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This illustrated atlas of North America combines maps, pictures, flags, globes, information panels, diagrams, and charts to give a complete overview of the region.

The death and removal of foreign, sick, or potentially harmful cells is a vital process in most multi-cellular animals. However, in Caenorhabditis elegans, a nematode model system which is genetically conserved with higher organisms, cell death and phagocytosis can be inhibited without lethal consequences to the animal. This model system has been a boon to the genetic dissection of programmed cell death. I show that germ cells, which in hermaphrodites can differentiate into sperm and oocytes, also undergo apoptotic cell death (Chapter 2). In adult hermaphrodites, over 300 germ cells die, using the same apoptotic execution machinery (ced-3, ced-4, and ced-9) as the previously described 131 somatic cell deaths. However, this machinery is activated by a distinct pathway, as loss of egl-1 function or gain of ced-9 function, which inhibits somatic cell death, does not affect germ cell apoptosis. Germ cell death requires ras/MAPK pathway activation and is used to maintain germline homeostasis. I suggest that apoptosis eliminates excess germ cells that acted as nurse cells to provide cytoplasmic components to maturing oocytes. Germ cell corpses are removed by the same genes that are required for the removal of developmental cell deaths. Interestingly, necrotic cell deaths also require the known engulfment genes for their timely removal, though egl-1, ced-9, ced-3, and ced-4 do not affect necrosis caused by a toxic MEC-4 channel (Chapter 3). A genetic screen for additional mutations that cause necrotic corpse persistence identified one previously unknown locus, ced-12, which is needed for both necrotic-like and programmed cell death corpse elimination. ced-12 is required not only for engulfment of dying cells, but also for a variety of cell migrations, including those that occur during embryonic elongation and migration of the gonad (Chapter 4). ced-12 is encoded by Y106G6E.5, a novel gene with homologs in Drosophila and mammals. CED-12 acts in the Rac1/CrkII/DOCK180 pathway, which induces the actin cytoskeleton rearrangements required for extending phagocytic arms and cell migration in mammals. Future studies may elucidate how CED-12 interacts with the Rac pathway (Chapter 5).

Abstract Context It remains unclear whether idiopathic short stature (ISS), defined as a height below −2.0 SD score (SDS) without an identifiable cause, adversely affects psychosocial well-being. Objective To assess the psychosocial impact of ISS in children using nationwide registry and survey data. Design The nationwide cohort study included children identified between 2012 and 2020 with follow-up questionnaire data up until 2022. Setting School-aged children in Denmark. Patients or Other Participants The National Child Health Register contained heights on 507 754 children of which 42 185 had heights below −2.0 SDS. Children with a diagnostic code associated with potential underlying causes for short stature in the Danish National Patient Registry were excluded. The final cohort included 16 121 children with ISS. Each child was matched to 5 controls by age, sex, and region. Intervention(s) None. Main Outcome Measure(s) Psychosocial well-being (bullying, loneliness, and insecurity) assessed by mandatory National Well-being Surveys (2015-2022). Odds ratios (ORs) were calculated across school grade levels. Results Children with ISS had higher odds of feeling bullied (school grade levels 0-3: OR 1.03 [95% confidence interval (CI) 0.95-1.12]; 4-6: OR 1.37 [95% CI 1.24-1.56]; 7-9: OR 1.19 [95% CI 1.02-1.40]), lonely (0-3: OR 1.02 [95% CI 0.93-1.12]; 4-6: OR 1.15 [95% CI 1.06-1.27]; 7-9: OR 1.11 [95% CI 1.01-1.25]), and insecure (0-3: OR 1.08 [95% CI 1.00-1.17]; 4-6: OR 1.07 [95% CI 1.02-1.15]; 7-9: OR 1.09 [95% CI 1.04-1.19]). Conclusion Children with ISS displayed increased psychosocial distress. These findings support psychosocial assessment in children with ISS to enable timely intervention.

Bloodstream infections (BSIs) often lead to critical illness and death. The primary aim of this study was to determine the diagnostic accuracy of the biomarkers C-reactive protein (CRP), procalcitonin (PCT), and leukocyte count for the diagnosis of BSI in critically ill patients.BackgroundBloodstream infections (BSIs) often lead to critical illness and death. The primary aim of this study was to determine the diagnostic accuracy of the biomarkers C-reactive protein (CRP), procalcitonin (PCT), and leukocyte count for the diagnosis of BSI in critically ill patients.This was a nested case-control study based on the Procalcitonin And Survival Study (PASS) trial (n = 1200). Patients who were admitted to the intensive care unit (ICU) <24 hours, and not expected to die within <24 hours, were recruited. For the current study, we included patients with a BSI within ±3 days of ICU admission and matched controls without a BSI in a 1:2 ratio. Diagnostic accuracy for BSI for the biomarkers on days 1, 2, and 3 of ICU admission was assessed. Sensitivity, specificity, and negative and positive predictive values were calculated for prespecified thresholds and for a data-driven cutoff.MethodsThis was a nested case-control study based on the Procalcitonin And Survival Study (PASS) trial (n = 1200). Patients who were admitted to the intensive care unit (ICU) <24 hours, and not expected to die within <24 hours, were recruited. For the current study, we included patients with a BSI within ±3 days of ICU admission and matched controls without a BSI in a 1:2 ratio. Diagnostic accuracy for BSI for the biomarkers on days 1, 2, and 3 of ICU admission was assessed. Sensitivity, specificity, and negative and positive predictive values were calculated for prespecified thresholds and for a data-driven cutoff.In total, there were 525 patients (n = 175 cases, 350 controls). The fixed low threshold for all 3 biomarkers (CRP = 20 mg/L; leucocytes = 10 × 109/L; PCT = 0.4 ng/mL) resulted in negative predictive values on day 1: CRP = 0.91; 95% CI, 0.75-1.00; leukocyte = 0.75; 95% CI, 0.68-0.81; PCT = 0.91; 95% CI, 0.84-0.96). Combining the 3 biomarkers yielded similar results as PCT alone (P = .5).ResultsIn total, there were 525 patients (n = 175 cases, 350 controls). The fixed low threshold for all 3 biomarkers (CRP = 20 mg/L; leucocytes = 10 × 109/L; PCT = 0.4 ng/mL) resulted in negative predictive values on day 1: CRP = 0.91; 95% CI, 0.75-1.00; leukocyte = 0.75; 95% CI, 0.68-0.81; PCT = 0.91; 95% CI, 0.84-0.96). Combining the 3 biomarkers yielded similar results as PCT alone (P = .5).CRP and PCT could in most cases rule out BSI in critically ill patients. As almost no patients had low CRP and ∼20% had low PCT, a low PCT could be used, along with other information, to guide clinical decisions.ConclusionsCRP and PCT could in most cases rule out BSI in critically ill patients. As almost no patients had low CRP and ∼20% had low PCT, a low PCT could be used, along with other information, to guide clinical decisions.

Background It is known that being on antiretroviral therapy reduces the risk of HIV transmission through sex. However it remains unknown what the absolute level of risk of transmission is in a person on ART with most recent measured HIV plasma viral load<50 c/mL in the absence of condom use. There are no data on risk of transmission for anal sex in MSM when the index partner is on ART. Methods/Design The PARTNER study is an international, observational multi-centre study, taking place from 2010 to 2014 in which HIV serodifferent partnerships who at enrolment reported recently having had condom-less vaginal or anal sexual intercourse are followed over time, with 46 monthly reporting of transmission risk behaviour through a confidential self completed risk behaviour questionnaire and with 46 monthly HIV testing for the HIV negative partner. The objective is to study (i) the risk of HIV transmission to partners, in particular in partnerships that continue not to use condoms consistently and the HIV-positive partner is on therapy with a viral load<50 copies/mL and (ii) why some partnerships do not use condoms, to describe the proportion who begin to adopt consistent condom use, and factors associated with this. For any negative partner who becomes infected phylogenetic analysis will be used following anonymisation of the samples to assess if transmission had been from the HIV infected partner. Discussion This observational study will provide missing information on the absolute risk of HIV transmission for both vaginal and anal sex when the index case is on ART with a VL<50 copies/mL in the absence of condom use.

Abstract Background Animal models of serious infection suggest that 24 hours of induced hypothermia improves circulatory and respiratory characteristics and enhances survival, but whether therapeutic mild hypothermia in such conditions is of clinical benefit remains unknown. We, therefore, tested whether reducing core temperature to 32–34oC in critically ill patients with septic shock and ventilator-demanding respiratory failure improves survival and reduces organ dysfunction. Methods In this multi-national trial, patients with septic shock were enrolled within 6 hours of onset of septic shock and ventilator-demanding respiratory failure and randomized 1:1, stratified by site (target sample = 560), to routine thermal management or 24 hours of induced hypothermia (target 32–34°C) followed by 48 hours of normothermia. Other aspects of care were per routine in each participating center. The primary endpoint was 30-day all-cause mortality. Results At the third ordinary interim analysis, after recruitment of 432 participants, the Data and Safety Monitoring Board recommended the trial be terminated for futility; the conditional power for rejection of the null hypothesis in favor of efficacy was null. In the induced hypothermia group, target temperature was reached within median 3.2 hours [IQR: 2.2, 4.8], and maintained for 24 hours [IQR: 24, 24] (Figure 1). There was no evidence for a difference in 30-day mortality risk in patients randomized to hypothermia (96/217) vs. routine thermal management (77/215): relative risk 1.24 [95% CI: 0.98, 1.56] (Figure 2). At the end of the temperature intervention (72 hours), more patients assigned to hypothermia were in continued shock (vasoactive medication 71% vs. 58%; P = 0.01), and fewer cooled patients had inflammatory control (32% vs. 47% had CRP decline of >30%, P = 0.005). More harm from cooling was seen in patients entering the trial with normal renal function and with normal platelet count (P for interaction < 0.05). Conclusion Among patients with septic shock and ventilator-demanding respiratory failure, induced hypothermia did not improve survival, but adversely affected the duration of shock, and inflammatory control. Induced hypothermia should not routinely be used in patients with septic shock. Disclosures All authors: No reported disclosures.