PATCH-DP: a single-arm phase II trial of intra-operative application of HEMOPATCH™ to the pancreatic stump to prevent post-operative pancreatic fistula following distal pancreatectomy.

BACKGROUND: Post-operative pancreatic fistula (POPF) is the most significant cause of morbidity following distal pancreatectomy. Hemopatch™ is a thin, bovine collagen-based hemostatic sealant. We hypothesized that application of Hemopatch™ to the pancreatic stump following distal pancreatectomy would decrease the incidence of clinically-significant POPF. METHODS: We conducted a prospective, single-arm, multicentre phase II study of application of Hemopatch™ to the pancreatic stump following distal pancreatectomy. The primary outcome was clinically-significant POPF within 90 days of surgery. A sample size of 52 patients was required to demonstrate a 50% relative reduction in Grade B/C POPF from a baseline incidence of 20%, with a type I error of 0.2 and power of 0.75. Secondary outcomes included incidence of POPF (all grades), 90-day mortality, 90-day morbidity, re-interventions, and length of stay. RESULTS: Adequate fixation Hemopatch™ to the pancreatic stump was successful in all cases. The rate of grade B/C POPF was 25% (95%CI: 14.0-39.0%). There was no significant difference in the incidence of grade B/C POPF compared to the historical baseline (p = 0.46). The 90-day incidence of Clavien-Dindo grade ≥3 complications was 26.9% (95%CI: 15.6-41.0%). CONCLUSION: The use of Hemopatch™ was not associated with a decreased incidence of clinically-significant POPF compared to historical rates. (NCT03410914).

Association Between Preoperative Patient-Reported Symptoms and Postoperative Outcomes in Rectal Cancer Patients: A Retrospective Cohort Study.

BACKGROUND: Rectal cancer patients undergoing preoperative radiotherapy experience a significant symptom burden. However, it is unknown whether symptoms during radiotherapy may portend adverse postoperative outcomes and healthcare utilization. METHODS: A retrospective cohort study was performed of rectal cancer patients undergoing neoadjuvant radiotherapy and proctectomy in Ontario from 2007 to 2014. The primary outcome was a complicated postoperative course-a dichotomous variable created as a composite of postoperative mortality, major morbidity, or hospital readmission. Patient-reported Edmonton Symptom Assessment System (ESAS) scores, collected routinely at outpatient provincial cancer center visits, were linked to administrative healthcare databases. The receiver-operating characteristic analysis was used to compare ESAS scoring approaches and to stratify patients into low versus high symptom score groups. Multivariable regression models were constructed to evaluate associations between preoperative symptom scores and postoperative outcomes. RESULTS: 1455 rectal cancer patients underwent sequential radiotherapy and proctectomy during the study period and recorded symptom assessments. Patients with high preoperative symptom scores were significantly more likely to experience a complicated postoperative course (OR 1.55, 95% CI 1.23-1.95). High preoperative ESAS scores were also associated with the secondary outcomes of emergency department visits (OR 1.34, 95% CI 1.08-1.66) and longer length of stay (IRR 1.23, 95% CI 1.04-1.45). CONCLUSIONS: Rectal cancer patients reporting elevated symptom scores during neoadjuvant radiotherapy have increased odds of experiencing a complicated postoperative course. Preoperative patient-reported outcome screening may be a useful tool to identify at-risk patients and to efficiently direct perioperative supportive care.

Prenatal diagnosis of rhombencephalosynapsis: neuroimaging features and severity of vermian anomaly.

OBJECTIVES: To describe the prenatal neuroimaging spectrum of rhombencephalosynapsis (RES) and criteria for its classification according to the severity of vermian anomaly. METHODS: In this multicenter retrospective study of fetuses with RES between 2002 and 2020, the medical records and brain ultrasound and magnetic resonance images were evaluated comprehensively to determine the severity of the vermian anomaly and the presence of associated brain findings. RES was classified, according to the pattern of vermian agenesis and the extent of the fusion of the hemispheres, as complete RES (complete absence of the vermis) or partial RES (further classified according to the part of the vermis that was missing and, consequently, the region of hemispheric fusion, as anterior, posterior, severe or mixed RES). Findings were compared between cases with complete and those with partial RES. RESULTS: Included in the study were 62 fetuses with a gestational age ranging between 12 and 37 weeks. Most had complete absence of the vermis (complete RES, 77.4% of cases), a 'round-shaped' cerebellum on axial views (72.6%) and a transverse cerebellar diameter (TCD) < 3rd centile (87.1%). Among the 22.6% of cases with partial RES, 6.5% were classified as severe partial, 6.5% as partial anterior, 8.1% as partial mixed and 1.6% as partial posterior. Half of these cases presented with normal or nearly normal cerebellar morphology and 28.5% had a TCD within the normal limits. Infratentorially, the fourth ventricle was abnormal in 88.7% of cases overall, and anomalies of the midbrain and pons were frequent (93.5% and 77.4%, respectively). Ventriculomegaly was observed in 80.6% of all cases, being more severe in cases with complete RES than in those with partial RES, with high rates of parenchymal and septal disruption. CONCLUSIONS: This study provides prenatal neuroimaging criteria for the diagnosis and classification of RES, and identification of related features, using ultrasound and magnetic resonance imaging. According to our findings, a diagnosis of RES should be considered in fetuses with a small TCD (severe cerebellar hypoplasia) and/or a round-shaped cerebellum on axial views, during the second or third trimester, especially when associated with ventriculomegaly. Partial RES is more common than previously thought, but presents an extreme diagnostic challenge, especially in cases with normal or nearly-normal cerebellar morphobiometric features. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Patient-reported symptoms in metastatic gastric cancer patients in the last 6 months of life.

BACKGROUND: Patients with metastatic gastric cancer have poor survival outcomes and may experience high symptom burden. We evaluated symptom trajectory and risk factors for increased symptom severity among metastatic gastric cancer patients during the last 6 months of life. METHODS: We conducted a retrospective cohort study among patients ≥ 18 years diagnosed with metastatic gastric cancer from January 2007 to December 2014 in the province of Ontario, Canada. We included patients who died during the study period and who reported at least one Edmonton Symptom Assessment System (ESAS) score during the last 6 months of life. We described the proportion of patients who reported moderate-to-severe symptom scores (≥ 4) by month. Multivariable logistic regression models were created to identify risk factors for moderate-to-severe symptom scores. RESULTS: Seven hundred eighty-eight eligible patients with 3286 unique symptom scores completed during their last 6 months of life were identified. The highest prevalence of moderate-to-severe scores was observed for tiredness and lack of appetite, while nausea and depression had the lowest prevalence of elevated scores. The prevalence of moderate-to-severe was consistently high for all symptoms, particularly approaching end-of-life. Timing of ESAS scores, receipt of cancer-directed therapy, urban residence, and female sex were associated with increased odds of reporting moderate-to-severe symptom scores. CONCLUSION: Patients with metastatic gastric cancer experience significant symptom burden at the end-of-life. Routine screening with patient-reported outcome tools may assist in shared decision-making and effective palliative care by ensuring patients' health status and supportive care needs are identified promptly at the time of clinical encounters.

Computer simulations of colloidal gels: how hindered particle rotation affects structure and rheology.

The effects of particle roughness and short-ranged non-central forces on colloidal gels are studied using computer simulations in which particles experience a sinusoidal variation in energy as they rotate. The number of minima n and energy scale K are the key parameters; for large K and n, particle rotation is strongly hindered, but for small K and n particle rotation is nearly free. A series of systems are simulated and characterized using fractal dimensions, structure factors, coordination number distributions, bond-angle distributions and linear rheology. When particles rotate easily, clusters restructure to favor dense packings. This leads to longer gelation times and gels with strand-like morphology. The elastic moduli of such gels scale as G'∝ω0.5 at high shear frequencies ω. In contrast, hindered particle rotation inhibits restructuring and leads to rapid gelation and diffuse morphology. Such gels are stiffer, with G'∝ω0.35. The viscous moduli G'' in the low-barrier and high-barrier regimes scale according to exponents 0.53 and 0.5, respectively. The crossover frequency between elastic and viscous behaviors generally increases with the barrier to rotation. These findings agree qualitatively with some recent experiments on heterogeneously-surface particles and with studies of DLCA-type gels and gels of smooth spheres.

Patterns of Symptoms Burden in Neuroendocrine Tumors: A Population-Based Analysis of Prospective Patient-Reported Outcomes.

BACKGROUND: How to best support patients with neuroendocrine tumors (NETs) remains unclear. Improving quality of care requires an understanding of symptom trajectories. Objective validated assessments of symptoms burden over the course of disease are lacking. This study examined patterns and risk factors of symptom burden in NETs, using patient-reported outcomes. SUBJECTS, MATERIALS, AND METHODS: A retrospective, population-based, observational cohort study of patients with NETs diagnosed from 2004 to 2015, who survived at least 1 year, was conducted. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to provincial administrative health data sets. Moderate-to-severe symptom scores were presented graphically for both the 1st year and 5 years following diagnosis. Multivariable Poisson regression identified factors associated with record of moderate-to-severe symptom scores during the 1st year after diagnosis. RESULTS: Among 2,721 included patients, 7,719 symptom assessments were recorded over 5 years following diagnosis. Moderate-to-severe scores were most frequent for tiredness (40%-51%), well-being (37%-49%), and anxiety (30%-40%). The proportion of moderate-to-severe symptoms was stable over time. Proportion of moderate-to-severe anxiety decreased by 10% within 6 months of diagnosis, followed by stability thereafter. Changes were below 5% for other symptoms. Similar patterns were observed for the 1st year after diagnosis. Primary tumor site, metastatic disease, younger age, higher comorbidity burden, lower socioeconomic status, and receipt of therapy within 30 days of assessment were independently associated with higher risk of elevated symptom burden. CONCLUSION: Patients with NETs have a high prevalence of moderate-to-severe patient-reported symptoms, with little change over time. Patients remain at risk of prolonged symptom burden following diagnosis, highlighting potential unmet needs. Combined with identified patient and disease factors associated with moderate-to-severe symptom scores, this information is important to support symptom management strategies to improve patient-centered care. IMPLICATIONS FOR PRACTICE: This study used population-level, prospectively collected, validated, patient-reported outcome measures to appraise the symptoms burden and trajectory of patients with neuroendocrine tumors (NETs) after diagnosis. It is the largest and most detailed analysis of patient-reported symptoms for NETs. Patients with NETs present a high burden of symptoms at diagnosis that persists up to 5 years later, highlighting unmet needs. Early and comprehensive symptom screening and management programs are needed. This information should serve to devise pathways and policies to better support patients, evaluate supportive interventions, and assess the effectiveness of symptom management at the provider, institutional, and system levels.

Patient-reported symptoms following mastectomy alone or lumpectomy plus radiation for early stage breast cancer: a cohort study.

PURPOSE: Studies examining symptom differences between surgeries for breast cancer patients rarely incorporate the effects of adjuvant treatment choice. We sought to understand differences in patient-reported symptoms between lumpectomy plus radiation and mastectomy in the year following surgery. METHODS: This cohort study used linked administrative datasets. The exposure was defined as lumpectomy plus radiation or mastectomy. The outcomes of moderate-to-severe (score ≥ 4) patient-reported symptoms were obtained using the Edmonton symptom assessment system (ESAS). Line plots were created to determine symptom trajectories in the 12 months following surgery, and the relationships between surgery and each of the nine symptoms were assessed using multivariable analyses. Clinical significance was determined as a difference of 10%. RESULTS: Of 13,865 Stage I-II breast cancer patients diagnosed 2007-2015, 11,497 underwent lumpectomy plus radiation and 2368 underwent mastectomy. Symptom trajectories were similar for all nine symptoms until approximately 5 months postoperatively when they diverged and mastectomy symptoms started becoming more severe. On multivariable analyses, patients undergoing mastectomy were at an increased risk of reporting moderate-to-severe depression (RR 1.19, 95% CI 1.09-1.30), lack of appetite (RR 1.11, 95% CI 1.03-1.20), and shortness of breath (RR 1.16, 95% CI 1.04-1.15) compared to those undergoing lumpectomy plus radiation. CONCLUSIONS: Even with the addition of adjuvant radiation, patients who are treated with lumpectomy fare better in three of nine patient-reported symptoms. Further examination of these differences will assist in better shared decision-making regarding surgical treatments.

Symptom Burden at the End of Life for Neuroendocrine Tumors: An Analysis of 2579 Prospectively Collected Patient-Reported Outcomes.

BACKGROUND: Given a slow course of disease, end-of-life issues are understudied in neuroendocrine tumors (NETs). To date, there are no data regarding symptoms at the end of life. This study examined symptom trajectories and factors associated with high symptom burden in NETs at the end of life. METHODS: We conducted a retrospective cohort study of NET patients diagnosed from 2004 to 2015 and who died between 2007 and 2016, in Ontario, Canada. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to administrative healthcare datasets. Moderate-to-severe symptom scores (≥ 4 out of 10) in the 6 months before death were analyzed, with multivariable modified Poisson regression identifying factors associated with moderate-to-severe symptoms scores. RESULTS: Among 677 NET decedents, 2579 symptom assessments were recorded. Overall, moderate-to-severe scores were most common for tiredness (86%), wellbeing (81%), lack of appetite (75%), and drowsiness (68%), with these proportions increasing as death approached. For symptoms of lack of appetite, drowsiness, and shortness of breath, the increase was steepest in the 8 weeks before death. On multivariable analyses, the risk of moderate-to-severe symptoms was significantly higher in the last 2 months before death and for patients with shorter survival (< 6 months). Women had higher risks of anxiety, nausea, and pain. CONCLUSION: A high prevalence of moderate-to-severe symptoms was observed for NETs at the end of life, not previously described. The proportion of moderate-to-severe symptoms increases steeply as death nears, highlighting an opportunity for improved management. Combined with identified factors associated with moderate-to-severe symptoms, this information is important to improve patient-centred and personalized supportive care for NETs at the end of life.

Economic Analysis of Adjuvant Chemoradiotherapy Compared with Chemotherapy in Resected Pancreas Cancer.

BACKGROUND: Population-based survival and costs of pancreas adenocarcinoma patients receiving adjuvant chemoradiation and chemotherapy following pancreaticoduodenectomy are poorly understood. METHODS: This retrospective cohort study used linked administrative and pathological datasets to identify all patients diagnosed with pancreas adenocarcinoma and undergoing pancreaticoduodenectomy in Ontario between April 2004 and March 2014, who received postoperative chemoradiation or chemotherapy. Stage and margin status were defined by using pathology reports. Kaplan-Meier and Cox proportional hazards regression survival analyses were used to determine associations between adjuvant treatment approach and survival, while stratifying by margin status. Median overall health system costs were calculated at 1 and 3 years for chemoradiation and chemotherapy, and differences were tested using the Kruskal-Wallis test. RESULTS: Among 709 patients undergoing pancreaticoduodenectomy for pancreas cancer during the study period, the median survival was 21 months. Median survival was 19 months for chemoradiation and 22 months for chemotherapy. Patients receiving chemoradiation were more likely to have positive margins: 47.7% compared with 19.2% in chemotherapy. After stratifying by margin status and controlling for confounders, adjusted hazard ratio of death were not statistically different between chemotherapy and chemoradiation [margin positive, hazard ratio (HR) = 0.99, 95% confidence interval (CI) = 0.88-1.27; margin negative, HR 0.95, 95% CI 0.91-1.18]. Overall 1-year health system costs were significantly higher for chemoradiation (USD $70,047) than chemotherapy (USD $54,005) (p ≤ 0.001). CONCLUSIONS: Chemotherapy and chemoradiation yielded similar survival, but chemoradiation resulted in higher costs. To create more sustainable healthcare systems, both the efficacy and costs of therapies should be considered.

Comparison of Patient-Reported Outcomes in Laparoscopic and Open Right Hemicolectomy: A Retrospective Cohort Study.

BACKGROUND: Open and laparoscopic resections for colon cancer have equivalent perioperative morbidity and mortality. However, there are little data concerning patient-reported outcomes in the early postdischarge period. OBJECTIVE: We examined patient-reported outcomes in the early postdischarge period for open and laparoscopic right hemicolectomy for colon cancer. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted using linked administrative healthcare databases in the province of Ontario, Canada. PATIENTS: Patients undergoing laparoscopic or open right hemicolectomy for colon cancer between January 2010 and December 2014 were identified using the Ontario Cancer Registry and physician billing data. MAIN OUTCOME MEASURES: The primary outcome was the presence of moderate-to-severe symptom scores on the Edmonton Symptom Assessment System (≥4 of 10) within 6 weeks of hospital discharge after right hemicolectomy. RESULTS: A total of 1022 patients completed ≥1 Edmonton Symptom Assessment System survey within 6 weeks of surgery and were included in the study. Patients undergoing laparoscopic resection were more likely to have an urban residence, to have undergone planned resections, and to have had proportionally more stage 1 disease compared with patients undergoing open resection. On multivariable analyses, adjusting for patient demographics, cancer stage, and planned versus unplanned admission status, there were no differences in the adjusted odds of moderate-to-severe symptom scores between the laparoscopic and open approaches. LIMITATIONS: Edmonton Symptom Assessment System scores are not collected for inpatients and thus only represent outpatient postoperative visits. Scores were reported by 19% of all resections in the population, with a bias to patients treated at cancer centers, and therefore they are not fully representative of the general population of right hemicolectomy. The Edmonton Symptom Assessment System is not a disease-specific tool and may not measure all relevant outcomes for patients undergoing right hemicolectomy. CONCLUSIONS: Receipt of the open or laparoscopic surgical technique was not associated with increased risk of elevated symptom burden in the early postdischarge period. See Video Abstract at http://links.lww.com/DCR/B27. REPORTE COMPARATIVO DE RESULTADOS INFORMADOS DE PACIENTES CON HEMICOLECTOMÍA DERECHA LAPAROSCÓPICA Y ABIERTA: UN ESTUDIO DE COHORTE RETROSPECTIVO: Las resecciones abiertas y laparoscópicas para el cáncer de colon, presentan semejante morbilidad y mortalidad perioperatoria. Sin embargo, en el período inicial posterior al alta, hay pocos datos sobre los resultados informados por los pacientes.Examinamos los resultados informados por los pacientes, en el período temprano posterior al alta, para hemicolectomía derecha abierta y laparoscópica en cáncer de colon.Estudio de cohorte retrospectivo.El estudio se realizó utilizando bases de datos administrativas de atención médica en la provincia de Ontario, Canadá.Pacientes sometidos a hemicolectomía derecha abierta o laparoscópica para cáncer de colon, de enero 2010 a diciembre 2014, se identificaron mediante el Registro de cáncer de Ontario y de los datos médicos de facturación.El resultado primario, después de la hemicolectomía derecha, fue la presencia de síntomas de moderados a graves en el Sistema de evaluación de síntomas de Edmonton (≥4 de cada 10) dentro de las seis semanas posteriores al alta hospitalaria.Un total de 1022 pacientes completaron al menos una encuesta del Sistema de evaluación de síntomas de Edmonton, dentro de las seis semanas de la cirugía y se incluyeron en el estudio. Los pacientes sometidos a resección laparoscópica fueron más propensos a residir en zona urbana, a resecciones planificadas y proporcionalmente más enfermedad en estadio 1; en comparación con los pacientes sometidos a resecciones abiertas. En los análisis multivariables, que se ajustaron a la demografía del paciente, al estadio del cáncer y del estado de ingreso planificado versus no planificado, no hubo diferencias en las probabilidades ajustadas de las puntuaciones de los síntomas moderados a severos entre el abordaje abierto o laparoscópico.Las puntuaciones del Sistema de evaluación de síntomas de Edmonton no se recopilan para pacientes hospitalizados y por lo tanto, solo representan las visitas postoperatorias de pacientes ambulatorios. Las puntuaciones informadas fueron del 19% de todas las resecciones en la población, con un sesgo en los pacientes tratados en los Centros de Cáncer y por lo tanto, no son totalmente representativos de la población general de hemicolectomía derecha. El Sistema de evaluación de síntomas de Edmonton no es una herramienta específica de la enfermedad y puede no medir todos los resultados relevantes para los pacientes que se someten a una hemicolectomía derecha.La recepción entre una técnica quirúrgica abierta o laparoscópica, no se asoció con un aumento del riesgo de síntomas en el período temprano posterior al alta. Vea el Resumen del Video en http://links.lww.com/DCR/B27.

Fourth ventricle index: sonographic marker for severe fetal vermian dysgenesis/agenesis.

OBJECTIVE: Prenatal diagnosis of midbrain-hindbrain (MB-HB) malformations relies primarily on abnormal size and shape of the cerebellum and retrocerebellar space, particularly 'open fourth ventricle' (4V), the most common indicator of MB-HB malformations. The aim of this study was to present the fourth ventricle index (4VI), and to evaluate its role as a marker for severe vermian dysgenesis/agenesis in cases without open 4V. METHODS: This was a prospective cross-sectional study of patients with singleton low-risk pregnancy at 14 + 1 to 36 + 6 gestational weeks presenting between May 2016 and November 2017 for routine ultrasound examination. Axial images of the fetal 4V were obtained and the 4VI was calculated as the ratio between the laterolateral and the anteroposterior diameters. Reference ranges were constructed and retrospectively collected values from 44 fetuses with confirmed anomalies involving severe vermian dysgenesis/agenesis (Joubert syndrome and related disorders, rhombencephalosynapsis, cobblestone malformations and cerebellar hypoplasia) but without open 4V were compared with the normal values. RESULTS: In total, 384 healthy fetuses were enrolled into the study, from which reference ranges were produced, and 44 cases were collected retrospectively. The 4VI in the normal fetuses was always > 1. In affected fetuses, it was always below mean -2 SD and < 1. CONCLUSIONS: The 4VI is a sonographic marker for severe fetal vermian dysgenesis/agenesis in the absence of an open 4V. It may be incorporated easily into the routine brain scan; 4VI < 1 indicates a need for dedicated fetal neuroimaging for diagnosis and prenatal counseling. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Microarray analysis has no additional value in fetal aberrant right subclavian artery: description of 268 pregnancies and systematic literature review.

OBJECTIVES: Fetal aberrant right subclavian artery (ARSA) is a relatively common sonographic finding. Several studies have reported a significant association between ARSA and Down syndrome, as well as 22q11.2 microdeletion. The objective of this study was to assess the risk of abnormal chromosomal microarray analysis (CMA) findings in a large cohort of pregnancies with fetal ARSA as an isolated, as well as a non-isolated, sonographic anomaly. A secondary objective was to review the literature, examining the frequency of chromosomal microarray aberrations in fetuses with isolated ARSA. METHODS: Data from all pregnancies referred for invasive testing and CMA due to sonographic diagnosis of fetal ARSA, between 2013 and 2017, were obtained retrospectively from the computerized database of the Israeli Ministry of Health. The rate of clinically significant CMA findings in these fetuses was compared to that in a local control population of 2752 low-risk pregnancies with normal ultrasound and serum screening results. In addition, a literature search was conducted in PubMed, from inception to February 2018, of original studies in the English language describing the frequency and nature of microscopic and submicroscopic aberrations in fetuses with isolated ARSA. RESULTS: Of 246 pregnancies with isolated ARSA that underwent CMA analysis, a clinically significant finding was detected in one (0.4%) pregnancy (trisomy 21). This rate did not differ significantly from that in the control population (P = 0.1574). Of 22 fetuses with non-isolated ARSA, one (4.5%) additional case of trisomy 21 was noted. The frequency of trisomy 21 in this cohort also did not differ from that in the control population (relative risk, 5.5 (95% CI, 0.8-37.6)). The literature search yielded 13 additional relevant papers, encompassing 333 cases of isolated ARSA. Of 579 cases overall (including those of the present study), 13 (2.2%) cases of trisomy 21 were detected, with no cases of 22q11.2 microdeletion. CONCLUSION: While an association may exist between non-isolated ARSA and Down syndrome, isolated ARSA might better serve as a soft marker for Down syndrome, rather than a routine indication for invasive prenatal testing. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Symptom trajectories and predictors of severe symptoms in pancreatic adenocarcinoma at the end-of-life: a population based analysis of 2,538 patients.

BACKGROUND: We evaluated symptom trajectories and predictors of reporting severe symptoms in the last 6 months of life among non-resected pancreatic adenocarcinoma (PAC) decedents. METHODS: A retrospective cohort study of non-resected PAC decedents receiving care at regional cancer centres between January 2007 and December 2015. Symptoms were measured using the Edmonton Symptom Assessment System (ESAS). We described the proportion of patients reporting severe (score ≥7) symptoms by 2-week intervals during the six months prior to death. Multivariable modified Poisson regression models identified predictors of reporting severe symptom scores in the last 6 months of life. RESULTS: 2538 non-resected PAC decedents treated at regional cancer centres had ≥1 symptom ESAS record in the last six months of life, totaling 10,893 unique symptom assessments. Tiredness was the most commonly reported symptom (59% reporting ≥1 severe score), followed by lack of appetite (57%), impaired-wellbeing (49%) and drowsiness (42%). All symptoms increased closer to death. Older age, female sex, higher comorbidity status, survival less than 6 months, and urban residence were associated with a significantly higher risk of reporting severe symptoms. CONCLUSION: Non-resected PAC patients experience significant symptom burden nearing death. Patient subsets may benefit from personalized supportive care interventions.

Prediction of microcephaly at birth using three reference ranges for fetal head circumference: can we improve prenatal diagnosis?

OBJECTIVE: To evaluate the prediction of microcephaly at birth (micB) using established and two new reference ranges for fetal head circumference (HC) and to assess whether integrating additional parameters can improve prediction. METHODS: Microcephaly in utero was defined as a fetal HC 3SD below the mean for gestational age according to Jeanty et al.'s reference range. The records of cases with fetal microcephaly (Fmic) were evaluated for medical history, imaging findings, biometry and postnatal examination/autopsy findings. Microcephaly was confirmed at birth (micB) by an occipitofrontal circumference (OFC) or a brain weight at autopsy 2SD below the mean for gestational age. The new INTERGROWTH-21(st) Project and a recent Israeli reference for fetal growth were applied for evaluation of the Fmic positive predictive value (PPV) for diagnosis of micB cases. Optimal HC cut-offs were determined for each of the new references with the aim of detecting all micB cases whilst minimizing the number of false positives found to have a normal HC at birth. We also assessed the difference between the Z-scores of the prenatal HC and the corresponding OFC at birth, the frequency of small-for-gestational age (SGA), decreased HC/abdominal circumference (AC) and HC/femur length (FL) ratios, the prevalence of associated malformations and family history. RESULTS: Forty-two fetuses were diagnosed as having Fmic according to the Jeanty reference, but micB was confirmed in only 24 (PPV, 57.1%). The optimal INTERGROWTH and Israeli reference HC cut-offs for micB diagnosis were mean - 3SD and mean - 2.3SD, resulting in a statistically non-significant improvement in PPV to 61.5% and 66.7%, respectively. The presence of a family history of microcephaly, SGA, associated malformations and application of stricter HC cut-offs resulted in a higher PPV of micB, although not statistically significant and with a concurrent increase in the number of false-negative results. The deviation of the HC from the mean, by all references, was significantly larger compared with the actual deviation of the OFC at birth, with mean differences between the corresponding Z-scores of -1.15, -1.95 and -0.74 for the Jeanty, INTERGROWTH and Israeli references, respectively. CONCLUSIONS: The evaluated reference ranges all result in considerable over-diagnosis of fetal microcephaly. The use of the two new HC reference ranges did not significantly improve micB prediction compared with that of Jeanty et al., whilst use of additional characteristics and stricter HC cut-offs could improve the PPV with an increase in false negatives. The postnatal OFC deviates significantly less from the mean compared with the prenatal HC, and we propose that adjustment for this would enable better prediction of the actual OFC deviation at birth. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Application of a novel prenatal vertical cranial biometric measurement can improve accuracy of microcephaly diagnosis in utero.

OBJECTIVE: To construct a reference range for a new vertical measurement of the fetal head and to assess whether its combination with fetal head circumference (HC) can prevent the misdiagnosis of microcephaly in fetuses with an acrocephalic-like head deformation. METHODS: A new vertical cranial biometric measurement was defined: the foramen magnum-to-cranium distance (FCD), measured between the foramen magnum and the upper inner cranial border along the posterior wall of the brainstem. The measurement was performed in a precise mid-sagittal plane using a three-dimensional multiplanar display of a sagittally acquired sonographic volume of the fetal head. The normal reference range was developed by measuring 396 healthy fetuses of low-risk singleton pregnancies between 15 and 40 gestational weeks. This reference was applied to 25 fetuses with microcephaly diagnosed prenatally (Fmic) based on HC ≥ 3 SD below the mean for gestational age. We determined an optimal FCD cut-off for combination with HC to detect all cases found with microcephaly at birth (micB), while excluding the fetuses with normal head circumference at birth (NHCB), who were described postnatally as having an acrocephalic-like cranial deformation. RESULTS: In the healthy singleton fetuses, FCD increased with gestational age, with a quadratic equation providing an optimal fit to the data (adjusted R(2) = 0.934). The measurement could be assessed in 95.2% of cases. Of the 25 cases diagnosed with Fmic prenatally, on the basis of HC alone, 14 were micB and 11 were NHCB. We observed FCD below the mean - 2SD for gestational age in all 14 micB cases, but in only four of the 11 NHCB cases (P < 0.003). An acrocephalic-like cranial deformation was described at birth in five of the seven NHCB cases with normal FCD. The mean ± SD FCD Z-score of the micB cases was significantly lower (P < 0.001) than that of the false-positive ones: -3.85 ± 0.96 SD and -1.59 ± 1.45 SD, respectively. Based on HC measurement alone, the positive predictive value (PPV) was 56%. Combination of the HC and FCD criteria raised the PPV to 78%, decreasing the number of false positives from 11 to four, without missing any of the 14 micB cases. CONCLUSIONS: Fetal vertical cranial biometric assessment in the mid-sagittal plane is feasible and correlates well with gestational age. In our series, a vertical cranial deformation was a frequent cause of a false Fmic diagnosis made on the basis of HC alone. Combination of the new vertical cranial biometric measurement with HC measurement can exclude these cases and thus improve diagnostic accuracy for Fmic. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Neuropsychological follow-up at school age of children with asymmetric ventricles or unilateral ventriculomegaly identified in utero.

OBJECTIVE: To examine the long-term neuropsychological outcome of children with a prenatal diagnosis of asymmetric ventricles or unilateral ventriculomegaly. DESIGN: A clinic-based neuropsychological study. SETTING: Paediatric neurology clinic. POPULATION: Thirty-three of 41 children, previously assessed at kindergarten age, with asymmetric ventricles or unilateral ventriculomegaly identified in utero, were recruited at school age for a neuropsychological follow-up. METHODS: All children, 9-11 years of age, underwent a battery of neuropsychological tests and the parents completed behavioural rating questionnaires. MAIN OUTCOME MEASURES: Results of the neuropsychological assessment and parents' questionnaires. RESULTS: There were no significant differences between children diagnosed with either asymmetric ventricles or unilateral ventriculomegaly in most parameters relative to the general population; the full-scale IQ scores were 103.13 ± 12.43 and 103.56 ± 10.5, respectively. A significantly lower performance was found only on one measure of attention among the unilateral ventriculomegaly group and on writing speed tasks among the asymmetric ventricles group. Both study groups showed significantly higher scores than expected in the normal population on a verbal fluency test. Comparison of both groups combined with the normative population yielded significantly lower scores only in attention tests. Yet, the clinical population showed significantly higher scores on writing accuracy, processing speed and verbal fluency and lower rates of executive dysfunction. CONCLUSIONS: Asymmetric ventricles or unilateral ventriculomegaly identified in utero does not appear to affect long-term mental development and school achievements. Further prospective research on a larger sample is needed in order to confirm our findings.

Effect of High Dose Statin Pretreatment on Endothelial Progenitor Cells After Percutaneous Coronary Intervention (HIPOCRATES Study).

BACKGROUND: Pretreatment with high-dose statins given before percutaneous coronary intervention (PCI) has been shown to have beneficial effects, in particular by reducing peri-procedural myocardial infarction. The mechanism of these lipid-independent beneficial statin effects is unclear. Circulating endothelial progenitor cells (EPCs) have an important role in the process of vascular repair, by promoting re-endothelization following injury. We hypothesized that statins can limit the extent of endothelial injury induced by PCI and promote re-endothelization by a positive effect on EPCs. We, therefore, aimed to examine the effect of high-dose statins given prior to PCI on EPCs profile. METHODS: Included were patients, either statin naïve or treated chronically with low-dose statins, with stable or unstable angina who underwent PCI. Patients were randomized to receive either high-dose atorvastatin (80 mg the day before PCI and 40 mg 2-4 h before PCI) or low- dose statin. EPCs profile was examined before PCI and 24 h after it. Circulating EPCs levels were assessed by flow cytometry as the proportion of peripheral mononuclear cells co-expressing VEGFR-2+ CD133+ and VEGFR-2+ CD34+. The capacity of the cells to form colony forming units (CFUs) was quantified after 7 days of culture. RESULTS: Twenty three patients (mean age 61.4 ± 7.4 years, 87.0% men) were included in the study, of which 12 received high-dose atorvastatin prior to PCI. The mean number of EPC-CFUs before PCI was higher in patients treated with high-dose atorvastatin vs. low-dose statins (165.8 ± 58.8 vs. 111.7 ± 38.2 CFUs/plate, respectively, p < 0.001). However, 24 h after the PCI, the number of EPC-CFUs was similar (188.0 ± 85.3 vs. 192.9 ± 66.5 CFUs/plate in patients treated with high-dose atorvastatin vs. low- dose statins, respectively, p = 0.15). There were no statistical significant differences in FACS analyses between the 2 groups. CONCLUSIONS: The current study showed higher EPC- CFUs levels in patients treated with high-dose atorvastatin before PCI and a lower increment in EPC-CFUs after PCI. These findings could account for the beneficial effects of statins given prior to PCI, yet further investigation is required.

Nested sampling of isobaric phase space for the direct evaluation of the isothermal-isobaric partition function of atomic systems.

Nested Sampling (NS) is a powerful athermal statistical mechanical sampling technique that directly calculates the partition function, and hence gives access to all thermodynamic quantities in absolute terms, including absolute free energies and absolute entropies. NS has been used predominately to compute the canonical (NVT) partition function. Although NS has recently been used to obtain the isothermal-isobaric (NPT) partition function of the hard sphere model, a general approach to the computation of the NPT partition function has yet to be developed. Here, we describe an isobaric NS (IBNS) method which allows for the computation of the NPT partition function of any atomic system. We demonstrate IBNS on two finite Lennard-Jones systems and confirm the results through comparison to parallel tempering Monte Carlo. Temperature-entropy plots are constructed as well as a simple pressure-temperature phase diagram for each system. We further demonstrate IBNS by computing part of the pressure-temperature phase diagram of a Lennard-Jones system under periodic boundary conditions.

A new methodological approach to estimation of IgA1 and IgA2 content in human serum using recombinant IgA1 protease from Neisseria meningitidis.

OBJECTIVES: A new approach to estimation of IgA subclass levels and IgA1/IgA2 ratio using enzymatically active and inactive forms of Neisseria meningitidis IgA1 protease was developed. RESULTS: The approach was tested using the sera of healthy volunteers and patients with meningococcal meningitis. There was a significant increase in the IgA1 level in patients with meningitis (mean titer 1:1546 ± 352) compared to healthy volunteers (mean titer 1:546 ± 282), while the IgA2 content remained unchanged. The IgA1/IgA2 ratio was 6.3 for the healthy volunteers and 12.8 for patients with meningitis. IgA2 for the patients with meningitis and the healthy volunteers were almost unchanged, 1:86 ± 61 and 1:121 ± 46, respectively. CONCLUSIONS: The proposed method is economical and reliable and can be used for evaluation of IgA1 and IgA2 in clinical laboratories or for research purposes.

The neuropsychological profile of patients with 3-methylglutaconic aciduria type III, Costeff syndrome.

Costeff syndrome is a rare genetic neuro-ophthalmological syndrome consisting of early-onset bilateral optic atrophy along with a progressive complex motor disorder with elevated levels of urinary 3-methylglutaconic acid and 3-methylglutaric acid. While borderline to mild cognitive deficits have been considered to be common in patients with this syndrome, a comprehensive cognitive assessment has never been performed. The aim of the current study was to explore the cognitive profile associated with Costeff syndrome. Sixteen adult patients diagnosed with Costeff syndrome were administered a neuropsychological test battery that was composed of standardized verbal tests adapted for the blind. General intelligence ranged from average to borderline, with a group mean consistent with intact general cognitive functioning (VIQmean = 85, z = -1) in the low-average range of the general population. The auditory immediate and delayed memory indexes were in the average range and were significantly higher than the general cognitive functioning, whereas the working memory index was significantly lower than the general cognitive functioning. Adult patients with Costeff syndrome have intact global cognition and learning abilities and strong auditory memory performance. © 2015 Wiley Periodicals, Inc.