The new small-angle X-ray scattering beamline for materials research at PETRA†III: SAXSMAT beamline P62.

The SAXSMAT beamline P62 (Small-Angle X-ray Scattering beamline for Materials Research) is a new beamline at the high-energy storage ring PETRA III at DESY. This beamline is dedicated to combined small- and wide-angle X-ray scattering (SAXS/WAXS) techniques for both soft and hard condensed matter systems. It works mainly in transmission geometry. The beamline covers an energy range from 3.5 keV to 35.0 keV, which fulfills the requirements of the user community to perform anomalous scattering experiments. Mirrors are used to reduce the intensity of higher harmonics. Furthermore, the mirrors and 2D compound refracting lenses can focus the beam down to a few micrometres at the sample position. This option with the high photon flux enables also SAXS/WAXS tensor tomography experiments to be performed at this new beamline in a relatively short time. The first SAXS/WAXS pattern was collected in August 2021, while the first user experiment was carried out two months later. Since January 2022 the beamline has been in regular user operation mode. In this paper the beamline optics and the SAXS/WAXS instrument are described and two examples are briefly shown.

Cardiac output and peripheral vascular resistance during normotensive and hypertensive pregnancy - a systematic review and meta-analysis.

BACKGROUND: In-depth insight into haemodynamic changes during normotensive pregnancy may help identify women at risk for gestational hypertensive complications. OBJECTIVES: To determine the magnitude of changes in cardiac output and its determinants stroke volume and heart rate, and total peripheral vascular resistance during singleton normotensive and hypertensive pregnancies. SEARCH STRATEGY: PubMed (NCBI) and Embase (Ovid) databases were searched from their inception up to November 2019. SELECTION CRITERIA: Studies reporting original measurements of haemodynamic parameters during pregnancy together with a non-pregnant reference measurement. Studies including women using antihypertensive medication were excluded. DATA COLLECTION AND ANALYSIS: Pooled mean differences between pregnant and non-pregnant women, and absolute values of haemodynamic parameters were calculated for predefined gestational intervals using a random-effects model in normotensive and hypertensive pregnancy. Meta-regression analysis was used to analyse group differences in adjustments and absolute values during pregnancy. MAIN RESULTS: In normotensive pregnancies, cardiac output increased from the first weeks on, reaching its highest level early in the third trimester (mean difference, 1.41 l·min1 ; 95% CI 1.18-1.63 l·min). In parallel, vascular resistance decreased progressively until its nadir in the early third trimester (mean difference, -331 dyn·sec-1 ·cm-5 ; 95% CI -384 to -277 dyn·sec-1 ·cm-5 ) and then increased slightly at term. In hypertensive pregnancies, the initial cardiac output increase was higher and vascular resistance did not change throughout gestation compared with reference values. CONCLUSIONS: Hemodynamic changes in women who eventually develop hypertensive complications are substantially different. Serial monitoring and plotting against developed normograms can identify women at risk and may allow timely intervention. TWEETABLE ABSTRACT: Monitoring haemodynamic changes in pregnancy helps identify women at risk for hypertensive complications.

Injection of freshly collected autologous adipose tissue into non-healing wounds after closed incision pilonidal surgery.

BACKGROUND: Chronic non-healing wounds are a major problem after closed incision pilonidal surgery. Freshly collected autologous adipose tissue injected into perianal fistulas in patients with Crohn's disease seems to promote healing. We investigated this technique in patients with non-healing wounds after cleft-lift surgery for pilonidal sinus disease (PSD). METHOD: In a prospective interventional pilot study conducted at our institution autologous adipose tissue from the abdominal wall was harvested, and injected into chronic non-healing PS wounds after surgical revision, healing rate being the primary outcome. The wounds were left open. Patients were followed every 2 to 3 weeks until complete healing (skin coverage, no undermining). RESULTS: 7 male patients were included (mean age 24 ± 0,6 SD years) and complete healing was achieved in 6 patients (86%). Median time to healing was 90 days (range 36-403 days ) and mean follow-up time was 388± 45 days. All patients reported major symptom relief shortly after the procedure. The mean operation time was 80 ± 23 minutes and the mean amount of freshly collected adipose tissue injected was 27.4± 12 ml. There were no complications. CONCLUSIONS: Freshly collected autologous adipose tissue injected into chronic non-healing pilonidal wounds seems safe and efficient.

Cortical processing to anorectal stimuli after rectal resection with and without radiotherapy.

BACKGROUND: Bowel dysfunction is common after surgery for rectal cancer, especially when neoadjuvant radiotherapy is used. The role of sensory function in the pathogenesis remains obscure, and the aim of the present study was to characterize the sensory pathways of the brain-gut axis in rectal cancer patients treated with resection ± radiotherapy compared with healthy volunteers. METHODS: Sensory evaluation by (neo)rectal distensions was performed and sensory evoked potentials (SEPs) were recorded during rapid balloon distensions of the (neo)rectum and anal canal in resected patients with (n = 8) or without (n = 12) radiotherapy. Twenty healthy volunteers were included for comparison. (Neo)rectal latencies and amplitudes of SEPs were compared and spectral band analysis from (neo)rectal and anal distensions was used as a proxy of neuronal processing. RESULTS: Neorectal sensation thresholds were significantly increased in both patient categories (all p < 0.008). There were no differences in (neo)rectal SEP latencies and amplitudes between groups. However, spectral analysis of (neo)rectal SEPs showed significant differences between all groups in all bands (all p < 0.01). On the other hand, anal SEP analyses only showed significant differences between the delta (0-4 Hz), theta (4-8 Hz) and, gamma 32-50 Hz) bands (all p < 0.02) between the subgroup of patients that also received radiotherapy and healthy volunteers. CONCLUSIONS: Surgery for rectal cancer leads to abnormal cortical processing of neorectal sensation. Additional radiotherapy leads to a different pattern of central sensory processing of neorectal and anal sensations. This may play a role in the functional outcome of these patients.

International survey of neurosurgical anesthesia (iSonata) : An international survey of current practices in neurosurgical anesthesia.

BACKGROUND: No standardized recommendations have been currently defined for anesthesia management of patients undergoing elective intracranial surgery. It can therefore be assumed that international clinical institutions have diverging approaches or standard operating procedures (SOP) which determine the type of general anesthesia, hemodynamic management, neuromuscular blockade, implementation of hypothermia and postoperative patient care. OBJECTIVE: This international survey aimed to assess perioperative patient management during elective intracranial procedures. This survey was performed from February to October 2018 and 311 neurosurgical, maximum care centers across 19 European countries were contacted. The aim was to evaluate the anesthesia management to provide relevant data of neuroanesthesia practices across European centers. The survey differentiated between vascular and non-vascular as well as supratentorial and infratentorial procedures. RESULTS: A total of 109 (35.0%) completed questionnaires from 15 European countries were analyzed. The results illustrated that total intravenous anesthesia was most commonly implemented during elective intracranial procedures (83.8%). All centers performed endotracheal intubation prior to major intracranial surgery (100%). Central venous lines were placed in 63.3% of cases. Moderate intraoperative hypothermia was carried out in 12.8% of the procedures, especially during vascular supratentorial and infratentorial surgery. A neuromuscular blockade during surgery was implemented in 74.1% of patients. Assessment of the neuromuscular junction was performed in 59.2% of cases, 76.7% of patients were immediately extubated in the operating room. 84.7% of these patients were directly transferred to a monitoring ward or an intensive care unit (ICU) and 55.1% of ventilated patients were transferred directly to an ICU. CONCLUSION: The data demonstrate that many aspects of anesthesia management during elective intracranial surgery vary between European institutions. The data also suggest that a broad consensus exists regarding the implementation of total intravenous anesthesia, airway management (endotracheal intubation), the implementation of urinary catheters, large bore peripheral venous lines and the broad availability of cross-matched red blood cell concentrates. Nevertheless, anesthesia management (e.g. central venous catheterization, moderate hypothermia, neuromuscular monitoring) is still handled differently across many European institutions. A lack of standardized guidelines defining anesthetic management in patients undergoing intracranial procedures could explain this variability. Further studies could help establish optimal anesthesia management for these patients. This in turn could help in the development of national and international guidelines and SOPs which could define optimal management strategies for intracranial procedures.

Maternal kidney function during pregnancy: systematic review and meta-analysis.

OBJECTIVES: To review systematically current literature on kidney function changes during pregnancy, in order to estimate the extent of adaptation over the course of both healthy physiological and complicated singleton pregnancies, and to determine healthy pregnancy reference values. METHODS: PubMed (NCBI) and EMBASE (Ovid) electronic databases were searched, from inception to July 2017, for studies on kidney function during uncomplicated and complicated pregnancies. Included studies were required to report a non-pregnant reference value of kidney function (either in a non-pregnant control group or as a prepregnancy or postpartum measurement) and a pregnancy measurement at a predetermined and reported gestational age. Kidney function measures assessed were glomerular filtration rate (GFR) measured by inulin clearance, GFR measured by creatinine clearance and serum creatinine level. Pooled mean differences between pregnancy measurements and reference values were calculated for predefined intervals of gestational age in uncomplicated and complicated pregnancies using a random-effects model described by DerSimonian and Laird. RESULTS: Twenty-nine studies met the inclusion criteria and were included in the analysis. As early as the first trimester, GFR was increased by up to 40-50% in physiological pregnancy when compared with non-pregnant values. Inulin clearance in uncomplicated pregnancy was highest at 36-41 weeks, with a 55.6% (53.7; 95% CI, 44.7-62.6 mL/min) increase when compared with non-pregnant values, and creatinine clearance was highest at 15-21 weeks' gestation, with a 37.6% (36.6; 95% CI, 26.2-46.9 mL/min) increase. Decrease in serum creatinine level in uncomplicated pregnancy was most prominent at 15-21 weeks, with a 23.2% (-0.19; 95% CI, -0.23 to -0.15 mg/dL) decrease when compared with non-pregnant values. Eight studies reported on pregnancies complicated by a hypertensive disorder. Meta-regression analysis showed a significant difference in all kidney function parameters when comparing uncomplicated and hypertensive complicated pregnancies. CONCLUSIONS: In healthy pregnancy, GFR is increased as early as the first trimester, as compared with non-pregnant values, and the kidneys continue to function at a higher rate throughout gestation. In contrast, kidney function is decreased in hypertensive pregnancy. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Effect of intravenous immunoglobulin administration on erythrocyte and leucocyte parameters.

BACKGROUND: Intravenous immunoglobulins (IVIG) are an attractive therapeutic tool for therapy of toxic epidermal necrolysis and severe forms of certain autoimmune diseases, including dermatomyositis, autoimmune blistering diseases, systemic vasculitis and lupus erythematodes. OBJECTIVES: Prompted by a case of IVIG-associated haemolytic anaemia, the effects of IVIG administrations on haematological parameters in patients with dermatological conditions were investigated. METHODS: Erythrocyte and leucocyte parameters were retrospectively analysed in 16 patients who had received IVIG at doses from 1 to 3 g/kg bodyweight (n = 35 cycles). The influence of IVIG on leucocyte survival was determined in vitro. RESULTS: Decreased absolute erythrocyte numbers, haemoglobin and haematocrit levels and a case of haemolytic anaemia were linked to transfusion of high-, but not low-dose IVIG. In contrast, leucopenia post-IVIG occurred in the vast majority of the recipients, unrelated to the administered IVIG amounts. In vitro investigations revealed a dose-dependent impairment of cell survival by IVIG in the neutrophil and monocyte, but not in the lymphocyte subpopulations. In several IVIG preparations, substantial amounts of blood group anti-A/anti-B antibodies were detected which could have accounted for the observed changes in the haematological parameters in our study cohort. CONCLUSIONS: IVIG products should be administered strictly according to indications. Commercially available IVIG products can contain blood group-specific antibodies that may induce haemolysis in some recipients. Monitoring of blood counts during applied IVIG therapy, especially when high doses are administered, is recommended.

Comparison of blood pressure monitoring by applanation tonometry and invasively assessed blood pressure in cardiological patients.

The aim of this study was to evaluate the accuracy and precision of non-invasive continuous blood pressure measurement by applanation tonometry (AT) in awake or anaesthetised cardiological intensive care patients. Patients suffering from highly impaired left ventricular function atrial fibrillation or severe aortic valve stenosis were included into the study. Arterial blood pressure was recorded by applanation tonometry (T-Line 400, Tensys Medical®, USA) and an arterial line in awake or anaesthetised patients. Discrepancies in mean (MAP), systolic (SAP), and diastolic (DAP) arterial pressure between the two methods were assessed as bias, limits of agreement and percentage error respectively. In 31 patients a total of 27,900 measurements were analyzed. The concordance correlation coefficient was 0.23, 0.45 and 0.06 for MAP, SAP and DAP, respectively. For all patients bias for MAPAT compared to MAPAL was 14.96 mmHg (SAPAT 4.51 mmHg; DAPAT 19.12 mmHg) with limits of agreement for MAPAT of 46.25 and - 16.33 mm Hg (SAPAT 48.00 and - 38.98 mmHg; DAPAT 50.12 and - 11.89 mmHg). Percentage error for MAPAT was 56.8% (42.7% for SAPAT; 75.2% for DAPAT). We conclude that the AT method is not reliable in ICU patients with severe cardiac comorbidities.

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Physiological adaptation of maternal plasma volume during pregnancy: a systematic review and meta-analysis.

OBJECTIVE: To describe the physiological pattern of gestational plasma volume adjustments in normal singleton pregnancy and compare this with the pattern in pregnancies complicated by pregnancy-induced hypertension, pre-eclampsia or fetal growth restriction. METHODS: We performed a meta-analysis of the current literature on plasma volume adjustments during physiological and complicated pregnancies. Literature was retrieved from PubMed (NCBI) and EMBASE (Ovid) databases. Included studies reported both reference plasma volume measurements (non-pregnant, prepregnancy or postpartum) and measurements obtained during predetermined gestational ages. Mean differences bet ween the reference and pregnancy plasma volume measurements were calculated for predefined intervals of gestational age using a random-effects model described by DerSimonian and Laird. RESULTS: Thirty studies were included in the meta-analysis with publication dates ranging from 1934 to 2007. Plasma volume increased in the first weeks of pregnancy, with the steepest increase occurring during the second trimester. Plasma volume continued to increase in the third trimester with a pooled maximum increase of 1.13 L (95% CI, 1.07-1.19 L), an increase of 45.6% (95% CI, 43.0-48.1%) in physiological pregnancies compared with the reference value. The plasma volume expansion in gestational hypertensive and growth-restricted pregnancies was 0.80 L (95% CI, 0.59-1.02 L), an increase of 32.3% (95% CI, 23.6-41.1%) in the third trimester, a smaller increase than in physiological pregnancies (P < 0.0001). CONCLUSIONS: During physiological pregnancy, plasma volume increases by, on average, more than 1 L as compared with non-pregnant conditions. In pregnancies complicated by pregnancy-induced hypertension, pre-eclampsia or fetal growth restriction, plasma volume increase in the third trimester is 13.3% lower than in normal pregnancy. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Adaptación fisiológica del volumen del plasma materno durante el embarazo: una revisi\xF3n sistemática y metaanálisis RESUMEN OBJETIVO: Describir el patrón fisiológico de los cambios en el volumen del plasma gestacional en embarazos normales con feto único y compararlo con el patrón en los embarazos complicados por hipertensión gestacional, preeclampsia o restricción del crecimiento fetal. MÉTODOS: Se realizó un metaanálisis de la literatura actual sobre los cambios en el volumen de plasma durante embarazos complicados y fisiológicos. La literatura se obtuvo de las bases de datos PubMed (NCBI) y EMBASE (Ovid). Los estudios incluidos mencionaban tanto mediciones de referencia del volumen plasmático (no embarazada, antes del embarazo o después del parto) como mediciones tomadas a edades gestacionales predeterminadas. Se calcularon las medias de las diferencias entre las mediciones de referencia y las del embarazo para el volumen plasmático a intervalos predefinidos de la edad gestacional, utilizando un modelo de efectos aleatorios descrito por DerSimonian y Laird. RESULTADOS: En el metaanálisis se incluyeron treinta estudios con fechas de publicación entre 1934 y 2007. El volumen plasmático aumentó en las primeras semanas de embarazo y el mayor incremento se produjo durante el segundo trimestre. El volumen de plasma continuó aumentando en el tercer trimestre con un aumento combinado máximo de 1,13L (IC 95%, 1,7-1,19 L), lo que supone un aumento del 45,6% (IC 95%, 43,0-48,1%) en embarazos fisiológicas en comparación con el valor de referencia. El aumento del volumen plasmático en los embarazos con hipertensión y con crecimiento intrauterino restringido fue de 0,80L (IC 95%, 0,59-1,02 L), lo que supone un aumento del 32,3% (IC 95%, 23,6-41,1%) en el tercer trimestre, y un incremento menor que en los embarazos fisiológicos (P <0,0001). CONCLUSIONES: Durante el embarazo fisiológico el volumen de plasma aumenta, en promedio, más de 1L, en comparación con el de las no embarazadas. En los embarazos complicados por hipertensión gestacional, preeclampsia o restricción del crecimiento fetal, el aumento del volumen plasmático en el tercer trimestre es un 13,3% menor que en el embarazo normal. :meta : ,、。 : meta。PubMed(NCBI)EMBASE(Ovid)。(、)。DerSimonianLaird,。 : Meta30,19342007。,。,1.13 L(95% CI,1.07~1.19 L),,45.6%(95% CI,43.0%~48.1%)。0.80 L(95%CI,0.59~1.02 L),32.3%(95% CI,23.6%~41.1%),(P<0.0001)。 : ,,1 L。、,13.3%。.

Physiological adaptation of endothelial function to pregnancy: systematic review and meta-analysis.

OBJECTIVES: To establish reference values for flow-mediated dilatation (FMD) and brachial artery diameter (BAD) in pregnancy and to provide insight into the physiological and pathological course of endothelial adaptation throughout human singleton pregnancy. METHODS: A meta-analysis was performed following a systematic review of current literature on FMD, as a derivative for endothelial function, and BAD, throughout uncomplicated and complicated pregnancy. PubMed (NCBI) and EMBASE (Ovid) electronic databases were used for the literature search, which was performed from inception to 9 June 2016. To allow judgment of changes in comparison with the non-pregnant state, studies were required to report both non-pregnant mean reference of FMD (matched control group, prepregnancy or postpartum measurement) and mean FMD at a predetermined and reported gestational age. Pooled mean differences between the reference and pregnant FMD values were calculated for predefined intervals of gestational age. RESULTS: Fourteen studies that enrolled 1231 participants met the inclusion criteria. Publication dates ranged from 1999 to 2014. In uncomplicated pregnancy, FMD was increased in the second and third trimesters. Between 15 and 21 weeks of gestation, absolute FMD increased the most, by a mean (95% CI) of 1.89% (0.25-3.53%). This was a relative increase of 22.5% (3.0-42.0%) compared with the non-pregnant reference. BAD increased progressively, in a steady manner, by the second trimester but not significantly in the first half of the second trimester. We could not discern differences in FMD and BAD between complicated and uncomplicated pregnancies at 29-35 weeks' gestation, reported in the three studies that met our inclusion criteria. Despite the increase in FMD and BAD throughout gestation, both reference curves were characterized by wide 95% CIs. CONCLUSION: During healthy pregnancy, endothelium-dependent vasodilatation and BAD increase. Women with a complicated pregnancy had FMD values within the lower range when compared with those with uncomplicated pregnancy but, as a group, did not differ from each other. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Cardiac remodeling in normotensive pregnancy and in pregnancy complicated by hypertension: systematic review and meta-analysis.

OBJECTIVE: The aim of this systematic review and meta-analysis was to describe comprehensively the pattern of cardiac remodeling during normotensive human singleton pregnancy and to compare it with that of pregnancy complicated by hypertension. METHODS: We performed a meta-analysis of the current literature on cardiac remodeling during normotensive and complicated pregnancies. Literature was retrieved from PubMed (NCBI) and EMBASE (Ovid) databases. Included studies needed to report a reference measurement (matched non-pregnant control group, prepregnancy or postpartum) and measurements made during predetermined gestational-age intervals. Mean differences between reference and pregnancy data were calculated using the random-effects model described by DerSimonian and Laird. RESULTS: Forty-eight studies were included in the meta-analysis, with publication dates ranging from 1977 to 2016. During normotensive pregnancy, most geometric indices started to increase in the second trimester. Left ventricular mass (LVM) increased by 28.36 (95% CI, 19.73-37.00) g (24%), and relative wall thickness (RWT) increased by 0.03 (95% CI, 0.02-0.05) (10%) compared with those in the reference group. During hypertensive pregnancy, LVM and RWT increased more than during normotensive pregnancy (92 (95% CI, 75.46-108.54) g (95%) and 0.14 (95% CI, 0.09-0.19) (56%), respectively). CONCLUSIONS: During normotensive pregnancy, most cardiac geometric indices change from the second trimester onwards. Both LVM and RWT increase, by 20% and 10%, respectively, consistent with concentric rather than eccentric remodeling. Cardiac adaptation in hypertensive pregnancy deviates from that in healthy pregnancy by a greater change in LVM (95% increase from reference) and RWT (56% increase from reference). Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Electrical impedance tomography for non-invasive assessment of stroke volume variation in health and experimental lung injury.

BACKGROUND: Functional imaging by thoracic electrical impedance tomography (EIT) is a non-invasive approach to continuously assess central stroke volume variation (SVV) for guiding fluid therapy. The early available data were from healthy lungs without injury-related changes in thoracic impedance as a potentially influencing factor. The aim of this study was to evaluate SVV measured by EIT (SVVEIT) against SVV from pulse contour analysis (SVVPC) in an experimental animal model of acute lung injury at different lung volumes. METHODS: We conducted a randomized controlled trial in 30 anaesthetized domestic pigs. SVVEIT was calculated automatically analysing heart-lung interactions in a set of pixels representing the aorta. Each initial analysis was performed automatically and unsupervised using predefined frequency domain algorithms that had not previously been used in the study population. After baseline measurements in normal lung conditions, lung injury was induced either by repeated broncho-alveolar lavage (n=15) or by intravenous administration of oleic acid (n=15) and SVVEIT was remeasured. RESULTS: The protocol was completed in 28 animals. A total of 123 pairs of SVV measurements were acquired. Correlation coefficients (r) between SVVEIT and SVVPC were 0.77 in healthy lungs, 0.84 after broncho-alveolar lavage, and 0.48 after lung injury from oleic acid. CONCLUSIONS: EIT provides automated calculation of a dynamic preload index of fluid responsiveness (SVVEIT) that is non-invasively derived from a central haemodynamic signal. However, alterations in thoracic impedance induced by lung injury influence this method.

Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study.

BACKGROUND: Trastuzumab emtansine (T-DM1) exhibited enhanced antitumor activity when combined with docetaxel or pertuzumab in preclinical studies. This phase Ib/IIa study assessed the feasibility of T-DM1 + docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and T-DM1 + docetaxel ± pertuzumab in patients with HER2-positive locally advanced breast cancer (LABC). PATIENTS AND METHODS: Phase Ib (part 1) explored dose escalation, with T-DM1 + docetaxel administered for greater than or equal to six cycles in patients with MBC. Phase Ib (part 2) began with the maximum tolerated dose (MTD) identified in part 1. Patients with LABC were administered less than or equal to six cycles of T-DM1 + docetaxel or T-DM1 + docetaxel + pertuzumab. Phase IIa explored the MTDs identified in phase Ib. RESULTS: Administered with T-DM1 (3.6 mg/kg), the docetaxel MTD was 60 mg/m(2) in MBC. In LABC, the MTD was 100 mg/m(2) docetaxel in combination with T-DM1 (3.6 mg/kg), given with granulocyte colony-stimulating factor (G-CSF). Administered with T-DM1 (3.6 mg/kg) + pertuzumab (840 mg, cycle 1; 420 mg, subsequent cycles), the docetaxel MTD in LABC was 75 mg/m(2) with G-CSF support. Neutropenia was the most common grade 3-4 adverse event (AE; MBC, 72% and LABC, 29%). In total, 48% (12/25) of MBC patients and 47% (34/73) of LABC patients experienced AEs requiring dose modification. In MBC (median prior systemic agents = 5), the objective response rate was 80.0% (20/25; 95% confidence interval [CI] 59.3-93.2) and the median progression-free survival was 13.8 months (range, 1.6-33.5). The pathologic complete response (ypT0/is, ypN0) rate in LABC was 60.3% (44/73; 95% CI 48.1-71.5). Pharmacokinetic analyses indicated a low risk of drug-drug interaction between T-DM1 and docetaxel. CONCLUSIONS: T-DM1 combined with docetaxel ± pertuzumab appeared efficacious in MBC or LABC; however, nearly half of patients experienced AEs requiring dose reductions with these T-DM1 combinations. CLINICALTRIALSGOV IDENTIFIER: NCT00934856.

New insights into Brunner syndrome and potential for targeted therapy.

We report two families with Brunner syndrome living in one state of Australia. The first family had a predicted protein-truncating variant of monoamine oxidase A (MAOA) (p.S251KfsX2). Affected males had mild intellectual disability (ID), obsessive behaviour, limited friendships and were introverted and placid during clinical interview. The family disclosed episodic explosive aggression after a diagnosis was made. The second family had a missense variant in MAOA (p.R45W). Affected males had borderline-mild ID, attention deficit disorder and limited friendships. One had a history of explosive aggression in childhood and episodic symptoms of flushing, headaches and diarrhoea. Their carrier mother had normal intelligence but similar episodic symptoms. Characteristic biochemical abnormalities included high serum serotonin and urinary metanephrines and low urinary 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid (VMA). Symptomatic individuals in the second family had particularly high serotonin levels, and treatment with a serotonin reuptake inhibitor and dietary modification resulted in reversal of biochemical abnormalities, reduction of 'serotonergic' symptoms and behavioural improvement. Brunner syndrome should be considered as a cause of mild ID with paroxysmal behavioural symptoms. It can be screened for with serum/urine metanephrine and serotonin measurement. Cautious treatment with a serotonin reuptake inhibitor, dietary modifications and avoidance of medications contraindicated in patients on monoamine oxidase inhibitors can improve symptoms.

Does Sacral Nerve Stimulation Improve Continence Through Enhanced Sensitivity of the Anal Canal? A Pilot Study.

BACKGROUND: It has been suggested that the effects of sacral nerve stimulation against fecal incontinence involve neuromodulation at spinal or supraspinal levels. OBJECTIVE: This study aims to investigate the afferent sensory pathways from the anorectum before and during sacral nerve stimulation. DESIGN: This is an explorative study. PATIENTS: Fifteen women with idiopathic fecal incontinence (mean age, 58 ± 12.2 years) were selected. INTERVENTIONS: Cortical evoked potentials were recorded during repeated rapid balloon distension of the rectum and the anal canal both before and during temporary sacral nerve stimulation. Stimuli applied were individualized according to the subjective urge to defecate. MAIN OUTCOME MEASURES: The main outcomes measured were 1) stimulus intensity, 2) latencies and amplitudes of cortical evoked potentials, and 3) spectral content in predefined frequency bands of cortical evoked potentials. RESULTS: The median Wexner fecal incontinence score improved from 15.5 ± 3.6 before to 6.7 ± 5 during sacral nerve stimulation (p < 0.001). Sacral nerve stimulation did not affect the threshold for urge to defecate during rectal distension (p = 0.64) but reduced the threshold from stimulation of the anal canal by 50% (p = 0.03). No statistically significant differences were found in latencies, amplitudes, or spectral analysis. LIMITATIONS: This is a pilot study of limited size. CONCLUSIONS: In patients with idiopathic fecal incontinence, sacral nerve stimulation reduced the threshold for urge to defecate elicited from the anal canal, whereas supraspinal responses remained unaltered. This may suggest that sacral nerve stimulation, at least in part, acts via somatic afferent fibers enhancing anal sensation.

Is applanation tonometry a reliable method for monitoring blood pressure in morbidly obese patients undergoing bariatric surgery?

BACKGROUND: The aim of this study was to evaluate the validity of non-invasive continuous BP measurement by applanation tonometry in morbidly obese patients undergoing bariatric surgery. METHODS: Arterial blood pressure (AP) was recorded intraoperatively both by applanation tonometry (AT) (T-Line 200pro, Tensys Medical(®), USA) and an arterial line (AL) after radial cannulation in obese patients undergoing bariatric surgery. Discrepancies between the two methods were assessed as bias, limits of agreement and percentage error. Mean, systolic, and diastolic arterial pressures were assessed (MAP, SAP, DAP respectively). Trending ability was assessed by concordance based on four-quadrant plotting. RESULTS: Mean (sd) BMI of the 28 patients was 49.4 (9.7 kg m(-2)). A total of 201 907 time points were available for analysis. Bias for MAPAT compared with MAPAL was +3.97 mm Hg (SAPAT +3.45 mm Hg; DAPAT +3.66 mm Hg) with limits of agreement for MAPAT of -14.47 and +22.41 mm Hg (SAPAT -22.0 and +28.9 mm Hg; DAPAT -15.7 and +23.1 mm Hg). Percentage error for MAPAT was 23.5% (23.4% for SAPAT; 30.5% for DAPAT). Trending ability for MAP, SAP, and DAP revealed a concordance of 0.74, 0.72, and 0.71, respectively. CONCLUSIONS: Continuous BP assessment by applanation tonometry is feasible in morbidly obese patients undergoing bariatric surgery. However, despite a low mean difference, 95% limits of agreement and trending ability indicate that the technology needs to be improved further, before being recommended for routine use in this group of patients.

Nurse-led clinics can manage faecal incontinence effectively: results from a tertiary referral centre.

AIM: In May 2010, a specialist nurse-initiated assessment and treatment algorithm for faecal incontinence (FI) was introduced at the department of Anal Physiology, Aarhus University Hospital, Denmark. This study aimed to evaluate the effectiveness of and patient satisfaction with the program. METHOD: A medical file audit was preformed on patients evaluated and treated for FI and discharged after September 2010. Patients were invited to participate in a structured telephone interview. This study aimed to enrol 100 patients. Patients were asked if they were satisfied with their current level of continence status (yes/no), and a numerical satisfaction score and Wexner score were recorded. These results were compared to baseline and at time of discharge. RESULTS: One-hundred patients completed the telephone interview; 73 of these patients were satisfied after a median of 420 (range: 114-586) days following discharge from the program. A median of one outpatient consultation followed by one telephone follow-up was required before the patients were discharged. The Wexner score was significantly reduced by 3.9 (±4.4) (P < 0.001) points among the satisfied and non-significantly reduced by 0.52 (± 3.3) (P = 0.42) points among the dissatisfied patients at follow-up compared to baseline. The satisfied and dissatisfied patients at follow-up did not differ in baseline characteristics including Wexner score. CONCLUSIONS: FI can successively be evaluated and conservatively managed by specialist nurses, and these nurses achived high satisfaction rates among their patients. The concept of specialist nurse-led clinics will reduce waiting lists, and descrease the number of patients needing to be evaluated by a surgeon.

[Goal-directed hemodynamic therapy: Concepts, indications and risks]. / Zielorientierte Volumen- und Kreislauftherapie : Konzepte, Indikationen und Risiken.

Goal-directed hemodynamic therapy is becoming increasingly more interesting for anesthesiologists and intensive care physicians. Meta-analyses of studies evaluating perioperative therapy algorithms demonstrated a reduction of postoperative morbidity compared to the previous clinical practices. In this review article the basic concepts of goal-directed hemodynamic therapy and the principles of previously employed therapy algorithms are described and discussed. Furthermore, the questions of how these therapy strategies can be transferred into daily clinical practice and whether these therapeutic approaches might even bear risks for patients are elucidated.