters related to lung protection protocols were kept within the safety range, and vital signs and blood gas were stable. The percentage of time that the respiratory pressures or volumes were out of safety range were plateau pressure >30 cm H2O: 0.00 %; driving pressure >15 cm H2O: 0.06 %; mechanical power >15 J/min: 0.00 %; and Tidal volume >8 mL/kg: 0.00 %. There were no adverse events related to the ventilator. The usability questionnaire retrieved a median score for all items between 9 and 10 (best score: 10), indicating great ease of use. Conclusion: The Unisabana-HERONS ventilator effectively provided adequate gas exchange and maintained the ventilatory parameters in the range of lung protection strategies in humans and an animal model. Furthermore, it is straightforward to use and is a low-cost medical device.

Dengue virus type 2: protein binding and active replication in human central nervous system cells.

An increased number of dengue cases with neurological complications have been reported in recent years. The lack of reliable animal models for dengue has hindered studies on dengue virus (DENV) pathogenesis and cellular tropism in vivo. We further investigate the tropism of DENV for the human central nervous system (CNS), characterizing DENV interactions with cell surface proteins in human CNS cells by virus overlay protein binding assays (VOPBA) and coimmunoprecipitations. In VOPBA, three membrane proteins (60, 70, and 130 kDa) from the gray matter bound the entire virus particle, whereas only a 70 kDa protein bound in white matter. The coimmunoprecipitation assays revealed three proteins from gray matter consistently binding virus particles, one clearly distinguishable protein (~32 kDa) and two less apparent proteins (100 and 130 kDa). Monoclonal anti-NS3 targeted the virus protein in primary cell cultures of human CNS treated with DENV-2, which also stained positive for NeuH, a neuron-specific marker. Thus, our results indicate (1) that DENV-2 exhibited a direct tropism for human neurons and (2) that human neurons sustain an active DENV replication as was demonstrated by the presence of the NS3 viral antigen in primary cultures of these cells treated with DENV-2.

Neuroimaging and serum biomarkers of neurodegeneration and neuroplasticity in Parkinson's disease patients treated by intermittent theta-burst stimulation over the bilateral primary motor area: a randomized, double-blind, sham-controlled, crossover trial study.

Background and objectives: Intermittent theta-burst stimulation (iTBS) is a patterned form of excitatory transcranial magnetic stimulation that has yielded encouraging results as an adjunctive therapeutic option to alleviate the emergence of clinical deficits in Parkinson's disease (PD) patients. Although it has been demonstrated that iTBS influences dopamine-dependent corticostriatal plasticity, little research has examined the neurobiological mechanisms underlying iTBS-induced clinical enhancement. Here, our primary goal is to verify whether iTBS bilaterally delivered over the primary motor cortex (M1) is effective as an add-on treatment at reducing scores for both motor functional impairment and nonmotor symptoms in PD. We hypothesize that these clinical improvements following bilateral M1-iTBS could be driven by endogenous dopamine release, which may rebalance cortical excitability and restore compensatory striatal volume changes, resulting in increased striato-cortico-cerebellar functional connectivity and positively impacting neuroglia and neuroplasticity. Methods: A total of 24 PD patients will be assessed in a randomized, double-blind, sham-controlled crossover study involving the application of iTBS over the bilateral M1 (M1 iTBS). Patients on medication will be randomly assigned to receive real iTBS or control (sham) stimulation and will undergo 5 consecutive sessions (5 days) of iTBS over the bilateral M1 separated by a 3-month washout period. Motor evaluation will be performed at different follow-up visits along with a comprehensive neurocognitive assessment; evaluation of M1 excitability; combined structural magnetic resonance imaging (MRI), resting-state electroencephalography and functional MRI; and serum biomarker quantification of neuroaxonal damage, astrocytic reactivity, and neural plasticity prior to and after iTBS. Discussion: The findings of this study will help to clarify the efficiency of M1 iTBS for the treatment of PD and further provide specific neurobiological insights into improvements in motor and nonmotor symptoms in these patients. This novel project aims to yield more detailed structural and functional brain evaluations than previous studies while using a noninvasive approach, with the potential to identify prognostic neuroprotective biomarkers and elucidate the structural and functional mechanisms of M1 iTBS-induced plasticity in the cortico-basal ganglia circuitry. Our approach may significantly optimize neuromodulation paradigms to ensure state-of-the-art and scalable rehabilitative treatment to alleviate motor and nonmotor symptoms of PD.

Intra- and interhemispheric symmetry of subcortical brain structures: a volumetric analysis in the aging human brain.

Here, we address the hemispheric interdependency of subcortical structures in the aging human brain. In particular, we investigated whether subcortical volume variations can be explained by the adjacency of structures in the same hemisphere or are due to the interhemispheric development of mirror subcortical structures in the brain. Seven subcortical structures in each hemisphere were automatically segmented in a large sample of 3312 magnetic resonance imaging (MRI) studies of elderly individuals in their 70s and 80s. We performed Eigenvalue analysis, and found that anatomic volumes in the limbic system and basal ganglia show similar statistical dependency whether considered in the same hemisphere (intrahemispherically) or different hemispheres (interhemispherically). Our results indicate that anatomic bilaterality of subcortical volumes is preserved in the aging human brain, supporting the hypothesis that coupling between non-adjacent subcortical structures might act as a mechanism to compensate for the deleterious effects of aging.

A Causal Analysis of the Effect of Age and Sex Differences on Brain Atrophy in the Elderly Brain.

We studied how brain volume loss in old age is affected by age, the APOE gene, sex, and the level of education completed. The quantitative characterization of brain volume loss at an old age relative to a young age requires-at least in principle-two MRI scans, one performed at a young age and one at an old age. There is, however, a way to address this problem when having only one MRI scan obtained at an old age. We computed the total brain losses of elderly subjects as a ratio between the estimated brain volume and the estimated total intracranial volume. Magnetic resonance imaging (MRI) scans of 890 healthy subjects aged 70 to 85 years were assessed. A causal analysis of factors affecting brain atrophy was performed using probabilistic Bayesian modelling and the mathematics of causal inference. We found that both age and sex were causally related to brain atrophy, with women reaching an elderly age with a 1% larger brain volume relative to their intracranial volume than men. How the brain ages and the rationale for sex differences in brain volume losses during the adult lifespan are questions that need to be addressed with causal inference and empirical data. The graphical causal modelling presented here can be instrumental in understanding a puzzling scientific area of study-the biological aging of the brain.

Prediction of Chronological Age in Healthy Elderly Subjects with Machine Learning from MRI Brain Segmentation and Cortical Parcellation.

Normal aging is associated with changes in volumetric indices of brain atrophy. A quantitative understanding of age-related brain changes can shed light on successful aging. To investigate the effect of age on global and regional brain volumes and cortical thickness, 3514 magnetic resonance imaging scans were analyzed using automated brain segmentation and parcellation methods in elderly healthy individuals (69-88 years of age). The machine learning algorithm extreme gradient boosting (XGBoost) achieved a mean absolute error of 2 years in predicting the age of new subjects. Feature importance analysis showed that the brain-to-intracranial-volume ratio is the most important feature in predicting age, followed by the hippocampi volumes. The cortical thickness in temporal and parietal lobes showed a superior predictive value than frontal and occipital lobes. Insights from this approach that integrate model prediction and interpretation may help to shorten the current explanatory gap between chronological age and biological brain age.

A Comparative Analysis of MRI Automated Segmentation of Subcortical Brain Volumes in a Large Dataset of Elderly Subjects.

In this study, we perform a comparative analysis of automated image segmentation of subcortical structures in the elderly brain. Manual segmentation is very time-consuming and automated methods are gaining importance as a clinical tool for diagnosis. The two most commonly used software libraries for brain segmentation -FreeSurfer and FSL- are put to work in a large dataset of 4,028 magnetic resonance imaging (MRI) scans collected for this study. We find a lack of linear correlation between the segmentation volume estimates obtained from FreeSurfer and FSL. On the other hand, FreeSurfer volume estimates tend to be larger thanFSL estimates of the areas putamen, thalamus, amygdala, caudate, pallidum, hippocampus, and accumbens. The characterization of the performance of brain segmentation algorithms in large datasets as the one presented here is a necessary step towards partially or fully automated end-to-end neuroimaging workflow both in clinical and research settings.

Host selection and forage ratio in West Nile virus-transmitting Culex mosquitoes: Challenges and knowledge gaps.

BACKGROUND: To date, no specific therapy or vaccination is available for West Nile virus (WNV) infections in humans; preventive strategies represent the only possibility to control transmission. To focus these strategies, detailed knowledge of the virus dynamics is of paramount importance. However, several aspects of WNV transmission are still unclear, especially regarding the role of potential vertebrate host species. Whereas mosquitoes' intrinsic characteristics cause them to favour certain hosts (host preference), absolute selection is impossible in natural settings. Conversely, the selection carried out among available hosts and influenced from hosts' availability and other ecological/environmental factors is defined as host selection. METHODOLOGY/PRINCIPAL FINDINGS: In July 2022, we searched PubMed database for original articles exploring host selection among WNV-transmitting Culex mosquitoes, the main WNV vector. We considered only original field studies estimating and reporting forage ratio. This index results from the ratio between the proportion of blood meals taken by mosquitoes on potential host species and the hosts' relative abundance. From the originally retrieved 585 articles, 9 matched the inclusion criteria and were included in this review. All but one of the included studies were conducted in the Americas, six in the United States, and one each in Mexico and Colombia. The remaining study was conducted in Italy. American Robin, Northern Cardinal, and House Finch were the most significantly preferred birds in the Americas, Common Blackbird in Italy. CONCLUSIONS/SIGNIFICANCE: Although ornithophilic, all observed WNV-transmitting mosquitoes presented opportunistic feeding behaviour. All the observed species showed potential to act as bridges for zoonotic diseases, feeding also on humans. All the observed mosquitoes presented host selection patterns and did not feed on hosts as expected by chance alone. The articles observe different species of mosquitoes in different environments. In addition, the way the relative host abundance was determined differed. Finally, this review is not systematic. Therefore, the translation of our results to different settings should be conducted cautiously.

Brain Structural and Functional Changes in Cognitive Impairment Due to Alzheimer's Disease.

Cognitive neuropsychology seeks a potential alignment between structural and functional brain features to explain physiological or pathological processes, such as Alzheimer's disease (AD). Several structural and functional brain changes occurring during the disease, including cognitive impairment, are found at the end of the patient's life, but we need to know more about what happens before its onset. In order to do that, we need earlier biomarkers at preclinical stages, defined by those biomarkers, to prevent the cognitive impairment. In this minireview, we have tried to describe the structural and functional changes found at different stages during AD, focusing on those features taking place before clinical diagnosis.

An epidemiological model for mosquito host selection and temperature-dependent transmission of West Nile virus.

We extend a previously developed epidemiological model for West Nile virus (WNV) infection in humans in Greece, employing laboratory-confirmed WNV cases and mosquito-specific characteristics of transmission, such as host selection and temperature-dependent transmission of the virus. Host selection was defined by bird host selection and human host selection, the latter accounting only for the fraction of humans that develop symptoms after the virus is acquired. To model the role of temperature on virus transmission, we considered five temperature intervals (≤ 19.25 °C; > 19.25 and < 21.75 °C; ≥ 21.75 and < 24.25 °C; ≥ 24.25 and < 26.75 °C; and > 26.75 °C). The capacity of the new model to fit human cases and the week of first case occurrence was compared with the original model and showed improved performance. The model was also used to infer further quantities of interest, such as the force of infection for different temperatures as well as mosquito and bird abundances. Our results indicate that the inclusion of mosquito-specific characteristics in epidemiological models of mosquito-borne diseases leads to improved modelling capacity.

Loneliness as Risk Factor for Alzheimer´s disease.

There is considerable empirical evidence that unequivocally points to loneliness as a modifiable risk factor for the development of Alzheimer's disease and other related dementias. With the emergence of the COVID-19 pandemic and the resulting lockdown and social distancing, there has been a renewed interest in studying this topic. The present review examines the links between loneliness and Alzheimer's disease, with particular emphasis on the mechanisms common to both conditions.