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In her recent book Atonement, Eleonore Stump objects to the Anselmian theory of atonement, claiming it is not consistent with God's love. I argue that her objection mischaracterizes Anselmian theories. First, Stump equivocates on the concept of forgiveness, conflating personal forgiveness with divine pardon, and second, Stump misrepresents the God of Anselm as unwilling to reconcile with sinners prior to receiving satisfaction. I suggest that Stump's real objection should be to the Anselmian view of divine justice as retributive, not to his conception of divine love. I suggest a model of an all-loving God acting as a retributive judge.
To assess the validity of multivariable models for predicting risk of surgical site infection (SSI) after colorectal surgery based on routinely collected data in national surveillance networks.
Retrospective analysis performed on 3 validation cohorts.
Colorectal surgery patients in Switzerland, France, and England, 2007–2017.
We determined calibration and discrimination (ie, area under the curve, AUC) of the COLA (contamination class, obesity, laparoscopy, American Society of Anesthesiologists [ASA]) multivariable risk model and the National Healthcare Safety Network (NHSN) multivariable risk model in each cohort. A new score was constructed based on multivariable analysis of the Swiss cohort following colorectal surgery, then based on colon and rectal surgery separately.
We included 40,813 patients who had undergone elective or emergency colorectal surgery to validate the COLA score, 45,216 patients to validate the NHSN colon and rectal surgery risk models, and 46,320 patients in the construction of a new predictive model. The COLA score’s predictive ability was poor, with AUC values of 0.64 (95% confidence interval [CI], 0.63–0.65), 0.62 (95% CI, 0.58–0.67), 0.60 (95% CI, 0.58–0.61) in the Swiss, French, and English cohorts, respectively. The NHSN colon-specific model (AUC, 0.61; 95% CI, 0.61–0.62) and the rectal surgery–specific model (AUC, 0.57; 95% CI, 0.53–0.61) showed limited predictive ability. The new predictive score showed poor predictive accuracy for colorectal surgery overall (AUC, 0.65; 95% CI, 0.64–0.66), for colon surgery (AUC, 0.65; 95% CI, 0.65–0.66), and for rectal surgery (AUC, 0.63; 95% CI, 0.60–0.66).
Models based on routinely collected data in SSI surveillance networks poorly predict individual risk of SSI following colorectal surgery. Further models that include other more predictive variables could be developed and validated.
Noonan syndrome and related disorders are a group of clinically and genetically heterogeneous conditions caused by mutations in genes of the RAS/MAPK pathway. Noonan syndrome causes multiple congenital anomalies, which are frequently accompanied by hypertrophic cardiomyopathy (HCM). We report here a Tunisian patient with a severe phenotype of Noonan syndrome including neonatal HCM, facial dysmorphism, severe failure to thrive, cutaneous abnormalities, pectus excavatum and severe stunted growth, who died in her eighth month of life. Using whole exome sequencing, we identified a de novo mutation in exon 7 of the RAF1 gene: c.776C > A (p.Ser259Tyr). This mutation affects a highly conserved serine residue, a main mediator of Raf-1 inhibition via phosphorylation. To our knowledge the c.776C > A mutation has been previously reported in only one case with prenatally diagnosed Noonan syndrome. Our study further supports the striking correlation of RAF1 mutations with HCM and highlights the clinical severity of Noonan syndrome associated with a RAF1 p.Ser259Tyr mutation.
GenomeAsia100K is a human genome project based at Nanyang Technological University in Singapore that aims to sequence one hundred thousand Asian genomes in an effort that addresses an ethnic bias towards Western populations in previous genomic research. GenomeAsia100K consists of a team of bioinformaticians, statisticians and population geneticists, and was initiated by the Nanyang Technological University in collaboration with industrial partners MedGenome (an Indian R&D company specializing in genomic data) and the California Biotech company Genentech. The GenomeAsia100K project is amongst the most ambitious precision medicine projects to date but it is not clear how the project will challenge or reshape understandings of ethnic and racial differences in Asian populations. Ian McGonigle, a scientist and cultural anthropologist, sat down with geneticist Stephan C. Schuster, the scientific chairman of GenomeAsia100K, to discuss the project and the implications of genomics for social identity in the 21st century.
Because obesity is associated with many co-morbidities, including diabetes mellitus, this study evaluated the second-meal effect of a commercial prebiotic, inulin-type fructans, and the effects of the prebiotic on faecal microbiota, metabolites and bile acids (BA). Nine overweight beagles were used in a replicated 3×3 Latin square design to test a non-prebiotic control (cellulose) against a low (equivalent to 0·5 % diet) and high dose (equivalent to 1·0 % diet) of prebiotic over 14-d treatments. All dogs were fed the same diet twice daily, with treatments provided orally via gelatin capsules before meals. On days 13 or 14 of each period, fresh faecal samples were collected, dogs were fed at 08.00 hours and then challenged with 1 g/kg body weight of maltodextrin in place of the 16.00 hours meal. Repeated blood samples were analysed for glucose and hormone concentrations to determine postprandial incremental AUC (IAUC) data. Baseline glucose, insulin and active glucagon-like peptide-1 levels were similar between all groups (P>0·10). Glucose and insulin IAUC after glucose challenge appeared lower following the high dose, but did not reach statistical relevance. Prebiotic intervention resulted in an increase in relative abundance of some Firmicutes and a decrease in the relative abundance of some Proteobacteria. Individual and total faecal SCFA were significantly increased (P<0·05) following prebiotic supplementation. Total concentration of excreted faecal BA tended to increase in dogs fed the prebiotic (P=0·06). Our results indicate that higher doses of inulin-type prebiotics may serve as modulators of gut microbiota, metabolites and BA pool in overweight dogs.
OBJECTIVES/SPECIFIC AIMS: Background: Delirium is a well described form of acute brain organ dysfunction characterized by decreased or increased movement, changes in attention and concentration as well as perceptual disturbances (i.e., hallucinations) and delusions. Catatonia, a neuropsychiatric syndrome traditionally described in patients with severe psychiatric illness, can present as phenotypically similar to delirium and is characterized by increased, decreased and/or abnormal movements, staring, rigidity, and mutism. Delirium and catatonia can co-occur in the setting of medical illness, but no studies have explored this relationship by age. Our objective was to assess whether advancing age and the presence of catatonia are associated with delirium. METHODS/STUDY POPULATION: Methods: We prospectively enrolled critically ill patients at a single institution who were on a ventilator or in shock and evaluated them daily for delirium using the Confusion Assessment for the ICU and for catatonia using the Bush Francis Catatonia Rating Scale. Measures of association (OR) were assessed with a simple logistic regression model with catatonia as the independent variable and delirium as the dependent variable. Effect measure modification by age was assessed using a Likelihood ratio test. RESULTS/ANTICIPATED RESULTS: Results: We enrolled 136 medical and surgical critically ill patients with 452 matched (concomitant) delirium and catatonia assessments. Median age was 59 years (IQR: 52–68). In our cohort of 136 patients, 58 patients (43%) had delirium only, 4 (3%) had catatonia only, 42 (31%) had both delirium and catatonia, and 32 (24%) had neither. Age was significantly associated with prevalent delirium (i.e., increasing age associated with decreased risk for delirium) (p=0.04) after adjusting for catatonia severity. Catatonia was significantly associated with prevalent delirium (p<0.0001) after adjusting for age. Peak delirium risk was for patients aged 55 years with 3 or more catatonic signs, who had 53.4 times the odds of delirium (95% CI: 16.06, 176.75) than those with no catatonic signs. Patients 70 years and older with 3 or more catatonia features had half this risk. DISCUSSION/SIGNIFICANCE OF IMPACT: Conclusions: Catatonia is significantly associated with prevalent delirium even after controlling for age. These data support an inverted U-shape risk of delirium after adjusting for catatonia. This relationship and its clinical ramifications need to be examined in a larger sample, including patients with dementia. Additionally, we need to assess which acute brain syndrome (delirium or catatonia) develops first.
To determine whether probiotic prophylaxes reduce the odds of Clostridium difficile infection (CDI) in adults and children.
Individual participant data (IPD) meta-analysis of randomized controlled trials (RCTs), adjusting for risk factors.
We searched 6 databases and 11 grey literature sources from inception to April 2016. We identified 32 RCTs (n=8,713); among them, 18 RCTs provided IPD (n=6,851 participants) comparing probiotic prophylaxis to placebo or no treatment (standard care). One reviewer prepared the IPD, and 2 reviewers extracted data, rated study quality, and graded evidence quality.
Probiotics reduced CDI odds in the unadjusted model (n=6,645; odds ratio [OR] 0.37; 95% confidence interval [CI], 0.25–0.55) and the adjusted model (n=5,074; OR, 0.35; 95% CI, 0.23–0.55). Using 2 or more antibiotics increased the odds of CDI (OR, 2.20; 95% CI, 1.11–4.37), whereas age, sex, hospitalization status, and high-risk antibiotic exposure did not. Adjusted subgroup analyses suggested that, compared to no probiotics, multispecies probiotics were more beneficial than single-species probiotics, as was using probiotics in clinical settings where the CDI risk is ≥5%. Of 18 studies, 14 reported adverse events. In 11 of these 14 studies, the adverse events were retained in the adjusted model. Odds for serious adverse events were similar for both groups in the unadjusted analyses (n=4,990; OR, 1.06; 95% CI, 0.89–1.26) and adjusted analyses (n=4,718; OR, 1.06; 95% CI, 0.89–1.28). Missing outcome data for CDI ranged from 0% to 25.8%. Our analyses were robust to a sensitivity analysis for missingness.
Moderate quality (ie, certainty) evidence suggests that probiotic prophylaxis may be a useful and safe CDI prevention strategy, particularly among participants taking 2 or more antibiotics and in hospital settings where the risk of CDI is ≥5%.
Cognitive models of obsessive–compulsive disorder (OCD) posit dysfunctional appraisal of disorder-relevant stimuli in patients, suggesting disturbances in the processes relying on amygdala–prefrontal connectivity. Recent neuroanatomical models add to the traditional view of dysfunction in corticostriatal circuits by proposing alterations in an affective circuit including amygdala–prefrontal connections. However, abnormalities in amygdala–prefrontal coupling during symptom provocation, and particularly during conditions that require stimulus appraisal, remain to be demonstrated directly.
Amygdala–prefrontal connectivity was examined in unmedicated OCD patients during appraisal (v. distraction) of symptom-provoking stimuli compared with an emotional control condition. Subsequent analyses tested whether hypothesized connectivity alterations could be also identified during passive viewing and the resting state in two independent samples.
During symptom provocation, reductions in positive coupling between amygdala and orbitofrontal cortex were observed in OCD patients relative to healthy control participants during appraisal and passive viewing of OCD-relevant stimuli, whereas abnormally high amygdala–ventromedial prefrontal cortex coupling was found when appraisal was distracted by a secondary task. In contrast, there were no group differences in amygdala connectivity at rest.
Our finding of abnormal amygdala–prefrontal connectivity during appraisal of symptom-related (relative to generally aversive) stimuli is consistent with the involvement of affective circuits in the functional neuroanatomy of OCD. Aberrant connectivity can be assumed to impact stimulus appraisal and emotion regulation, but might also relate to fear extinction deficits, which have recently been described in OCD. Taken together, we propose to integrate abnormalities in amygdala–prefrontal coupling in affective models of OCD.
People living in poverty are particularly vulnerable to shocks, including those caused by natural disasters such as floods and droughts. This paper analyses household survey data and hydrological riverine flood and drought data for 52 countries to find out whether poor people are disproportionally exposed to floods and droughts, and how this exposure may change in a future climate. We find that poor people are often disproportionally exposed to droughts and floods, particularly in urban areas. This pattern does not change significantly under future climate scenarios, although the absolute number of people potentially exposed to floods or droughts can increase or decrease significantly, depending on the scenario and region. In particular, many countries in Africa show a disproportionally high exposure of poor people to floods and droughts. For these hotspots, implementing risk-sensitive land-use and development policies that protect poor people should be a priority.
There is a high and increasing proportion of
single-parent families in Jamaica. This has raised
concerns about the potential impact of single-parent
families on the social, cognitive and behavioural
development of children, including their sexual
relationships. The aim of this study was to
investigate the association between being raised in
a single-parent family and age of sexual debut among
young people in Jamaica. The study was
cross-sectional in design, and based on a
multi-stage sampling procedure. The study was
conducted in July/September 2016. The study sample
comprised 233 respondents (110 males and 123
females) aged from 18 to 35 years (mean 26.37 years;
SD 5.46). Respondents completed a self-administered
questionnaire with questions on socio-demographic
characteristics, family structure, sexual debut and
current sexual behaviour. Ninety-seven (41.7%)
respondents grew up in single-parent families. A
total of 201 (86.3%) had had sex (102 males and 99
females). Their mean age of sexual debut was 15.51
years (SD 3.41). Sixty-five (32.3%) had early sexual
debut (<16 years). Respondents from
single-parent families were more likely to have had
early sexual debut (56.9%; n=37)
compared with those from two-parent families (43.1%,
p=0.004). Only 44.6%
(n=29) of those who experienced
early sexual debut used a condom during their first
sexual encounter compared with 73%
(n=100) of those who had a later
sexual debut (≥16 years;
p=<0.001). A single-father
family structure was a significant predictor of
early sexual debut (AOR 5.5; 95%CI: 1.1–25.8). The
study found a significant association between
single-parent family structure and age of sexual
Previous studies find that both schizophrenia and mood disorder risk alleles contribute to adult depression and anxiety. Emotional problems (depression or anxiety) begin in childhood and show strong continuities into adult life; this suggests that symptoms are the manifestation of the same underlying liability across different ages. However, other findings suggest that there are developmental differences in the etiology of emotional problems at different ages. To our knowledge, no study has prospectively examined the impact of psychiatric risk alleles on emotional problems at different ages in the same individuals.
Data were analyzed using regression-based analyses in a prospective, population-based UK cohort (the National Child Development Study). Schizophrenia and major depressive disorder (MDD) polygenic risk scores (PRS) were derived from published Psychiatric Genomics Consortium genome-wide association studies. Emotional problems were assessed prospectively at six time points from age 7 to 42 years.
Schizophrenia PRS were associated with emotional problems from childhood [age 7, OR 1.09 (1.03–1.15), p = 0.003] to mid-life [age 42, OR 1.10 (1.05–1.17), p < 0.001], while MDD PRS were associated with emotional problems only in adulthood [age 42, OR 1.06 (1.00–1.11), p = 0.034; age 7, OR 1.03 (0.98–1.09), p = 0.228].
Our prospective investigation suggests that early (childhood) emotional problems in the general population share genetic risk with schizophrenia, while later (adult) emotional problems also share genetic risk with MDD. The results suggest that the genetic architecture of depression/anxiety is not static across development.
A multidecadal-scale lake-level reconstruction for Lago Wiñaymarca, the southern basin of Lake Titicaca, has been generated from diatom species abundance data. These data suggest that ~6500 cal yr BP Lago Wiñaymarca was dry, as indicated by a sediment unconformity. At ~4400 cal yr BP, the basin began to fill, as indicated by the dominance of shallow epiphytic species. It remained somewhat saline with extensive wetlands and abundant aquatic plants until ~3800 cal yr BP, when epiphytic species were replaced by planktic saline-indifferent species, suggesting a saline shallow lake. Wiñaymarca remained a relatively shallow lake that fluctuated on a multidecadal scale until ~1250 cal yr BP, when freshwater planktic species increased, suggesting a rise in lake level with a concomitant decrease in salinity. The lake became gradually fresher, dominated by deep, freshwater species from ~850 cal yr BP. By ~80 cal yr BP, saline-tolerant species were rare, and the lake was dominated by freshwater planktic diatoms, resembling the fresh and deep lake of today. These results reveal a more dynamic and chronologically specific record of lake-level fluctuations and associated ecological conditions that provide important new data for paleoclimatologists and archaeologists, to better understand human-environmental dynamics during the mid- to late Holocene.
Monitoring the glacier mass balance of summer-accumulation-type Himalayan glaciers is critical to not only assess the impact of climate change on the volume of such glaciers but also predict the downstream water availability and the global sea-level change in future. To better understand the change in meteorological parameters related to glacier mass balance and runoff in a glacierized basin and to assess the highly heterogeneous glacier responses to climate change in the Nepal Himalaya and nearby ranges, the Cryosphere Monitoring Project (CMP) carries out meteorological observations in Langtang Valley and mass-balance measurements on Yala Glacier, a debris-free glacier in the same valley. A negative annual mass balance of –0.89m w.e. and the rising equilibrium-line altitude of Yala Glacier indicate a continuation of a secular trend toward more negative mass balances. Lower temperature lapse rate during the monsoon, the effect of convective precipitation associated with mesoscale thermal circulation in the local precipitation and the occurrence of distinct diurnal cycles of temperature and precipitation at different stations in the valley are other conclusions of this comprehensive scientific study initiated by CMP which aims to yield multi-year glaciological, hydrological and meteorological observations in the glacierized Langtang River basin.
During summer 2011, seismic activity in the ablation zone of the western Greenland ice sheet (GrIS) was monitored using a network of three-component seismometers. The seismic record includes a large variety of icequakes and seismic tremors that demonstrate a clear correlation with subglacial water flow. We verified the existence of well-known shallow icequakes (related to surface crevasse formation), deep icequakes (located at 100–160 m depth) and narrow-banded short-term seismic tremors (tens of seconds in duration). In addition, we present previously unreported long-term tremors lasting several hours. Using attenuation of the measured tremor amplitude, we locate the epicentre of this long-term tremor to a large moulin within our study area. Between 3 and 11 Hz, our continuous seismic record is dominated by this ‘moulin tremor’ and shows strong correlation with the water level of the generating moulin. We argue that monitoring of icequake and glacial tremor sources bears high potential for investigating glacier hydraulics and dynamics, and is thus an ideal supplement to traditional glaciological measurements.