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Strong associations between neural tube defects (NTDs) and monozygotic (MZ) twinning have long been noted, and it has been suggested that NTD cases who do not present as MZ twins may be the survivors of MZ twinning events. We have recently shown that MZ twins carry a strong, distinctive DNA methylation signature and have developed an algorithm based on genomewide DNA methylation array data that distinguishes MZ twins from dizygotic twins and other relatives at well above chance level. We have applied this algorithm to published methylation data from five fetal tissues (placental chorionic villi, kidney, spinal cord, brain and muscle) collected from spina bifida cases (n = 22), anencephalic cases (n = 15) and controls (n = 19). We see no difference in signature between cases and controls, providing no support for a common etiological role of MZ twinning in NTDs. The strong associations therefore continue to await elucidation.

Clinical Medicine is an Art which is learned, together with hard work, as an apprentice-observing how a master works, and improving with experience and exposure. Clinicians are performing multiple things at the same time-trying to make a diagnosis, providing best therapies and preventative strategies, and looking for the underlying mechanism(s). Families want to know what to expect over time-the natural history of their disorder. Rare disease networks and parent support groups are helping in this effort. Information technologies and international collaborative efforts are changing the way clinical genetics is provided.

Monozygotic (MZ) twins ("identical twins") are essentially unique to human beings. Why and how they arise is not known. This article reviews the possible different types of MZ twinning recognized in the previous article on twins and arthrogryposis. There appear to be at least three subgroups of MZ twinning: spontaneous, familial, and those related to artificial reproductive technologies. Each is likely to have different etiologies and different secondary findings. Spontaneous MZ twinning may relate to "overripe ova." Amyoplasia, a specific nongenetic form of arthrogryposis, appears to occur in spontaneous MZ twinning and may be related to twin-twin transfusion.

Amyoplasia is a very specific, nongenetic clinically recognizable form of arthrogryposis, representing about one-third of individuals with arthrogryposis surviving the newborn period. There is a markedly increased number of individuals with Amyoplasia who are one of monozygotic (MZ) twins, with the other twin being normal. Thus, it would appear that Amyoplasia is definitely associated with and may be caused by an MZ twinning event. The twin-twin transfusion seen in MZ twins could play an etiologic role in producing Amyoplasia. In this article, Amyoplasia twinning is compared to twinning in other forms of arthrogryposis. The accompanying paper examines various types of MZ twinning (Hall, 2021). Amyoplasia is primarily associated with spontaneous MZ twinning.

Thin slices, or excerpts of behavior, are commonly used by researchers to represent behaviors in their full stimulus. The present study asked how slices of different lengths and locations, as well as different measurement methodologies, influence correlations between the measured behavior and different variables (predictive validity). We collected self-rated, perceiver-rated, and objectively measured data on 60 participants who participated in a 5-min interaction with a confederate on video. These videos were split into five 1-min slices and rated for verbal and nonverbal behaviors via global impressions, using the same rater for all five slices and also using a different rater for each slice. For single slices, results indicated no clear pattern for optimal slice locations. In general, single slices had weaker predictive validity than the total. Slices of 2 or 3 min were, in general, equal to 5-min total in predictive validity. The magnitude of correlations was similar when same versus different coders were used, and the predictive validity correlations of the two methods covaried strongly across behavior-outcome variable combinations.

Several recurrent malformation associations affecting the development of the embryo have been described in which a genetic etiology has not been found, including LBWC, MURCS, OAVS, OEIS, POC, VACTERL, referred to here as "recurrent constellations of embryonic malformations" (RCEM). All are characterized by an excess of reported monozygotic discordant twins and lack of familial recurrence. We performed a comprehensive review of published twin data across all six phenotypes to allow a more robust assessment of the association with twinning and potential embryologic timing of a disruptive event. We recorded the type of twinning, any overlapping features of another RCEM, maternal characteristics, and the use of ART. Statistically significant associations included an excess of monozygotic twins and 80% discordance rate for the phenotype across all twins. There was an 18.5% rate of ART and no consistently reported maternal adverse events during pregnancy. We found 24 instances of co-occurrence of two RCEM, suggesting a shared pathogenesis across all RCEM phenotypes. We hypothesize the following timing for RCEM phenotypes from the earliest perturbation in development to the latest: LBWC, POC, OEIS, VACTERL, OAVS, then MURCS. The RCEM group of conditions should be considered a spectrum that could be studied as a group.

SummaryBackgroundUnderstanding the effects of anaesthetic drugs on cortical oscillations can help to elucidate the mechanistic link between receptor physiology and their clinical effects. Propofol produces divergent effects on visual cortical activity: increasing induced gamma-band responses (GBR) while decreasing stimulus-onset-evoked responses) 1. Dexmedetomidine, an α2-adrenergic agonist, differs from GABA-ergic sedatives both mechanistically and clinically as it allows easy arousability from deeper sedation with less cognitive side-effects. Here we use magnetoencephalography (MEG) to characterize and compare the effects of GABAergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation, on visual and motor cortical oscillations.MethodsSixteen male participants received target-controlled infusions of propofol and dexmedetomidine, producing mild-sedation, in a placebo-controlled, cross-over study. MEG data was collected during a combined visual and motor task.ResultsThe key findings were that propofol significantly enhanced visual stimulus induced GBR (44% increase in amplitude) while dexmedetomidine decreased it (40%). Propofol also decreased the amplitudes of the M100 (27%) and M150 (52%) evoked responses, whilst dexmedetomidine had no effect on these. During the motor task, neither drug had any significant effect on motor GBR or movement related beta de-synchronisation (MRBD). However, dexmedetomidine increased (92%) post-movement beta synchronisation/rebound (PMBR) power while propofol reduced it (70%).ConclusionsDexmedetomidine and propofol, at equi-sedative doses, have contrasting effects on visual stimulus induced GBR, visual evoked responses and PMBR. These findings provide a mechanistic link between the known receptor physiology of these sedative drugs and their known clinical effects and may be used to explore mechanisms of other anaesthetic drugs on human consciousness.

Immunoglobulin IgM is important for controlling viral and bacterial infections, and low immunoglobulin levels have been found in sepsis. There is a clear need to stratify sepsis patients according to the presence of an invading organism, compared to no organism identified, and SIRS patients, where organ dysfunction is a result of a non-infective process. The aim of this pilot study in a small cohort of patients with sepsis was to evaluate the association between IgM plasma levels and survival in 47 patients with sepsis and 11 patients diagnosed with organ failure without the identification of a pathogen (SIRS). Patients were admitted to the intensive care unit (ICU) at The Royal Glamorgan Hospital, Llantrisant, UK between 2010 and 2014. We found that low IgM levels were associated with sepsis, but not SIRS. IgM levels did not differ significantly for culture-positive (CP) compared with culture-negative (CN, no organism found) sepsis samples. Kaplan–Meier analysis was used to compare survival curves according to IgM levels, with no significant difference. We observed significantly higher survival in the CP samples when comparing with CN. Cut-off value for IgM (266 μg/mL) for diagnosis of sepsis patients was determined using receiver operator characteristic (ROC) curves with 70% sensitivity, 69% specificity and 92% negative predictive values (NPV), respectively. The corresponding area under the curve (AUC) for the discrimination of sepsis patients was AUC = 0.73, and in a subgroup analysis of CP was AUC = 0.77 and for CN was AUC = 0.79. We confirm IgM as a good diagnostic marker of sepsis. These findings indicate a difference in the pathology between culture-positive versus negative sepsis, SIRS and survival. This indicates that IgM is likely relevant to pathology, because of its role in the early immune response against pathogens, the potentially protective role of natural IgM antibodies, and supports its application in immunoglobulin therapy.

Supplemental Digital Content is available in the text., OBJECTIVES: To compare the performance of Sequential Organ Failure Assessment, systemic inflammatory response syndrome, Red Flag Sepsis, and National Institute of Clinical Excellence sepsis risk stratification tools in the identification of patients at greatest risk of mortality from sepsis in nonintensive care environments. DESIGN: Secondary analysis of three annual 24-hour point-prevalence study periods. SETTING: The general wards and emergency departments of 14 acute hospitals across Wales. Studies were conducted on the third Wednesday of October in 2017, 2018, and 2019. PATIENTS: We screened all patients presenting to the emergency department and on the general wards. MEASUREMENTS AND MAIN RESULTS: We recruited 1,271 patients, of which 724 (56.9%) had systemic inflammatory response syndrome greater than or equal to 2, 679 (53.4%) had Sequential Organ Failure Assessment greater than or equal to 2, and 977 (76.9%) had Red Flag Sepsis. When stratified according to National Institute of Clinical Excellence guidelines, 450 patients (35.4%) were in the “High risk” category in comparison with 665 (52.3%) in “Moderate to High risk” and 156 (12.3%) in “Low risk” category. In a planned sensitivity analysis, we found that none of the tools accurately predicted mortality at 90 days, and Sequential Organ Failure Assessment and National Institute of Clinical Excellence tools showed only moderate discriminatory power for mortality at 7 and 14 days. Furthermore, we could not find any significant correlation with any of the tools at any of the mortality time points. CONCLUSIONS: Our data suggest that the sepsis risk stratification tools currently utilized in emergency departments and on the general wards do not predict mortality adequately. This is illustrated by the disparity in mortality risk of the populations captured by each instrument, as well as the weak concordance between them. We propose that future studies on the development of sepsis identification tools should focus on identifying predicator values of both the short- and long-term outcomes of sepsis.

Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co-twins with abnormal brain imaging and compared them to population-based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11). The MCD group included 37/39 (95%) with polymicrogyria (PMG), 8/39 (21%) with pia-ependymal clefts (schizencephaly), and 15/39 (38%) with periventricular nodular heterotopia (PNH) including 2 with PNH but not PMG. Cerebellar malformations were found in 19 individuals including 13 with a cerebellar malformation only and another 6 with cerebellar malformation and MCD. The pattern varied from diffuse cerebellar hypoplasia to classic Dandy-Walker malformation. Brain disruptions were seen in 11 individuals with hydranencephaly, porencephaly, or white matter loss without cysts. Our series included an expected statistically significant excess of monozygotic (MZ) twin pairs (22/41 MZ, 54%) compared to population data (482/1448 MZ, 33.3%; p = .0110), and an unexpected statistically significant excess of dizygotic (DZ) twins (19/41, 46%) compared to the literature cohort (1/46 DZ, 2%; p < .0001. Recurrent association with twin-twin transfusion syndrome, intrauterine growth retardation, and other prenatal factors support disruption of vascular perfusion as the most likely unifying cause.

Arthrogryposis multiplex congenita (AMC) describes disorders with multiple joint contractures that arise from neurological, neuromuscular, or mechanical origin. Although impaired fetal movement is the typical clinical presentation, the etiology underlying this phenotype for a number of conditions remains unknown. In an effort to better characterize and define the etiologies underlying these disorders, we recommend a standardized autopsy protocol that will allow for appropriate diagnosis and a methodical approach for examination that will facilitate subsequent study by investigators across disciplines. To further support investigation, we have also established an AMC autopsy registry to bank tissue obtained at autopsy for subsequent study.

In 2016, we published an article applying Gene Ontology Analysis to the genes that had been reported to be associated with arthrogryposis (multiple congenital contractures) (Hall & Kiefer, 2016). At that time, 320 genes had been reported to have mutations associated with arthrogryposis. All were associated with decreased fetal movement. These 320 genes were analyzed by biological process and cellular component categories, and yielded 22 distinct groupings. Since that time, another 82 additional genes have been reported, now totaling 402 genes, which when mutated, are associated with arthrogryposis (arthrogryposis multiplex congenita). So, we decided to update the analysis in order to stimulate further research and possible treatment. Now, 29 groupings can be identified, but only 19 groups have more than one gene.

A pediatric registry for arthrogryposis multiplex congenita (AMC) proposes to advance research by providing the platform to inform the distribution, etiology, and natural history of AMC. The registry was piloted on 40 families of children (mean = 8.25 years, 48% males) presenting with AMC across two hospitals in North America. Data on the child's demographic and newborn variables, mothers' and fathers' demographic variables, lifestyle habits, and medical history were collected using a telephone interview with the primary caregiver and review of medical charts. Mean gestational age was 38 weeks, 97% of children presented with lower extremity deformities, and 74% of neonatal interventions targeted the lower extremity. Newborns spent an average of 14 days in the hospital (range 2-56 days) mostly for diagnostic workup and feeding difficulties. Half (49%) of the sample had internal organ involvement. Genetic testing was done on 48% of the children, including chromosome studies, single gene, whole-exome/genome sequencing, and/or microarray studies. Genetic findings were inconclusive in most. Two-thirds of mothers (67%) reported inconsistently feeling fetal movements. This pilot study contributed to the refinement of participant selection, identification of data source, expansion of data sets, and areas for future exploration prior to the implementation of a multisite AMC pediatric registry.

Perhaps the most dramatic position of a newborn after delivery is when there is hyperextension of the neck and spine. It will have been presented in utero and today, almost always, such babies will have been delivered by C-section. The associated anomalies are variable. The process(es) that can lead to cervical hyperextension is/are largely unknown. The outcome is variable from lethal to completely resolve. Individuals with arthrogryposis and in particular with Amyoplasia appear to have an increased frequency of neck, cervical, and spine hyperextension at birth. We present here 41 cases of arthrogryposis (mainly Amyoplasia) with fetal cervical hyperextension. The outlook is surprisingly good if spinal cord trauma does not occur. Ultrasound late in pregnancy when arthrogryposis is recognized prenatally should determine whether cervical hyperextension has developed, so that appropriate preventive measures can be taken.

Antenatal identification of fetuses with multiple congenital contractures or arthrogryposis multiplex congenita (AMC) may be challenging. The first clinical sign is often reduced fetal movement and/or contractures, as seen on prenatal ultrasounds. This can be apparent at any point, from early to late pregnancy, may range from mild to severe involvement, with or without associated other structural anomalies. Possible etiologies and their prognosis need to be interpreted with respect to developmental timing. The etiology of AMC is highly heterogeneous and making the specific diagnosis will guide prognosis, counseling and prenatal and perinatal management. Current ultrasound practice identifies only approximately 25% of individuals with arthrogryposis prenatally before 24 weeks of pregnancy in a general obstetrics care population. There are currently no studies and guidelines that address the question of when and how to assess for fetal contractures and movements during pregnancy. The failure to identify fetuses with arthrogryposis before 24 weeks of pregnancy means that physicians and families are denied reproductive options and interventions that may improve outcome. We review current practice and recommend adjusting the current prenatal imaging and genetic diagnostic strategies to achieve early prenatal detection and etiologic diagnosis. We suggest exploring options for in utero therapy to increase fetal movement for ongoing pregnancies.

Fetal movement is essential to normal human development. If the fetus does not move for whatever reason, then multiple organs and organ systems develop secondary and tertiary effects not normally present. Most of these are deformations with secondary structural damage.

Indigenous Art often expresses the complex culture of their creators and provides insight into the origins, histories, and values of that culture. Two examples of Northwest Indigenous Art suggest deeper meanings and the "power" of congenital anomalies.

OBJECTIVE: To identify differences in patient-physician interactions associated with improvements in GERD symptoms in a randomized controlled trial comparing integrative medicine and primary care/standard visits. METHODS: We analyzed video recordings of 2-minute excerpts (thin slices) from the beginning, middle, and end of 21 study visits (11 standard, 10 integrative medicine). RESULTS: According to blind coders’ analysis of the excerpts, prospective improvement in GERD symptoms was most highly correlated with patients appearing pleased (r=0.71, p

Objective To determine associations between patient affect and physician liking of the patient, and their associations with physician behavior and patient-reported outcomes. Methods Structural equation modeling based on coding of 497 videotaped hospital encounters, with questionnaires assessing pre-visit patient affect, post-visit patient affect and encounter evaluations, and physician liking of the patient, involving 71 physicians. Results In first visits, patient reported outcomes were strongly correlated with physician behavior and less so with physician liking, while in later visits, patient reported outcomes were directly related to physician liking and not mediated by physician behavior. Physician liking predicted physician behavior, more for female physicians in first visits. Patient negative affect before the visit was negatively associated with male physicians’ liking. When acquainted, both patient positive and negative affect were associated with physician liking. Conclusion Physician liking of the patient plays a dynamic role in a consultation, is influenced by patient pre-encounter affect, and influences physician behavior. The dynamics are different in first and later visits, and influenced by physician gender. Practice implications Physicians should be aware how patient affect influences their behavior, and administrators should take any prior relationship between patient and physician into account when evaluating patient reported outcomes.

Mechanisms of anesthetic drug-induced sedation and unconsciousness are still incompletely understood. Functional neuroimaging modalities provide a window to study brain function changes during anesthesia allowing us to explore the sequence of neuro-physiological changes associated with anesthesia. Cerebral perfusion change under an assumption of intact neurovascular coupling is an indicator of change in large-scale neural activity. In this experiment, we have investigated resting state cerebral blood flow (CBF) changes in the human brain during mild sedation, with propofol. Arterial spin labeling (ASL) provides a non-invasive, reliable, and robust means of measuring cerebral blood flow (CBF) and can therefore be used to investigate central drug effects. Mild propofol sedation-related CBF changes were studied at rest (n = 15), in a 3 T MR scanner using a PICORE-QUIPSS II ASL technique. CBF was reduced in bilateral paracingulate cortex, premotor cortex, Broca’s areas, right superior frontal gyrus and also the thalamus. This cerebral perfusion study demonstrates that propofol induces suppression of key cortical (frontal lobe) and subcortical (thalamus) regions during mild sedation.

BackgroundPain self-efficacy is one’s belief in the ability to control and persist through pain. The purpose of this study was to examine the relationships between pain self-efficacy, immediate and delayed pain ratings, and accurate pain recall two weeks after an acute pain procedure.Participants and procedureTwo hundred three participants completed a tourniquet pain procedure. Pain self-efficacy was measured. An immediate pain rating was collected immediately following the procedure. A delayed pain rating was assessed in a two-week follow-up survey. Accurate pain recall was assessed by examining the difference between participants’ immediate pain rating and their delayed pain rating.ResultsHigher levels of pain self-efficacy were related to lower delayed pain rating two weeks later but not related to immediate pain ratings. Participants with higher pain self-efficacy were significantly more likely to underestimate their pain two weeks later than participants with lower pain self-efficacy, who tended to overestimate their previous pain.ConclusionsThis research highlights the important role of pain self-efficacy on the recall of pain. Those with higher pain self-efficacy were more likely to underestimate their pain two weeks later, while those with lower pain self-efficacy tended to overestimate their previous pain. Healthcare providers and caregivers should consider patients’ pain self-efficacy in interpreting reports of pain, especially when these reports recall past pain.

Clinical genetics is the application of advances in genetics and medicine to real human families. It involves diagnosis, care, and counseling concerning options available to affected individuals and their family members. Advances in medicine and genetics have led to dramatic changes in the scope and responsibilities of clinical genetics. This reflection on the last 50+ years of clinical genetics comes from personal experience, with an emphasis on the important contributions that clinical geneticists have made to the understanding of disease/disorder processes and mechanisms. The genetics clinic is a research laboratory where major advances in knowledge can and have been made.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Compassionate behavior in clinicians is described as seeking to understand patients’ psychosocial, physical and medical needs, timely attending to these needs, and involving patients as they desire. The goal of our study was to evaluate compassionate behavior in patient interactions, pain management, and the informed consent process of anesthesia residents in a simulated preoperative evaluation of a patient in pain scheduled for urgent surgery. Methods Forty-nine Clinical Anesthesia residents in year 1 and 16 Clinical Anesthesia residents in year 3 from three residency programs individually obtained informed consent for anesthesia for an urgent laparotomy from a standardized patient complaining of pain. Encounters were assessed for ordering pain medication, for patient-resident interactions by using the Empathic Communication Coding System to code responses to pain and nausea cues, and for the content of the informed consent discussion. Results Of the 65 residents, 56 (86%) ordered pain medication, at an average of 4.2 min (95% CI, 3.2 to 5.1) into the encounter; 9 (14%) did not order pain medication. Resident responses to the cues averaged between perfunctory recognition and implicit recognition (mean, 1.7 [95% CI, 1.6 to 1.9]) in the 0 (less empathic) to 6 (more empathic) system. Responses were lower for residents who did not order pain medication (mean, 1.2 [95% CI, 0.8 to 1.6]) and similar for those who ordered medication before informed consent signing (mean, 1.9 [95% CI, 1.6 to 2.1]) and after signing (mean, 1.9 [95% CI, 1.6 to 2.0]; F (2, 62) = 4.21; P = 0.019; partial η2 = 0.120). There were significant differences between residents who ordered pain medication before informed consent and those who did not order pain medication and between residents who ordered pain medication after informed consent signing and those who did not. Conclusions In a simulated preoperative evaluation, anesthesia residents have variable and, at times, flawed recognition of patient cues, responsiveness to patient cues, pain management, and patient interactions.

This Special Issue on Interdisciplinary Care in Arthrogryposis highlights a collection of articles spanning topics in interdisciplinary care, genetic discoveries, and clinical research. An international group of clinicians and researchers from various backgrounds who attended the "3rd International Symposium on Arthrogryposis", held in Philadelphia, September 24-26, 2018, were invited to contribute to this issue. The goal of the 2018 Symposium and of this Special Issue is to provide momentum to advancing evidence-based practice and research in arthrogryposis, by working collaboratively with adults and families of children with arthrogryposis, clinicians, and researchers. The contents of this issue cover a range of topics from defining and classifying arthrogryposis multiplex congenita to early detection, rehabilitation, and orthopedic management, advances in genetic pathways, patient registries, autopsy guidelines, and research findings in the pediatric and adult populations with arthrogryposis. We hope that this issue provides an overview as well as new knowledge on arthrogryposis to generate more conversations at the international level, and advance care and research for individuals with arthrogryposis.

Arthrogryposis multiplex congenita, or AMC, is a clinical sign defined as congenital contractures of at least two joint levels. These joint contractures are always secondary to diminished fetal movement which can have numerous causes that affect any part of the anatomical structures implicated in movement: the central nervous system, the anterior horn cell, the nerve, the neuromuscular junction, the muscle, or the joint itself. Make a precise diagnosis of the cause in a patient with multiple joint contractures is therefore challenging. The aim of this article is to summarize the use and diagnostic value of common examinations and analyses performed postnatally in patients affected by AMC from a literature review. We also compare this data with results from our clinical practice. Even though it is difficult to give precise guidelines today, it appears that genetic studies, such as whole exome or genome analysis in all patients and chromosomal microarray analysis in patients with intellectual disability and AMC should be preferred as first tier investigations over EMG and muscle biopsy.

Arthrogryposis or AMC, arthrogryposis multiplex congenita, is defined as multiple congenital joint contractures in more than two joints and in different body areas. The common cause of all AMC is lack of movement in utero, which in turn can have different causes, one of which is CNS involvement. Intellectual disability/CNS involvement is found in approximately 25% of all AMC. AMC with CNS involvement includes a large number of genetic syndromes. So far, more than 400 genes have been identified as linked to AMC, with and without CNS involvement. A number of neonatally lethal syndromes and syndromes resulting in severe disability due to CNS malfunction belong to this group of syndromes. There are several X-linked disorders with AMC, which are primarily related to intellectual disability. A number of neuromuscular disorders may include AMC and CNS/brain involvement. Careful clinical evaluation by a geneticist and a pediatrician/pediatric neurologist is the first step in making a specific diagnosis. Further investigations may include MRI of the brain and spinal cord, electroencephalogram, blood chemistry for muscle enzymes, other organ investigations (ophtalmology, cardiology, gastrointestinal, and genitourinary systems). Nerve conduction studies, electromyogram, and muscle pathology may be of help when there is associated peripheral nervous system involvement. But most importantly, genetic investigations with targeted or rather whole exome or genome sequencing should be performed. A correct diagnosis is important in planning adequate treatment, in genetic counselling and also for future understanding of pathogenic mechanisms and possible new treatments. A multidiciplinary team is needed both in investigation and treatment.

There is a need for a system to classify various forms of arthrogryposis. None is satisfactory or complete. Nevertheless, several have been developed to meet the needs of clinicians, prenatal diagnosticians, researchers, and basic scientists. They all await more insight into basic mechanisms.

The 1st international symposium on arthrogryposis (ISA) was held in 2007 in Birmingham, UK, to bring together a multinational group of experts in the field of arthrogryposis, patients and their families to discuss various aspects of care for individuals with Arthrogryposis Multiplex Congenita (AMC). These "lessons learnt" set the tone for the 2nd ISA held in Saint Petersburg, Russia in 2014. Clinical and research advances have recently been made in the field of arthrogryposis and were shared at the 3rd ISA, in Philadelphia, in 2018. Highlights of the 3ISA and future directions are presented.

Arthrogryposis multiplex congenita (AMC) is considered a rare disorder resulting in multiple congenital contractures in two or more areas. Considerable literature is available on managing the contractures during an affected child's development but little information is available to those managing these ongoing issues in adulthood. Due to the heterogeneity etiological factors and presentation of AMC, and the small sample sizes of previous studies, it has been difficult to generalize results to the adult population. This current study presents the several steps taken to create an international AMC database for adults to populate with their own data over time. The methods included a scoping review of the literature for valid and reliable outcome measures used for AMC, a Delphi methodology to create the database with a team of clinicians, researchers and patients, a Beta testing of the database, and a final launch of the Adult AMC Registry. This registry includes 48 nonstandardized questions and 12 standardized questionnaires. It takes 35-45 min for a participant to complete. A shorter version will be created for participants to complete for years 2 and 3, followed by this longer version every 4 years. The protocol for referring English-speaking patients and access to the registry is provided. Data will be reviewed every year to ensure quality. The registry will be maintained for a minimum of 10 years and data will be comprehensively analyzed every 5 years. Our goal is to have 500 adults with AMC from around the world as participants.

The aerodigestive and communicative behaviors of anencephalic and hydranencephalic patients are assessed from literature sources and are compared with documented neural structures present in the brainstem, subcortical, and cortical regions of the brain. Much of the data analyzed corroborate previous neurological studies, which focus on central pattern generators and development in model organisms. However, findings suggest that further research is necessary to determine which components of these systems support these behaviors. A low reporting rate of behavior in tandem with pathology is observed throughout the literature. More data pairing behavior and pathology is recommended, both in the interest of understanding the relationship between neural structures and functions, and to provide clinicians with more information about a patient's signs and symptoms. Potential clinical practices are recommended to increase documentation about patients within this population.

The present study investigated individual differences in nonverbal self-accuracy (NVSA), which is the ability to accurately recall one's own nonverbal behavior following a social interaction. Participants were videotaped during a social interaction with a stranger and then asked to recall how often they displayed five common nonverbal behaviors. Correlations between the self-reported recall of nonverbal behavior and judges' behavioral coding indicated that individuals can accurately recall their own nonverbal behavior at better than chance levels. Higher NVSA also was associated with more public self-awareness, less positive expressivity, more accurate recognition of anger in facial expressions, and higher neuroticism. The results suggest that NVSA is a measurable individual difference construct with potential implications for self-awareness in social interactions.

Pallister-Hall syndrome was initially recognized under fairly unique circumstances involving exhumation of the very first case. The first two cases had dramatic and unusual features including a hypothalamic hamartoblastoma, imperforate anus, an unusual type of polydactyly with the extra digit being central, hypopituitarism with secondary hypoadrenalism, and lethality after birth (probably due to hypoadrenalism). Within a short time frame, four additional cases were identified. As the full spectrum and variability of anomalies was recognized, it became clear that it was not such a rare disorder. Shortly after familial cases were recognized, the responsible gene was identified at GLI3. However, since other different conditions also involved GLI3, elaborating the domains of the gene and the types of mutations needed to be defined in order to have a clear correlation of the genotype-phenotype relations.

Two studies examined the expression and detection of suppressed, genuine, and exaggerated pain. In Study 1, videotaped participants underwent an acute laboratory pain stressor and completed pain ratings. In Study 2, the lens model examined the cues encoders displayed while in pain (facial expressions of pain and viewers' global impressions), the cues decoders used to infer pain in the videotaped encoders, and decoders' accuracy in making judgments of pain. Results revealed expression differences between the suppressed, genuine, and exaggerated pain such that exaggerated expressions contained more tightened facial expressions while genuine expressions of pain contained more open facial expressions of pain. Decoders were accurate at detecting pain only in the exaggerated pain expressions. These results highlight the need for improving providers' accuracy in detecting pain intensity for suppressed, genuine, and exaggerated pain displays. Trainings should focus on teaching providers that patients who appear more agitated and less composed may be suppressing pain, while patients who appear more tense and determined may be exaggerating pain. Finally, patients who seem to not be in that much pain because they are not showing tightened facial expressions may actually be experiencing higher intensities of genuine pain.

Our aim was to prospectively determine the predictive capabilities of SEPSIS-1 and SEPSIS-3 definitions in the emergency departments and general wards. Patients with National Early Warning Score (NEWS) of 3 or above and suspected or proven infection were enrolled over a 24-h period in 13 Welsh hospitals. The primary outcome measure was mortality within 30 days. Out of the 5422 patients screened, 431 fulfilled inclusion criteria and 380 (88%) were recruited. Using the SEPSIS-1 definition, 212 patients had sepsis. When using the SEPSIS-3 definitions with Sequential Organ Failure Assessment (SOFA) score ≥ 2, there were 272 septic patients, whereas with quickSOFA score ≥ 2, 50 patients were identified. For the prediction of primary outcome, SEPSIS-1 criteria had a sensitivity (95%CI) of 65% (54-75%) and specificity of 47% (41-53%); SEPSIS-3 criteria had a sensitivity of 86% (76-92%) and specificity of 32% (27-38%). SEPSIS-3 and SEPSIS-1 definitions were associated with a hazard ratio (95%CI) 2.7 (1.5-5.6) and 1.6 (1.3-2.5), respectively. Scoring system discrimination evaluated by receiver operating characteristic curves was highest for Sequential Organ Failure Assessment score (0.69 (95%CI 0.63-0.76)), followed by NEWS (0.58 (0.51-0.66)) (p < 0.001). Systemic inflammatory response syndrome criteria (0.55 (0.49-0.61)) and quickSOFA score (0.56 (0.49-0.64)) could not predict outcome. The SEPSIS-3 definition identified patients with the highest risk. Sequential Organ Failure Assessment score and NEWS were better predictors of poor outcome. The Sequential Organ Failure Assessment score appeared to be the best tool for identifying patients with high risk of death and sepsis-induced organ dysfunction.

Cerebral autoregulation ensures constant cerebral blood flow during periods of increased blood pressure by increasing cerebrovascular resistance. However, whether this increase in resistance occurs at the level of major cerebral arteries as well as at the level of smaller pial arterioles is still unknown in humans. Here, we measure cerebral arterial compliance, a measure that is inversely related to cerebrovascular resistance, with our novel non-invasive magnetic resonance imaging-based measurement, which employs short inversion time pulsed arterial spin labelling to map arterial blood volume at different phases of the cardiac cycle. We investigate the differential response of the cerebrovasculature during post exercise ischemia (a stimulus which leads to increased cerebrovascular resistance because of increases in blood pressure and sympathetic outflow). During post exercise ischemia in eight normotensive men (30.4 ± 6.4 years), cerebral arterial compliance decreased in the major cerebral arteries at the level of and below the Circle of Willis, while no changes were measured in arteries above the Circle of Willis. The reduction in arterial compliance manifested as a reduction in the arterial blood volume during systole. This study provides the first evidence that in humans the major cerebral arteries may play an important role in increasing cerebrovascular resistance.

At subanaesthetic doses, ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has demonstrated remarkable and rapid antidepressant efficacy in patients with treatment-resistant depression. The mechanism of action of ketamine is complex and not fully understood, with altered glutamatergic function and alterations of high-frequency oscillatory power (Wood et al., 2012) noted in animal studies. Here we used magnetoencephalography (MEG) in a single blind, crossover study to assess the neuronal effects of 0.5 mg/kg intravenous ketamine on task-related high-frequency oscillatory activity in visual and motor cortices. Consistent with animal findings, ketamine increased beta amplitudes, decreased peak gamma frequency in visual cortex and significantly amplified gamma-band amplitudes in motor and visual cortices. The amplification of gamma-band activity has previously been linked in animal studies to cortical pyramidal cell disinhibition. This study provides direct translatable evidence of this hypothesis in humans, which may underlie the anti-depressant actions of ketamine.

Recently, lower thrombin generation has been associated with excess bleeding post-cardiopulmonary bypass (CPB). Therefore, treatment to correct thrombin generation is a potentially important aspect of management of bleeding in this group of patients. The objective of the present study was to investigate the effects of fresh frozen plasma (FFP), recombinant factor VIIa (rFVIIa), prothrombin complex concentrate (PCC) and tissue factor pathway inhibitor (TFPI) inhibition on thrombin generation when added ex vivo to the plasma of patients who had undergone cardiac surgery requiring CPB. Patients undergoing elective cardiac surgery were recruited. Blood samples were collected before administration of heparin and 30 min after its reversal. Thrombin generation was measured in the presence and absence of different concentrations of FFP, rFVIIa, PCC and an anti-TFPI antibody. A total of 102 patients were recruited. Thrombin generation following CPB was lower compared with pre-CPB (median endogenous thrombin potential pre-CPB 339 nmol/l per min, post-CPB 155 nmol/l per min, P < 0.0001; median peak thrombin pre-CPB 35 nmol/l, post-CPB 11 nmol/l, P < 0.0001). Coagulation factors and anticoagulants decreased, apart from total TFPI, which increased (55-111 ng/ml, P < 0.0001), and VWF (144-170 IU/dl, P < 0.0001). Thrombin generation was corrected to pre-CPB levels by the equivalent of 15 ml/kg FFP, 45 [mu]g/kg rFVIIa and 25 U/kg of PCC. Inhibition of TFPI resulted in an enhancement of thrombin generation significantly beyond pre-CPB levels. This study shows that FFP, rFVIIa, PCC and inhibition of TFPI correct thrombin generation in the plasma of patients who have undergone surgery requiring CPB. Inhibition of TFPI may be a further potential therapeutic strategy for managing bleeding in this group of patients.

Neuromuscular diseases (NMD) account for a significant proportion of infant and childhood mortality and devastating chronic disease. Determining the specific diagnosis of NMD is challenging due to thousands of unique or rare genetic variants that result in overlapping phenotypes. We present four unique childhood myopathy cases characterized by relatively mild muscle weakness, slowly progressing course, mildly elevated creatine phosphokinase (CPK), and contractures. We also present two additional cases characterized by severe prenatal/neonatal myopathy. Prior extensive genetic testing and histology of these cases did not reveal the genetic etiology of disease. Here, we applied whole exome sequencing (WES) and bioinformatics to identify likely causal pathogenic variants in each pedigree. In two cases, we identified novel pathogenic variants in COL6A3. In a third case, we identified novel likely pathogenic variants in COL6A6 and COL6A3. We identified a novel splice variant in EMD in a fourth case. Finally, we classify two cases as calcium channelopathies with identification of novel pathogenic variants in RYR1 and CACNA1S. These are the first cases of myopathies reported to be caused by variants in COL6A6 and CACNA1S. Our results demonstrate the utility and genetic diagnostic value of WES in the broad class of NMD phenotypes.

The following is a review of 50 X-linked syndromes and conditions associated with either arthrogryposis or other types of early contractures. These entities are categorized as those with known responsible gene mutations, those which are definitely X-linked, but the responsible gene has not been identified, and those suspected from family history to be X-linked. Several important ontology pathways for known disease genes have been identified and are discussed in relevance to clinical characteristics. Tables are included which help to identify distinguishing clinical features of each of the conditions.

Background We set out to validate the accuracy of gravimetric quantification of blood loss during simulated major postpartum haemorrhage and to evaluate the technique in a consecutive cohort of women experiencing major postpartum haemorrhage. The study took part in a large UK delivery suite over a one-year period. All women who experienced major postpartum haemorrhage were eligible for inclusion. Methods For the validation exercise, in a simulated postpartum haemorrhage scenario using known volumes of artificial blood, the accuracy of gravimetric measurement was compared with visual estimation made by delivery suite staff. In the clinical observation study, the blood volume lost during postpartum haemorrhage was measured gravimetrically according to our routine institutional protocol and was correlated with fall in haemoglobin. The main outcome measure was the accuracy of gravimetric measurement of blood loss. Results Validation exercise: the mean percentage error of gravimetrically measured blood volume was 4.0 ± 2.7% compared to visually estimated blood volume with a mean percentage error of 34.7 ± 32.1%. Clinical observation study: 356 out of 6187 deliveries were identified as having major postpartum haemorrhage. The correlation coefficient between measured blood loss and corrected fall in haemoglobin for all patients was 0.77; correlation was stronger (0.80) for postpartum haemorrhage >1500 mL, and similar during routine and out-of-hours working. Conclusion The accuracy of the gravimetric method was confirmed in simulated postpartum haemorrhage. The clinical study shows that gravimetric measurement of blood loss is correlated with the fall in haemoglobin in postpartum haemorrhage where blood loss exceeds 1500 mL. The method is simple to perform, requires only basic equipment, and can be taught and used by all maternity services during major postpartum haemorrhage

Novel dispersions of the volatile inhalation anesthetic sevoflurane have been formulated that can provide controlled, sustainable release of anesthetic over clinically useful timescales. The emulsions can be simply formed with manual shaking, reproducibly yielding droplets of the order of 250 nm diameter, i.e. within the nanoemulsion range. Using a custom flow-rig, release of anesthetic gas from the emulsion has been evaluated, and clinically useful levels achieved through appropriate stirring of the formulation. Stirring can also be used to temporarily increase or decrease the amount of anesthetic released. Once consideration of the unusual nature of the fluorinated systems (phase separation by sedimentation rather than creaming), and the highly perturbed environment of their evaluation (under stirring and flow of gas), the observed behavior regarding sevoflurane evaporation can be reasonably well explained by existing theoretical models. Links between anesthetic release and emulsion structure have been defined, providing the basis for future development.

Patients benefit when their healthcare providers accurately recognize their affect. The efficacy of three short-term training components, practice, practice with feedback, and discussion with practice and feedback, to improve accuracy for judging patients' affect was experimentally assessed. Undergraduate participants were randomly assigned in pairs to one of the training conditions or an untrained control condition and the effect of training was measured using the Test of Accurate Perception of Patients' Affect (TAPPA). Participants were significantly more accurate on the TAPPA in the discussion with feedback and practice condition compared with the control condition. There was a significant linear trend in accuracy across training elements. Results suggest that a 40-min discussion with feedback and practice training can significantly improve interpersonal accuracy.

Arthrogryposis multiplex congenital is a relatively uncommon condition, with little consensus on treatment. In 2007, the 1st International Symposium on Arthrogryposis was held in Birmingham, United Kingdom, to bring together patients, their families, and a multinational group of health care experts in the field of arthrogryposis, to discuss various aspects of the care of patients with arthrogryposis multiplex congenital. From that meeting, there was a coalescence of thought on diagnosis and classification, a sharing of practices on treatments and their outcomes, and an agreement on future directions. At the beginning of the 2nd International Symposium on Arthrogryposis held in Saint Petersburg in September 2014, Russia, these "lessons learnt" were synopsized to set the tone for the new meeting.