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Objective To develop and evaluate the performance of artificial intelligence (AI) models that can identify safe and dangerous zones of dissection, and anatomical landmarks during laparoscopic cholecystectomy (LC). Summary background data Many adverse events during surgery occur due to errors in visual perception and judgment leading to misinterpretation of anatomy. Deep learning, a subfield of AI, can potentially be used to provide real-time guidance intraoperatively. Methods Deep learning models were developed and trained to identify safe (Go) and dangerous (No-Go) zones of dissection, liver, gallbladder, and hepatocystic triangle during LC. Annotations were performed by four high-volume surgeons. AI predictions were evaluated using 10-fold cross-validation against annotations by expert surgeons. Primary outcomes were intersection-over-union (IOU) and F1 score (validated spatial correlation indices), and secondary outcomes were pixel-wise accuracy, sensitivity, specificity, ± standard deviation. Results AI models were trained on 2627 random frames from 290 LC videos, procured from 37 countries, 136 institutions and 153 surgeons. Mean IOU, F1 score, accuracy, sensitivity, and specificity for the AI to identify Go zones were 0.53 (±0.24), 0.70 (±0.28), 0.94 (±0.05), 0.69 (±0.20) and 0.94 (±0.03) respectively. For No-Go zones, these metrics were 0.71 (±0.29), 0.83 (±0.31), 0.95 (±0.06), 0.80 (±0.21) and 0.98 (±0.05), respectively. Mean IOU for identification of the liver, gallbladder and hepatocystic triangle were: 0.86 (±0.12), 0.72 (±0.19) and 0.65 (±0.22), respectively. Conclusions AI can be used to identify anatomy within the surgical field. This technology may eventually be used to provide real-time guidance and minimize the risk of adverse events.

Patient-derived xenograft (PDX) tumor models represent a valuable platform for identifying new biomarkers and novel targets, to evaluate therapy response and resistance mechanisms. This study aimed at establishment, characterization and therapy testing of colorectal carcinoma-derived PDX. We generated 49 PDX and validated identity between patient tumor and corresponding PDX. Sensitivity of PDX toward conventional and targeted drugs revealed that 92% of PDX responded toward irinotecan, 45% toward 5-FU, 65% toward bevacizumab, and 61% toward cetuximab. Expression of epidermal growth factor receptor (EGFR) ligands correlated to the sensitivity toward cetuximab. Proto-oncogene B-RAF, EGFR, Kirsten rat sarcoma virus oncogene homolog gene copy number correlated positively with cetuximab and erlotinib sensitivity. The mutational analyses revealed an individual mutational profile of PDX and mainly identical profiles of PDX from primary tumor vs corresponding metastasis. Mutation in PIK3CA was a determinant of accelerated tumor doubling time. PDX with wildtype Kirsten rat sarcoma virus oncogene homolog, proto-oncogene B-RAF, and phosphatidylinositol-4,5-bisphosphate 3-kinaseM catalytic subunit alfa showed higher sensitivity toward cetuximab and erlotinib. To study the molecular mechanism of cetuximab resistance, cetuximab resistant PDX models were generated, and changes in HER2, HER3, betacellulin, transforming growth factor alfa were observed. Global proteome and phosphoproteome profiling showed a reduction in canonical EGFR-mediated signaling via PTPN11 (SHP2) and AKT1S1 (PRAS40) and an increase in anti-apoptotic signaling as a consequence of acquired cetuximab resistance. This demonstrates that PDX models provide a multitude of possibilities to identify and validate biomarkers, signaling pathways and resistance mechanisms for clinically relevant improvement in cancer therapy.

The neuronal underpinning of learning cause-and-effect associations in the adolescent brain remains poorly understood. Two fundamental forms of associative learning are Pavlovian (classical) conditioning, where a stimulus is followed by an outcome, and operant (instrumental) conditioning, where outcome is contingent on action execution. Both forms of learning, when associated with a rewarding outcome, rely on midbrain dopamine neurons in the ventral tegmental area (VTA) and substantia nigra (SN). We find that in adolescent male rats, reward-guided associative learning is encoded differently by midbrain dopamine neurons in each conditioning paradigm. Whereas simultaneously recorded VTA and SN adult neurons have a similar phasic response to reward delivery during both forms of conditioning, adolescent neurons display a muted reward response during operant but a profoundly larger reward response during Pavlovian conditioning suggesting that adolescent neurons assign a different value to reward when it is not gated by action. The learning rate of adolescents and adults during both forms of conditioning was similar further supporting the notion that differences in reward response in each paradigm are due to differences in motivation and independent of state versus action value learning. Static characteristics of dopamine neurons such as dopamine cell number and size were similar in the VTA and SN but there were age differences in baseline firing rate, stimulated release and correlated spike activity suggesting that differences in reward responsiveness by adolescent dopamine neurons are not due to differences in intrinsic properties of these neurons but engagement of different networks.

In July 2020, the Florida Department of Health was alerted to three Candida auris bloodstream infections and one urinary tract infection in four patients with coronavirus disease 2019 (COVID-19) who received care in the same dedicated COVID-19 unit of an acute care hospital (hospital A). C. auris is a multidrug-resistant yeast that can cause invasive infection. Its ability to colonize patients asymptomatically and persist on surfaces has contributed to previous C. auris outbreaks in health care settings (1-7). Since the first C. auris case was identified in Florida in 2017, aggressive measures have been implemented to limit spread, including contact tracing and screening upon detection of a new case. Before the COVID-19 pandemic, hospital A conducted admission screening for C. auris and admitted colonized patients to a separate dedicated ward.

Emotional disorder symptoms are highly prevalent and a common cause of disability among children and adolescents. Screening and early detection are needed to identify those who need help and to improve treatment outcomes. Nowadays, especially with the arrival of the COVID-19 outbreak, assessment is increasingly conducted online, resulting in the need for brief online screening measures. The aim of the current study was to examine the reliability and different sources of validity evidence of a new web-based screening questionnaire for emotional disorder symptoms, the DetectaWeb-Distress Scale, which assesses mood (major depression and dysthymic disorder), anxiety (separation anxiety, generalized anxiety, social phobia, panic disorder/agoraphobia, and specific phobia), obsessive–compulsive disorder, post-traumatic stress disorder, suicidality (suicidal ideation, plans, and attempts), and global distress. A total of 1,499 participants (aged 8–18) completed the DetectaWeb-Distress Scale and specific questionnaires for emotional disorder symptoms, suicidal behaviors, and well-being through a web-based survey. Results indicated that a structural model of 10 correlated factors fits reasonably better in comparison to the remaining models; measurement invariance for age and gender; good internal consistency (McDonald's ω ranging from 0.65 to 0.94); and significant positive correlation with other measures of anxiety, depression, PTSD, or distress, and negative correlation with well-being measures, displaying support for convergent-discriminant validity. We also found that girls scored higher than boys on most of the subscales, and children had higher scores for social anxiety, specific phobia, panic disorder, and obsessive–compulsive symptoms, whereas adolescents scored higher on depressive symptoms, suicidality, and generalized anxiety, but the effect sizes were small to medium for all comparisons. The DetectaWeb-Distress Scale is a valid, innovative, and useful online tool for the screening and evaluation of preventive programs for mental health in children and adolescents. This study was supported by research grants conceded to the JP by the Vicerrectorado for Research and Technological Development from the Miguel Hernández University (BANCAJA-UMH, call 2010), the Department of Health Care (Consejeria de Sanidad) from the Valencian Community (SMI 10/2014), and the Vicerrectorado for Research from the Miguel Hernández University (YS0017VF); and a grant for the hiring of a pre-doctoral research assistant awarded to the MR-R (ACIF/2015/155; VALi+d Program; Department of Education, Research, Culture and Sport from the Valencian Community).

Background: Additional safe and effective vaccines are needed to control the COVID-19 pandemic. Methods: HERALD is an ongoing phase 2b/3 randomised, observer-blinded, placebo-controlled clinical trial in ten countries in Europe and Latin America. SARS-CoV-2 naive adults were randomised 1:1 to receive two doses of CVnCoV mRNA vaccine candidate or placebo 28 days apart. Primary efficacy analysis included symptomatic COVID-19 more than 14 days after second dose. Solicited adverse events (AEs) were assessed in phase 2b participants and unsolicited AEs in all participants. The study is registered at ClinicalTrials.gov (NCT04652102). Findings: Between 11 December 2020 and 12 April 2021, 39 680 participants were randomised and 39 529 received CVnCoV (19 783) or placebo (19 746). Overall VE was 48·2% (95% CI: 31·0–61·4; 83/12 851 vs. 145/12 221 in CVnCoV and placebo recipients, respectively). Overall VE against moderate-to-severe COVID-19 was 70·7% (95% CI: 42·5–86·1; 12/12 851 vs. 37/12 211, respectively). In participants aged 18–60 years VE was 52·5% (95% CI: 36·2–64·8; 71/11 532 vs. 136/11 031, respectively). Too few cases occurred in participants aged ≥61 years (CVnCoV: 12, placebo: 9) precluding VE evaluation. Wild type SARS-CoV-2 was detected in 7/204 (3%) sequenced cases, with 14 variants being responsible for the other cases. Solicited adverse events, mostly systemic, were more common in CVnCoV recipients; 542/2002 CVnCoV recipients and 61/1980 placebo recipients reported grade 3 events. Unsolicited serious AEs were reported for 82/19 746 CVnCoV recipients and 66/19 746 placebo recipients; 8 and 2 SAEs, respectively were considered related to vaccination. Fatal SAEs were reported for 8 and 6 CVnCoV and placebo recipients. Interpretation: CVnCoV is efficacious in the prevention of COVID-19 of any severity and has an acceptable safety profile. Trial Registration: Study number: ClinicalTrials.gov Identifier: NCT04652102. Funding: This trial was funded by the German Federal Ministry of Education and Research (grant 01KI20703), and CureVac AG. Declaration of Interest: MB declares institutional funding from CureVac during the conduct of this study, from Janssen Vaccines, molecular partners, and Merck outside of the submitted work, and consulting fees from Janssen Vaccines. EJLDB, and MFMR, TO and XSL declare institutional funding from CureVac during the conduct of this study. LE, and LG declare institutional funding from CureVac during the conduct of this study and outside of the submitted work. CFL declares institutional funding from CureVac during the conduct of this study, and outside of the submitted work, and is a member of WHO Covid-19 Vaccine Effectiveness Working Group and WHO Product Development for Vaccines Advisory Committee (PDVAC). CL declares institutional funding from CureVac during the conduct of this study, and is a member of the of German Society of Infection board. ILR declares institutional funding from CureVac during the conduct of this study and from J &J, and OSE Immunotherapeutics outside of the submitted work. PGK declares institutional funding from CureVac during the conduct of this study, and is a member of the scientific advisory board for the HERALD clinical trial. VVRH declares institutional funding from CureVac during the conduct of this study, and speakers fees from Gilead outside of the submitted work. HJ declares consultant fees from CureVac, is the Medical Responsible Person for the HERALD clinical trial, and is co-chair of DSMB for the HERALD clinical trial. AK and PM are employed by CureVac, and hold stock options. OSK declares consultant fees from CureVac during the conduct of this study, and is a member of the DSMB for a CVnCoV phase 1 trial. TV declares consultant fees from CureVac during the conduct of this study, and consultant fees from CureVac, AstraZeneca, Pfizer, Johnson&Johnson, and Moderna outside of the submitted work. LO is employed by CureVac, and holds stock options, and is the holder of a pending patent. The other authors declare no competing interests. Ethical Approval: The trial protocol and amendments have been approved by the appropriate independent ethics committee or institutional review board at each study centre

In colorectal cancer (CRC), the prevalence of NRAS mutations (5–9%) is inferior to that of KRAS mutations (40–50%). NRAS mutations feature lately during tumour progression and drive resistance to anti-EGFR therapy in KRAS wild-type tumours. To elucidate specific functions of NRAS mutations in CRC, we expressed doxycycline-inducible G12D and Q61K mutations in the CRC cell line Caco-2. A focused phospho-proteome analysis based on the Bio-Plex platform, which interrogated the activity of MAPK, PI3K, mTOR, STAT, p38, JNK and ATF2, did not reveal significant differences between Caco-2 cells expressing NRASG12D, NRASQ61K and KRASG12V. However, phenotypic read-outs were different. The NRAS Q61K mutation promoted anchorage-independent proliferation and tumorigenicity, similar to features driven by canonical KRAS mutations. In contrast, expression of NRASG12D resulted in reduced proliferation and apoptosis. At the transcriptome level, we saw upregulation of cytokines and chemokines. IL1A, IL11, CXCL8 (IL-8) and CCL20 exhibited enhanced secretion into the culture medium. In addition, RNA sequencing results indicated activation of the IL1-, JAK/STAT-, NFκB- and TNFα signalling pathways. These results form the basis for an NRASG12D-driven inflammatory phenotype in CRC.

Expression of the epidermal growth factor ligands amphiregulin (AREG) and epiregulin (EREG) is positively correlated with a response to EGFR-targeted therapies in colorectal cancer. Gene-body methylation sites, which show a strong inverse correlation with AREG and EREG gene expression, were identified in cell lines using targeted 454 FLX-bisulfite sequencing and SIRPH analyses for AREG/EREG promoters and intragenic CpGs. Upon treatment of colorectal cancer cells with 5-aza-2'-desoxycytidine, methylation decreases at specific intragenic CpGs accompanied by upregulation of AREG and EREG gene expression. The same AREG gene-body methylation was also found in human colorectal cancer samples and is independent of KRAS and NRAS mutations. Methylation is specifically decreased in the tumor epithelial compartment as compared to stromal tissue and normal epithelium. Investigation of a promoter/enhancer function of the AREG exon 2 region revealed a potential promoter function in reverse orientation. Retrospective comparison of the predictive power of AREG gene-body methylation versus AREG gene expression using samples from colorectal cancer patients treated with anti-EGFR inhibitors with complete clinical follow-up revealed that AREG expression is superior to AREG gene methylation. AREG and EREG genes undergo a complex regulation involving both intragenic methylation and promoter-dependent control.

Oxygen and carbon isotopes from herbivore teeth have previously been used as paleoenvironmental proxies. However, their use in white-tailed deer (Odocoileus virginianus) remains rare. Here, we present the results of analysis of sequential sub-samples from second and third molars of wild and non-wild deer from Georgia, United States in order to assess their application in humid subtropical climates. In wild deer, enamel carbonate δ18O corresponds broadly to the recorded precipitation δ18O over the 10-month period of tooth formation, capturing the rainfall seasonality across the physiogeographic regions of the state. Non-wild deer show significantly lower values compared to both measured and modeled δ18O precipitation. While δ13C in tooth enamel carbonate appears to reflect diet, it does not reflect seasonality in either population. The δ13C and δ15N from bone collagen values suggest that diet and source of drinking water influence the potential of white tailed deer tooth enamel carbonate to record the δ18O seasonality in the study area; therefore, special attention on the provenance of deer are necessary for obtaining accurate paleoclimate reconstruction.

CDC has updated the interim guidance for U.S. health care providers caring for pregnant women with possible Zika virus exposure in response to 1) declining prevalence of Zika virus disease in the World Health Organization's Region of the Americas (Americas) and 2) emerging evidence indicating prolonged detection of Zika virus immunoglobulin M (IgM) antibodies. Zika virus cases were first reported in the Americas during 2015-2016; however, the incidence of Zika virus disease has since declined. As the prevalence of Zika virus disease declines, the likelihood of false-positive test results increases. In addition, emerging epidemiologic and laboratory data indicate that, as is the case with other flaviviruses, Zika virus IgM antibodies can persist beyond 12 weeks after infection. Therefore, IgM test results cannot always reliably distinguish between an infection that occurred during the current pregnancy and one that occurred before the current pregnancy, particularly for women with possible Zika virus exposure before the current pregnancy. These limitations should be considered when counseling pregnant women about the risks and benefits of testing for Zika virus infection during pregnancy. This updated guidance emphasizes a shared decision-making model for testing and screening pregnant women, one in which patients and providers work together to make decisions about testing and care plans based on patient preferences and values, clinical judgment, and a balanced assessment of risks and expected outcomes.

The impact of electronic health record (EHR) immunization clinical alert systems on the delivery of other preventive services remains unknown. We assessed for spillover effects of an EHR immunization alert on delivery of 6 other preventive services, in children 18 to 30 months of age needing immunizations. We conducted a secondary data analysis, with additional primary data collection, of a randomized, historically controlled trial to improve immunization rates with EHR alerts, in an urban, primary care clinic. No significant differences were found in screening for anemia, lead, development, nutrition, and injury prevention counseling in children prompting EHR immunization alerts (n = 129), compared with controls (n = 135). Significant increases in oral health screening in patients prompting EHR alerts (odds ratio = 4.8, 95% CI = 1.8-13.0) were likely due to practice changes over time. An EHR clinical alert system targeting immunizations did not have a spillover effect on the delivery of other preventive services.

To evaluate fetal ultrasound and magnetic resonance imaging findings among a series of pregnant women with confirmed Zika virus infection to evaluate the signs of congenital Zika syndrome with respect to timing of infection.We conducted a retrospective case series of pregnant women referred to two perinatal clinics in Barranquilla and Ibagué, Colombia, who had findings consistent with congenital Zika syndrome and Zika virus infection confirmed in maternal, fetal, or neonatal samples. Serial ultrasound measurements, fetal magnetic resonance imaging results, laboratory results, and perinatal outcomes were evaluated.We describe 17 cases of confirmed prenatal maternal Zika virus infection with adverse fetal outcomes. Among the 14 symptomatic women, the median gestational age for maternal Zika virus symptoms was 10 weeks (range 7-14 weeks of gestation). The median time between Zika virus symptom onset and microcephaly (head circumference less than 3 standard deviations below the mean) was 18 weeks (range 15-24 weeks). The earliest fetal head circumference measurement consistent with microcephaly diagnosis was at 24 weeks of gestation. The earliest sign of congenital Zika syndrome was talipes equinovarus, which in two patients was noted first at 19 weeks of gestation. Common findings on fetal magnetic resonance imaging were microcephaly, ventriculomegaly, polymicrogyria, and calcifications.Our analysis suggests a period of at least 15 weeks between maternal Zika virus infection in pregnancy and development of microcephaly and highlights the importance of serial and detailed neuroimaging.

Background The Zika Contraception Access Network (Z-CAN) was designed to provide women in Puerto Rico who chose to delay or avoid pregnancy during the 2016–2017 Zika virus outbreak access to high-quality client-centered contraceptive counseling and the full range of reversible contractive methods on the same day and at no cost through a network of trained providers. We evaluated the implementation of Z-CAN from the patient perspective. Methods An online survey, administered to a subset of women served by the Z-CAN program approximately 2 weeks after their initial Z-CAN visit, assessed patient satisfaction and receipt of services consistent with select program strategies: receipt of high-quality client-centered contraceptive counseling, same-day access to the contraceptive method they were most interested in after counseling, and no-cost contraception. Results Of 3,503 respondents, 85.2% reported receiving high-quality client-centered contraceptive counseling. Among women interested in a contraceptive method after counseling (n = 3,470), most reported same-day access to that method (86.8%) and most reported receiving some method of contraception at no cost (87.4%). Women who reported receiving services according to Z-CAN program strategies were more likely than those who did not to be very satisfied with services. Women who received high-quality client-centered contraceptive counseling and same-day access to the method they were most interested in after counseling were also more likely to be very satisfied with the contraceptive method received. Conclusions A contraception access program can be rapidly implemented with high fidelity to program strategies in a fast-moving and complex public health emergency setting.

Background Childhood diarrhoea mortality has declined substantially in Peru in recent decades. We documented trends in childhood diarrhoea mortality from 1980 to 2015, along with trends in coverage of diarrhoea-related interventions and risk factors, to identify the main drivers of mortality reduction. Methods We conducted desk reviews on social determinants, policies and programmes, and diarrhoea-related interventions implemented during the study period. We reviewed different datasets on child mortality, and on coverage of diarrhoea-related interventions. We received input from individuals familiar with implementation of diarrhoea-related policies and programmes. We used the Lives Saved Tool (LiST) to help explain the reasons for the decline in diarrhoea mortality from 1980 to 2015 and to predict additional reduction with further scale up of diarrhoea-related interventions by 2030. Results In Peru under-five diarrhoea mortality declined from 23.3 in 1980 to 0.8 per 1000 livebirths in 2015. The percentage of under-five diarrhoea deaths as related to total under-five deaths was reduced from 17.8% in 1980 to 4.9% in 2015. Gross domestic product increased and poverty declined from 1990 to 2015. Access to improved water increased from 56% in 1986 to 79.3% in 2015. Oral rehydrating salts (ORS) use during an episode of diarrhoea increased from 3.6% in 1986 to 32% in 2015. Vertical programmes focused on diarrhoea management with ORS were implemented successfully in the 1980s and 1990s, and were replaced by integrated crosscutting interventions since the early 2000s. LiST analyses showed that about half (53.9%) of the reduction in diarrhoea mortality could be attributed to improved water, sanitation and hygiene, 25.0% to direct diarrhoea interventions and 21.1% to nutrition. The remaining mortality could be reduced by three-quarters by 2030 with improved diarrhoea treatment and further with enhanced breastfeeding practices and reduction in stunting. LiST does not take into account the role of social determinants. Conclusions The reduction of diarrhoeal under-five mortality in Peru can be explained by a combination of factors, including improvement of social determinants, child nutrition, diarrhoea treatment with ORS and prevention with rotavirus vaccine and increased access to water and sanitation. The already low rate of diarrhoea mortality could be further reduced by a number of interventions, especially additional use of ORS and zinc for diarrhoea treatment. Peru is a remarkable example of a country that was able to reduce childhood diarrhoea mortality by implementing interventions through vertical programmes initially, and afterwards through implementation of integrated multisectoral packages targeting prevalent illnesses and multi-causal problems like stunting.

Chronic mountain sickness (CMS) is a pathological condition resulting from chronic exposure to high-altitude hypoxia. While its prevalence is high in native Andeans (>10%), little is known about the genetic architecture of this disease. Here, we performed the largest genome-wide association study (GWAS) of CMS (166 CMS patients and 146 controls living at 4,380 m in Peru) to detect genetic variants associated with CMS. We highlighted four new candidate loci, including the first CMS-associated variant reaching GWAS statistical significance (rs7304081; P = 4.58 × 10−9). By looking at differentially expressed genes between CMS patients and controls around these four loci, we suggested AEBP2, CAST, and MCTP2 as candidate CMS causal genes. None of the candidate loci were under strong natural selection, consistent with the observation that CMS affects fitness mainly after the reproductive years. Overall, our results reveal new insights on the genetic architecture of CMS and do not provide evidence that CMS-associated variants are linked to a strong ongoing adaptation to high altitude.

Type 1 diabetes (T1D) is one of the most common chronic childhood diseases, and its prevalence is rapidly increasing. The management of glucose in T1D is challenging, as youth must consider a myriad of factors when making diabetes care decisions. This task often leads to significant hyperglycemia, hypoglycemia, and glucose variability throughout the day, which have been associated with short- and long-term medical complications. At present, most of what is known about each of these complications and the health behaviors that may lead to them have been uncovered in the clinical setting or in laboratory-based research. However, the tools often used in these settings are limited in their ability to capture the dynamic behaviors, feelings, and physiological changes associated with T1D that fluctuate from moment to moment throughout the day. A better understanding of T1D in daily life could potentially aid in the development of interventions to improve diabetes care and mitigate the negative medical consequences associated with it. Therefore, there is a need to measure repeated, real-time, and real-world features of this disease in youth. This approach is known as ecological momentary assessment (EMA), and it has considerable advantages to in-lab research. Thus, this viewpoint aims to describe EMA tools that have been used to collect data in the daily lives of youth with T1D and discuss studies that explored the nuances of T1D in daily life using these methods. This viewpoint focuses on the following EMA methods: continuous glucose monitoring, actigraphy, ambulatory blood pressure monitoring, personal digital assistants, smartphones, and phone-based systems. The viewpoint also discusses the benefits of using EMA methods to collect important data that might not otherwise be collected in the laboratory and the limitations of each tool, future directions of the field, and possible clinical implications for their use.

Zika virus infection during pregnancy can cause congenital microcephaly and brain abnormalities (1,2). Since 2015, Zika virus has been spreading through much of the World Health Organization's Region of the Americas, including U.S. territories. Zika virus is spread through the bite of Aedes aegypti or Aedes albopictus mosquitoes, by sex with an infected partner, or from a pregnant woman to her fetus during pregnancy.* CDC estimates that 41 states are in the potential range of Aedes aegypti or Aedes albopictus mosquitoes (3), and on July 29, 2016, the Florida Department of Health identified an area in one neighborhood of Miami where Zika virus infections in multiple persons are being spread by bites of local mosquitoes. These are the first known cases of local mosquito-borne Zika virus transmission in the continental United States.(†) CDC prevention efforts include mosquito surveillance and control, targeted education about Zika virus and condom use to prevent sexual transmission, and guidance for providers on contraceptive counseling to reduce unintended pregnancy. To estimate the prevalence of contraceptive use among nonpregnant and postpartum women at risk for unintended pregnancy and sexually active female high school students living in the 41 states where mosquito-borne transmission might be possible, CDC used 2011-2013 and 2015 survey data from four state-based surveillance systems: the Behavioral Risk Factor Surveillance System (BRFSS, 2011-2013), which surveys adult women; the Pregnancy Risk Assessment Monitoring System (PRAMS, 2013) and the Maternal and Infant Health Assessment (MIHA, 2013), which surveys women with a recent live birth; and the Youth Risk Behavior Survey (YRBS, 2015), which surveys students in grades 9-12. CDC defines an unintended pregnancy as one that is either unwanted (i.e., the pregnancy occurred when no children, or no more children, were desired) or mistimed (i.e., the pregnancy occurred earlier than desired). The proportion of women at risk for unintended pregnancy who used a highly effective reversible method, known as long-acting reversible contraception (LARC), ranged from 5.5% to 18.9% for BRFSS-surveyed women and 6.9% to 30.5% for PRAMS/MIHA-surveyed women. The proportion of women not using any contraception ranged from 12.3% to 34.3% (BRFSS) and from 3.5% to 15.3% (PRAMS/MIHA). YRBS data indicated that among sexually active female high school students, use of LARC at last intercourse ranged from 1.7% to 8.4%, and use of no contraception ranged from 7.3% to 22.8%. In the context of Zika preparedness, the full range of contraceptive methods approved by the Food and Drug Administration (FDA), including LARC, should be readily available and accessible for women who want to avoid or delay pregnancy. Given low rates of LARC use, states can implement strategies to remove barriers to the access and availability of LARC including high device costs, limited provider reimbursement, lack of training for providers serving women and adolescents on insertion and removal of LARC, provider lack of knowledge and misperceptions about LARC, limited availability of youth-friendly services that address adolescent confidentiality concerns, inadequate client-centered counseling, and low consumer awareness of the range of contraceptive methods available.

CDC has updated its interim guidance for U.S. health care providers caring for women of reproductive age with possible Zika virus exposure to include recommendations on counseling women and men with possible Zika virus exposure who are interested in conceiving. This guidance is based on limited available data on persistence of Zika virus RNA in blood and semen. Women who have Zika virus disease should wait at least 8 weeks after symptom onset to attempt conception, and men with Zika virus disease should wait at least 6 months after symptom onset to attempt conception. Women and men with possible exposure to Zika virus but without clinical illness consistent with Zika virus disease should wait at least 8 weeks after exposure to attempt conception. Possible exposure to Zika virus is defined as travel to or residence in an area of active Zika virus transmission ( http://www.cdc.gov/zika/geo/active-countries.html), or sex (vaginal intercourse, anal intercourse, or fellatio) without a condom with a man who traveled to or resided in an area of active transmission. Women and men who reside in areas of active Zika virus transmission should talk with their health care provider about attempting conception. This guidance also provides updated recommendations on testing of pregnant women with possible Zika virus exposure. These recommendations will be updated when additional data become available.

Consistent with global trends of infections due to multiple-drug resistant Gram-negative bacteria, we report the first official case of native mitral valve endocarditis due to multi-resistant Klebsiella Pneumonia Carbapenemase (KPC) producing Serratia marcescens. The patient underwent mitral valve replacement and was successfully treated with monotherapy ceftazidime-avibactam.

Context The purpose of this paper is to synthesize and evaluate the evidence on the effectiveness of repeat teen pregnancy prevention programs offered in clinical settings. Evidence acquisition Multiple databases were searched for peer-reviewed articles published from January 1985 to April 2016 that included key terms related to adolescent reproductive health services. Analysis of these studies occurred in 2017. Studies were excluded if they focused solely on sexually transmitted disease/HIV prevention services, or occurred outside of a clinic setting or the U.S., Canada, Europe, Australia, or New Zealand. Inclusion and exclusion criteria further narrowed the studies to those that included information on at least one short-term (e.g., increased knowledge); medium-term (e.g., increased contraceptive use); or long-term (e.g., decreased repeat teen pregnancy) outcome, or identified contextual barriers or facilitators for providing adolescent-focused family planning services. Standardized abstraction methods and tools were used to synthesize the evidence and assess its quality. Only studies of clinic-based programs focused on repeat teen pregnancy prevention were included in this review. Evidence synthesis The search strategy identified 27,104 citations, 940 underwent full-text review, and 120 met the adolescent-focused family planning services inclusion criteria. Only five papers described clinic-based programs focused on repeat teen pregnancy prevention. Four studies found positive (n=2) or null (n=2) effects on repeat teen pregnancy prevention; an additional study described facilitators for helping teen mothers remain linked to services. Conclusions This review identified clinic-based repeat teen pregnancy prevention programs and few positively affect factors that may reduce repeat teen pregnancy. Access to immediate postpartum contraception or home visiting programs may be opportunities to meet adolescents where they are and reduce repeat teen pregnancy. Theme information This article is part of a theme issue entitled Updating the Systematic Reviews Used to Develop the U.S. Recommendations for Providing Quality Family Planning Services, which is sponsored by the Office of Population Affairs, U.S. Department of Health and Human Services.

Objectives. We estimated the number of women of reproductive age in need who would gain coverage for contraceptive services after implementation of the Affordable Care Act, the extent to which there would remain a need for publicly funded programs that provide contraceptive services, and how that need would vary on the basis of state Medicaid expansion decisions. Methods. We used nationally representative American Community Survey data (2009), to estimate the insurance status for women in Massachusetts and derived the numbers of adult women at or below 250% of the federal poverty level and adolescents in need of confidential services. We extrapolated findings to simulate the impact of the Affordable Care Act nationally and by state, adjusting for current Medicaid expansion and state Medicaid Family Planning Expansion Programs. Results. The number of low-income women at risk for unintended pregnancy is expected to decrease from 5.2 million in 2009 to 2.5 million in 2016, based on states’ current Medicaid expansion plans. Conclusions. The Affordable Care Act increases women’s insurance coverage and improves access to contraceptive services. However, for women who remain uninsured, publicly funded family planning programs may still be needed.

The developing human fetus is able to cope with the physiological reduction in oxygen supply occurring in utero. However, it is not known if microvascularization of the fetus is augmented when pregnancy occurs at high altitude. Fifty-three healthy term newborns in Puno, Peru (3,840 m) were compared with sea-level controls. Pre- and postductal arterial oxygen saturation (SpO2) was determined. Cerebral and calf muscle regional tissue oxygenation was measured using near infrared spectroscopy (NIRS). Skin microcirculation was noninvasively measured using incident dark field imaging. Pre- and postductal SpO2 in Peruvian babies was 88.1 and 88.4%, respectively, which was 10.4 and 9.7% lower than in newborns at sea level ( P < 0.001). Cerebral and regional oxygen saturation was significantly lower in the Peruvian newborns (cerebral: 71.0 vs. 74.9%; regional: 68.5 vs. 76.0%, P < 0.001). Transcutaneously measured total vessel density in the Peruvian newborns was 14% higher than that in the newborns born at sea level (29.7 vs. 26.0 mm/mm2; P ≤ 0.001). This study demonstrates that microvascular vessel density in neonates born to mothers living at high altitude is higher than that in neonates born at sea level.

Context When caring for an adolescent client, providers of contraceptive services must consider whether and how to encourage parent/guardian–child communication about the adolescent’s reproductive health. The objective of this systematic review was to summarize the evidence on the effectiveness of programs designed to increase parent–child communication about reproductive health. The review was used to inform national recommendations on quality family planning services. Data analysis occurred from mid-2011 through 2012. Evidence acquisition Several electronic bibliographic databases were used to identify relevant articles, including PubMed, CINAHL, PsycINFO, and Popline, published from January 1985 through February 2011. Evidence synthesis Sixteen articles met the inclusion criteria: all studies examined the impact on at least one medium- or short-term outcome, and two studies assessed the impact on teen pregnancy. One study examined the impact of a program conducted in a clinic setting; the remainder examined the impact of programs in community settings. All studies showed a positive impact on at least one short-term outcome, and 12 of 16 studies showed an increase in parent–child communication about reproductive health. Four of seven studies found an impact on sexual risk behavior. Conclusions Most programs increased parent–child communication, and several resulted in reduced sexual risk behavior of adolescents. This suggests that delivering a clinic-based program that effectively helps parents/guardians talk to their adolescent child(ren) about reproductive health, or referring parents/guardians to an evidence-based program in the community, may be beneficial. However, further rigorous research on delivery of these programs in clinical settings is needed.

High altitude natives are reported to have outstanding work capacity in spite of the challenge of oxygen transport and delivery in hypoxia. To evaluate the developmental effect of lifelong exposure to hypoxia on aerobic capacity, VO2peak was measured on two groups of Peruvian Quechua subjects (18-35 years), who differed in their developmental exposure to altitude. Male and female volunteers were recruited in Lima, Peru (150 m), and were divided in two groups, based on their developmental exposure to hypoxia, those: a) Born at sea-level individuals (BSL), with no developmental exposure to hypoxia (n = 34) and b) Born at high-altitude individuals (BHA) with full developmental exposure to hypoxia (n = 32), but who migrated to sea-level as adults (>16-years-old). Tests were conducted both in normoxia (BP = 750 mm Hg) and normobaric hypoxia at sea-level (BP = 750 mm Hg, FiO2 = 0.12, equivalent to 4,449 m), after a 2-month training period (in order to control for initial differences in physical fitness) at sea-level. BHA had a significantly higher VO2peak at hypoxia (40.31 ± 1.0 ml/min/kg) as compared to BSL (35.78 ± 0.96 ml/min/kg, P = 0.001), adjusting for sex. The decrease of VO2peak at HA relative to SL (ΔVO2peak ) was not different between groups, controlling for baseline levels (VO2peak at sea-level) and sex (BHA = 0.35 ± 0.04 l/min, BSL = 0.44 ± 0.04 l/min; P = 0.12). Forced vital capacity (controlling for height) and the residuals of VO2peak (controlling for weight) had a significant association in the BHA group only (r = 0.155; P = 0.031). In sum, results indicate that developmental exposure to altitude constitutes an important factor to determine superior exercise performance.

Accumulation of the COMMD1 protein as a druggable pharmacology event to target cancer cells has not been evaluated so far in cancer animal models. We have previously demonstrated that a second-generation peptide, with cell-penetrating capacity, termed CIGB-552, was able to induce apoptosis mediated by stabilization of COMMD1. Here, we explore the antitumor effect by subcutaneous administration of CIGB-552 in a therapeutic schedule. Outstandingly, a significant delay of tumor growth was observed at 0.2 and 0.7 mg/kg (p

Objectives To assess feasibility of calculating clinical performance measures for contraceptive care for National Quality Forum submission: the percentage of women aged 15–44 years provided the following: (1) a most or moderately effective contraceptive method (MME) and (2) a long-acting reversible contraceptive (LARC) method. Methods We used 2013 Iowa Department of Public Health (IDPH) Title X and Iowa Medicaid data. We stratified Title X data by age and Medicaid data by age and benefit type (family planning waiver (FPW) vs. general Medicaid), and examined variation by residence, public health region and health plan based on program interest. Findings Among women attending IDPH Title X clinics in 2013 ( N =11,584), 86% of women aged 15–20 years and 83% of women aged 21–44 years were provided MME; and 20% of women aged 15–20 years and 20% of women aged 21–44 years were provided LARC. Estimates varied across Title X subrecipient agencies, which receive federal funds from IDPH. Among Medicaid FPW clients ( N =30,013), 79% of women aged 15–20 years and 73% of women aged 21–44 years were provided MME; and 12% of women aged 15–20 years and 11% of women aged 21–44 years were provided LARC. Among general Medicaid clients ( N =14,737), 40% of women aged 15–20 years and 28% of women aged 21–44 years were provided MME; and 5% of women aged 15–20 years and 5% of women aged 21–44 years were provided LARC. Conclusion A high percentage of IDPH Title X and FPW clients were provided an MME method. No reporting entity had a LARC percentage less than 1%–2%. Implications Measure calculation using Title X and Medicaid data is feasible and can potentially be used to identify ways to increase access to contraceptive methods.

High-altitude (HA) natives have blunted ventilatory responses to hypoxia (HVR), but studies differ as to whether this blunting is lost when HA natives migrate to live at sea level (SL), possibly because HVR has been assessed with different durations of hypoxic exposure (acute vs. sustained). To investigate this, 50 HA natives (>3,500 m, for >20 yr) now resident at SL were compared with 50 SL natives as controls. Isocapnic HVR was assessed by using two protocols: protocol 1, progressive stepwise induction of hypoxia over 5–6 min; and protocol 2, sustained (20-min) hypoxia (end-tidal Po 2 = 50 Torr). Acute HVR was assessed from both protocols, and sustained HVR from protocol 2. For HA natives, acute HVR was 79% [95% confidence interval (CI): 52–106%, P = not significant] of SL controls for protocol 1 and 74% (95% CI: 52–96%, P < 0.05) for protocol 2. By contrast, sustained HVR after 20-min hypoxia was only 30% (95% CI: −7–67%, P < 0.001) of SL control values. The persistent blunting of HVR of HA natives resident at SL is substantially less to acute than to sustained hypoxia, when hypoxic ventilatory depression can develop.

Objective To determine the etiology and clinical predictors of peripheral lymphadenopathy in HIV-infected individuals during the antiretroviral (ARV) era in a non-Tuberculosis endemic setting.

Gram-positive bacteria cause a broad spectrum of disease in immunocompetent and immunocompromised hosts. Despite increasing knowledge about resistance transmission patterns and new antibiotics, these organisms continue to cause significant morbidity and mortality, especially in the health care setting. Methicillin-resistant Staphylococcus aureus poses major problems worldwide as a cause of nosocomial infection and has emerged as a cause of community-acquired infections. This change in epidemiology affects choices of empirical antibiotics for skin and skin-structure infections and community-acquired pneumonia in many settings. Throughout the world, the treatment of community-acquired pneumonia and other respiratory tract infections caused by penicillin-resistant Streptococcus pneumoniae has been complicated by resistance to β-lactam and macrolide antibacterial drugs. Vancomycin-resistant enterococci are a major cause of infection in the hospital setting and remain resistant to treatment with most standard antibiotics. Treatment of diseases caused by resistant gram-positive bacteria requires appropriate use of available antibiotics and stewardship to prolong their effectiveness. In addition, appropriate and aggressive infection control efforts are vital to help prevent the spread of resistant pathogens.

Congenital Zika virus (ZIKV) infection can be detected in both the presence and absence of microcephaly and manifests as a number of signs and symptoms that are detected clinically and by neuroimaging. However, to date, qualitative and quantitative measures for the purpose of diagnosis and prognosis are limited.Main objectives of this study conducted on fetuses and infants with confirmed congenital Zika virus infection and detected brain abnormalities were (1) to assess the prevalence of microcephaly and the frequency of the anomalies that include a detailed description based on ultrasound and magnetic resonance imaging in fetuses and ultrasound, magnetic resonance imaging, and computed tomography imaging postnatally, (2) to provide quantitative measures of fetal and infant brain findings by magnetic resonance imaging with the use of volumetric analyses and diffusion-weighted imaging, and (3) to obtain additional information from placental and fetal histopathologic assessments and postnatal clinical evaluations.This is a longitudinal cohort study of Zika virus-infected pregnancies from a single institution in Colombia. Clinical and imaging findings of patients with laboratory-confirmed Zika virus infection and fetal brain anomalies were the focus of this study. Patients underwent monthly fetal ultrasound scans, neurosonography, and a fetal magnetic resonance imaging. Postnatally, infant brain assessment was offered by the use of ultrasound imaging, magnetic resonance imaging, and/or computed tomography. Fetal head circumference measurements were compared with different reference ranges with2 or3 standard deviations below the mean for the diagnosis of microcephaly. Fetal and infant magnetic resonance imaging images were processed to obtain a quantitative brain volumetric assessment. Diffusion weighted imaging sequences were processed to assess brain microstructure. Anthropometric, neurologic, auditory, and visual assessments were performed postnatally. Histopathologic assessment was included if patients opted for pregnancy termination.All women (n=214) had been referred for Zika virus symptoms during pregnancy that affected themselves or their partners or if fetal anomalies that are compatible with congenital Zika virus syndrome were detected. A total of 12 pregnant patients with laboratory confirmation of Zika virus infection were diagnosed with fetal brain malformations. Most common findings that were assessed by prenatal and postnatal imaging were brain volume loss (92%), calcifications (92%), callosal anomalies (100%), cortical malformations (89%), and ventriculomegaly (92%). Results from fetal brain volumetric assessment by magnetic resonance imaging showed that 1 of the most common findings associated with microcephaly was reduced supratentorial brain parenchyma and increased subarachnoid cerebrospinal fluid. Diffusion weighted imaging analyses of apparent diffusion coefficient values showed microstructural changes. Microcephaly was present in 33.3-58.3% of the cases at referral and was present at delivery in 55.6-77.8% of cases. At birth, most of the affected neonates (55.6-77.8%) had head circumference measurements3 standard deviations below the mean. Postnatal imaging studies confirmed brain malformations that were detected prenatally. Auditory screening results were normal in 2 cases that were assessed. Visual screening showed different anomalies in 2 of the 3 cases that were examined. Pathologic results that were obtained from 2 of the 3 cases who opted for termination showed similar signs of abnormalities in the central nervous system and placental analyses, including brain microcalcifications.Congenital microcephaly is not an optimal screening method for congenital Zika virus syndrome, because it may not accompany other evident and preceding brain findings; microcephaly could be an endpoint of the disease that results from progressive changes that are related to brain volume loss. Long-term studies are needed to understand the clinical and developmental relevance of these findings.

Mother-to-child transmission during pregnancy provides a unique system for studying the correlation between HLA phenotype and susceptibility to HIV infection. We studied this relationship in a Spanish cohort. We determined frequencies of HLA class I and II alleles in 120 infants born to HIV-infected mothers and 67 HIV-infected mothers. Although there was no statistical difference in the frequency of HLA-B35 between transmitting and non-transmitting mothers, the allele was more frequent in infected children than in uninfected children. HLA-B35 has been consistently reported as a risk factor in the progression to AIDS. In addition, it has been proposed that whether a given allele can confer susceptibility to, or protection against, progression depends on maternal versus paternal inheritance patterns, since the child inherits a virus that reflects the history of CTL encounters of the mother. Our results on vertical HIV transmission combine for the first time the 'HLA-B35 disadvantage' and the 'pattern of inheritance' theories.

Monge's disease is characterized by an excessive erythrocytosis, frequently associated with pulmonary hypertension, in high-altitude dwellers. It has a considerable impact on public health in high-altitude regions. A preliminary study demonstrated the efficiency of acetazolamide (Acz) (250 mg/d for 3 wk) in reducing serum erythropoietin and hematocrit.Evaluate the efficacy and tolerance of a 6-month treatment with 250 mg Acz that could be chronically implemented and its effects on pulmonary artery pressure and cardiac function.A two-phase study was performed in patients (hematocritor = 63%) from Cerro de Pasco, Peru (4,300 m). First phase: a double-blind, placebo-controlled study in 55 patients who received a single dose of either 250 mg Acz (n = 40) or placebo (n = 15) by daily oral administration for 12 weeks. Second phase (open label): after a 4-week washout period, all patients received 250 mg Acz for 12 weeks. Hematocrit, blood gases, clinical outcome, and pulmonary artery circulation were evaluated.First phase: Acz decreased by 44% the number of polycythemic subjects (P = 0.02), decreased hematocrit from 69 to 64% (P0.001), and increased arterial O(2) pressure from 42 to 45 mm Hg (P0.001). No severe adverse effect or hypokalemia was recorded. The second phase reproduced the effects observed during the first phase, without cumulative effects on hematocrit. A 4-week washout restored basal hematocrit. Only patients who received Acz for 6 months showed a clear reduction in pulmonary vascular resistance.Acz reduces erythrocytosis and improves pulmonary circulation in Monge's disease without adverse effects. Its implementation as a chronic treatment for this disease appears efficient and safe.

Bigham, Abigail W., Melisa Kiyamu, Fabiola León-Verlarde, Esteban J. Parra, Maria Rivera-Ch, Mark D. Shriver, and Tom D. Brutsaert. Angiotensin-converting enzyme genotype and arterial oxygen saturation at high altitude in Peruvian Quechua. High Alt. Med. Biol. 9:167–178, 2008.—The I-allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with performance benefits at high altitude (HA). In n = 142 young males and females of largely Quechua origins in Peru, we evaluated 3 specific hypotheses with regard to the HA benefits of the I-allele: (1) the I-allele is associated with higher arterial oxygen saturation (\documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland,xspace}\usepackage{amsmath,amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}$${\rm Sa}_{\rm O_2}$$\end{document}) at HA, (2) the I-allele effect depends on the acclimatization state of the subjects, and (3) the putative I-allele effect on \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland,xspace}\usepackage{amsmath,amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}$${\rm Sa}_{\rm O_2}$$\end{document} is mediated by the isocapnic hypoxic ventilatory response (HVR, \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland,xspace}\usepackage{amsmath,amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}$$1 / {\rm min}^{- 1} / \%{\rm Sa}_{\rm O_2}{- 1}$$\end{document}). The subject participants comprised two different study groups including BLA subjects (born at low altitude) who were lifelong sea-level residents transiently exposed to hypobaric hypoxia (

This study seeks the unique perspective of Latin American— trained nurses on barriers and strategies to improve the health of Baltimore's Latino community. Individual in-depth interviews are conducted in Spanish with one male and seven female nurses recruited by Baltimore's Latino Providers Network. Audiotaped home interview transcripts are manually reviewed for common themes. Strategies include professional medical interpreters, workshops on the U.S. health care system, media campaign on affordable/bilingual care sources, licensing foreign-trained nurses, and outreach clinics linked to trusted community-based organizations. Findings can be used to develop culturally appropriate programs to better administer health care to Latino communities.

A review is made on the different treatment strategies essayed to date in the management of chronic mountain sickness (CMS). After a brief presentation of the epidemiology and of the pathophysiological mechanisms proposed for explaining the disease, the advantages and drawbacks of the different treatment approaches are discussed, along with their pathopysiological rationale. A particular emphasis is dedicated to the scientific foundations underlying the development of acetazolamide and angiotensin-converting enzyme inhibitors as promising therapeutic agents for CMS, as well as the clinical evidence existing so far on their usefulness in the treatment of CMS. Various methodological issues that need to be addressed in future clinical studies on efficacy of therapies for CMS are discussed. There is also a brief discussion on potential treatment options for chronic high altitude pulmonary hypertension. Closing remarks on the need of taking increasingly into account the development and implementation of preventive measures are made.

In 2003, the Centers for Disease Control and Prevention began developing a social marketing campaign, Prevention IS Care, to encourage physicians to routinely screen HIV-infected patients for HIV transmission behaviors and to deliver HIV prevention messages. The planning team selected behavioral theories on the basis of formative research conducted during 2004–2005 and integrated these theories into the social marketing framework. The team decided to use the diffusion of innovation model and social cognitive theory. They selected as their target audience primary care and infectious disease physicians in private practice who deliver care to 50 or more persons living with HIV (PLWH). The social marketing framework, the diffusion of innovation model, and the social cognitive theory facilitated the development of this audience-centered campaign and provided elements that may encourage physicians to adopt the innovation: routine screening of HIV-infected patients for HIV transmission behaviors and delivery of HIV prevention messages during office visits.

This report is a comparison of orthostatic tolerance and autonomic function in three groups of high-altitude dwellers: Andeans with and without chronic mountain sickness (CMS) and healthy Ethiopians. Results are compared with those from healthy sea-level residents. The aim was to determine whether different high-altitude populations adapted differently to the prevailing hypobaric hypoxia. Orthostatic tolerance was assessed using a test involving head-up tilt (HUT) and graded lower body suction. This was performed at the subjects' resident altitude. Blood pressure (Portapres) and R–R interval (ECG) were recorded during the test, and spectral and cross-spectral analyses of heart period and systolic blood pressure time series were performed using data obtained both while supine and during HUT. The transfer function gain in the low-frequency range (LF, ∼0.1 Hz) at the point of maximal coherence was used as a measure of cardiac baroreflex sensitivity (BRS). As previously reported, Peruvians displayed an unusually good orthostatic tolerance, while Ethiopians showed an orthostatic tolerance comparable to that of healthy sea-level residents. There were no significant differences between groups in the supine values of the spectral analysis results. Head-up tilt induced the expected changes in Ethiopians (an increase in the LF components and a decrease in the respiratory components) but not in Andeans. Cross-spectral analysis showed abnormal results from all groups of high-altitude dwellers. These results indicate that Ethiopians, but not Peruvians, behave similarly to sea-level residents in terms of orthostatic tolerance and autonomic responses to orthostatic stress, as assessed from spectral analyses, and this indicates good adaptation to their environment. However, in all the high-altitude groups the results of cross-spectral analysis were atypical, suggesting some degree of impairment in baroreflex function.

Catheter-related bacteremia (CRB), along with liver failure is the leading cause of mortality and morbidity in parenteral nutrition dependent children. Immunosuppressant therapy following transplantation increases the risk of CRB. Previous reports in pediatric cancer patients have described the use of antibiotic lock solutions (ABL) for prophylaxis of CRB. In our institution, we evaluated five children (ages between one and four yr old), three with intestinal transplantation and two with short gut syndrome, who were high risk for recurrent CRB defined by their incidence of bacteremias in the observation period (>2 CRB/six months or life-threatening CRB). These children received the prophylactic ABL protocol with tobramycin-tissue plasminogen activator, four h per day, on alternating ports for six to eight months. Each patient was his/her own historical control. We observed decreased incidence of CRB's (p

The effects of hypobaric hypoxia in visitors depend not only on the actual elevation but also on the rate of ascent. Sympathetic activity increases and there are increases in blood pressure and heart rate. Pulmonary vasoconstriction leads to pulmonary hypertension, particularly during exercise. The sympathetic excitation results from hypoxia, partly through chemoreceptor reflexes and partly through altered baroreceptor function. High pulmonary arterial pressures may also cause reflex systemic vasoconstriction. Most permanent high altitude dwellers show excellent adaptation although there are differences between populations in the extent of the ventilatory drive and the erythropoiesis. Some altitude dwellers, particularly Andeans, may develop chronic mountain sickness, the most prominent characteristic of which being excessive polycythaemia. Excessive hypoxia due to peripheral chemoreceptor dysfunction has been suggested as a cause. The hyperviscous blood leads to pulmonary hypertension, symptoms of cerebral hypoperfusion, and eventually right heart failure and death.

Kiyamu, Melisa, Fabiola Leon-Velarde, Maria Rivera-Chira, Gianpietro Elias, and Tom D. Brutsaert. Developmental effects determine submaximal arterial oxygen saturation in Peruvian Quechua. High Alt Med Biol 16, 138-146, 2015.--Andean high altitude natives show higher arterial oxygen saturation (Sao(2)) during exercise in hypoxia, compared to acclimatized sojourners. In order to evaluate the effects of life-long exposure to high altitude on Sao(2), we studied two groups of well-matched, self-identified Peruvian Quechua natives who differed in their developmental exposure to hypoxia before and after a 2-month training period. Male and female volunteers (18-35 years) were recruited in Lima, Peru (150 m). The two groups were: a) Individuals who were born and raised at sea-level (BSL, n=34) and b) Individuals who were born and raised at high altitude (BHA, n=32), but who migrated to sea-level as adults (>16 years old). Exercise testing was conducted using a submaximal exercise protocol in normobaric hypoxia in Lima (BP=750 mmHg, Fio(2)=0.12), in order to measure Sao(2) (%), ventilation (VE L/min) and oxygen consumption (Vo(2), L/min). Repeated-measures ANOVA, controlling for VE/VO(2) (L/min) and sex during the submaximal protocol showed that BHA maintained higher Sao(2) (%) compared to BSL at all workloads before (p=0.005) and after training (p=0.017). As expected, both groups showed a decrease in Sao(2) (%) (p

We investigated carotid baroreflex control of vascular resistance in two groups of high-altitude natives: healthy subjects (HA) and a group with chronic mountain sickness (CMS), a maladaptation condition characterized by high haematocrit values and symptoms attributable to chronic hypoxia. Eleven HA controls and 11 CMS patients underwent baroreflex testing, using the neck collar method in which the pressure distending the carotid baroreceptors was changed by applying pressures of −40 to +60 mmHg to the chamber. Responses of forearm vascular resistance were assessed from changes in the quotient of blood pressure divided by brachial artery blood velocity. Stimulus–response curves were defined at high altitude (4338 m) and within 1 day of descent to sea level. We applied a sigmoid function or third-order polynomial to the curves and determined the maximal slope (equivalent to peak gain) and the corresponding carotid pressure (equivalent to ‘set point’). The results showed that the peak gains of the reflex were similar in both groups and at both locations. The ‘set point’ of the reflex, however, was significantly higher in the CMS patients compared to HA controls, indicating that the reflex operates over higher pressures in the patients (94.4 ± 3.0 versus 79.6 ± 4.1 mmHg; P < 0.01). This, however, was seen only when subjects were studied at altitude; after descent to sea level the curve reset to a lower pressure with no significant difference between HA and CMS subjects. These results indicate that carotid baroreceptor control of vascular resistance may be abnormal in CMS patients but that descent to sea level rapidly normalizes it. We speculate that this may be explained by CMS patients having greater vasoconstrictor activity at altitude owing to greater hypoxic stimulation of chemoreceptors.

Cerebral blood flow is known to increase in response to hypoxia and to decrease with hypocapnia. It is not known, however, whether these responses are altered in high-altitude dwellers who are not only chronically hypoxic and hypocapnic, but also polycythaemic. Here we examined cerebral blood flow responses to hypoxia and hypocapnia, separately and together, in Andean high-altitude dwellers, including some with chronic mountain sickness (CMS), which is characterized by excessive polycythaemia. Studies were carried out at high altitude (Cerro de Pasco (CP), Peru; barometric pressure (P(B)) 450 mmHg) and repeated, following relief of the hypoxia, on the day following arrival at sea level (Lima, Peru; P(B) 755 mmHg). We compared these results with those from eight sea-level residents studied at sea level. In nine high-altitude normal subjects (HA) and nine CMS patients, we recorded middle cerebral artery mean blood flow velocity (MCAVm) using transcranial Doppler ultrasonography, and expressed responses as changes from baseline. MCAVm responses to hypoxia were determined by changing end-tidal partial pressure of oxygen (P(ET,O2)) from 100 to 50 mmHg, with end-tidal partial pressure of carbon dioxide clamped. MCAVm responses to hypocapnia were studied by voluntary hyperventilation with (P(ET,O2)) clamped at 100 and 50 mmHg. There were no significant differences between the cerebrovascular responses of the two groups to any of the interventions at either location. In both groups, the MCAVm responses to hypoxia were significantly greater at Lima than at CP (HA, 12.1 +/- 1.3 and 6.1 +/- 1.0%; CMS, 12.5 +/- 0.8 and 5.6 +/- 1.2%; P < 0.01 both groups). The responses at Lima were similar to those in the sea-level subjects (13.6 +/- 2.3%). The responses to normoxic hypocapnia in the altitude subjects were also similar at both locations and greater than those in sea-level residents. During hypoxia, both high-altitude groups showed responses to hypocapnia that were significantly smaller at Lima than at CP (HA, 2.17 +/- 0.23 and 3.29 +/- 0.34% mmHg(-1), P < 0.05; CMS, 1.87 +/- 0.16 and 3.23 +/- 0.24% mmHg(-1); P < 0.01). The similarity of the results from the two groups of altitude dwellers suggests that haematocrit is unlikely to greatly affect cerebrovascular reactivity to hypoxia and hypocapnia. The smaller vasodilatation to hypoxia and larger vasoconstriction to hypoxic hypocapnia at high altitude suggest that cerebrovascular responses may be impaired at the high altitude, i.e. a maladaptation. The changes in the responses within less than 24 h at sea level indicate that this impairment is rapidly reversible.

Orthostatic tolerance is a measure of the ability to prevent hypotension during gravitational stress. It is known to be dependent on the degree of vasoconstriction and the magnitude of plasma volume, but the possible influence of packed cell volume (PCV) is unknown. High altitude residents have high haematocrits and probably high packed cell volumes. However, it is not known whether plasma volume and blood volume are affected, or whether their orthostatic tolerance is different from low altitude residents. In this study we determined plasma volume, PCV and orthostatic tolerance in a group of high altitude dwellers (HA), including a subgroup of highland dwellers with chronic mountain sickness (CMS) and extreme polycythaemia. Plasma volume and PCV were determined using Evans Blue dye dilution and peripheral haematocrit. Orthostatic tolerance was assessed as the time to presyncope in a test of head-up tilting and lower body suction. All studies were performed at 4338 m. Results showed that plasma volumes were not significantly different between CMS and HA, or in highland dwellers compared to those seen previously in lowlanders. PCV and haematocrit were greater in CMS than in HA. Orthostatic tolerance was high in both CMS and HA, although the heart rate responses to orthostasis were smaller in CMS than HA. Orthostatic tolerance was correlated with haematocrit (r= 0.57, P < 0.01) and PCV (r= 0.54, P < 0.01). This investigation has shown that although high altitude residents have large PCV, their plasma volumes were similar to lowland dwellers. The group with CMS have a particularly large PCV and also have a very high orthostatic tolerance, despite smaller heart rate responses. These results are compatible with the view that PCV is of importance in determining orthostatic tolerance.

Background Restless legs syndrome (RLS) and chronic mountain sickness (CMS) share physiological traits. Our objective was to explore a possible association between RLS and CMS. Methods We carried a cross-sectional study with male subjects living between 4100 and 4300 m above sea level. Participants underwent a clinical interview, physical examination, electrocardiographic (EKG) recording, and spirometry. We classified subjects into CMS, Limbo, and healthy high-altitude dwellers (hHAD), according to their Quinghai score and hematocrit levels. We applied the "Paradigm of questions for epidemiological studies of RLS," The International Restless Leg Syndrome Study Group Scale, and the Pittsburgh Sleep Quality Index. Logistic regression analysis was used to determine the association between variables. Results Seventy-eight male subjects were included. Forty subjects were hHAD, 23 were CMS patients, and 15 participants were considered as Limbo. CMS and Limbo subjects had a higher frequency of RLS ( p 0.05). Limbo subjects had the highest severity score for RLS. There were no differences in age, body mass index (BMI), or tobacco use between RLS patients and non-sufferers. In the multivariate analysis, CMS was not associated with RLS diagnosis. Oxygen saturation ( p = 0.019), poor sleep quality ( p 0.01), and Quinghai score of ≥6 ( p = 0.026) were independently associated with RLS diagnosis. Conclusions Our results did not show a direct association between RLS and CMS; however, RLS was associated with reduced oxygen saturation. Hence, RLS could represent an early clinical manifestation of hypoxia, or, in CMS natural history, an early sign of maladaptation to high altitude.