Impact of performance and information feedback on medical interns' confidence-accuracy calibration.

Diagnostic errors are a major, largely preventable, patient safety concern. Error interventions cannot feasibly be implemented for every patient that is seen. To identify cases at high risk of error, clinicians should have a good calibration between their perceived and actual accuracy. This experiment studied the impact of feedback on medical interns' calibration and diagnostic process. In a two-phase experiment, 125 medical interns from Dutch University Medical Centers were randomized to receive no feedback (control), feedback on their accuracy (performance feedback), or feedback with additional information on why a certain diagnosis was correct (information feedback) on 20 chest X-rays they diagnosed in a feedback phase. A test phase immediately followed this phase and had all interns diagnose an additional 10 X-rays without feedback. Outcome measures were confidence-accuracy calibration, diagnostic accuracy, confidence, and time to diagnose. Both feedback types improved overall confidence-accuracy calibration (R2No Feedback = 0.05, R2Performance Feedback = 0.12, R2Information Feedback = 0.19), in line with the individual improvements in diagnostic accuracy and confidence. We also report secondary analyses to examine how case difficulty affected calibration. Time to diagnose did not differ between conditions. Feedback improved interns' calibration. However, it is unclear whether this improvement reflects better confidence estimates or an improvement in accuracy. Future research should examine more experienced participants and non-visual specialties. Our results suggest that feedback is an effective intervention that could be beneficial as a tool to improve calibration, especially in cases that are not too difficult for learners.

Echoes of shame: a comparison of the characteristics and psychological sequelae of recalled shame experiences across the voice hearing continuum.

BACKGROUND: Voice hearing occurs across a number of psychiatric diagnoses and appears to be present on a continuum within the general population. Previous research has highlighted the potential role of past experiences of shame in proneness to voice hearing in the general population. AIMS: This study aimed to extend this past research and compare people with distressing voices, people with voices but no distress, and a non-voice hearing control group, on various dimensions of shame and shame memory characteristics. METHOD: In a cross-sectional, online study 39 distressed voice hearers, 31 non-distressed voice hearers and 50 non-voice hearers undertook a shame memory priming task in which they were prompted to recall a memory of a shaming experience from their past. They then completed questionnaires assessing the characteristics of the recalled shame event and the psychological sequalae of this event (i.e. intrusions, hyperarousal, avoidance, the centrality of shame memories, external shame, and self-criticism). RESULTS: The majority of recalled shame memories involved experiences such as interpersonal criticism or experiences of being devalued. Univariate analyses found no significant differences between the three groups with regard to the shame events that were recalled, but the distressed voice hearer group reported significantly more hyperarousal, intrusions, self-criticism, and external shame in relation to their experience. CONCLUSIONS: The findings suggest that voice hearers recall similar types of shame experiences to non-voice hearers, but that problematic psychological sequelae of these shame experiences (in the form of intrusive memories, hyperarousal, external shame, and self-criticism) may specifically contribute to distressing voice hearing.

Auditory verbal hallucinations and childhood trauma subtypes across the psychosis continuum: a cluster analysis.

Introduction: A strong link between voice-hearing experience and childhood trauma has been established. The aim of this study was to identify whether there were unique clusters of childhood trauma subtypes in a sample across the clinical spectrum of auditory verbal hallucinations (AVH) and to examine clinical and phenomenological features across these clusters.Methods: Combining two independent international datasets (the Netherlands and Australia), childhood trauma subtypes were examined using hierarchical cluster analysis. Clinical and phenomenological characteristics were compared across emerging clusters using MANOVA and chi-squared analyses.Results: The total sample (n = 413) included 166 clinical individuals with a psychotic disorder and AVH, 122 non-clinical individuals with AVH and 125 non-clinical individuals without AVH. Three clusters emerged: (1) low trauma (n = 299); (2) emotion-focused trauma (n = 71); (3) multi-trauma (n = 43). The three clusters differed significantly on their AVH ratings of amount of negative content, with trend-level effects for loudness, degree of negative content and degree of experienced distress. Furthermore, perceptions of voices being malevolent, benevolent and resistance towards voices differed significantly.Conclusion: The data revealed different types of childhood trauma had different relationships between clinical and phenomenological features of voice-hearing experiences. Thus, implicating different mechanistic pathways and a need for tailored treatment approaches.

Does a suggested diagnosis in a general practitioners' referral question impact diagnostic reasoning: an experimental study.

BACKGROUND: Diagnostic errors are a major cause of preventable patient harm. Studies suggest that presenting inaccurate diagnostic suggestions can cause errors in physicians' diagnostic reasoning processes. It is common practice for general practitioners (GPs) to suggest a diagnosis when referring a patient to secondary care. However, it remains unclear via which underlying processes this practice can impact diagnostic performance. This study therefore examined the effect of a diagnostic suggestion in a GP's referral letter to the emergency department on the diagnostic performance of medical interns. METHODS: Medical interns diagnosed six clinical cases formatted as GP referral letters in a randomized within-subjects experiment. They diagnosed two referral letters stating a main complaint without a diagnostic suggestion (control), two stating a correct suggestion, and two stating an incorrect suggestion. The referral question and case order were randomized. We analysed the effect of the referral question on interns' diagnostic accuracy, number of differential diagnoses, confidence, and time taken to diagnose. RESULTS: Forty-four medical interns participated. Interns considered more diagnoses in their differential without a suggested diagnosis (M = 1.85, SD = 1.09) than with a suggested diagnosis, independent of whether this suggestion was correct (M = 1.52, SD = 0.96, d = 0.32) or incorrect ((M = 1.42, SD = 0.97, d = 0.41), χ2(2) =7.6, p = 0.022). The diagnostic suggestion did not influence diagnostic accuracy (χ2(2) = 1.446, p = 0.486), confidence, (χ2(2) = 0.058, p = 0.971) or time to diagnose (χ2(2) = 3.128, p = 0.209). CONCLUSIONS: A diagnostic suggestion in a GPs referral letter did not influence subsequent diagnostic accuracy, confidence, or time to diagnose for medical interns. However, a correct or incorrect suggestion reduced the number of diagnoses considered. It is important for healthcare providers and teachers to be aware of this phenomenon, as fostering a broad differential could support learning. Future research is necessary to examine whether these findings generalize to other healthcare workers, such as more experienced specialists or triage nurses, whose decisions might affect the diagnostic process later on. TRIAL REGISTRATION: The study protocol was preregistered and is available online at Open Science Framework ( https://osf.io/7de5g ).

Osteoporotic hip fractures: the burden of fixation failure.

Osteoporotic hip fractures are a major cause of morbidity and mortality in the elderly. Furthermore, reduced implant anchorage in osteoporotic bone predisposes towards fixation failure and with an ageing population, even low failure rates represent a significant challenge to healthcare systems. Fixation failure in fragility fractures of the hip ranges from 5% in peritrochanteric fractures through to 15% and 41% in undisplaced and displaced fractures of the femoral neck, respectively. Our findings, in general, support the view that failed internal fixation of these fragility fractures carries a poor prognosis: it leads to a twofold increase in the length of hospital stay and a doubling of healthcare costs. Patients are more likely to suffer a downgrade in their residential status upon discharge with a consequent increase in social dependency. Furthermore, the marked disability and reduction in quality of life evident before salvage procedures may persist at long-term followup. The risk, of course, for the elderly patient with a prolonged period of decreased functioning is that the disability becomes permanent. Despite this, however, no clear link between revision surgery and an increase in mortality has been demonstrated in the literature.

Diagnosing the doctors' departure: survey on sources of dissatisfaction among Irish junior doctors.

There has been a significant decline in the number of applications for non-consultant hospital doctor (NCHD) posts in Ireland over the last 18 months. We conducted an online, anonymous survey of Irish NCHDs to establish levels of satisfaction, sources of dissatisfaction and the major reasons for junior doctors seeking work abroad. 522 NCHDs took the survey, including 64 (12.3%) currently working outside of the Republic. 219 (45.8%) were slightly dissatisfied and 142 (29.7%) were extremely dissatisfied with practising medicine in Ireland. Major sources of dissatisfaction included the state of the health care system, staffing cover for leave and illness, the dearth of consultant posts and the need to move around Ireland. The most important reason for NCHDs wishing to leave was to seek better training and career opportunities abroad.

Comparative Pharmacokinetics and Local Tolerance of Tenofovir Alafenamide (TAF) From Subcutaneous Implant in Rabbits, Dogs, and Macaques.

The administration of antiretrovirals (ARVs) for HIV pre-exposure prophylaxis (PrEP) is highly efficacious and may benefit from new long-acting (LA) drug delivery approaches. This paper describes a subcutaneous, reservoir-style implant for the LA delivery of tenofovir alafenamide (TAF) and documents the preclinical assessment of implant safety and pharmacokinetics (PK) in New Zealand White (NZW) rabbits (3 groups of n = 5), beagle dogs (2 groups of n = 6), and rhesus macaques (2 groups of n = 3). Placebo implants were placed in rabbits (n = 10) and dogs (n = 12). Implant parameters, including selection of the TAF form, choice of excipient, and PCL formulation were tuned to achieve targeted concentrations of the active anabolite of TAF, tenofovir diphosphate (TFV-DP), within peripheral blood mononuclear cells (PBMCs) and mucosal tissues relevant to HIV transmission. Sustained concentrations of TFV-DP in PBMCs over 100 fmol/106 cells were achieved in all animal species indicating that the implants effectively delivered TAF for 3-6 months. Unlike placebo implants without TAF, all active implants resulted in local adverse events (AEs) proximal to the implant ranging in severity from mild to moderate and included dermal inflammation and necrosis across all species. Despite these AEs, the implant performed as designed and achieved a constant drug release profile, supporting the continued development of this drug delivery platform.

A randomized comparison of transfusion triggers in elective orthopaedic surgery using leucocyte-depleted red blood cells.

OBJECTIVE: In elective orthopaedic hip- and knee replacement surgery patients, we studied the effect of implementation of a uniform transfusion policy on RBC usage. STUDY DESIGN AND METHODS: A randomized, controlled study. A new uniform, restrictive transfusion policy was compared with standard care, which varied among the three participating hospitals. Only prestorage leucocyte-depleted RBC(s) were used. Primary end-point was RBC usage, related to length of hospital stay. Secondary end-points were Hb levels, mobilization delay and postoperative complications. RESULTS: Six hundred and three patients were evaluated. Adherence to the protocol was over 95%. Overall mean RBC usage was 0.78 U/patient in the new policy group and 0.86 U/patient in the standard care policy group (mean difference 0.08;95% CI [-0.3; 0.2]; P = 0.53). In two hospitals, the new transfusion policy resulted in a RBC reduction of 30% (0.58U RBC/patient) (P = 0.17) and 41% (0.29 U RBC/patient) (P = 0.05) respectively. In the third hospital, however, RBC usage increased by 39% (0.31 U RBC/patient) (P = 0.02) with the new policy, due to a more restrictive standard care policy in that hospital. Length of hospital stay was not influenced by either policy. CONCLUSIONS: Implementation of a uniform transfusion protocol for elective lower joint arthroplasty patients is feasible, but does not always lead to a RBC reduction. Length of hospital stay was not affected.

Iron dynamics in Al-Cu-Fe quasicrystals and approximants: Mössbauer and neutron experiments.

We present new results on the iron dynamics in the icosahedral quasicrystal i-AlCuFe and two cubic approximants as well as the non-approximant Al-Cu-Fe cubic B2 phase. Conventional Mössbauer spectroscopy is used as well as, for the i-AlCuFe phase, high Doppler velocity Mössbauer spectroscopy and quasielastic neutron scattering for samples with different Fe isotope contents. We show that in the i-phase the Fe Lamb-Mössbauer recoilless fraction decreases below that predicted for lattice vibrations alone for temperatures above about 550 K. This decrease is correlated with the onset of a quasielastic signal seen in both Mössbauer and neutron backscattering spectroscopy, which indicates the presence above 550 K of Fe jump processes confined in a local cage. The timescale of the Fe jumps (660 ps at 1000 K) and their temperature dependence differ widely from those of Cu jumps in the same i-AlCuFe quasicrystal. From the temperature dependence of the quadrupole splitting of the (57)Fe Mössbauer spectrum, one can distinguish two kinds of Fe jumps, one starting at 550 K and the second above 800 K. In the two cubic approximants, a loss in the Fe recoilless fraction also occurs above 550 K, revealing the same kind of Fe dynamics as in the i-phase but the effect is smaller. On the other hand, no anomalous Fe dynamics (other than lattice vibrations) is detected in the B2-AlCuFe phase. Since the cubic approximants possess similar local configurations as the quasicrystal, we conclude that locally a Penrose tile description is appropriate. This shows that the detected Fe jumps can be interpreted in terms of phason-like local tiling flips.

Surveillance for pancreatic cancer in high-risk individuals.

Background: Surveillance of individuals at high risk of pancreatic ductal adenocarcinoma (PDAC) and its precursors might lead to better outcomes. The aim of this study was to determine the prevalence and outcomes of PDAC and high-risk neoplastic precursor lesions among such patients participating in surveillance programmes. Methods: A multicentre study was conducted through the International CAncer of the Pancreas Screening (CAPS) Consortium Registry to identify high-risk individuals who had undergone pancreatic resection or progressed to advanced PDAC while under surveillance. High-risk neoplastic precursor lesions were defined as: pancreatic intraepithelial neoplasia (PanIN) 3, intraductal papillary mucinous neoplasia (IPMN) with high-grade dysplasia, and pancreatic neuroendocrine tumours at least 2 cm in diameter. Results: Of 76 high-risk individuals identified in 11 surveillance programmes, 71 had undergone surgery and five had been diagnosed with inoperable PDAC. Of the 71 patients who underwent resection, 32 (45 per cent) had PDAC or a high-risk precursor (19 PDAC, 4 main-duct IPMN, 4 branch-duct IPMN, 5 PanIN-3); the other 39 patients had lesions thought to be associated with a lower risk of neoplastic progression. Age at least 65 years, female sex, carriage of a gene mutation and location of a lesion in the head/uncinate region were associated with high-risk precursor lesions or PDAC. The survival of high-risk individuals with low-risk neoplastic lesions did not differ from that in those with high-risk precursor lesions. Survival was worse among patients with PDAC. There was no surgery-related mortality. Conclusion: A high proportion of high-risk individuals who had surgical resection for screening- or surveillance-detected pancreatic lesions had a high-risk neoplastic precursor lesion or PDAC at the time of surgery. Survival was better in high-risk individuals who had either low- or high-risk neoplastic precursor lesions compared with that in patients who developed PDAC.

Antecedentes: Se podrían obtener mejores resultados con el seguimiento de individuos de alto riesgo para adenocarcinoma ductal pancreático (pancreatic ductal adenocarcinoma, PDAC) y lesiones precursoras. El objetivo de este estudio fue determinar la prevalencia y los resultados del PDAC y de las lesiones precursoras de alto riesgo neoplásico en pacientes que participaron en programas de seguimiento. Métodos: Se llevó a cabo un estudio multicéntrico a través del registro internacional del consorcio CAPS (Common Automotive Platform Standard) para identificar a las personas de alto riesgo que se habían sometido a una resección pancreática o habían progresado a PDAC avanzado mientras estaban en seguimiento. Se definieron como lesiones neoplásicas precursoras de alto riesgo la neoplasia intraepitelial pancreática de tipo 3 (PanIN­3), la neoplasia papilar mucinosa intraductal (intraductal papillary mucinous neoplasia, IPMN) con displasia de alto grado y los tumores neuroendocrinos pancreáticos (pancreatic neuroendocrine tumours, PanNET) de ≥ 2 cm de diámetro. Resultados: De 76 individuos con lesiones de alto riesgo identificados en 11 programas de seguimiento, 71 fueron tratados quirúrgicamente y 5 fueron diagnosticados de un PDAC inoperable. De las 71 resecciones, 32 (45%) tenían PDAC o una lesión precursora de alto riesgo (19 PDAC, 4 IPMN de conducto principal, 4 IPMN de rama secundaria y 5 PanIN­3). Los otros 39 pacientes tenían lesiones que se consideraron asociadas con un menor riesgo de progresión neoplásica. La edad ≥ 65 años, el sexo femenino, el ser portador de una mutación genética y la localización de la lesión en la cabeza/proceso uncinado fueron factores asociados a las lesiones precursoras de alto riesgo o al PDAC. No hubo diferencias en la supervivencia de individuos de alto riesgo con lesiones neoplásicas de bajo riesgo frente a aquellos que presentaron lesiones precursoras de alto riesgo. La supervivencia fue peor en los pacientes con PDAC. No hubo mortalidad relacionada con la cirugía. Conclusión: Un elevado porcentaje de individuos de alto riesgo que se sometieron a resección quirúrgica tras la detección de lesiones pancreáticas en el seguimiento tenían una lesión precursora neoplásica de alto riesgo o un PDAC. La supervivencia fue mejor en individuos de alto riesgo que tenían lesiones precursoras neoplásicas de bajo o alto riesgo en comparación con aquellos pacientes que habían desarrollado un PDAC.

Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia.

Pancreatic cancer is a highly lethal malignancy with a dismal 5-year survival of less than 5%. The scarcity of early biomarkers has considerably hindered our ability to launch preventive measures for this malignancy in a timely manner. Neutrophil gelatinase-associated lipocalin (NGAL), a 24-kDa glycoprotein, was reported to be upregulated nearly 27-fold in pancreatic cancer cells compared to normal ductal cells in a microarray analysis. Given the need for biomarkers in the early diagnosis of pancreatic cancer, we investigated the expression of NGAL in tissues with the objective of examining if NGAL immunostaining could be used to identify foci of pancreatic intraepithelial neoplasia, premalignant lesions preceding invasive cancer. To examine a possible correlation between NGAL expression and the degree of differentiation, we also analysed NGAL levels in pancreatic cancer cell lines with varying grades of differentiation. Although NGAL expression was strongly upregulated in pancreatic cancer, and moderately in pancreatitis, only a weak expression could be detected in the healthy pancreas. The average composite score for adenocarcinoma (4.26+/-2.44) was significantly higher than that for the normal pancreas (1.0) or pancreatitis (1.0) (P<0.0001). Further, although both well- and moderately differentiated pancreatic cancer were positive for NGAL, poorly differentiated adenocarcinoma was uniformly negative. Importantly, NGAL expression was detected as early as the PanIN-1 stage, suggesting that it could be a marker of the earliest premalignant changes in the pancreas. Further, we examined NGAL levels in serum samples. Serum NGAL levels were above the cutoff for healthy individuals in 94% of pancreatic cancer and 62.5% each of acute and chronic pancreatitis samples. However, the difference between NGAL levels in pancreatitis and pancreatic cancer was not significant. A ROC curve analysis revealed that ELISA for NGAL is fairly accurate in distinguishing pancreatic cancer from non-cancer cases (area under curve=0.75). In conclusion, NGAL is highly expressed in early dysplastic lesions in the pancreas, suggesting a possible role as an early diagnostic marker for pancreatic cancer. Further, serum NGAL measurement could be investigated as a possible biomarker in pancreatitis and pancreatic adenocarcinoma.

Female-versus-male alloreactivity as a model for minor histocompatibility antigens in hematopoietic stem cell transplantation.

H-Y encoded gene products were the first to be recognized as clinically relevant minor histocompatibility antigens. Compared to other gender combinations, female donor/male recipient (FDMR) transplants are associated with increased graft-versus-host disease (GvHD), increased transplant-related mortality (TRM) and reduced risk of relapse. Still, their relative impact on transplant outcome remains controversial. We analyzed donor/recipient sex combination in 53,988 patients treated with allogeneic hematopoietic stem cell transplantation (HSCT) between 1980 and 2005. We found a strong increase in chronic GvHD and late TRM and decreased survival in FDMR transplants irrespective of underlying disease. Conversely, FDMR patients had lower relapse rates. The negative effect on survival decreased with advancing disease stage as relapse protection became more important. Effects of H-Y alloreactivity were most pronounced in patients transplanted from HLA-matched donors and in those receiving transplants from an adult donor. Adjustment for acute and chronic GvHD only partially corrected the effects of H-Y alloreactivity. Analysis of the FDMR proportion over time indicated that the frequency of this gender combination has declined in unrelated transplants over the last 10 years. These data define the role of H-Y mismatching in allogeneic HSCT and support the current practice of avoiding female donors for male patients, if possible.

A retrospective comparison of autologous and unrelated donor hematopoietic cell transplantation in myelodysplastic syndrome and secondary acute myeloid leukemia: a report on behalf of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

Hematopoietic cell transplantation (HCT) is an effective treatment for myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML). In this study, outcome of 593 patients with MDS/sAML after autologous and allogeneic HCT from a matched unrelated donor (MUD) were compared. A total of 167 (28%) patients received HCT from MUD without prior chemotherapy (MUD-U). The rest received HCT in first complete remission (CR1) (Autologous (Auto-CR1), n=290 (49%), HCT from MUD (MUD-CR1), n=136 (23%)). Survival at 3 years was best in MUD-CR1 (50%) compared to Auto-CR1 (41%) and MUD-U (40%) (P=0.01). Similarly, disease-free survival was 44% for MUD-CR1 compared to Auto-CR1 (28%) and MUD-U (34%) (P=0.03). Treatment-related mortality was 17% in Auto-CR1 compared to MUD-CR1 (38%) and MUD-U (49%) (P<0.001). Relapse for Auto-CR1 was 62% compared to 24 and 30% for MUD-CR1 and MUD-U, respectively (P<0.001). Outcome was best for patients with low tumor burden transplanted 6-12 months after diagnosis. Factors influencing outcome at 3 years were mainly significant in the first 6 months. Only, relapse after autologous HCT remained constant over time. Outcomes after allogeneic HCT in patients of 20-40 and >40 years were similar. Autologous and Allogeneic HCT from MUD offer the possibility of long-term survival to patients with MDS/sAML.

Chronic ethanol ingestion alters xenobiotic absorption through the skin: potential role of oxidative stress.

Alcohol ingestion is correlated with several skin disorders and it has been proposed that changes in skin properties may be an early indicator of alcohol misuse. Topically applied ethanol is an effective transdermal penetration enhancer; however, little is known about the effects of chronic ethanol ingestion on skin. Rats were pair fed a diet containing 36% ethanol for twelve weeks. The animals were then switched to a non-ethanol diet and were monitored for up to four weeks. Non-invasive measurements for changes in dermal blood flow using laser Doppler velocimetry (LDV), damage to skin barrier via transepidermal water loss (TEWL) and changes in skin moisture content were obtained for the experimental duration. At 0, 1 day or 1, 2, 3, 4 weeks after alcohol removal rats were euthanized and their skin was analyzed for alcohol and aldehyde dehydrogenase, and lipid peroxidation. Transdermal penetration of the herbicide paraquat, industrial solvent dimethyl formamide (DMF), insect repellant N,N-diethyl-m-toluamide (DEET) and herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) was also determined. Transdermal absorption, LDV, TEWL, skin alcohol and aldehyde dehydrogenase, as well as lipid peroxidation significantly increased after continuous ethanol exposure (p<0.05). These factors remain elevated for up to four weeks after termination of ethanol consumption, showing that skin changes induced by alcohol are not immediately reversible and reflect fundamental changes in the skin itself. This work provides a starting point for examining the link between ethanol ingestion and skin disorders associated with alcohol use.

[More cot deaths in child care settings than during the same hours at home: 10-year statistics]. / Meer wiegendood tijdens kinderopvang dan in dezelfde uren thuis: 10-jaarscijfers.

OBJECTIVE: To determine whether the incidence of sudden infant death syndrome (SIDS) in child care settings (child care centres or child minders) is different from that in the home setting, and to search for any differences in the prevalence of SIDS risk factors in both settings. DESIGN: Descriptive and comparative. METHOD: All SIDS cases (< 2 years), that occurred between September 1996-August 2006 and known to the 'Landelijke Werkgroep Wiegendood' (the National Cot Death Study Group) of the Dutch Paediatric Association were analysed. The percentage of children involved in child care and the mean duration of their participation in child care, was calculated from national surveys carried out in well-baby clinics. RESULTS: In the 10 years of the study, 216 cases of SIDS became known to the Cot Death Study Group. In the first year of life, the number was 75% of the number registered by Statistics Netherlands. 28 of these infants died from SIDS between the ages of 3-6 months and on Monday-Friday between 8:00 am-5:00 pm: the usual hours of opening of child care facilities. Based on the uptake of child care during this period, 15% of this mortality was expected to have occurred in a child care setting and 85% at home. In reality, 61% (17/28) of the deaths occurred at a child care facility and 39% (11/28) at home. The relative risk was 8.8 (95% CI: 4.1-19.0). This high incidence of SIDS in a child care setting did not appear to be due to a higher prevalence of known risk factors for SIDS at child care facilities i.e. sleeping position (prone or side), passive smoking, heat congestion, or use of a quilt or pillow. CONCLUSION: For infants aged 3-6 months, the relative risk ofSIDS during child care appeared to be increased 8.8 times (95% CI: 4.1-19.0) when compared with home settings in The Netherlands in September 1996-August 2006.

Spontaneous buckling of contractile poroelastic actomyosin sheets.

Shape transitions in developing organisms can be driven by active stresses, notably, active contractility generated by myosin motors. The mechanisms generating tissue folding are typically studied in epithelia. There, the interaction between cells is also coupled to an elastic substrate, presenting a major difficulty for studying contraction induced folding. Here we study the contraction and buckling of active, initially homogeneous, thin elastic actomyosin networks isolated from bounding surfaces. The network behaves as a poroelastic material, where a flow of fluid is generated during contraction. Contraction starts at the system boundaries, proceeds into the bulk, and eventually leads to spontaneous buckling of the sheet at the periphery. The buckling instability resulted from system self-organization and from the spontaneous emergence of density gradients driven by the active contractility. The buckling wavelength increases linearly with sheet thickness. Our system offers a well-controlled way to study mechanically induced, spontaneous shape transitions in active matter.

Elevated insulin receptor content in human breast cancer.

The growth of breast cancer cells is under the regulation of hormones, growth factors, and their receptors. In the present study, we have employed a new, sensitive, and specific radioimmunoassay for the direct measurement of insulin receptors in surgical specimens of breast cancers. In 159 specimens the insulin receptor content was 6.15 +/- 3.69 ng/0.1 mg protein. This value was more than sixfold higher than the mean value found in both 27 normal breast tissues obtained at total mastectomy (0.95 + 0.68, P less than 0.001) and in six normal specimens obtained from reduction mammoplasty (0.84 +/- 0.78, P less than 0.001). The insulin receptor content in breast cancer tissues was also higher than in any normal tissue investigated including liver (Pezzino, V., V. Papa, V. Trischitta, A. Brunetti, P.A. Goodman, M.K. Treutelaar, J.A. Williams, B.A. Maddux, R. Vigneri, and I.D. Goldfine, 1989. Am. J. Physiol. 257:E451-457). The insulin receptor in breast cancer retained its ability to both bind insulin and undergo insulin-induced tyrosine kinase activation. Immunostaining of the specimens revealed that the insulin receptor was present in malignant epithelial cells, but was not detected in stromal and inflammatory cells. Univariant analysis revealed that the insulin receptor content of the tumors correlated positively with tumor size (P = 0.014), histological grading (P = 0.030), and the estrogen receptor content (P = 0.035). There were no significant correlations between insulin receptor content and the age, body weight, menopausal status, and nodal involvement of the patients. These studies indicate, therefore, that the insulin receptor content is increased in breast cancers and raise the possibility that the insulin receptor may have a role in the biology of these tumors.

Clonal gammopathies following alemtuzumab-based reduced intensity conditioning haematopoietic stem cell transplantation: association with chronic graft-versus-host disease and improved overall survival.

The presence of clonal gammopathies (CG) has been reported following both conventional myeloablative and autologous haematopoietic stem cell transplantation (HSCT). We monitored the occurrence of CG in a cohort of patients with myeloid malignancies receiving FBC (fludarabine-busulphan-alemtuzumab)-based reduced intensity conditioned (RIC) HSCT, and assessed its correlation with infections, graft-versus-host disease (GvHD) and survival. Serial serum protein electrophoresis was analysed in a total of 138 patients and CG were detected in 49 patients (36%). The predominant Ig isotype was IgG (82%). There was no difference in the incidence of viral infections between patient groups. However, patients with gammopathies were more likely to have had prior chronic GvHD (OR 2.7, 95% CI 1.3-5.5, P<0.001). On multivariate analysis, the only factors that were found to influence overall survival (OS) were presence of gammopathies, which was associated with an improved OS (OR 0.35 95% CI 0.14-0.86, P=0.02) as well as disease stage, patients with advanced disease having a higher risk of death (OR 2.20 95% CI 1.18-4.11, P=0.02). Disease stage was the only variable that influenced relapse incidence on multivariate analysis (OR 4.22 95% CI 1.82-9.78, P<0.01). Clonal gammopathies are a frequent but benign occurrence following alemtuzumab-based RIC HSCT, and their appearance may define a group of patients with a favourable overall outcome.

Potential mechanisms by which a single drink of alcohol can increase transdermal absorption of topically applied chemicals.

BACKGROUND: Both chronic and acute ethanol consumption increase transdermal penetration of topically applied xenobiotics. The mechanisms by which this enhancement occurs are unknown. We hypothesized that either the vasodilatory effects of ethanol or its ability to disrupt the lipid bilayer via lipid peroxidation, may be contributing to the increased transdermal absorption observed in alcohol consuming animals. METHODS: Male Wistar rats were gavaged with 1.5, 3, 4.3, 6 or 10 g/kg ethanol or saline control or were treated with either the vasoconstrictor epinephrine or with the vasodilator prilocaine. Dermal blood flow, transepidermal water loss (TEWL), and skin moisture were non-invasively measured. Transdermal penetration was then determined for four xenobiotics (paraquat, dimethyl formamide (DMF), 2,4-dichlorophenoxyacetic acid (2,4-D) and N,N-diethyl-m-toluamide (DEET)). Lipid peroxidation was also determined by monitoring the formation of malondialdehyde. RESULTS: Dermal blood flow increased by approximately 27% (p<0.05), TEWL increased 1.12+/-0.2-fold while skin lipid peroxidation increased 1.4-fold (p<0.05) 2h after gavage with 10 g/kg alcohol. Transdermal penetration of paraquat was increased by prilocaine (ER=2.1+/-0.4, p<0.05), but the absorption of DEET, 2,4-D and DMF were not influenced by greater blood flow. Reducing dermal blood flow with epinephrine did not cause any significant changes in transdermal penetration. CONCLUSIONS: Vasodilation triggered by a single episode of ethanol ingestion is not responsible for the observed increase in transdermal absorption. Ethanol induced changes in lipid peroxidation and TEWL demonstrate that drinking alcohol induces transdermal absorption of xenobiotics.

Transdermal absorption of the herbicide 2,4-dichlorophenoxyacetic acid is enhanced by both ethanol consumption and sunscreen application.

Xenobiotics absorption is a health concern and skin is a major exposure site for many of these chemicals. Both alcohol consumption and topical sunscreen application act as transdermal penetration enhancers for model xenobiotics. The effect of combining these two treatments on transdermal absorption of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) was therefore examined. Skin from rats ingesting low (1.5 g/kg) medium (4.3 g/kg) or high (6 g/kg) ethanol doses or saline control was treated with a commercially available sunscreen containing titanium dioxide and octyl methoxycinnimate and transdermal absorption of 2,4-D was monitored. Ethanol increased penetration by a factor of 1.9, 2.0 and 2.5 for animals treated with 1.5, 4.3 and 6 g/kg respectively, demonstrating an ethanol-induced dose response. Sunscreen application to skin from ethanol gavaged rats caused 2,4-D absorption above that induced by ethanol alone by an additional factor of 1.3, 2.1 and 2.9 for 1.5, 4.3 and 6 g/kg respectively. Comparing 2,4-D transdermal absorption after exposure to both ethanol and sunscreen with a theoretical value (sum of penetration after ethanol or sunscreen treatment) demonstrates that these two treatments enhance additively at the higher doses tested. Results of this study emphasize the importance of limiting excessive alcohol consumption in individuals with potential herbicide exposure rather than discouraging the use of sunscreens, since the consequences of UV-induced skin cancer are far more series than the risks that would be associated with observed increases in chemical exposure.