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Zusammenfassung Die Anfange der Kreuzbandchirurgie stellte die Naht uber eine invasive Arthrotomie dar, was jedoch aufgrund einer hohen Komplikations- und Re-Rupturrate alsbald wieder verlassen wurde. Heutzutage ist der operative Goldstandard die arthroskopische VKB Rekonstruktion mittels autologem Sehnenmaterial. Diese Technik liefert reproduzierbare gute Resultate, ist jedoch auch mit einer Graftentnahme-Morbiditat, vorderen Knieschmerzen und postoperativer Quadrizepsschwache assoziiert. Die neuesten technischen Entwicklungen im Bereich der arthroskopischen Chirurgie haben daher das Interesse an der VKB Naht wiederbelebt. So wurden fur die Naht und Augmentation mittels InternalBraceTM gute klinische Ergebnisse beschrieben, jedoch bleibt die Literatur bislang noch den Beweis des funktionell-biomechanischen Vorteils dieser Technik schuldig.

Summary We report a case of painful snapping pes anserinus. A 21-year-old man presented with medial knee pain. After arthroscopy for medial partial meniscectomy the pain persisted. After failed conservative treatment with physical therapy surgery was performed. The pes anserinus was released, but the pain persisted. After a revision surgery with further release of the pes the symptoms disappeared.

Background Magnetic resonance imaging (MRI) examinations are increasingly used in antenatal clinical practice. Incidental findings are a recognized association with imaging and although in some circumstances their identification can alter management, they are often associated with increased anxiety, for both patient and clinician, as well as increased health care costs. Objective This study aimed to evaluate the incidence of unexpected findings in both the mother and fetus during antenatal MRI examinations. Materials and methods A retrospective study was undertaken over a five-year period at St.. Thomas’ Hospital in London. Maternal incidental findings were recorded from all clinical reports of all fetal MRIs performed (for clinical reasons and in healthy volunteers) during this period. Fetal incidental findings were recorded only in cases where women with uncomplicated pregnancies were participating as healthy volunteers. Results A total of 2,569 MRIs were included; 17% of women had maternal incidental findings. Of these, 1,099 were women with uncomplicated pregnancies who undertook research MRIs as healthy volunteers; fetal incidental findings were identified in 12.3%. Conclusion Incidental findings are a common occurrence in antenatal MRI. Consideration should be given to counseling women appropriately before imaging and ensuring that robust local protocols are in place for follow-up and further management of such cases.

The absolute number of total knee arthroplasties (TKA) continues to rise every year. About 10% of the patients are less than 55 years of age, although it is known that functional results and patient satisfaction are lower combined with an increased likelihood of revision compared to older patients. Higher physical activity and patient expectations are a major challenge in this age group. At the same time, the incidence of posttraumatic/postoperative alterations is high, including ligamentous or bony deficiencies, which can make the surgical procedure challenging. In view of these facts conservative treatments and joint sparing procedures should always be considered first. The potential correction of lower-limb deformities and unicompartmental knee arthroplasties need to be carefully evaluated before considering total knee arthroplasty. Only in advanced cases of osteoarthritis in more than one compartment of the knee of with combined ligamentous instability, can a TKA provide satisfactory results in the young patient. However, the strongest predictor of satisfaction is a realistic expectation.Die Zahl der durchgeführten Knietotalendoprothesen (KTEP) nimmt jedes Jahr kontinuierlich zu. Ungefähr 10 % davon betreffen Patienten unter 55 Jahren, obwohl bekannt ist, dass in dieser Altersgruppe die Zufriedenheit und die funktionellen Ergebnisse geringer und die Revisionsrate höher ausfällt. Vermehrte Aktivität und erhöhtes Anspruchsdenken machen die Endoprothetik in dieser Altersgruppe zu einer besonderen Herausforderung. Gleichzeitig ist der Anteil posttraumatischer Gonarthrosen deutlich erhöht, was in Anbetracht ligamentärer und knöcherner Vorschäden eine schwierigere operative Versorgung bedeutet. Bei fortgeschrittenen Arthrosen in mehreren Kompartimenten mit/ohne begleitender ligamentärer Instabilität muss jedoch ein totalendoprothetischer Ersatz auch bei jüngeren Patienten erwogen werden. Die sorgfältige Indikationsstellung für die KTEP und die eingehende Patientenaufklärung (Chancen, Risiken, erreichbare Leistungsfähigkeit in Beruf und Alltag) sind gerade bei jüngeren Patienten starke Prädiktoren für ein gutes Resultat.

The diverse cerebral consequences of preterm birth create significant challenges for understanding pathogenesis or predicting later outcome. Instead of focusing on describing effects common to the group, comparing individual infants against robust normative data offers a powerful alternative to study brain maturation. Here we used Gaussian process regression to create normative curves characterising brain volumetric development in 274 term-born infants, modelling for age at scan and sex. We then compared 89 preterm infants scanned at termequivalent age to these normative charts, relating individual deviations from typical volumetric development to perinatal risk factors and later neurocognitive scores. To test generalisability, we used a second independent dataset comprising of 253 preterm infants scanned using different acquisition parameters and scanner. We describe rapid, non-uniform brain growth during the neonatal period. In both preterm cohorts, cerebral atypicalities were widespread, often multiple, and varied highly between individuals. Deviations from normative development were associated with respiratory support, nutrition, birth weight, and later neurocognition, demonstrating their clinical relevance. Group-level understanding of the preterm brain disguise a large degree of individual differences. We provide a method and normative dataset that offer a more precise characterisation of the cerebral consequences of preterm birth by profiling the individual neonatal brain.

Purpose: In a head and neck squamous cell carcinoma (HNSCC) “window of opportunity” clinical trial, we reported that trametinib reduced MEK-Erk1/2 activation and resulted in tumor responses in a subset of patients. Here, we investigated resistance to trametinib and molecular correlates in HNSCC cell lines and patient samples. Experimental Design: HNSCC cell lines were treated with trametinib to generate resistant lines. Candidate bypass pathways were assessed using immunoblotting, CRISPR knockout, and survival assays. Effectiveness of combined trametinib and verteporfin targeting was evaluated. Patient-derived xenografts (PDXs) from responder patients were treated with trametinib and resistant tumors were analyzed. Window trial clinical samples were subjected to whole-exome and RNA sequencing. Results: HNSCC cell lines developed resistance (CAL27-TR and HSC3-TR) after prolonged trametinib exposure. Downstream effectors of the Hippo pathway were activated in CAL27-TR and HSC3-TR, and combined trametinib and verteporfin treatment resulted in synergistic treatment response. We defined the Hippo pathway effector Yap1 as an induced survival pathway promoting resistance to trametinib in HSC3-TR. Yap1 was necessary for HSC3-TR trametinib resistance, and constitutively active Yap1 was sufficient to confer resistance in parental HSC3. Analysis of trametinib neoadjuvant trial patient tumors indicated canonical MEK-Erk1/2 pathway activating mutations were infrequent, and Yap1 activity increased following trametinib treatment. Trametinib treatment of a PDX from a responder patient resulted in evolution of resistance with increased Yap1 expression and activity. Conclusions: These studies identify a Yap1-dependent resistance to trametinib therapy in HNSCCs. Combined Yap1 and MEK targeting may represent a strategy to enhance HNSCC response.

Kinematic changes associated with knee osteoarthritis (OA) have been traditionally measured with camera-based gait analysis. Lately, inertial sensors have become popular for gait analysis with the advantage of being less time consuming and not requiring a dedicated laboratory.Do spatiotemporal and discrete kinematic gait parameters measured with the inertial sensor system RehaGait® differ between the affected and unaffected side in patients with unilateral knee OA and between patients with severe knee OA and asymptomatic control subjects? Do these differences have a similar magnitude as those reported in the literature?Twenty-two patients with unilateral knee OA scheduled for total knee replacement and 46 age matched control subjects were included in this study. Spatiotemporal parameters and sagittal kinematics at the hip, knee, and ankle joint were measured using the RehaGait® system while walking at a self-selected speed for a distance of 20 m and compared between groups.Patients with knee OA had slower walking speed, longer stride duration, shorter stride length and lower cadence (P 0.001). Peak knee flexion during stance and swing was lower in the affected than the unaffected leg (-4.8° and -6.1°; P 0.01). Peak knee flexion during stance and swing (-5.2° and -8.8°; P 0.01) and knee range of motion during loading response and swing (-3.6° and -4.4°; P 0.01) were lower than in the control group.These side to side differences within patients and differences between patients with knee OA and control subjects agree with known gait alterations measured with camera-based systems. The RehaGait® inertial sensor system can detect gait alterations in patients with knee OA and is suitable for gait analysis in a clinical environment.

Introduction The purpose of this study was to describe the indications and technical aspects as well as evaluate the clinical and functional outcome of lengthening osteotomy of the lateral trochlear ridge in patients with patellofemoral pain and/or patella instability and presence of trochlear dysplasia Dejour type A or lack of Dejour type dysplasia and short lateral articular trochlea. Materials and methods Six consecutive adult patients were treated with a lateral trochlear lengthening osteotomy. Five patients received a concomitant medial patellofemoral ligament reconstruction. Three patients had prior patella stabilization surgeries. Trochlea dysplasia (Dejour classification), Caton–Dechamps index, tibial tubercle trochlear groove (TT-TG) distance, patellar tilt and lateral condylar index were measured in preoperative MRIs. Clinical and functional evaluation included the Kujala Anterior Knee Pain Scale, the Lysholm Knee Score, the Tegner Activity Score, a subjective evaluation form and isokinetic muscle strength. Results Four patients had a Dejour type A dysplasia, two patients had no dysplasia. The mean (range) Caton-Dechamps index was 1.09 (0.95–1.16), TT-TG distance 10.9 mm (9.2–15.6 mm), patellar tilt 15° (4–32°) and lateral condylar index 82.0% (74–90%). One patient was lost to follow up, all others were followed for 2–5 years. All patients were satisfied with the clinical outcome. The Lysholm score increased from 55 (37–79) to 89 (76–100), the Tegner activity score from 3.6 (2–6) to 5.6 (5–7). The Kujala score postoperative was 90 (75–96). Some but not all patients had full strength recovery compared to the contralateral leg. Conclusion We recommend measuring the lateral condylar index and considering the indication of a lateral trochlear lengthening osteotomy as an additional or isolated procedure in selected patients with trochlear dysplasia Dejour type A or lack of dysplasia and short lateral articular trochlea depending on the extent of the patellar instability. Level of evidence Level IV, Case Series. Trial registration number NCT04378491, clinicaltrials.gov, May 7, 2020.

Cancer is characterized by an accumulation of somatic mutations that represent a source of neoantigens for targeting by antigen‐specific T cells. Head and neck squamous cell carcinoma (HNSCC) has a relatively high mutation burden across all cancer types, and cellular immunity to neoantigens likely plays a key role in HNSCC clinical outcomes. Immune checkpoint inhibitors (CPIs) have brought new treatment options and hopes to patients with recurrent and/or metastatic HNSCC. However, many patients do not benefit from CPI therapies, highlighting the need for novel immunotherapy or combinatorial strategies. One such approach is personalized cancer vaccination targeting tumor‐associated antigens and tumor‐specific antigens, either as single agents or in combination with other therapies. Recent advances in next‐generation genomic sequencing technologies and computational algorithms have enabled efficient identification of somatic mutation‐derived neoantigens and are anticipated to facilitate the development of cancer vaccine strategies. Here, we review cancer vaccine approaches against HNSCC, including fundamental mechanisms of a cancer vaccine, considerations for selecting appropriate antigens, and combination therapies., Many patients with head and neck squamous cell carcinoma (HNSCC) do not benefit from checkpoint inhibitor therapies, which highlights the need for novel immunotherapy or combinatorial strategies. One such approach is personalized cancer vaccination targeting tumor‐associated antigens and tumor‐specific antigens, either as single agents or in combination with other therapies. Here, we review cancer vaccine approaches against HNSCC, including fundamental mechanisms of cancer vaccine, considerations for selecting appropriate antigens, and combination therapies.

Background Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. Methods We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. Results We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. Conclusions Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research.

Purpose Prior findings suggest that women and elderly persons are more sensitive to pressure than men and younger persons; however, the magnitudes of these differences are substantially inconsistent. We answered the question whether the higher sensitivity of women and elderly persons is quantitatively meaningful. Specifically, we investigated if it is large enough to hamper the diagnosis, classification and follow-up of pain conditions by clinicians. Materials and methods From each age stratum (18-20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, and >80 years), 40 pain-free women and 40 pain-free men were recruited. They rated the intensity of pressure of ten Newtons over ten seconds on an analogue zero to ten rating scale. The pressure was applied on their middle fingers and ear lobes with a threshold algometer. Centile curves visualized the sex- and age-dependent fluctuation of pressure sensitivity. Results Over the entire age range from 20 to 80 years, the median curves fluctuated within the interval of less than two points. The distance between the median curves of men and women was also less than two points. On the average, the median difference was half a point on the finger (p = 0.249) and the ear lobe (p = 0.083). Conclusion Less than two points is below the minimal clinically important difference for a zero to ten analogue pain rating scale; differences smaller than one point are even below the resolution of the scale. Sex differences and age fluctuations of pressure sensitivity are negligible.

Background and objectives Obtaining IgM and IgG titres is important in numerous clinical situations, including solid-organ transplant, obstetrics, and for testing of out-of-group plasma-containing components. Tube method is the most prevalent testing modality, though it is both labour-intensive and known for intra- and inter-laboratory variability. The utility of automated gel testing as a method to improve both inter- and intra-laboratory reproducibility is unknown. Materials and methods Two academic centres participated in a study evaluating automated gel titreing. Group O plasma samples were used to measure titres of antibodies against ABO (IgM) with buffered gel cards and 4 minor and minor red-blood-cell antigens (IgG) anti-IgG gel cards. Multiple ORTHO VISION automated analyzers were used to assess inter-instrument variation. A subset of ABO (IgM) samples were compared between laboratories to evaluate inter-laboratory variability. Multiple samples were titred by tube and by automated gel technology to determine similarity of results. Results Testing demonstrated no significant difference between analysers or between sites when performing automated titrations (P ≥ 0·99). Non-ABO IgG titres were evaluated and demonstrated little inter-instrument variability. The IgM anti-A and -B titres obtained by automated gel testing were neither consistently higher nor lower than tube titres. Greater than 90% of titre values were within one dilution. Conclusion Based on this study, our data suggest that titreing by automated gel testing is both highly reproducible (IgM and IgG) and does not differ significantly from manual tube testing results of direct agglutination (IgM).

Background Stimulants such as methylphenidate and modafinil are frequently used as cognitive enhancers in healthy people, whereas 3,4-methylenedioxymethamphetamine (ecstasy) is proposed to enhance mood and empathy in healthy subjects. However, comparative data on the effects of methylphenidate and modafinil on negative emotions in healthy subjects have been partially missing. The aim of this study was to compare the acute effects of methylphenidate and modafinil on the neural correlates of fearful face processing using 3,4-methylenedioxymethamphetamine as a positive control. Methods Using a double-blind, within-subject, placebo-controlled, cross-over design, 60 mg methylphenidate, 600 mg modafinil, and 125 mg 3,4-methylenedioxymethamphetamine were administrated to 22 healthy subjects while performing an event-related fMRI task to assess brain activation in response to fearful faces. Negative mood states were assessed with the State-Trait Anxiety Inventory and subjective ratings. Results Relative to placebo, modafinil, but not methylphenidate or 3,4-methylenedioxymethamphetamine, increased brain activation within a limbic-cortical-striatal-pallidal-thalamic circuit during fearful face processing. Modafinil but not methylphenidate also increased amygdala responses to fearful faces compared with 3,4-methylenedioxymethamphetamine. Furthermore, activation in the middle and inferior frontal gyrus in response to fearful faces correlated positively with subjective feelings of fearfulness and depressiveness after modafinil administration. Conclusions Despite the cognitive enhancement effects of 600 mg modafinil in healthy people, potential adverse effects on emotion processing should be considered.

OBJECTIVES: This study aimed to analyze the associations among depressive/anxiety and pain symptoms in patients diagnosed with chronic pain. METHODS: Four hundred and fifty-four inpatients who were consecutively admitted in a multimodal 3-weeks treatment in a tertiary psychosomatic university clinic completed 25 items from the Brief Pain Inventory and the Hospital Anxiety and Depression Scale at baseline and after treatment termination. Associations among symptoms were explored by network analyses using the graphical least absolute shrinkage and selection operator to estimate their partial correlations, while Extended Bayesian Information Criterion was used to select the best network solution for the data. We explored symptoms' centrality and expected influence within the network as well as the minimum spanning tree for the network. RESULTS: Besides expected associations within depressive/anxiety and pain symptoms, the estimated network showed several local associations between depressive and pain interference symptoms. The lacks of being cheerful and of laughing are two of the depressive symptoms that showed the greatest associations with pain interference and a strong centrality within the network. Sleep problems were both associated with anxiety/depressive symptoms and pain intensity symptoms. Although at post-treatment, most of the symptoms showed a significant decrease, the strength of the associations between the symptoms within the network were significantly higher than at baseline. DISCUSSION: The results support focusing psychosocial interventions in chronic pain treatment not only on reducing pain, anxiety and sleep symptoms but also on enhancing positive affect. Future research is needed to replicate these findings using repeated within-person measures designs.

Objective Neural tube defects (NTDs) are one of the most common congenital anomalies caused by a complex interaction of many genetic and environmental factors. In about 10% of cases, NTDs are associated with genetic syndromes or chromosomal anomalies. Among these, SOX3 duplication has been reported in some isolated cases. The phenotype associated with this microduplication is variable and includes myelomeningocele (MMC) in both sexes as well as hypopituitarism and cognitive impairment in males. In order to determine the prevalence of this anomaly in fetuses with MMC, a retrospective cohort of fetuses with MMC was analyzed by quantitative PCR (qPCR) targeting SOX3 locus. Methods The detection of an SOX3 microduplication by chromosomal microarray analysis (CMA) in two female fetuses with MMC prompted us to analyze retrospectively by qPCR this gene in a cohort of 53 fetuses with MMC. Results In addition to our two initial cases, one fetus harboring an Xq27.1q28 duplication that encompasses the SOX3 gene was detected. Conclusion Our data demonstrate that SOX3 duplication is a genomic imbalance involved in the pathogenesis of NTDs. In addition, our survey highlights the importance of CMA testing in fetuses with NTDs to enable genetic counseling upstream of any considerations of in utero fetal surgery.

Die interdisziplinare multimodale Schmerztherapie (IMST) soll auf der Grundlage eines individuellen Fallverstandnisses personalisiert, mechanismenbasiert und zielorientiert erfolgen. Ein praxisnahes Instrument zur Behandlungsplanung fur die individualisierte Planung der IMST liegt bislang unseres Wissens nicht vor. Das hier vorgestellte Modell soll als Wegleitung dienen, die IMST optimiert zu planen und effizient durchzufuhren. Ausgehend von relevanten Storungsmechanismen werden die Veranderungs- und Behandlungsziele festgelegt und mogliche Interventionen vorgeschlagen. Dabei werden die Ressourcen des Patienten explizit miteinbezogen.

ABC exporters harness the energy of ATP to pump substrates across membranes. Extracellular gate opening and closure are key steps of the transport cycle, but the underlying mechanism is poorly understood. Here, we generated a synthetic single domain antibody (sybody) that recognizes the heterodimeric ABC exporter TM287/288 exclusively in the presence of ATP, which was essential to solve a 3.2 Å crystal structure of the outward-facing transporter. The sybody binds to an extracellular wing and strongly inhibits ATPase activity by shifting the transporter’s conformational equilibrium towards the outward-facing state, as shown by double electron-electron resonance (DEER). Mutations that facilitate extracellular gate opening result in a comparable equilibrium shift and strongly reduce ATPase activity and drug transport. Using the sybody as conformational probe, we demonstrate that efficient extracellular gate closure is required to dissociate the NBD dimer after ATP hydrolysis to reset the transporter back to its inward-facing state., ABC exporters hydrolyze ATP to pump substrates across membranes, but critical steps of the transport mechanism remain poorly understood. Here, the authors solve the crystal structure of outward-facing TM287/288 with the help of a state-specific sybody and gain insights into the role of the extracellular gate.

Cyclin-dependent kinase 9 (CDK9), the kinase component of positive transcription elongation factor b (P-TEFb), is essential for transcription of most protein-coding genes by RNA polymerase II (RNAPII). By releasing promoter-proximally paused RNAPII into gene bodies, CDK9 controls the entry of RNAPII into productive elongation and is, therefore, critical for efficient synthesis of full-length messenger (m)RNAs. In recent years, new players involved in P-TEFb-dependent processes have been identified and an important function of CDK9 in coordinating elongation with transcription initiation and termination has been unveiled. As the regulatory functions of CDK9 in gene expression continue to expand, a number of human pathologies, including cancers, have been associated with aberrant CDK9 activity, underscoring the need to properly regulate CDK9. Here, I provide an overview of CDK9 function and regulation, with an emphasis on CDK9 dysregulation in human diseases.

OBJECTIVE. The purpose of this study was to compare breast cancer characteristics and treatment regimens among women undergoing annual versus nonannual screening mammography. MATERIALS AND METHODS. In this retrospective, institutional review board-approved, HIPAA-compliant cohort study, a breast cancer database was queried for patients who received a mammographic or clinical diagnosis of breast cancer during 2016-2017. Annual versus biennial and annual versus nonannual (biennial and triennial) mammography screening cohorts were compared using t tests or Wilcoxon rank sum tests for continuous variables and chi-square or Fisher exact tests for categoric variables. RESULTS. A total of 490 patients were diagnosed with breast cancer during 2016-2017. Among these women, 245 had an assignable screening frequency and were 40-84 years old (mean, 61.8 ± 9.9 [SD] years; median, 62 years). Screening frequency was annual for 200 of these 245 patients (81.6%), biennial for 32 (13.1%), and triennial for 13 (5.3%). Annual screening resulted in fewer late-stage presentations (AJCC stage II, III, or IV in 48 of 200 patients undergoing annual [24.0%] vs 14 of 32 undergoing biennial [43.8%; p = .02] and vs 20 of 45 undergoing nonannual screening [44.4%; p = .006]), fewer interval cancers (21 of 200 for annual [10.5%] vs 12 of 32 for biennial [37.5%; p < .001] and vs 15 of 45 for nonannual [33.3%; p < .001]), and smaller mean tumor diameter (1.4 ± 1.2 cm for annual vs 1.8 ± 1.6 cm for biennial [p = .04] and vs 1.8 ± 1.5 cm nonannual [p = .03]). Lower AJCC stage, fewer interval cancers, and smaller tumor diameter also persisted among postmenopausal women undergoing annual screening. Patients undergoing biennial and nonannual screening showed nonsignificant greater use of axillary lymph node dissection (annual, 24 of 200 [12.0%]; biennial, 6 of 32 [18.8%]; nonannual, 7 of 45 [15.6%]) and chemotherapy (annual, 55 of 200 [27.5%]; biennial, 12 of 32 [37.5%]; nonannual, 16 of 45 [35.6%]). CONCLUSION. Annual mammographic screening was associated with lower breast cancer stage and fewer interval cancers than biennial or nonannual screening.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of antiresorptive medication. The aim of this study was to evaluate the incidence of denosumab-related osteonecrosis of the jaw and to compare the clinical and radiological extent of osteonecrosis. A retrospective study of patients who received Xgeva® at the Institut de Cancérologie de Lorraine (ICL) was performed. Patients for whom clinical and radiological (CBCT) data were available were divided into two groups: “exposed” for patients with bone exposure and “fistula” when only a fistula through which the bone could be probed was observed. The difference between clinical and radiological extent was assessed. The p-value was set at 0.05, and a total of 246 patients were included. The cumulative incidence of osteonecrosis was 0.9% at 6 months, 7% at 12 months, and 15% from 24 months. The clinical extent of MRONJ was significantly less than their radiological extent: in the “exposed” group, 17 areas (45%) were less extensive clinically than radiologically (p &lt, 0.001) and respectively 6 (67%) for the “fistula” group (p &lt, 0.031). It would seem that a CBCT is essential to know the real extent of MRONJ. Thus, it would seem interesting to systematically perform a CBCT during the diagnosis of MRONJ, exploring the entire affected dental arch.

International audience; Highlights d The 7SK snRNA is dispensable for cell proliferation under standard growth conditions d After UV exposure, 7SK/P-TEFb is needed for proper stress response and cell survival d P-TEFb extracted from 7SK/P-TEFb triggers UV-induced general RNAPII pause release d P-TEFb from 7SK/P-TEFb supports activation of important UV-responsive genes; Conversion of promoter-proximally paused RNA polymerase II (RNAPII) into elongating polymerase by the positive transcription elongation factor b (P-TEFb) is a central regulatory step of mRNA synthesis. The activity of P-TEFb is controlled mainly by the 7SK small nuclear ribonucleoprotein (snRNP), which sequesters active P-TEFb into inactive 7SK/P-TEFb snRNP. Here we demonstrate that under normal culture conditions, the lack of 7SK snRNP has only minor impacts on global RNAPII transcription without detectable consequences on cell proliferation. However, upon ultraviolet (UV)-light-induced DNA damage, cells lacking 7SK have a defective transcriptional response and reduced viability. Both UV-induced release of “lesion-scanning” polymerases and activation of key early-responsive genes are compromised in the absence of 7SK. Proper induction of 7SK-dependent UV-responsive genes requires P-TEFb activity directly mobilized from the nucleoplasmic 7SK/P-TEFb snRNP. Our data demonstrate that the primary function of the 7SK/P-TEFb snRNP is to orchestrate the proper transcriptional response to stress.

Gambling disorder and gaming disorder have recently been recognized as behavioral addictions in the ICD-11 (International Classification of Diseases, 11th edition). The association between behavioral addictions and personality has been examined before, yet there is a lack of studies on maladaptive traits and their relationship to specific outcome expectancies. In study 1, we recruited a community sample (n = 365), in study 2 a sample of treatment-seekers was enrolled (n = 208). Maladaptive personality traits were assessed by the brief form of the Personality Inventory for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition). Internet-related outcome expectancies were measured by the Virtual Expectancy Questionnaire. In the clinical sample, the Global Assessment of Functioning was additionally administered. Behavioral Addictions were closely associated with maladaptive traits that in turn were related to a poorer level of psychosocial functioning. There is evidence for an exacerbated risk of internet-related disorders when specific outcome expectancies and maladaptive traits interact. Implications for phenomenology and treatment are discussed.

Infants with congenital heart disease are at risk of neurodevelopmental impairments, the origins of which are currently unclear. This study aimed to characterize the relationship between neonatal brain development, cerebral oxygen delivery and neurodevelopmental outcome in infants with congenital heart disease. A cohort of infants with serious or critical congenital heart disease (N = 66; N = 62 born ≥37 weeks) underwent brain MRI before surgery on a 3T scanner situated on the neonatal unit. T2-weighted images were segmented into brain regions using a neonatal-specific algorithm. We generated normative curves of typical volumetric brain development using a data-driven technique applied to 219 healthy infants from the Developing Human Connectome Project (dHCP). Atypicality indices, representing the degree of positive or negative deviation of a regional volume from the normative mean for a given gestational age, sex and postnatal age, were calculated for each infant with congenital heart disease. Phase contrast angiography was acquired in 53 infants with congenital heart disease and cerebral oxygen delivery was calculated. Cognitive and motor abilities were assessed at 22 months (N = 46) using the Bayley scales of Infant and Toddler Development–Third Edition. We assessed the relationship between atypicality indices, cerebral oxygen delivery and cognitive and motor outcome. Additionally, we examined whether cerebral oxygen delivery was associated with neurodevelopmental outcome through the mediating effect of brain volume. Negative atypicality indices in deep grey matter were associated with both reduced neonatal cerebral oxygen delivery and poorer cognitive abilities at 22 months across the whole sample. In infants with congenital heart disease born ≥37 weeks, negative cortical grey matter and total tissue volume atypicality indices, in addition to deep grey matter structures, were associated with poorer cognition. There was a significant indirect relationship between cerebral oxygen delivery and cognition through the mediating effect of negative deep grey matter atypicality indices across the whole sample. In infants born ≥37 weeks, cortical grey matter and total tissue volume atypicality indices were also mediators of this relationship. In summary, lower cognitive abilities in toddlers with congenital heart disease were associated with smaller grey matter volumes before cardiac surgery. The aetiology of poor cognition may encompass poor cerebral oxygen delivery leading to impaired grey matter growth. Interventions to improve cerebral oxygen delivery may promote early brain growth and improve cognitive outcomes in infants with congenital heart disease., Bonthrone et al. assessed individualized brain growth in infants with congenital heart disease compared with a large normative sample to determine atypicality indices in the patient group. Low cerebral oxygen delivery was associated with impaired grey matter development and resulted in poor cognitive outcome in this population., Graphical Abstract Graphical Abstract

Near-infrared (NIR) fluorescence-guided surgery is an innovative technique for the real-time visualization of resection margins. The aim of this study was to develop a head and neck multicellular tumor spheroid model and to explore the possibilities offered by it for the evaluation of cameras for NIR fluorescence-guided surgery protocols. FaDu spheroids were incubated with indocyanine green (ICG) and then included in a tissue-like phantom. To assess the capability of Fluobeam® NIR camera to detect ICG in tissues, FaDu spheroids exposed to ICG were embedded in 2, 5 or 8 mm of tissue-like phantom. The fluorescence signal was significantly higher between 2, 5 and 8 mm of depth for spheroids treated with more than 5 µg/mL ICG (p &lt, 0.05). The fluorescence intensity positively correlated with the size of spheroids (p &lt, 0.01), while the correlation with depth in the tissue-like phantom was strongly negative (p &lt, 0.001). This multicellular spheroid model embedded in a tissue-like phantom seems to be a simple and reproducible in vitro tumor model, allowing a comparison of NIR cameras. The ideal configuration seems to be 450 μm FaDu spheroids incubated for 24 hours with 0.05 mg/ml of ICG, ensuring the best stability, toxicity, incorporation and signal intensity.

Fibromyalgia is characterized by chronic pain and a striking discrepancy between objective signs of tissue damage and severity of pain. Function and structural alterations in brain areas involved in pain processing may explain this feature. Previous case-control studies in fibromyalgia focused on acute pain processing using experimentally-evoked pain paradigms. Yet, these studies do not allow conclusions about chronic, stimulus-independent pain. Resting-state cerebral blood flow (rsCBF) acquired by arterial spin labelling (ASL) may be a more accurate marker for chronic pain. The objective was to integrate four different functional and structural neuroimaging markers to evaluate the neural correlate of chronic, stimulus-independent pain using a resting-state paradigm. In line with the pathophysiological concept of enhanced central pain processing we hypothesized that rsCBF is increased in fibromyalgia in areas involved in processing of acute pain.We performed an age matched case-control study of 32 female fibromyalgia patients and 32 pain-free controls and calculated group-differences in rsCBF, resting state functional connectivity, grey matter density and cortical thickness using whole-brain and region of interest analyses. We adjusted all analyses for depression and anxiety. As centrally acting drugs are likely to interfere with neuroimaging markers, we performed a subgroup analysis limited to patients not taking such drugs.We found no differences between cases and control in rsCBF of the thalamus, the basal ganglia, the insula, the somatosensory cortex, the prefrontal cortex, the anterior cingulum and supplementary motor area as brain previously identified to be involved in acute processing in fibromyalgia. The results remained robust across all four neuroimaging markers and when limiting the study population to patients not taking centrally acting drugs and matched controls.In conclusion, we found no evidence for functional or structural alterations in brain areas involved in pain processing in fibromyalgia that could reflect neural correlates of chronic stimulus-independent pain.

Crystal structures of NTSR1 bound to agonists, inverse agonists, and in the apo state enabled by a novel fusion to DARPin D12., Neurotensin receptor 1 (NTSR1) and related G protein–coupled receptors of the ghrelin family are clinically unexploited, and several mechanistic aspects of their activation and inactivation have remained unclear. Enabled by a new crystallization design, we present five new structures: apo-state NTSR1 as well as complexes with nonpeptide inverse agonists SR48692 and SR142948A, partial agonist RTI-3a, and the novel full agonist SRI-9829, providing structural rationales on how ligands modulate NTSR1. The inverse agonists favor a large extracellular opening of helices VI and VII, undescribed so far for NTSR1, causing a constriction of the intracellular portion. In contrast, the full and partial agonists induce a binding site contraction, and their efficacy correlates with the ability to mimic the binding mode of the endogenous agonist neurotensin. Providing evidence of helical and side-chain rearrangements modulating receptor activation, our structural and functional data expand the mechanistic understanding of NTSR1 and potentially other peptidergic receptors.

Objectives The role of tumor‐associated neutrophils (TANs) in the nodal spread of cancer cells remains unexplored. The present study evaluates the occurrence and clinical significance of human nodal TANs. Methods The relevance, derivation, phenotype and interactions of nodal TANs were explored via a large immunohistochemical analysis of carcinoma‐draining lymph nodes, and their clinical significance was evaluated on a retrospective cohort of oral squamous cell carcinomas (OSCC). The tumor‐promoting function of nodal TAN was probed in the OSCC TCGA dataset combining TAN and epithelial‐to‐mesenchymal transition (EMT) signatures. Results The pan‐carcinoma screening identified a consistent infiltration (59%) of CD66b+ TANs in tumor‐draining lymph nodes (TDLNs). Microscopic findings, including the occurrence of intra‐lymphatic conjugates of TANs and cancer cells, indicate that TANs migrate through lymphatic vessels. In vitro experiments revealed that OSCC cell lines sustain neutrophil viability and activation via release of GM‐CSF. Moreover, by retrospective analysis, a high CD66b+ TAN density in M‐TDLNs of OSCC (n = 182 patients) predicted a worse prognosis. The analysis of the OSCC‐TCGA dataset unveiled that the expression of a set of neutrophil‐specific genes in the primary tumor (PT) is highly associated with an EMT signature, which predicts nodal spread. Accordingly, in the PT of OSCC cases, CD66b+TANs co‐localised with PDPN+S100A9− EMT‐switched tumor cells in areas of lymphangiogenesis. The pro‐EMT signature is lacking in peripheral blood neutrophils from OSCC patients, suggesting tissue skewing of TANs. Conclusion Our findings are consistent with a novel pro‐tumoral TAN compartment that may promote nodal spread via EMT, through the lymphatics., Our findings propose a novel pro‐tumoral TAN (tumor‐associated neutrophil) compartment with a role in promoting the nodal metastatic colonisation via EMT (epithelial‐to‐mesenchymal transition), through the lymphatic route.

This prognostic study evaluates whether psychosis transition can be predicted in patients with clinical high-risk syndromes or recent-onset depression by multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging, and polygenic risk scores for schizophrenia., Key Points Question Can a transition to psychosis be predicted in patients with clinical high-risk states or recent-onset depression by optimally integrating clinical, neurocognitive, neuroimaging, and genetic information with clinicians’ prognostic estimates? Findings In this prognostic study of 334 patients and 334 control individuals, machine learning models sequentially combining clinical and biological data with clinicians’ estimates correctly predicted disease transitions in 85.9% of cases across geographically distinct patient populations. The clinicians’ lack of prognostic sensitivity, as measured by a false-negative rate of 38.5%, was reduced to 15.4% by the sequential prognostic model. Meaning These findings suggest that an individualized prognostic workflow integrating artificial and human intelligence may facilitate the personalized prevention of psychosis in young patients with clinical high-risk syndromes or recent-onset depression., Importance Diverse models have been developed to predict psychosis in patients with clinical high-risk (CHR) states. Whether prediction can be improved by efficiently combining clinical and biological models and by broadening the risk spectrum to young patients with depressive syndromes remains unclear. Objectives To evaluate whether psychosis transition can be predicted in patients with CHR or recent-onset depression (ROD) using multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging (sMRI), and polygenic risk scores (PRS) for schizophrenia; to assess models’ geographic generalizability; to test and integrate clinicians’ predictions; and to maximize clinical utility by building a sequential prognostic system. Design, Setting, and Participants This multisite, longitudinal prognostic study performed in 7 academic early recognition services in 5 European countries followed up patients with CHR syndromes or ROD and healthy volunteers. The referred sample of 167 patients with CHR syndromes and 167 with ROD was recruited from February 1, 2014, to May 31, 2017, of whom 26 (23 with CHR syndromes and 3 with ROD) developed psychosis. Patients with 18-month follow-up (n = 246) were used for model training and leave-one-site-out cross-validation. The remaining 88 patients with nontransition served as the validation of model specificity. Three hundred thirty-four healthy volunteers provided a normative sample for prognostic signature evaluation. Three independent Swiss projects contributed a further 45 cases with psychosis transition and 600 with nontransition for the external validation of clinical-neurocognitive, sMRI-based, and combined models. Data were analyzed from January 1, 2019, to March 31, 2020. Main Outcomes and Measures Accuracy and generalizability of prognostic systems. Results A total of 668 individuals (334 patients and 334 controls) were included in the analysis (mean [SD] age, 25.1 [5.8] years; 354 [53.0%] female and 314 [47.0%] male). Clinicians attained a balanced accuracy of 73.2% by effectively ruling out (specificity, 84.9%) but ineffectively ruling in (sensitivity, 61.5%) psychosis transition. In contrast, algorithms showed high sensitivity (76.0%-88.0%) but low specificity (53.5%-66.8%). A cybernetic risk calculator combining all algorithmic and human components predicted psychosis with a balanced accuracy of 85.5% (sensitivity, 84.6%; specificity, 86.4%). In comparison, an optimal prognostic workflow produced a balanced accuracy of 85.9% (sensitivity, 84.6%; specificity, 87.3%) at a much lower diagnostic burden by sequentially integrating clinical-neurocognitive, expert-based, PRS-based, and sMRI-based risk estimates as needed for the given patient. Findings were supported by good external validation results. Conclusions and Relevance These findings suggest that psychosis transition can be predicted in a broader risk spectrum by sequentially integrating algorithms’ and clinicians’ risk estimates. For clinical translation, the proposed workflow should undergo large-scale international validation.

Summary Objective Different stress modalities have been used to provoke a load induced mechanoresponse in blood markers of articular cartilages. The challenge in in vivo experiments is to alter specific loading characteristics. Here, we aimed to develop a load modification framework that changes ambulatory load magnitude without changing load frequency or joint kinematics. Design Spatiotemporal parameters, sagittal joint kinematics and vertical ground reaction force (vGRF) of 24 healthy participants were recorded while walking with reduced (80%), normal (100%) and increased (120%) bodyweight (BW) on three separate test days in a block randomized cross-over design. The reduced and increased load conditions were compared to the normal load condition using paired sample t-tests for spatiotemporal parameters and statistical parametric mapping for vGRF and joint kinematics. Results Load modification resulted in measured vGRF differences of −19.5%BW (reduced) and +16.8%BW (increased). Spatiotemporal parameters with reduced and increased load did not differ from normal load except of a shorter stance time under reduced load (−21 ms). Joint kinematics for both conditions did not differ from normal load except of decreased ankle dorsiflexion (maximum −5.9°) and increased knee flexion (maximum +6.5°) for the reduced load condition during pre-swing when the support limb is already unloaded. Conclusion Overall, we did not observe relevant differences in spatiotemporal parameters or joint kinematics between loading conditions. Mean absolute joint angle deviations below 4.1° demonstrate that the proposed load modification framework changes ambulatory load magnitude without changing load frequency or joint kinematics.

International audience; Objective: Fever is a very common reason for emergency consultation during pregnancy, and may be associated with maternal, obstetrical and/or fetal adverse outcomes. The aim of this study was to determine the etiologies and to analyze the maternal or fetal complications of fever in pregnancy.Study design: A retrospective single center study including all patients who consulted for fever above 38 °C during pregnancy in the gynecological emergency ward from August 2016 to July 2017.Results: A total of 100 pregnant women who consulted for fever were included. The etiologies were common viral infections (37 %), influenza (21 %), pyelonephritis (11 %), viral gastroenteritis (6%), chorioamnionitis (5%), other (5%). The etiology was unknown for 15 %. Fever was confirmed during consultation in 45/100 patients (45 %). Among patients with confirmed fever, 21/45 (47 %) were hospitalized with a median stay of 3 days [IQR 2-4] and 10/45(22 %) developed fetal or maternal complications. Probabilistic antibiotics were delivered for 34/45, 76 % patients. Only 14/45, 31 % had confirmed bacterial infections. Of the 32 patients with confirmed fever who had no etiologic diagnosis at the initial work-up in the emergency room, 19/32, 59 % received presumptive treatment with amoxicillin against Listeria monocytogenes. None had confirmed listeriosis, and all were probably common viral infections. Among all patients, the complications rate was 13 % and 22 % in the subgroup with fever confirmed at presentation.Conclusions: This study quantifies the main etiologies and complications of fever during pregnancy. A challenge is to reduce excessive antibiotic use by improving rapid diagnosis of bacterial and viral infections. Prospective studies are needed to target patients at risk of complications in an optimal way and to study new management strategies.

International audience; Effective synthesis of mammalian messenger (m)RNAs depends on many factors that together direct RNA polymerase II (pol II) through the different stages of the transcription cycle and ensure efficient cotranscriptional processing of mRNAs. In addition to the many proteins involved in transcription initiation, elongation, and termination, several noncoding (nc)RNAs also function as global transcriptional regulators. Understanding the mode of action of these non-protein regulators has been an intense area of research in recent years. Here, we describe how these ncRNAs influence key regulatory steps of the transcription process, to affect large numbers of genes. Through direct association with pol II or by modulating the activity of transcription or RNA processing factors, these regulatory RNAs perform critical roles in gene expression.

Primary uterine inertia (PUI) is the most common type of dystocia in dogs. We hypothesized that PUI develops because of lower than normal expression of the basic contractile elements in the uterus, i.e., smooth muscle (SM) α- and γ-actin and SM-myosin, and that the expression of these proteins is influenced by the number of fetuses present in utero. Full-thickness inter-placental uterine biopsies were collected during Cesarean sections from dogs with PUI (n = 11), and from bitches with obstructive dystocia (OD) still presenting strong labor contractions (designated as the control group, n = 7). Relative gene expression was determined by semi-quantitative real-time (TaqMan) PCR, and protein localization by immunohistochemistry. Gene expression between PUI and OD bitches, and between PUI bitches carrying small, large, or average number of fetuses according to their breed, were compared. Uterine SM-γ-actin and SM-myosin mRNA levels were significantly higher in PUI than in OD dogs, while SM-α-actin did not differ. PUI bitches carrying large litters had lower uterine SM-γ-actin gene expression than those with small litters (P = 0.008). Immunostaining for SM-actin isoforms and SM-myosin was present in the myometrium, and localization pattern and staining intensity appeared similar in the PUI and OD groups. All proteins stained in blood vessels, and SM-γ-actin was also present in endometrial luminal and glandular epithelium. In conclusion, higher uterine SM-γ-actin and SM-myosin gene expression in PUI bitches, compared with OD dogs, might be an indication of abnormal progression with labor. Whether this is the cause of PUI due to an intrinsic error of the myometrium not becoming committed to labor, or the consequence of inadequate endocrine or mechanical stimuli, is not clear. Litter size was previously shown to be one of the risk factors for the development of uterine inertia in dogs, and our findings suggest possible differing uterine pathophysiology of PUI with respect to litter size.

Retinal coloboma is a rare condition which is difficult to diagnose in foetuses. It can cause blindness. It can be isolated or associated with other malformations in various syndromes. Our objective is to describe the different prenatal ultrasound findings and management of coloboma. We describe a case of prenatal ultrasound diagnosis of retinal coloboma at 27.5 weeks of gestation. Our case adds to the 8 previously reported in the prenatal ultrasound literature, which together illustrate that microphthalmia is the main associated sign, present in 66.6% (6/9) of cases followed by retro-orbital cysts (44.4%) (4/9). These two ultrasound findings should alert us to a close examination of the eye to look for a posterior retinal cleft, the main direct sign of a chorioretinal coloboma.

Background and PurposeHead motion causes image degradation in brain MRI examinations, negatively impacting image quality, especially in pediatric populations. Here, we used a retrospective motion correction technique in children and assessed image quality improvement for 3D MRI acquisitions.Material and MethodsWe prospectively acquired brain MRI at 3T using 3D sequences, T1-weighted MPRAGE, T2-weighted Turbo Spin Echo and FLAIR, in 32 unsedated children, including 7 with epilepsy (age range 2–18 years). We implemented a novel motion correction technique: Distributed and Incoherent Sample Orders for Reconstruction Deblurring using Encoding Redundancy (DISORDER). For each subject and modality, we obtained 3 reconstructions: as acquired (Aq), after DISORDER motion correction (Di), and Di with additional outlier rejection (DiOut).We analyzed 288 images quantitatively, measuring 2 objective no-reference image quality metrics: Gradient Entropy (GE) and MPRAGE White Matter Homogeneity (WM-H). As a qualitative metric, we presented blinded and randomized images to 2 expert neuroradiologists who scored them for clinical readability.ResultsBoth image quality metrics improved after motion correction for all modalities and improvement correlated with the amount of intrascan motion. Neuroradiologists also considered the motion corrected images as of higher quality (Wilcoxon’s z = −3.164 MPRAGE, z = −2.066 TSE, z = −2.645 FLAIR, for all p < 0.05).ConclusionsRetrospective image motion correction with DISORDER increased image quality both from an objective and qualitative perspective. In 75% of sessions, at least one sequence was improved by this approach, indicating the benefit of this technique in unsedated children for both clinical and research environments.

Introduction: Infection and inflammation have been implicated in the etiology and subsequent morbidity associated with preterm birth. At present, there are no tests to assess for fetal compartment infection. The thymus, a gland integral in the fetal immune system, has been shown to involute in animal models of antenatal infection, but its response in human fetuses has not been studied. This study aims: (a) to generate magnetic resonance imaging (MRI) -derived fetal thymus volumes standardized for fetal weight; (b) to compare standardized thymus volumes from fetuses that delivered before 32 weeks of gestation with fetuses that subsequently deliver at term; (c) to assess thymus size as a predictor of preterm birth; and (d) to correlate the presence of chorioamnionitis and funisitis at delivery with thymic volumes in utero in fetuses that subsequently deliver preterm. Material and methods: Women at high-risk of preterm birth at 20-32 weeks of gestation were recruited. A control group was obtained from existing data sets acquired as part of three research studies. A fetal MRI was performed on a 1.5T or 3T MRI scanner: T2 weighted images were obtained of the entire uterine content and specifically the fetal thorax. A slice-to-volume registration method was used for reconstruction of three-dimensional images of the thorax. Thymus segmentations were performed manually. Body volumes were calculated by manual segmentation and thymus:body volume ratios were generated. Comparison of groups was performed using multiple regression analysis. Normal ranges were created for thymus volume and thymus:body volume ratios using the control data. Receiver operating curves (ROC) curves were generated for thymus:body volume ratio and gestation-adjusted thymus volume centiles as predictors of preterm birth. Placental histology was analyzed where available from pregnancies that delivered very preterm and the presence of chorioamnionitis/funisitis was noted. Results: Normative ranges were created for thymus volume, and thymus volume was standardized for fetal size from fetuses that subsequently delivered at term, but were imaged at 20-32 weeks of gestation. Image data sets from 16 women that delivered 37 weeks were included. Mean gestation at MRI of the study group was 28 +4 weeks (SD 3.2) and for the control group was 25 +5 weeks (SD 2.4). Both absolute fetal thymus volumes and thymus:body volume ratios were smaller in fetuses that delivered preterm (P

While SARS-CoV-2 infection has spread rapidly worldwide, data remains scarce about the natural history of infection in pregnant women and the risk of mother-to-fetal transmission. Current data indicates that viral RNA levels in maternal blood are low and there is no evidence of placental infection with SARS-CoV-2. Published reports to date suggest that perinatal transmission of SARSCoV- 2 can occur but is rare. Among 179 newborns tested for SARS-CoV2 at birth from mothers with COVID-19, transmission was suspected in 8 cases, 5 with positive nasopharyngeal SARS-CoV-2 RT-PCR and 3 with SARS-CoV-2 IgM. However, these cases arise from maternal infection close to childbirth and there are no information about exposition during first or second trimester of pregnancy. Welldesigned prospective cohort studies with rigorous judgement criteria are needed to determine the incidence and risk factors for perinatal transmission of SARS-CoV-2.

BackgroundIn cemented primary total knee arthroplasty (TKA), aseptic loosening remains a major cause for failure. Cementing techniques and characteristics of a chosen cement play a key role for good fixation and implant survival. A pastry bone cement was developed to facilitate the cement preparation and to rule out most of preparation-associated application errors. The pastry bone cement was compared to a conventional polymethyl methacrylate cement in a TKA setting.MethodsStandardized implantations of total knee endoprostheses were performed in bilateral knee cadavers to investigate handling properties, variables of cement application, working time, and temperature development. Mechanical aspects and cementation quality were assessed by pull-out trials and microscopic interface analysis.ResultsBoth cements expressed similar characteristics during preparation and application, only the curing time of the pastry cement was about 3 min longer and the temperature peak was lower. Fractures of the conventional cement specimens differed from the pastry cement specimens in the tibial part, while no differences were found in the femoral part. Penetration depth of the pastry cement was similar (tibia) or deeper (femur) compared to the conventional cement.ConclusionsThe pastry cement facilitates the feasibility of cemented TKA. The pre-clinical tests indicate that the pastry bone cement fulfills the requirements for bone cement in the field of knee arthroplasty. A clinical trial is needed to further investigate the approach and ensure patient safety.

Summary This Review depicts the evolving role of MRI in the diagnosis and prognostication of anomalies of the fetal body, here including head and neck, thorax, abdomen and spine. A review of the current literature on the latest developments in antenatal imaging for diagnosis and prognostication of congenital anomalies is coupled with illustrative cases in true radiological planes with viewable three-dimensional video models that show the potential of post-acquisition reconstruction protocols. We discuss the benefits and limitations of fetal MRI, from anomaly detection, to classification and prognostication, and defines the role of imaging in the decision to proceed to fetal intervention, across the breadth of included conditions. We also consider the current capabilities of ultrasound and explore how MRI and ultrasound can complement each other in the future of fetal imaging.

Here, we provide a protocol to generate synthetic nanobodies, known as sybodies, against any purified protein or protein complex within a 3-week period. Unlike methods that require animals for antibody generation, sybody selections are carried out entirely in vitro under controlled experimental conditions. This is particularly relevant for the generation of conformation-specific binders against labile membrane proteins or protein complexes and allows selections in the presence of non-covalent ligands. Sybodies are especially suited for cases where binder generation via immune libraries fails due to high sequence conservation, toxicity or insufficient stability of the target protein. The procedure entails a single round of ribosome display using the sybody libraries encoded by mRNA, followed by two rounds of phage display and binder identification by ELISA. The protocol is optimized to avoid undesired reduction in binder diversity and enrichment of non-specific binders to ensure the best possible selection outcome. Using the efficient fragment exchange (FX) cloning method, the sybody sequences are transferred from the phagemid to different expression vectors without the need to amplify them by PCR, which avoids unintentional shuffling of complementary determining regions. Using quantitative PCR (qPCR), the efficiency of each selection round is monitored to provide immediate feedback and guide troubleshooting. Our protocol can be carried out by any trained biochemist or molecular biologist using commercially available reagents and typically gives rise to 10-30 unique sybodies exhibiting binding affinities in the range of 500 pM-500 nM.

SUMMARYBackgroundPembrolizumab improved survival of patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this phase 2 trial were to determine if pembrolizumab administered to patients with resectable locally advanced, human papillomavirus (HPV)-unrelated HNSCC would be safe, result in pathologic tumor response (pTR), and lower the relapse rate.MethodsNeoadjuvant pembrolizumab (200 mg) was administered 2-3 weeks before surgery. Resection of the primary tumor and involved/at-risk nodes was performed. Post-operative (chemo) radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) were to receive adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (NCT02296684), and is ongoing but closed to accrual.FindingsBetween June 30, 2015, and March 30, 2018, 36 patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). pTR ≥10% correlated with baseline tumor PD-L1 expression, immune infiltrate, and IFN-γ pathway activity. Matched sample analysis showed compensatory upregulation of multiple immune inhibitory checkpoints in patients with pTR-0, and confirmed that clonal loss occurred in some patients. The one-year relapse rate among the eighteen patients with high-risk pathology was 16.7% (95%CI: 3.6-41.4%).ConclusionsAmong patients with locally advanced, HPV-unrelated HNSCC, neoadjuvant pembrolizumab was safe, and resulted in pTR-1 or pTR-2 in 44% of patients. The one-year relapse rate in patients with high-risk-pathology was lower than historical.FundingMerck, NCI, NIDCR, NHGRI and The V Foundation.

ObjectivesThe vast majority of residents’ working time is spent away from patients. In hospital practice, many factors may influence the resident’s working day structure.Using an innovative method, we aimed to compare working time allocation among internal medicine residents using time-motion observations. The first study goal was to describe how the method could be used for inter-hospital comparison. The secondary goal was to learn about specific differences in the resident’s working day structure in university and non-university hospital settings.DesignTwo separate time-motion studies. Trained peer-observers followed the residents during weekday day shifts with a tablet, able to record 22 different activities and corresponding context (with patient, phone, colleague or computer).SettingInternal medicine residencies at a university (May–July 2015) and a non-university (September–October 2016) community hospital.Participants28 residents (mean age: 29 years, average postgraduate training: 30 months) at university hospital, 21 residents (mean age: 30 years, average postgraduate training: 17 months) at non-university hospital.OutcomesTime spent with patients and time dedicated to activities directly related to patients; description of main differences of time allocation between hospitals.ResultsCumulatively 1051 hours of observation (566 (university hospital)+486 (non-university hospital)) and 92 day shifts (49+43) were evaluated. Daily working time was 11.5 versus 11.3 hours. A median daily period of 195 min (IQR 179–211, 27.9%) and 116 min (IQR 98–134, 17.2%) (pConclusionsWe successfully identified differences potentially related to each hospital structure and organisation. Inter-hospital comparisons could help set up interventions aiming to improve workday structure and experience of residents.

The association of glycated hemoglobin (HbA1c) with venous thromboembolism (VTE) and death in the elderly is unknown. In the SWEETCO 65+ study we analyzed prospectively a Swiss Cohort of Elderly Patients with Venous Thromboembolism (SWITCO 65+). 888 patients were enrolled for the SWEETCO 65+ analysis. HbA1c was determined at baseline and divided into three categories (HbA1c 6.5%, diabetic range). Median follow-up was 2.5 years. The primary endpoint was recurrent VTE. Secondary endpoints included all-cause mortality and major bleeds. The total prevalence of diabetes was 22.1%. The risk of recurrent VTE was similar in patients with HbA1c with pre-diabetes (adjusted subhazard ratio (aSHR) 1.07 [0.70 to 1.63]) and diabetes (aSHR 0.73 [0.39 to 1.37]) as compared to those with a HbA1c in the normal range. However, a HbA1c ≥ 6.5% (median IQ range 7.0 [6.70;7.60]) was significantly associated with a higher risk of all-cause mortality (adjusted hazard ratio [aHR] 1.83 [1.21 to 2.75]). In summary we found no association between HbA1c and major bleeding. Elevated HbA1c levels are not associated with recurrent VTE but with increased all-cause mortality in an elderly population with acute VTE.

There are mixed reports on structural neuroimaging correlates of aggression in schizophrenia with weak evidence due to cohort overlaps and lack of replications. To our knowledge, no study examined volumetric neuroimaging correlates of aggression in early stages of psychosis. An agitated-aggressive syndrome is present in at-risk mental state (ARMS) and in first-episode psychosis (FEP) – it is unclear whether this syndrome is associated with structural brain abnormalities in early stages of psychosis. Using three-dimensional magnetic resonance imaging and a whole brain voxel-based morphometry approach, we examined 56 ARMS patients, 55 FEP patients and 25 healthy controls. We operationalized aggression using the Excited Component of the Brief Psychiatric Rating Scale (BPRS-EC) and dichotomized our patient group by median split into “BPRS-EC high” (n = 49) and “BPRS-EC low” groups (n = 62). The “BPRS-EC high” group had significantly smaller left lingual gyrus volume than HC. This finding was not present in the “BPRS-EC low” group. In addition, grey matter volume in the left lingual gyrus showed a negative linear correlation with BPRS-EC over all subjects (ρ = −0.318; p = 0.0001) and in the patient group (ρ = −0.202; p = 0.033). These findings provide first hints on structural brain abnormalities associated with an agitated-aggressive syndrome in ARMS and FEP patients.

Mechanically induced itch is an important cofactor in many patients with chronic itch. However, studying mechanical itch in a controlled environment is challenging because it is difficult to evoke. We investigated the use of whole body vibration (WBV) exercise, a training method used for musculoskeletal rehabilitation, to experimentally evoke mechanical itch. Mild to severe itch ascending from the soles to the groins was evoked in 16 of 20 healthy participants. We observed a characteristic on/off itch crescendo pattern reflecting the alternating intervals of vibration and no vibration. Wheals or an angioedema was absent, and serum mast cell tryptase was not increased by the exercise. Participants described the evoked sensation primarily as "itching" with some nociceptive components. Itch intensity correlated with the intensity of a concomitant erythema (R = 0.45, P = 0.043) and with the rise in skin temperature (R = 0.54, P = 0.017). Hence, WBV can be used as an easily applicable, noninvasive, investigator- and user-friendly framework for studying mechanical itch. Moreover, WBV allows to "switch itch on and off" rapidly and to simultaneously study interactions between itch, skin blood flow and skin temperature.

In schizophrenic psychoses, the normal sexual dimorphism of the brain has been shown to be disrupted or even reversed. Little is known, however, at what time point in emerging psychosis this occurs. We have therefore examined, if these alterations are already present in the at-risk mental state (ARMS) for psychosis and in first episode psychosis (FEP) patients.; Data from 65 ARMS (48 (73.8%) male; age=25.1±6.32) and 50 FEP (37 (74%) male; age=27±6.56) patients were compared to those of 70 healthy controls (HC; 27 (38.6%) male; age=26±4.97). Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging (MRI) scanner. Linear mixed effects models were used to investigate whether subcortical brain volumes are dependent on sex.; We found men to have larger total brain volumes (p

Purpose: T-DM1 is an antibody drug conjugate with proven efficacy in metastatic breast cancer for progressive disease refractory to trastuzumab. Drug-induced pneumonitis is a rare serious potential adverse effect. The purpose of this review was to estimate the incidence of pulmonary toxicity at our institution. Methods: A retrospective analysis of electronic medical record data inclusive of all women and men aged 18 years and older treated with T-DM1 at out institution was undertaken. The records were reviewed for clinical symptoms and/or radiographic evidence concerning for pneumonitis. We identified variables of interest with regard to potential risk factors for toxicity. Results: A total of 50 patients were included, 6 (12%) of whom had radiographic and/or clinical symptoms concerning for T-DM1-induced pneumonitis. All 6 patients had metastatic or unresectable breast cancer. Of the 6 patients, 5 (83%) had suspected pulmonary metastases, 1 (17%) had a history of underlying lung disease, and 5 (83%) had a history of prior taxane therapy. Pulmonary metastases (p = 0.38), the median number of treatment cycles (p = 0.29), prior taxane therapy (p = 0.99), underlying lung disease (p = 0.99), and hormone receptor positivity (p = 0.66) did not have any statistical significance for an association with pneumonitis. Conclusion: Pneumonitis is a recognized toxic effect of T-DM1. While our sample size was small, the number of events was higher than described in the literature, which may be an artifact of referral bias. Future studies with a larger sample population may detect potential risk factors for toxicity.

Objective Pyruvate dehydrogenase deficiency (PDHD) and pyruvate carboxylase deficiency (PCD) are diseases with severe neonatal forms, and their low prevalence makes them difficult to diagnose during pregnancy. Our objective was to describe prenatal ultrasound features that may be suggestive of these diagnoses. Methods We analyzed 3 cases from our institution and reviewed 12 published cases of PDHD and 6 cases of PCD, recording all of the ultrasound signs, as well as magnetic resonance findings when available. Because of the small number of cases of PCD, we also included postnatal signs that could have been observed during imaging during pregnancy, for a total of 11 cases of PCD. Results We conclude that PDHD can be suggested in the presence of ventriculomegaly or paraventricular cysts, associated with an abnormality of the cerebral parenchyma such as abnormal gyration or involvement of the corpus callosum. Pyruvate carboxylase deficiency can be suggested in the presence of ventriculomegaly, frontal horn impairment associated with subependymal, and paraventricular cysts. Conclusion When confronted to the ultrasound abnormalities we described, and after eliminating the most frequent etiologies, a metabolic deficiency should be considered. Furthermore, the hereditary character of these diseases makes that it is important to send the family with genetic advice in particular in case of history of a fetal death in utero or a death neonatal unexplained.

Introduction : La nouvelle attache préencollée APC™ Flash-Free du groupe 3M Unitek® permet-elle une simplification du protocole de collage sans en diminuer la précision ? Objectifs : L’objectif de cette étude est de comparer la morphologie du joint de colle entre les attaches préencollées classiques APC™PLUS et les attaches APC™ Flash-Free. Matériels et méthodes : Le collage in vitro des attaches esthétiques de la gamme CLARITY™ ADVANCED permet de comparer la morphologie des excès de colle entre les attaches APC™ PLUS et APC™ Flash-Free. Résultats : Aucune différence statistiquement significative concernant la morphologie des excès de colle n’est constatée entre les attaches APC™ PLUS et APC™ Flash-Free. Une différence statistiquement significative concernant l’épaisseur de colle existe entre les deux types d’attaches. L’épaisseur de colle au niveau des attaches APC™ Flash-Free est significativement plus importante que l’épaisseur au niveau des attaches APC™ PLUS (P=0,0001). L’épaisseur de colle est également plus homogène au niveau des attaches APC™ Flash-Free (P=0,001 pour la différence relative). Conclusion : L’épaisseur de colle au niveau des attaches APC™ Flash-Free est plus importante mais plus homogène qu’au niveau des attaches APC™ PLUS.

Die Typisierung chronischer Schmerzpatienten anhand ihrer Schmerzverarbeitungsprofile kann einen wichtigen Beitrag leisten zum besseren Verstandnis der Schmerzproblematik, zur gezielteren Indikation fur bestehende Behandlungsverfahren sowie zur Weiterentwicklung von Therapien. Es wird untersucht, ob sich anhand des im deutschen Sprachraum gebrauchlichen Fragebogens zur Erfassung der Schmerzverarbeitung (FESV) verschiedene Subgruppen chronischer Schmerzpatienten mit homogenen Schmerzverarbeitungsmustern identifizieren lassen und ob sich diese Schmerzverarbeitungstypen hinsichtlich demografischer sowie schmerz- und behandlungsrelevanter Merkmale unterscheiden. 166 Patienten mit einer chronischen Schmerzstorung gemas ICD-10 F45.41 wurden im Rahmen einer stationaren multimodalen Schmerztherapie untersucht. Kognitive und behaviorale Schmerzbewaltigung sowie schmerzbedingte psychische Beeintrachtigung wurden als Komponenten der Schmerzverarbeitung mit dem FESV erfasst. Mithilfe von Clusteranalysen auf der Basis der Schmerzverarbeitungsdaten wurden homogene Subgruppen von Patienten gebildet. Die resultierenden Subgruppen wurden daraufhin hinsichtlich soziodemografischer Merkmale, ihrer schmerzbedingten Beeintrachtigung, allgemeinen psychischen Belastung, Depressivitat und Angst, ihres habituellen Stresserlebens, ihrer wahrgenommenen sozialen Unterstutzung und Psychotherapiemotivation verglichen. Drei hinsichtlich ihrer Schmerzverarbeitungsmuster distinkte Subgruppen konnten identifiziert werden: (1) stark Beeintrachtigte mit hohen Bewaltigungskompetenzen, (2) wenig Beeintrachtigte mit hohen Bewaltigungskompetenzen und (3) stark Beeintrachtigte mit geringen Bewaltigungskompetenzen. Die Subgruppen unterschieden sich signifikant in fast allen Merkmalen, nicht jedoch hinsichtlich Schmerzdauer und -intensitat. Die Kategorisierung in die genannten drei Schmerzverarbeitungstypen kann Klinikern helfen, die Schmerzbehandlung auf die jeweiligen Patientenbedurfnisse abzustimmen.

AIM Gender differences in the current symptomatology of patients with psychotic disorders have previously been described in the literature. However, it has not yet been investigated whether gender differences exist in the very first self-perceived signs or symptoms of illness onset. The aim of this study was to investigate this aspect in at-risk mental state (ARMS) and first-episode psychosis (FEP) patients. METHODS ARMS and FEP were recruited via the early detection of psychosis (FePsy) clinic Basel, Switzerland. The Basel Interview for Psychosis (BIP) was used to retrospectively assess the first 3 self-perceived signs and symptoms at illness onset. Differences between gender and patient groups on single item and symptom cluster levels were analysed using logistic regression models. RESULTS One-hundred-thirty six ARMS (91 men, 45 women) and 89 FEP patients (63 men, 26 women) could be recruited for this study. On a single item level, women more frequently reported "unusual anxiety, fears" and men (at a trend level) "social withdrawal" as being among their 3 first self-perceived symptoms, independent of diagnostic group. On the symptom cluster level, women more frequently reported "increased worrying/anxiety" and (sub-threshold) "hallucinations", independent of diagnostic group. Problems with "thinking, concentration" were reported more frequently by men in the ARMS group only. CONCLUSION Our results suggest that only few and relatively small gender differences exist in the first self-perceived signs and symptoms. While men initially mainly notice negative/cognitive symptoms, women first notice (sub-threshold) positive and affective symptoms.