Lynch syndrome in Mexican-Mestizo families: Genotype, phenotypes, and challenges in cascade testing among relatives at risk.

Lynch syndrome (LS) is the most frequent cancer predisposition syndrome affecting the colon and rectum. A pathogenic variant (PV) disrupting one of the mismatch repair (MMR) genes is responsible for the disease. The spectrum of tumors in LS is heterogeneous and includes cancer of the colon and rectum (CRC), endometrium, ovaries, stomach, small bowel, urinary tract, bladder, pancreas, and skin. Knowledge of the phenotypic variation of patients with LS, the type and frequency of PVs, and cascade testing studies in the Latin American population is limited. The present study aims to recognize the PVs in MMR genes, describe the phenotype in Mexican-Mestizo patients and their relatives, and identify the acceptance rate of cascade testing of relatives at risk. We included 40 carriers of a MMR gene PV and 142 relatives that developed a LS-related neoplasm. Patients' clinical data, number, and type of malignancies were obtained from their medical records. Amsterdam I-II, Bethesda criteria, and PREMM5® predictive model score were estimated. Available immunohistochemistry (IHC) reports were analyzed. Relatives at risk were determined from index cases pedigrees. The distribution of MMR gene mutations among 40 probands was: MLH1 (67.5 %), MSH2 (22.5 %), MSH6 (7.5 %), and PMS2 (2.5 %). Out of the 182 LS cases, 58 % exhibited the LS phenotype before age 50. The most common tumor was CRC, followed by endometrial cancer in women and gastric cancer in males. We found a 90.0 % concordance between the IHC and germline PV. The most frequent PV in our sample was MLH1 c.676C > T, occurring in 1/6 index cases. All probands disclosed their molecular test result to their family. Out of the 451 asymptomatic relatives at risk, 28.2 % underwent germline testing. Our results highlight the importance of conducting germline genetic studies in LS since it allows the establishment of appropriate cancer screening, risk-reducing measures, and genetic cascade testing among relatives at risk. Interestingly, we observed a significantly higher prevalence of the c.676C > T variant in MLH1, probably a singular characteristic of the Mexican-Mestizo population. New strategies to facilitate accurate communication between index cases and relatives should be implemented to improve the cascade testing acceptance rate.

Critical care specialists, the missing link in organ procurement for transplantation.

The procurement process for organ donation begins with the identification of potential organ donors in emergency or critical care units (CCU), followed by their clinical evaluation, diagnostic procedures, and therapeutic interventions, mostly conducted in CCUs. It concludes with the request for organ donation and, if accepted, the retrieval of organs. Despite most interventions occurring in detection units, there has been a neglect of the strategic role played by critical care specialists (CCS) in managing and caring for brain-dead or near-brain-death patients. Questions arise: Are they willing to undertake this responsibility? Do they fully comprehend the nature of organ procurement? Are they aware of the specific interventions required to maintain possible organ donors in optimal physiological condition? Our objective is to examine the role of CCS in organ procurement and propose ways to enhance it, ultimately aiming to increase and enhance organ donation rates.

Mechanical Thrombectomy Workshops Improve Procedural Knowledge and Skills Among Neurointerventional Teams in Low- to Middle-Income Countries.

BACKGROUND: While mechanical thrombectomy (MT) is proven to be lifesaving and disability sparing, there remains a disparity in its access in low- to middle-income countries. We hypothesized that team-based MT workshops would improve MT knowledge and skills. METHODS: We designed a 22-hour MT workshop, conducted as 2 identical events: in English (Jamaica, January 2022) and in Spanish (Dominican Republic, May 2022). The workshops included participating neurointerventional teams (practicing neurointerventionalists, neurointerventional nurses, and technicians) focused on acute stroke due to large vessel occlusion. The course faculty led didactic and hands-on components, covering topics from case selection and postoperative management to device technology and MT surgical techniques. Attendees were evaluated on stroke knowledge and MT skills before and after the course using a multiple choice exam and simulated procedures utilizing flow models under fluoroscopy, respectively. Press conferences for public education with invited government officials were included to raise stroke awareness. RESULTS: Twenty-two physicians and their teams from 8 countries across the Caribbean completed the didactic and hands-on training. Overall test scores (n=18) improved from 67% to 85% (P<0.002). Precourse and postcourse hands-on assessments demonstrated reduced time to completion from 36.5 to 21.1 minutes (P<0.001). All teams showed an improvement in measures of good MT techniques, with 39% improvement in complete reperfusion. Eight teams achieved a Thrombolysis in Cerebral Infarction score of 3 on pre-course versus 15 of 18 teams on post-course. There was a significant reduction in total potentially dangerous maneuvers (70% pre versus 20% post; P<0.002). Universally, the workshop was rated as satisfactory and likely to change practice in 93% Dominican Republic and 75% Jamaica. CONCLUSIONS: A team-based hands-on simulation approach to MT training is novel, feasible, and effective in improving procedural skills. Participants viewed these workshops as practice-changing and instrumental in creating a pathway for increasing access to MT in low- to middle-income countries.

Fear in general populations: A cross-sectional study on perceived fear of common diseases, COVID-19, life events, and environmental threats in 30 countries.

Background: In this study, we assessed the general population's fears towards various diseases and events, aiming to inform public health strategies that balance health-seeking behaviours. Methods: We surveyed adults from 30 countries across all World Health Organization (WHO) regions between July 2020 and August 2021. Participants rated their fear of 11 factors on an 11-point Likert scale. We stratified the data by age and gender and examined variations across countries and regions through multidimensional preference analysis. Results: Of the 16 512 adult participants, 62.7% (n = 10 351) were women. The most feared factor was the loss of family members, reported by 4232 participants (25.9%), followed by cancer (n = 2248, 13.7%) and stroke (n = 1416, 8.7%). The highest weighted fear scores were for loss of family members (mean (x̄) = 7.46, standard deviation (SD) = 3.04), cancer (x̄ = 7.00, SD = 3.09), and stroke (x̄ = 6.61, SD = 3.24). The least feared factors included animals/insects (x̄ = 3.72, SD = 2.96), loss of a mobile phone (x̄ = 4.27, SD = 2.98), and social isolation (x̄ = 4.83, SD = 3.13). Coronavirus disease 2019 (COVID-19) was the sixth most feared factor (x̄ = 6.23, SD = 2.92). Multidimensional preference analyses showed distinct fears of COVID-19 and job loss in Australia and Burundi. The other countries primarily feared loss of family members, cancer, stroke, and heart attacks; this ranking was consistent across WHO regions, economic levels, and COVID-19 severity levels. Conclusions: Fear of family loss can improve public health messaging, highlighting the need for bereavement support and the prevention of early death-causing diseases. Addressing cancer fears is crucial to encouraging the use of preventive services. Fear of non-communicable diseases remains high during health emergencies. Top fears require more resources and countries with similar concerns should collaborate internationally for effective fear management.

West Nile Virus Seroprevalence in Wild Birds and Equines in Madrid Province, Spain.

West Nile virus (WNV) is a re-emerging flavivirus, primarily circulating among avian hosts and mosquito vectors, causing periodic outbreaks in humans and horses, often leading to neuroinvasive disease and mortality. Spain has reported several outbreaks, most notably in 2020 with seventy-seven human cases and eight fatalities. WNV has been serologically detected in horses in the Community of Madrid, but to our knowledge, it has never been reported from wild birds in this region. To estimate the seroprevalence of WNV in wild birds and horses in the Community of Madrid, 159 wild birds at a wildlife rescue center and 25 privately owned equines were sampled. Serum from thirteen birds (8.2%) and one equine (4.0%) tested positive with a WNV competitive enzyme-linked immunosorbent assay (cELISA) designed for WNV antibody detection but sensitive to cross-reacting antibodies to other flaviviruses. Virus-neutralization test (VNT) confirmed WNV antibodies in four bird samples (2.5%), and antibodies to undetermined flavivirus in four additional samples. One equine sample (4.0%) tested positive for WNV by VNT, although this horse previously resided in a WN-endemic area. ELISA-positive birds included both migratory and resident species, juveniles and adults. Two seropositive juvenile birds suggest local flavivirus transmission within the Community of Madrid, while WNV seropositive adult birds may have been infected outside Madrid. The potential circulation of flaviviruses, including WNV, in birds in the Madrid Community raises concerns, although further surveillance of mosquitoes, wild birds, and horses in Madrid is necessary to establish the extent of transmission and the principal species involved.

Soluble antigen arrays provide increased efficacy and safety over free peptides for tolerogenic immunotherapy.

Autoantigen-specific immunotherapy using peptides offers a more targeted approach to treat autoimmune diseases, but clinical implementation has been challenging. We previously showed that multivalent delivery of peptides as soluble antigen arrays (SAgAs) efficiently protects against spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse model. Here, we compared the efficacy, safety, and mechanisms of action of SAgAs versus free peptides. SAgAs, but not their corresponding free peptides at equivalent doses, efficiently prevented the development of diabetes. SAgAs increased the frequency of regulatory T cells among peptide-specific T cells or induce their anergy/exhaustion or deletion, depending on the type of SAgA used (hydrolysable (hSAgA) and non-hydrolysable 'click' SAgA (cSAgA)) and duration of treatment, whereas their corresponding free peptides induced a more effector phenotype following delayed clonal expansion. Over time, the peptides induced an IgE-independent anaphylactic reaction, the incidence of which was significantly delayed when peptides were in SAgA form rather than in free form. Moreover, the N-terminal modification of peptides with aminooxy or alkyne linkers, which was needed for grafting onto hyaluronic acid to make hSAgA or cSAgA variants, respectively, influenced their stimulatory potency and safety, with alkyne-functionalized peptides being more potent and less anaphylactogenic than aminooxy-functionalized peptides. Immunologic anaphylaxis occurred in NOD mice in a dose-dependent manner but not in C57BL/6 or BALB/c mice; however, its incidence did not correlate with the level of anti-peptide antibodies. We provide evidence that SAgAs significantly improve the efficacy of peptides to induce tolerance and prevent autoimmune diabetes while at the same time reducing their anaphylactogenic potential.

Type 2 diabetes in latin America: recommendations on the flash glucose monitoring system.

OBJECTIVE: To establish recommendations through the consensus of a Latin American experts panel on the use of the flash glucose monitoring system (fCGM) in people living with type 2 diabetes mellitus (T2DM) regarding the benefits and challenges of using the fCGM. METHODS: An executive committee of experts was created, comprised by a panel of fifteen physicians, including endocrinologists and internal medicine physicians, with expertise in management of adult patients with T2DM. The experts were from various countries: Colombia, Chile, Peru, Mexico, Argentina, and Brazil. The modified Delphi method was used, considering a consensus level of at least 80% of the participants. A seventeen-item instrument was developed to establish recommendations on the use of fCGM in patients with T2DM in Latin American. RESULTS: The number of glucose scans recommended per day with the fCGM for patients managed with oral antidiabetic drugs or basal insulin was a median of 6 scans per day, and for those managed with multiple insulin doses, a median of 10 scans per day was recommended. Additionally, a holistic and individualized management approach was recommended, taking into account new treatment directions and identifying patients who would benefit from the use of the fCGM. CONCLUSION: Continuous use of the fCGM is recommended for people living with T2DM, regardless of their type of treatment. These metrics must be evaluated individually for each patient profile.

Impact of Fee For Service on the Efficiency and Survival of Seguro Popular's Patients With Acute Lymphoblastic Leukemia in Mexico.

PURPOSE: Cost containment and efficiency in the provision of health care are primary concerns for health systems that aim to provide affordable, high-quality care. Between 2005 and 2015, Seguro Poplar's Fund against Catastrophic Expenditures (FPGC) funded ALL treatment in Mexico. Before January 1, 2011, FPGC reimbursed a fixed amount per patient according to risk. In 2011, the per capita reimbursement method changed to fee for service. We used this natural experiment to estimate the impact of the reimbursement policy change on average expenditure and quality of care for ALL treatment in Mexico. METHODS: We used nationwide reimbursement data from the Seguro Poplar's FPGC from 2005 to 2015. We created a patient cohort to assess 3-year survival and estimate the average reimbursement before and after the fee-for-service policy. We examined survival and expenditure impacts, controlling for patients' and providers' characteristics, including sex, risk (standard and high), the volume of patients served, type of institution (federally funded v other), and level of care. To quantify the impact, we used a regression discontinuity approach. RESULTS: The average reimbursement for standard-risk patients in the 3-year survival cohort was $16,512 US dollars (USD; 95% CI, 16,042 to 17,032) before 2011 and $10,205 USD (95% CI, 4,659 to 12,541) under the fee-for-service reimbursement scheme after 2011. The average annual reimbursement per patient decreased by 136% among high-risk patients. The reduction was also significant for the standard-risk cohort, although the magnitude was substantially smaller (34%). CONCLUSION: As Mexico's government is currently restructuring the health system, our study provides evidence of the efficiency and effectiveness of the funding mechanism in the Mexican context. It also serves as a proof of concept for using administrative data to evaluate economic performance and quality of care of publicly funded health programs.

Impact of STAT-signaling pathway on cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression.

Colorectal cancer (CRC) remains one of the most commonly diagnosed and deadliest types of cancer worldwide. CRC displays a desmoplastic reaction (DR) that has been inversely associated with poor prognosis; less DR is associated with a better prognosis. This reaction generates excessive connective tissue, in which cancer-associated fibroblasts (CAFs) are critical cells that form a part of the tumor microenvironment. CAFs are directly involved in tumorigenesis through different mechanisms. However, their role in immunosuppression in CRC is not well understood, and the precise role of signal transducers and activators of transcription (STATs) in mediating CAF activity in CRC remains unclear. Among the myriad chemical and biological factors that affect CAFs, different cytokines mediate their function by activating STAT signaling pathways. Thus, the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors. Here, we analyze the impact of different STATs on CAF activity and their immunoregulatory role.

Exploring the Prevalence and Resistance of Campylobacter in Urban Bird Populations.

The increasing urbanization of ecosystems has had a significant impact on wildlife over the last few years. Species that find an unlimited supply of food and shelter in urban areas have thrived under human presence. Wild birds have been identified as amplifying hosts and reservoirs of Campylobacter worldwide, but the information about its transmission and epidemiology is still limited. This study assessed the prevalence of Campylobacter in 137 urban birds admitted at a wildlife rescue center, with 18.8% of individuals showing positive. C. jejuni was the most frequent species (82.6%), followed by C. coli and C. lari (4.3% each). The order Passeriformes (33.3%) showed significant higher presence of Campylobacter when compared to orders Columbiformes (0%) and Ciconiiformes (17.6%), as well as in samples collected during the summer season (31.9%), from omnivorous species (36.8%) and young individuals (26.8%). Globally, Campylobacter displayed a remarkable resistance to ciprofloxacin (70.6%), tetracycline (64.7%), and nalidixic acid (52.9%). In contrast, resistance to streptomycin was low (5.8%), and all the isolates showed susceptibility to erythromycin and gentamycin. The results underline the importance of urban birds as reservoirs of thermophilic antimicrobial-resistant Campylobacter and contribute to enhancing the knowledge of its distribution in urban and peri-urban ecosystems.

Predicting outcomes after kidney transplantation: Can Pareto's rules help us to do so?

Kidney transplantation is the best option for kidney replacement therapy, even considering that most of the times the grafts do not survive as long as their recipients. In the Khalil et al's experience, published in this issue of the Journal, they analyze their second kidney graft survival and describe those significant predictors of early loss. This editorial comments on the results and put in perspec tive that most of the times, long-term graft survival could be inadvertently jeopardized if the immunosuppressive therapy is reduced or withdrawn for any reason, and that it could happen frequently if the transplant physician intends to innovate with the clinical care without proper evidence-based data.

Hip joint center lateralization minimally affects the biomechanics of patient-specific flanged acetabular components: A computational model.

Patient-specific flanged acetabular components are utilized to treat failed total hip arthroplasties with large acetabular defects. Previous clinical studies from our institution showed that these implants tend to lateralize the acetabular center of rotation. However, the clinical impact of lateralization on implant survivorship is debated. Our goal was to develop a finite element model to quantify how lateralization of the native hip center affects periprosthetic strain and implant-bone micromotion distributions in a static level gait loading condition. To build the model, we computationally created a superomedial acetabular defect in a computed tomography 3D reconstruction of a native pelvis and designed a flanged acetabular implant to address this simulated bone defect. We modeled two implants, one with ~1 cm and a second with ~2 cm of hip center lateralization. We applied the maximum hip contact force and corresponding abductor force observed during level gait. The resulting strains were compared to bone fatigue strength (0.3% strain) and the micromotions were compared to the threshold for bone ingrowth (20 µm). Overall, the model demonstrated that the additional lateralization only slightly increased the area of bone at risk of failure and decreased the areas compatible with bone ingrowth. This computational study of patient-specific acetabular implants establishes the utility of our modeling approach. Further refinement will yield a model that can explore a multitude of variables and could be used to develop a biomechanically-based acetabular bone loss classification system to guide the development of patient-specific implants in the treatment of large acetabular bone defects.

Key lifestyles and health outcomes across 16 prevalent chronic diseases: A network analysis of an international observational study.

Background: Central and bridge nodes can drive significant overall improvements within their respective networks. We aimed to identify them in 16 prevalent chronic diseases during the coronavirus disease 2019 (COVID-19) pandemic to guide effective intervention strategies and appropriate resource allocation for most significant holistic lifestyle and health improvements. Methods: We surveyed 16 512 adults from July 2020 to August 2021 in 30 territories. Participants self-reported their medical histories and the perceived impact of COVID-19 on 18 lifestyle factors and 13 health outcomes. For each disease subgroup, we generated lifestyle, health outcome, and bridge networks. Variables with the highest centrality indices in each were identified central or bridge. We validated these networks using nonparametric and case-dropping subset bootstrapping and confirmed central and bridge variables' significantly higher indices through a centrality difference test. Findings: Among the 48 networks, 44 were validated (all correlation-stability coefficients >0.25). Six central lifestyle factors were identified: less consumption of snacks (for the chronic disease: anxiety), less sugary drinks (cancer, gastric ulcer, hypertension, insomnia, and pre-diabetes), less smoking tobacco (chronic obstructive pulmonary disease), frequency of exercise (depression and fatty liver disease), duration of exercise (irritable bowel syndrome), and overall amount of exercise (autoimmune disease, diabetes, eczema, heart attack, and high cholesterol). Two central health outcomes emerged: less emotional distress (chronic obstructive pulmonary disease, eczema, fatty liver disease, gastric ulcer, heart attack, high cholesterol, hypertension, insomnia, and pre-diabetes) and quality of life (anxiety, autoimmune disease, cancer, depression, diabetes, and irritable bowel syndrome). Four bridge lifestyles were identified: consumption of fruits and vegetables (diabetes, high cholesterol, hypertension, and insomnia), less duration of sitting (eczema, fatty liver disease, and heart attack), frequency of exercise (autoimmune disease, depression, and heart attack), and overall amount of exercise (anxiety, gastric ulcer, and insomnia). The centrality difference test showed the central and bridge variables had significantly higher centrality indices than others in their networks (P < 0.05). Conclusion: To effectively manage chronic diseases during the COVID-19 pandemic, enhanced interventions and optimised resource allocation toward central lifestyle factors, health outcomes, and bridge lifestyles are paramount. The key variables shared across chronic diseases emphasise the importance of coordinated intervention strategies.

Carcinogenic, non-carcinogenic risk, and attributable cases to organochlorine pesticide exposure in women from Northern Mexico.

This study aimed to estimate the carcinogenic and non-carcinogenic risk as well as the attributable cases due to exposure to organochlorine pesticides (OCPs): hexachlorobenzene (HCB), dichlorophenyltrichloroethane (DDT), hexachlorocyclohexane (HCH), heptachlor, and chlordane. From serum concentrations of pesticides of interest in a sample of 908 women from Northern Mexico, the risk for both cancer and non-cancer health effects was evaluated. The population attributable fraction (PAF) was also calculated based on summary association estimates between exposure to OCPs and different health events. Findings revealed that due to their OCP exposure slightly less than half of the women in the sample were at increased risk of developing non-cancerous diseases. Moreover, approximately 25% and 75% of participants were at risk of develop some type of cancer associated with their HCB and DDE concentrations, respectively. In addition, it was estimated that 40.5% of type 2 diabetes, 18.7% of endometriosis, and 23.1% of non-Hodgkin's lymphoma cases could have been prevented if women had not been exposed to these OCPs. Results suggest that the use of OCPs may have contributed to the disease burden in the study area and, based on the time required for these substances to be eliminated from the body, there are probably some women who are still at elevated risk of developing diseases associated to OCPs.

Most Promising Approaches to Improve Brain AVM Management: ARISE I Consensus Recommendations.

Brain arteriovenous malformations (bAVMs) are complex, and rare arteriovenous shunts that present with a wide range of signs and symptoms, with intracerebral hemorrhage being the most severe. Despite prior societal position statements, there is no consensus on the management of these lesions. ARISE (Aneurysm/bAVM/cSDH Roundtable Discussion With Industry and Stroke Experts) was convened to discuss evidence-based approaches and enhance our understanding of these complex lesions. ARISE identified the need to develop scales to predict the risk of rupture of bAVMs, and the use of common data elements to perform prospective registries and clinical studies. Additionally, the group underscored the need for comprehensive patient management with specialized centers with expertise in cranial and spinal microsurgery, neurological endovascular surgery, and stereotactic radiosurgery. The collection of prospective multicenter data and gross specimens was deemed essential for improving bAVM characterization, genetic evaluation, and phenotyping. Finally, bAVMs should be managed within a multidisciplinary framework, with clinical studies and research conducted collaboratively across multiple centers, harnessing the collective expertise and centralization of resources.

Impact of pharmaceutical care for asthma patients on health-related outcomes: An umbrella review.

Recent systematic reviews suggest that pharmacists' interventions in asthma patients have a positive impact on health-related outcomes. Nevertheless, the association is not well established, and the role of clinical pharmacists is poorly represented. The aim of this overview of systematic reviews is to identify published systematic reviews assessing the impact of pharmacists' interventions on health-related outcomes measured in asthma patients. PubMed, Embase, Scopus, and Cochrane Library were searched from inception to December 2022. Systematic reviews of all study designs and settings were included. Methodological quality was assessed using AMSTAR 2. Two investigators performed study selection, quality assessment and data collection independently. Nine systematic reviews met the inclusion criteria. Methodological quality was rated as high in one, low in two, and critically low in six. Reviews included 51 primary studies reporting mainly quality of life, asthma control, lung capacity, and therapeutic adherence. Only four studies were carried out in a hospital setting and only two reviews stated the inclusion of severe asthma patients. The quality of the systematic reviews was generally low, and this was the major limitation of this overview of systematic reviews. However, solid evidence supports that pharmaceutical care improves health-related outcomes in asthma patients.

CD8+ NKs as a potential biomarker of complete response and survival with lenalidomide plus R-GDP in the R2-GDP-GOTEL trial in recurrent/refractory diffuse large B cell lymphoma.

Background: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. DLBCL is an aggressive disease that can be cured with upfront standard chemoimmunotherapy schedules. However, in approximately 35-40% of the patients DLBCL relapses, and therefore, especially in this setting, the search for new prognostic and predictive biomarkers is an urgent need. Natural killer (NK) are effector cells characterized by playing an important role in antitumor immunity due to their cytotoxic capacity and a subset of circulating NK that express CD8 have a higher cytotoxic function. In this substudy of the R2-GDP-GOTEL trial, we have evaluated blood CD8+ NK cells as a predictor of treatment response and survival in relapsed/refractory (R/R) DLBCL patients. Methods: 78 patients received the R2-GDP schedule in the phase II trial. Blood samples were analyzed by flow cytometry. Statistical analyses were carried out in order to identify the prognostic potential of CD8+ NKs at baseline in R/R DLBCL patients. Results: Our results showed that the number of circulating CD8+ NKs in R/R DLBCL patients were lower than in healthy donors, and it did not change during and after treatment. Nevertheless, the level of blood CD8+ NKs at baseline was associated with complete responses in patients with R/R DLBCL. In addition, we also demonstrated that CD8+ NKs levels have potential prognostic value in terms of overall survival in R/R DLBCL patients. Conclusion: CD8+ NKs represent a new biomarker with prediction and prognosis potential to be considered in the clinical management of patients with R/R DLBCL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001620-29 EudraCT, ID:2014-001620-29.

Simulated Dopamine Modulation of a Neurorobotic Model of the Basal Ganglia.

The vertebrate basal ganglia play an important role in action selection-the resolution of conflicts between alternative motor programs. The effective operation of basal ganglia circuitry is also known to rely on appropriate levels of the neurotransmitter dopamine. We investigated reducing or increasing the tonic level of simulated dopamine in a prior model of the basal ganglia integrated into a robot control architecture engaged in a foraging task inspired by animal behaviour. The main findings were that progressive reductions in the levels of simulated dopamine caused slowed behaviour and, at low levels, an inability to initiate movement. These states were partially relieved by increased salience levels (stronger sensory/motivational input). Conversely, increased simulated dopamine caused distortion of the robot's motor acts through partially expressed motor activity relating to losing actions. This could also lead to an increased frequency of behaviour switching. Levels of simulated dopamine that were either significantly lower or higher than baseline could cause a loss of behavioural integration, sometimes leaving the robot in a 'behavioral trap'. That some analogous traits are observed in animals and humans affected by dopamine dysregulation suggests that robotic models could prove useful in understanding the role of dopamine neurotransmission in basal ganglia function and dysfunction.

Is Tibial Bone Mineral Density Related to Sex, Age, Preoperative Alignment, or Fixation Method in Primary Total Knee Arthroplasty?

BACKGROUND: Cementless total knee arthroplasty (TKA) has regained interest for its potential for long-term biologic fixation. The density of the bone is related to its ability to resist static and cyclic loading and can affect long-term implant fixation; however, little is known about the density distribution of periarticular bone in TKA patients. Thus, we sought to characterize the bone mineral density (BMD) of the proximal tibia in TKA patients. METHODS: We included 42 women and 50 men (mean age 63 years, range: 50 to 87; mean body mass index 31.6, range: 20.5 to 49.1) who underwent robotic-assisted TKA and had preoperative computed tomography scans with a BMD calibration phantom. Using the robotic surgical plan, we computed the BMD distribution at 1 mm-spaced cross-sections parallel to the tibial cut from 2 mm above the cut to 10 mm below. The BMD was analyzed with respect to patient sex, age, preoperative alignment, and type of fixation. RESULTS: The BMD decreased from proximal to distal. The greatest changes occurred within ± 2 mm of the tibial cut. Age did not affect BMD for men; however, women between 60 and 70 years had higher BMD than women ≥ 70 years for the total cut (P = .03) and the medial half of the cut (P = .03). Cemented implants were used in 1 86-year-old man and 18 women (seven < 60 years, seven 60 to 70 years, and four ≥ 70 year old). We found only BMD differences between cemented or cementless fixation for women < 60 years. CONCLUSIONS: To our knowledge, this is the first study to characterize the preoperative BMD distribution in TKA patients relative to the intraoperative tibial cut. Our results indicate that while sex and age may be useful surrogates of BMD, the clinically relevant thresholds for cementless knees remain unclear, offering an area for future studies.

Income, stress, and sex ratios over 1895-2010.

The medical literature has shown that populations under high stress have a lower sex ratio at birth (i.e. number of males for every 100 females). In this paper, I examine the relationship between income, as a source of economic stress, and the sex ratio at a subnational level for the 1895-2010 period. For this, I use census microdata from Argentina -a developing country that experienced rapid growth at the end of the 19th century and stagnated in recent decades- and I estimate from a two-way fixed effects model that exploits the wide temporal and geographic variability in income. The results show that as per capita income increases, the sex ratio at birth also increases. In particular, for every US$ 1,000 increase in per capita income, the sex ratio increases between 0.3 and 0.6 points. These findings make it possible to quantify the lost boys (i.e. those boys who were not born due to high economic stress on their parents) and constitute a call for attention in favor of the implementation of prenatal care policies -especially in periods of stagnation or income decline- to maintain a more balanced sex ratio.