Patient empowerment improves follow-up data collection after fetal surgery for spina bifida: institutional audit.

OBJECTIVES: To define and grade fetal and maternal adverse events following fetal surgery for spina bifida and to report on the impact of engaging patients in collecting follow-up data. METHODS: This prospective single-center audit included 100 consecutive patients undergoing fetal surgery for spina bifida between January 2012 and December 2021. In our setting, patients return to their referring unit for further pregnancy care and delivery. On discharge, referring hospitals were requested to return outcome data. For this audit, we prompted patients and referring hospitals to provide data in cases of missing outcomes. Outcomes were categorized as missing, returned spontaneously or returned following additional request, by the patient and/or referring center. Postoperative maternal and fetal complications until delivery were defined and graded according to Maternal and Fetal Adverse Event Terminology (MFAET) and the Clavien-Dindo classification. RESULTS: There were no maternal deaths, but severe maternal complications occurred in seven women (anemia in pregnancy, postpartum hemorrhage, pulmonary edema, lung atelectasis, urinary tract obstruction and placental abruption). No cases of uterine rupture were reported. Perinatal death occurred in 3% of fetuses and other severe fetal complications in 15% (perioperative fetal bradycardia/cardiac dysfunction, fistula-related oligohydramnios, chorioamnionitis and preterm prelabor rupture of membranes (PPROM) before 32 weeks). PPROM occurred in 42% of patients and, overall, delivery took place at a median gestational age of 35.3 weeks (interquartile range, 34.0-36.6 weeks). Information provided following additional request, from both centers and patients but mainly from the latter, reduced missing data by 21% for gestational age at delivery, 56% for uterine-scar status at birth and 67% for shunt insertion at 12 months. Compared with the generic Clavien-Dindo classification, the MFAET system ranked complications in a more clinically relevant way. CONCLUSIONS: The nature and rate of severe complications following fetal surgery for spina bifida were similar to those reported in other large series. Spontaneous return of outcome data by referring centers was low, yet patient empowerment improved data collection. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Buccal Versus Lingual Mucosa Graft in Anterior Urethroplasty: A Prospective Comparison of Surgical Outcome and Donor Site Morbidity.

PURPOSE: We prospectively compared buccal mucosa graft and lingual mucosa graft urethroplasty with respect to donor site morbidity and urethroplasty outcome. MATERIALS AND METHODS: Patients treated with buccal mucosa graft (29) or lingual mucosa graft (29) urethroplasty were included in the study. Oral pain and morbidity were assessed using the numeric rating scale (scale 0 to 10) as well as an in-home questionnaire administered 3 days, 2 weeks and 6 months postoperatively. RESULTS: After a mean (± SD) followup of 30 (± 13) months successful urethroplasty was achieved in 24 (82.8%) and 26 (89.7%) patients treated with buccal mucosa graft and lingual mucosa graft, respectively (p = 0.306). Median numeric rating scale after 3 days, 2 weeks and 6 months was 4, 2 and 0 for buccal mucosa graft and 6, 3 and 0 for lingual mucosa graft, respectively, with no statistical differences between the groups. At day 3 significantly more patients in the lingual mucosa graft group had severe difficulties with eating and drinking (62.1% vs 24.1%, p = 0.004) and speaking (93.1% vs 55.2%, p = 0.001), and had dysgeusia (48.3% vs 13.8%, p = 0.01). Two weeks postoperatively speech impairment was still more frequent with lingual mucosa graft (55.2% vs 13.8%, p = 0.002), whereas oral tightness was more frequent with buccal mucosa graft (41.4% vs 6.9%, p = 0.005). After 6 months 44.8% and 31% of patients treated with buccal mucosa graft and lingual mucosa graft, respectively, still reported sensitivity disorders (p = 0.279). CONCLUSIONS: The success of urethroplasty with lingual and buccal mucosa grafts was similar. Oral pain was not different after both grafts. In the early postoperative period there were differences in oral morbidity between buccal and lingual mucosa grafts. Long-term oral morbidity was not infrequent with both grafts.

Simultaneous Parenchyma-Preserving Liver Resection, Cytoreductive Surgery and Intraperitoneal Chemotherapy for Stage IV Colorectal Cancer.

BACKGROUND: The outcome of stage IV colorectal cancer (CRC) has improved with modern systemic therapy. However, the concomitant presence of liver metastases (LM) and peritoneal carcinomatosis (PC) remains associated with a dismal prognosis and surgery in this context remains exceptional. METHODS: Stage IV CRC patients with LM and PC undergoing simultaneous cytoreductive surgery, intraperitoneal chemotherapy (IPC) and liver resection/ablation were identified from prospectively collected databases. We assessed response to neoadjuvant chemotherapy (NACT), postoperative complications, progression free survival (PFS), and overall survival (OS). RESULTS: Twenty-one patients with resectable disease were treated between 2007 and 2014. In 16 patients (76%), NACT was administered and tumour response defined their selection. The remaining 5 (24%) were selected according to the pattern of recurrence. Median peritoneal cancer index was 5 (range: 3-10.5). Liver surgery included 34 wedge resections, 5 ablations and one bisectionectomy to treat a total of 45 hepatic lesions with a median of 2 per patient (range: 1-2) and a median size of 1.35 cm (range: 0.8-2). Tumour regression grade 4 (fibrosis but residual cancer cells predominate) was seen in 50% of the resected metastases after NACT. Median hospital stay was 17 days (range: 14-24); severe morbidity (Clavien-Dindo grade 3-4) occurred in 24% and no perioperative mortality (0-90 days) was recorded. The median OS was 44 months (range: 31-57) while the median PFS was 10 months (range: 8-12). CONCLUSIONS: Combined parenchyma-preserving liver resection, cytoreductive surgery and IPC in patients with LM and PC from CRC can be performed safely and results in promising mid-term overall survival.

A Swedish national twin study of criminal behavior and its violent, white-collar and property subtypes.

BACKGROUND: We sought to clarify the etiological contribution of genetic and environmental factors to total criminal behavior (CB) measured as criminal convictions in men and women, and to violent (VCB), white-collar (WCCB) and property criminal behavior (PCB) in men only. METHOD: In 21 603 twin pairs from the Swedish Twin Registry, we obtained information on all criminal convictions from 1973 to 2011 from the Swedish Crime Register. Twin modeling was performed using the OpenMx package. RESULTS: For all criminal convictions, heritability was estimated at around 45% in both sexes, with the shared environment accounting for 18% of the variance in liability in females and 27% in males. The correlation of these risk factors across sexes was estimated at +0.63. In men, the magnitudes of genetic and environmental influence were similar in the three criminal conviction subtypes. However, for violent and white-collar convictions, nearly half and one-third of the genetic effects were respectively unique to that criminal subtype. About half of the familial environmental effects were unique to property convictions. CONCLUSIONS: The familial aggregation of officially recorded CB is substantial and results from both genetic and familial environmental factors. These factors are moderately correlated across the sexes suggesting that some genetic and environmental influences on criminal convictions are unique to men and to women. Violent criminal behavior and property crime are substantially influenced respectively by genetic and shared environmental risk factors unique to that criminal subtype.

Conservative treatment of spontaneous dissection of the subclavian artery.

Dissection of the subclavian artery usually occurs as a result of trauma, endovascular interventions or connective tissue disorders. Only rarely has it been described occurring spontaneously. The treatment can be endovascular, open surgery, conservative or a combination of the above. There are no guidelines. The best approach is the one tailored to the lesion itself. This case presents a 73-year-old man with a tiresome and heavy feeling in the right arm. He was diagnosed having a spontaneous dissection of the right subclavian artery, accompanied by a complete occlusion more distally. Because of the relatively minor symptoms he was treated conservatively using anticoagulants. After 6 months of treatment there was complete revascularisation with good pulsations at the right wrist.

Conservative Treatment of Spontaneous Dissection of the Subclavian Artery.

Dissection of the subclavian artery usually occurs as a result of trauma, endovascular interventions or connective tissue disorders. Only rarely has it been described occurring spontaneously. The treatment can be endovascular, open surgery, conservative or a combination of the above. There are no guidelines. The best approach is the one tailored to the lesion itself. This case presents a 73-year-old man with a tiresome and heavy feeling in the right arm. He was diagnosed having a spontaneous dissection of the right subclavian artery, accompanied by a complete occlusion more distally. Because of the relatively minor symptoms he was treated conservatively using anticoagulants. After 6 months of treatment there was complete revascularisation with good pulsations at the right wrist.

Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells.

Vemurafenib (PLX4032), an inhibitor of BRAF(V600E), has demonstrated significant clinical anti-melanoma effects. However, the majority of treated patients develop resistance, due to a variety of molecular mechanisms including MAPK reactivation through MEK. The induction of a cancer cell death modality associated with danger-signalling resulting in surface mobilization of crucial damage-associated-molecular-patterns (DAMPs), e.g. calreticulin (CRT) and heat shock protein-90 (HSP90), from dying cells, is emerging to be crucial for therapeutic success. Both cell death and danger-signalling are modulated by autophagy, a key adaptation mechanism stimulated during melanoma progression. However, whether melanoma cell death induced by MAPK inhibition is associated with danger-signalling, and the reliance of these mechanisms on autophagy, has not yet been scrutinized. Using a panel of isogenic PLX4032-sensitive and resistant melanoma cell lines we show that PLX4032-induced caspase-dependent cell death and DAMPs exposure in the drug-sensitive cells, but failed to do so in the drug-resistant cells, displaying heightened MEK activation. MEK inhibitor, U0126, treatment sensitized PLX4032-resistant cells to death and re-established their danger-signalling capacity. Only melanoma cells exposing death-induced danger-signals were phagocytosed and induced DC maturation. Although the PLX4032-resistant melanoma cells displayed higher basal and drug-induced autophagy, compromising autophagy, pharmacologically or by ATG5 knockdown, was insufficient to re-establish their PLX4032 sensitivity. Interestingly, autophagy abrogation was particularly efficacious in boosting cell death and ecto-CRT/ecto-HSP90 in PLX4032-resistant cells upon blockage of MEK hyper-activation by U0126. Thus combination of MEK inhibitors with autophagy blockers may represent a novel treatment regime to increase both cell death and danger-signalling in Vemurafenib-resistant metastatic melanoma.

The etiologic role of genetic and environmental factors in criminal behavior as determined from full- and half-sibling pairs: an evaluation of the validity of the twin method.

BACKGROUND: Twin studies have shown that criminal behavior (CB) is influenced by both genetic and shared environmental factors. Could these results be replicated using full-siblings and half-siblings? METHOD: In 911 009 full-siblings reared together (FSRT), 41 872 half-siblings reared together (HSRT) and 52 590 half-siblings reared apart (HSRA), CB was assessed from the Swedish Crime Register. Modeling, including testing for age differences and rearing status, was performed using the OpenMx package. RESULTS: Five sibling models were fitted examining FSRT and HSRT 0-2 years different in age, and both FSRT and HSRT, and FSRT, HSRT and HSRA 0-10 years different in age with and without a specified shared environment indexing age differences. Heritability estimates for CB ranged from 33 to 55% in females and 39 to 56% in males, similar to those found in our prior twin study on the same population. Estimates for the shared environment varied from 1 to 14% in females and 10 to 23% in males, lower than those estimated in the twin study. The specified shared environment indexed by sibling age differences was significant in all models tested. CONCLUSIONS: Heritability estimates for CB from full- and half-siblings closely approximated those found from twins in the same population, validating the twin method. Shared environmental estimates were lower, suggesting the presence of shared environmental factors for CB specific to twins. When rearing status can be assessed, full- and half-siblings offer an additional method for assessing the role of genetic and environmental factors in complex disorders. However, age differences in siblings may need to be included in the models.

BNIP3 supports melanoma cell migration and vasculogenic mimicry by orchestrating the actin cytoskeleton.

BNIP3 is an atypical BH3-only member of the BCL-2 family of proteins with reported pro-death as well as pro-autophagic and cytoprotective functions, depending on the type of stress and cellular context. In line with this, the role of BNIP3 in cancer is highly controversial and increased BNIP3 levels in cancer patients have been linked with both good as well as poor prognosis. In this study, using small hairpin RNA (shRNA) lentiviral transduction to stably knockdown BNIP3 (BNIP3-shRNA) expression levels in melanoma cells, we show that BNIP3 supports cancer cell survival and long-term clonogenic growth. Although BNIP3-shRNA increased mitochondrial mass and baseline levels of reactive oxygen species production, which are features associated with aggressive cancer cell behavior, it also prevented cell migration and completely abolished the ability to form a tubular-like network on matrigel, a hallmark of vasculogenic mimicry (VM). We found that this attenuated aggressive behavior of these melanoma cells was underscored by severe changes in cell morphology and remodeling of the actin cytoskeleton associated with loss of BNIP3. Indeed, BNIP3-silenced melanoma cells displayed enhanced formation of actin stress fibers and membrane ruffles, while lamellopodial protrusions and filopodia, tight junctions and adherens junctions were reduced. Moreover, loss of BNIP3 resulted in re-organization of focal adhesion sites associated with increased levels of phosphorylated focal adhesion kinase. Remarkably, BNIP3 silencing led to a drop of the protein levels of the integrin-associated protein CD47 and its downstream signaling effectors Rac1 and Cdc42. These observations underscore that BNIP3 is required to maintain steady-state levels of intracellular complexes orchestrating the plasticity of the actin cytoskeleton, which is integral to cell migration and other vital processes stimulating cancer progression. All together these results unveil an unprecedented pro-tumorigenic role of BNIP3 driving melanoma cell's aggressive features, like migration and VM.

Genetic innovation and stability in externalizing problem behavior across development: a multi-informant twin study.

The use of cross-informant ratings in previous longitudinal studies on externalizing behavior may have obscured the presence of continuity of genetic risk. The current study included latent factors representing the latent estimates of externalizing behavior based on both parent and self-report which eliminated rater-specific effects from these latent estimates. Symptoms of externalizing behavior of 1,480 Swedish twin pairs were obtained at ages 8-9, 13-14, 16-17 and 19-20 both by parent and self-report. Mx modeling was used to estimate additive genetic, shared and specific environmental influences. Genetic continuity was found over the entire developmental period as well as additional sources of genetic influence emerging around early and late adolescence. New unique environmental effects (E) on externalizing behavior arose early in adolescence. The results support both the presence of genetic continuity and change in externalizing behavior during adolescence due to newly emerging genetic and environmental risk factors.

Disentangling the causal inter-relationship between negative life events and depressive symptoms in women: a longitudinal twin study.

BACKGROUND: Negative life events are strongly associated with the development of depression. However, the etiologic relationship between life events and depression is complex. Evidence suggests that life events can cause depression, and depression increases the risk for life events. Additionally, third factors influencing both phenotypes may be involved. In this work we sought to disentangle these relationships using a genetically informative longitudinal design. METHOD: Adult female twins (n=536, including 281 twin pairs) were followed up for measurements of negative life event exposure and depressive symptoms. Four follow-ups were completed, each approximately 3 months apart. Model fitting was carried out using the Mx program. RESULTS: The best-fitting model included causal paths from life events to depressive symptoms for genetic and shared environmental risk factors, whereas paths from depressive symptoms to life events were apparent for shared environmental factors. Shared latent influence on both phenotypes was found for individual-specific effects. CONCLUSIONS: Life events and depressive symptoms have complex inter-relationships that differ across sources of variance. The results of the model, if replicated, indicate that reducing life event exposure would reduce depressive symptoms and that lowering depressive symptoms would decrease the occurrence of negative life events.

International round-robin study on the Ames fluctuation test.

An international round-robin study on the Ames fluctuation test [ISO 11350, 2012], a microplate version of the classic plate-incorporation method for the detection of mutagenicity in water, wastewater and chemicals was performed by 18 laboratories from seven countries. Such a round-robin study is a precondition for both the finalization of the ISO standardization process and a possible regulatory implementation in water legislation. The laboratories tested four water samples (spiked/nonspiked) and two chemical mixtures with and without supplementation of a S9-mix. Validity criteria (acceptable spontaneous and positive control-induced mutation counts) were fulfilled by 92-100%, depending on the test conditions. A two-step method for statistical evaluation of the test results is proposed and assessed in terms of specificity and sensitivity. The data were first subjected to powerful analysis of variance (ANOVA) after an arcsine-square-root transformation to detect significant differences between the test samples and the negative control (NC). A threshold (TH) value based on a pooled NC was then calculated to exclude false positive test results. Statistically, positive effects observed by the William's test were considered negative, if the mean of all replicates of a sample did not exceed the calculated TH. By making use of this approach, the overall test sensitivity was 100%, and the test specificity ranged from 80 to 100%.

[Prevalence of mood disorders in Parkinson's disease patients treated with subthalamic nucleus deep brain stimulation]. / Prévalence des troubles de l'humeur dans la maladie de Parkinson traitée par stimulation cérébrale profonde.

Subthalamic nucleus deep brain stimulation (STN-DBS) is a recognized treatment for advanced and severe forms of Parkinson's Disease. The procedure improves motor signs and often allows a reduction of the medication. The impact of the procedure on cognitive and neuropsychiatric signs of the disease is more debated and there is an international consensus for the need of a multidisciplinary evaluation of patients undergoing such programs, including a neuropsychiatric assessment. We present a review of the literature as well as the experience at our centre focused on the short and long term outcome on mood following STN-DBS.

Sex differences and developmental stability in genetic and environmental influences on psychoactive substance consumption from early adolescence to young adulthood.

BACKGROUND: Genetic and environmental factors are important in the etiology of substance use. However, little is known about the stability of these factors across development. We aimed to answer three crucial questions about this etiology that have never been addressed in a single study: (1) Is there a general vulnerability to substance consumption from early adolescence to young adulthood? (2) If so, do the genetic and environmental influences on this vulnerability change across development? (3) Do these developmental processes differ in males and females? METHOD: Subjects included 1480 twin pairs from the Swedish Twin Study of Child and Adolescent Development who have been followed since 1994. Prospective, self-reported regular smoking, alcohol intoxication and illicit drug use were assessed at ages 13-14, 16-17 and 19-20 years. Structural modeling was performed with the program Mx. RESULTS: An underlying common factor accounted for the association between smoking, alcohol and illicit drug consumption for the three age groups. Common genetic and shared environmental effects showed substantial continuity. In general, as participants aged, the influence of the shared environment decreased, and genetic effects became more substance specific in their effect. CONCLUSIONS: The current report answers three important questions in the etiology of substance use. The genetic and environmental risk for substance consumption is partly mediated through a common factor and is partly substance specific. Developmentally, evidence was strongest for stability of common genetic effects, with less evidence for genetic innovation. These processes seem to be the same in males and females.

A population-based twin study of the genetic and environmental relationship of major depression, regular tobacco use and nicotine dependence.

BACKGROUND: Numerous epidemiological studies have reported a positive association between major depression (MD) and regular tobacco use (RU) or nicotine dependence (ND). However, few have used a genetically informative design to assess whether these traits share a common genetic and/or environmental liability. METHOD: We assessed MD, RU and ND in same-sex twins from the population-based Swedish Twin Registry. In males, we examined both cigarette use and snus (smokeless tobacco) use. We used structural equation modeling to examine the relationship between MD, RU, and ND given RU. RESULTS: The results suggest modest correlations between MD and RU, and between MD and ND. In males, the liability shared between MD and RU is solely genetic for both cigarettes and snus, while MD and ND share both genetic and unique environmental influences. The continuation to ND given RU differed considerably between cigarette and snus users. In females, both MD-RU and MD-ND relationships are partially attributable to genetic and unique environmental correlations. CONCLUSIONS: The relationship among MD, RU and ND is at least partially attributable to shared genetic and environmental risk factors. The genetic and environmental correlations between traits are modest. The nature of the shared liability differs by sex, and in males, by the type of tobacco product used. Differences between previous reports and results presented in the current study are suggestive of population differences in how MD and tobacco use inter-relate.

Circulating tumour cell detection: a direct comparison between the CellSearch System, the AdnaTest and CK-19/mammaglobin RT-PCR in patients with metastatic breast cancer.

BACKGROUND: The detection, enumeration and isolation of circulating tumour cells (CTCs) have considerable potential to influence the clinical management of patients with breast cancer. There is, however, substantial variability in the rates of positive samples using existing detection techniques. The lack of standardisation of technology hampers the implementation of CTC measurement in clinical routine practice. METHODS: This study was designed to directly compare three techniques for detecting CTCs in blood samples taken from 76 patients with metastatic breast cancer (MBC) and from 20 healthy controls: the CellSearch CTC System, the AdnaTest Breast Cancer Select/Detect and a previously developed real-time qRT-PCR assay for the detection of CK-19 and mammaglobin transcripts. RESULTS: As a result, 36% of patients with MBC were positive by the CellSearch System, 22% by the AdnaTest, 26% using RT-PCR for CK-19 and 54% using RT-PCR for mammaglobin. Samples were significantly more likely to be positive for at least one mRNA marker using RT-PCR than using the CellSearch System (P=0.001) or the AdnaTest (P<0.001). CONCLUSION: We observed a substantial variation in the detection rates of CTCs in blood from breast cancer patients using three different techniques. A higher rate of positive samples was observed using a combined qRT-PCR approach for CK-19 and mammaglobin, which suggests that this is currently the most sensitive technique for detecting CTCs.

Deregulation of cell-death pathways as the cornerstone of skin diseases.

Deregulation of cell-death pathways plays a key role in the pathogenesis of various skin diseases. The different types of cell death are mainly defined by morphological criteria, and include apoptosis, autophagic cell death, and necrosis. The process of apoptosis is well characterized at the molecular level and involves the activation of two main pathways, the intrinsic and extrinsic pathways, converging into the execution of apoptosis by intracellular cysteine proteases, called caspases. The relevance and implication of these apoptotic pathways in the pathophysiology of skin diseases, such as toxic epidermal necrolysis, graft-versus-host disease and skin cancer, has been extensively studied. The role of autophagic cell death in progression of skin tumours and response to cytotoxic drugs is only beginning to be elucidated.

The presence of circulating total DNA and methylated genes is associated with circulating tumour cells in blood from breast cancer patients.

Circulating tumour cells (CTC) and tumour-related methylated DNA in blood have been separately assessed for their utility as a marker for subclinical metastasis in breast cancer. However, no studies have looked into the relation between the both molecular markers in this type of cancer. In this study, we investigated the correlations between total/methylated DNA and CTC in the blood from metastatic breast cancer patients. We simultaneously obtained whole blood, plasma and serum samples from 80 patients and 20 controls. The CellSearch System was used to enumerate CTC in blood samples. Plasma total DNA levels were determined by a QPCR method. Sera were analysed by methylation-specific QPCR for three markers: adenomatous polyposis coli (APC), ras association domain family protein 1A (RASSF1A) and oestrogen receptor 1 (ESR1). Total DNA levels in patients were significantly increased when compared with controls (P<0.001) and correlated with the number of CTC (r=0.418, P<0.001). Hypermethylation of one or more genes was detected in 42 (53%) serum samples from breast cancer patients and in three (16%) serum samples from controls (P=0.003). APC was hypermethylated in 29%, RASSF1A in 35% and ESR1 in 20% of breast cancer cases. Detection of a methylated gene in serum was associated with the detection of CTC in blood (P=0.03). The detection of large amounts of circulating total/methylated DNA correlated with the presence of CTC in the blood from patients with breast cancer. This can be interpreted in two ways: (a) CTC are a potential source of circulating tumour-specific DNA; (b) high numbers of CTC and circulating methylated DNA are both a phenotypic feature of more aggressive tumour biology.