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A previously unrecognized specimen ofProtoichthyosaurus prostaxalis, LEICT G142.1991, from the Lower Jurassic of Barrow-upon-Soar, Leicestershire, UK, includes an almost complete three-dimensional skull that provides new information on the configuration of the skull roof. The position of the pineal foramen (between the frontals and the parietals) and an elongated internasal foramen in a depression along the midline of the nasals are clearly shown. The maxilla makes up a significant portion of the external naris ventral margin, an unusual character for the genus/species. This reflects intraspecific variation, not evidence of a new taxon. The specimen enables comparisons of skull roof morphology withIchthyosaurusandStenopterygius, two common Early Jurassic taxa. In particular, the position of the pineal foramen is similar toStenopterygius, but distinguishesProtoichthyosaurusfromIchthyosaurus. The lack of a frontal–prefrontal contact and the posteriorly wide nasals distinguishesProtoichthyosaurusfromStenopterygius. We also present a revised reconstruction of the skull roof morphology ofIchthyosaurus. Three additional specimens ofProtoichthyosaurusare referred to the genus: another partial skull, referred toP. prostaxalis, and two isolated forefins, identified by their unique morphology.

Throughout the northern extent of its range, Chinook salmon (Oncorhynchus tshawytscha) adult returns have been in decline for over a decade, leading to severe harvest restrictions on subsistence, commercial, and recreational fisheries. In addition to these overall declines in abundance, changes in size structure and age structure, including a proportional decrease of older age classes returning to spawn, suggest that late-stage marine mortality for this species may be more frequent than currently assumed. To examine this late-stage mortality hypothesis, we examined diagnostic evidence of predation on large (57–100 cm fork length) Chinook salmon (n = 33) from depth, temperature, and light records collected during recent satellite tagging research. Satellite tags provided evidence of predation on tagged Chinook salmon by salmon sharks (Lamna ditropis) (n = 14), marine mammals (n = 2), ectothermic fish(es) (n = 3), and unidentified predators (n = 5) in the Bering Sea and Gulf of Alaska. High mortality rates in this study suggest that fisheries scientists should consider that late-stage mortality by marine apex predators may be shaping this species’ abundance and demographics.

Electronic fetal monitoring (EFM) has been used extensively for almost 50 years but performs poorly in predicting and preventing adverse neonatal outcome. In recent years, the current "enhanced" classification of patterns (category I-III system [CAT]) were introduced into routine practice without corroborative studies, which has resulted in even EFM experts lamenting its value. Since abnormalities of arterial cord blood parameters correlate reasonably well with risk of fetal injury, here we compare the statistical performance of EFM using the current CAT system with the Fetal Reserve Index (FRI) for predicting derangements in base excess (BE), pH, and pOWe utilized a research database of labor data, including umbilical cord blood measurements to assess patients by both worst CAT and last FRI classifications. We compared these approaches for their ability to predict BE, pH, and pOThe FRI showed a clear correlation with cord blood BE and pH with BE being more highly correlated than pH. The CAT was much less predictive than FRI (The Fetal Reserve Index (FRI) provides superior performance over CAT classification of FHR patterns in predicting the BE and pH in umbilical cord blood. Furthermore, the CAT system fails to satisfy multiple fundamental principles required for successful screening programs. Limitations of CAT are further compounded by assumptions about physiology that are not consistent with clinical observations.

OBJECTIVE: To quantify age-related variability of insulin needs during day and night closed-loop insulin delivery. RESEARCH DESIGN AND METHODS: We retrospectively analyzed data from hybrid closed-loop studies involving young children (1-6 years old, n = 20), children (7-12 years, n = 21), adolescents (13-17 years, n = 15), and adults (>18 years, n = 58) with type 1 diabetes. The coefficient of variation quantified variability of insulin needs during 3 weeks of unrestricted-living hybrid closed-loop use. RESULTS: Data from 2,365 nights and 2,367 days in 114 participants were analyzed. The coefficient of variation of insulin delivery was higher in young children compared with adults (mean difference at nighttime 10.7 percentage points [95% CI 2.9-18.4], P = 0.003; daytime 6.4 percentage points [95% CI 2.0-10.9], P = 0.002) and compared with adolescents (mean difference at nighttime 10.2 percentage points [95% CI 0.0-20.4], P = 0.049; daytime 7.0 percentage points [95% CI 1.1-12.8], P = 0.014). CONCLUSIONS: Diabetes management in young children is complicated by higher variability in insulin requirements, supporting fast-track clinical practice adoption of closed-loop in this vulnerable population. With increasing application of insulin pump therapy and continuous glucose monitors, hybrid closed-loop has become a feasible treatment modality for people with type 1 diabetes (1,2). Apart from manual meal-time boluses, insulin delivery is autonomously modulated by a control algorithm based on real-time sensor glucose values. Insulin delivery may vary considerably from day to day and night to night due to varying activity levels, insulin set-changes, meal timings and composition, and other factors(3,4).Todate,theassociationbetweenageandinsulinvariabilityhasnotbeen assessed.Inthepresentanalysis,weinvestigatewhetherinsulinrequirementsmaybe more variable in younger age.

BACKGROUND Glucose management is challenging in patients who require nutritional support in hospital. We aimed to assess whether fully closed-loop insulin delivery would improve glycaemic control compared with conventional subcutaneous insulin therapy in inpatients receiving enteral or parenteral nutrition or both. METHODS We did a two-centre (UK and Switzerland), open-label, randomised controlled trial in adult inpatients receiving enteral or parenteral nutrition (or both) who required subcutaneous insulin therapy. Patients recruited from non-critical care surgical and medical wards were randomly assigned (1:1) using a computer-generated minimisation schedule (stratified by type of nutritional support [parenteral nutrition on or off] and pre-study total daily insulin dose [

The delivery of healthy babies is the primary goal of obstetric care. Many technologies have been developed to reduce both maternal and fetal risks for poor outcomes. For 50 years, electronic fetal monitoring (EFM) has been used extensively in labor attempting to prevent a large proportion of neonatal encephalopathy and cerebral palsy. However, even key opinion leaders admit that EFM has mostly failed to achieve this goal. We believe this situation emanates from a fundamental misunderstanding of differences between screening and diagnostic tests, considerable subjectivity and inter-observer variability in EFM interpretation, failure to address the pathophysiology of fetal compromise, and a tunnel vision focus. To address these suboptimal results, several iterations of increasingly sophisticated analyses have intended to improve the situation. We believe that part of the continuing problem is that the focus of EFM has been too narrow ignoring important contextual issues such as maternal, fetal, and obstetrical risk factors, and increased uterine contraction frequency. All of these can significantly impact the application of EFM to intrapartum care. We have recently developed a new clinical approach, the Fetal Reserve Index (FRI), contextualizing EFM interpretation. Our data suggest the FRI is capable of providing higher accuracy and earlier detection of emerging fetal compromise. Over time, artificial intelligence/machine learning approaches will likely improve measurements and interpretation of FHR characteristics and other relevant variables. Such future developments will allow us to develop more comprehensive models that increase the interpretability and utility of interfaces for clinical decision making during the intrapartum period.

In this recent 2019–2020 audit, 96% (168/173) of paediatric diabetes teams submitted data and included a total of 29,242 children and young people (CYP) up to the age of 24 years, and type 1 diabetes consisted of 27,653 CYP. One of the key findings was that CYP with type 1 diabetes from minority ethnic communities have higher HbA1 compared to white ethnicity and that significantly lower use of insulin pumps or real‐time continuous glucose monitoring systems was used among black children. There has been an increasing trend of widening health inequalities reported the past 6 years. As chairs of Diabetes UK Diabetes Research Study Groups, the authors urge that research into barriers of access to technology for T1D in CYP in the UK specifically looking at provider bias, systemic issues within the health system, and individual and family factors are conducted with urgency.

Objective: We evaluated hybrid closed-loop glucose control with faster-acting insulin aspart (Fiasp) in adults with type 1 diabetes (T1D). We hypothesised that closed-loop with Fiasp provides similar efficacy as closed-loop with standard insulin aspart. Research design and methods: In a double-blind, multinational, randomised, crossover study, 25 adults with T1D using insulin pump therapy (mean ± SD, age 38 ± 9 years, HbA1c 7.4 ± 0.8% [57 ± 8 mmol/mol]) underwent two 8-week periods of unrestricted living comparing hybrid closed-loop with Fiasp and hybrid closed-loop with standard insulin aspart in random order. During both interventions, the CamAPS FX closed-loop system incorporating Cambridge model predictive control algorithm was used. Results: In an intention-to-treat analysis, the proportion of time sensor glucose was in target range (3.9-10.0 mmol/L; primary endpoint) was not different between interventions (75 ± 8% vs. 75 ± 8% for hybrid closed-loop with Fiasp vs. hybrid closed-loop with standard insulin aspart; mean-adjusted difference - 0.6 [95%CI -1.8 to 0.7%]; P < 0.001 for non-inferiority [non-inferiority margin 5%]). The proportion of time with sensor glucose

Background: Cotadutide is a GLP1/glucagon receptor dual agonist under development for the treatment of nonalcoholic steatohepatitis and type 2 diabetes (T2D) with diabetic kidney disease. Early-phase clinical studies show that cotadutide achieves clinically significant weight loss. We aimed to establish mechanistically to what extent this effect is mediated via changes in energy intake (EI) or energy expenditure (EE). Methods: We conducted a phase 2a single-center randomized double-blind placebo-controlled trial in overweight/obese adults (BMI 27-40 kg/m2) with T2D (HbA1c 6.5-8%). Participants underwent a 16-day single-blind placebo run-in and were randomized to double-blind 42-day cotadutide or placebo. Cotadutide was given subcutaneously, up to 300 µg daily. Primary outcome: % weight change from day 17 to day 59. Secondary outcomes: % and absolute changes in EI (ad libitum lunch), and EE (indirect calorimetry). Results: A total of 19 (63%) cotadutide and 9 (78%) placebo participants completed the study. Least-squares (LS) mean weight change was -3.98% (90% CI -4.85%, -3.10%) and -1.40% (90% CI -2.66%, -0.13%) for cotadutide and placebo, respectively, p= 0.011 between groups. The cotadutide group had a striking 35% lower EI vs. placebo: LS mean -35.0% (90% CI -61.8%, -8.2%), p=0.037. Total EE (kJ/kg lean mass) after cotadutide treatment decreased vs. placebo: -6.0% vs. 0.3%, p Conclusions: Weight loss caused by cotadutide is predominantly due to reduced EI rather than increased EE. Transient preservation of EE in the early phases of cotadutide treatment may reflect glucagon receptor engagement. Disclosure R. Golubic: None. M. Evans: Advisory Panel; Self; Pila Pharma, Zucara Therapeutics Inc., Other Relationship; Self; Abbott Diabetes, Medtronic, Novo Nordisk, Research Support; Self; AstraZeneca, Imcyse. J. Kennet: None. V. E. Parker: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. D. Robertson: Employee; Self; AstraZeneca, Employee; Spouse/Partner; GlaxoSmithKline plc., Stock/Shareholder; Self; AstraZeneca. D. Luo: None. L. Hansen: Employee; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. A. Park: Other Relationship; Self; Novo Nordisk.

OBJECTIVE To characterise variability of exogenous insulin requirements during fully closed-loop insulin delivery in hospitalised patients with type 2 diabetes (T2D) or new-onset hyperglycaemia, and to determine patient-related characteristics associated with higher variability of insulin requirements. RESEARCH DESIGN AND METHODS We retrospectively analysed data from two fully closed-loop inpatient studies involving adults with T2D or new-onset hyperglycaemia requiring insulin therapy. The coefficient of variation quantified day-to-day variability of exogenous insulin requirements during up to 15 days using fully automated closed-loop insulin delivery. RESULTS Data from 535 days in 67 participants were analysed. The coefficient of variation of day-to-day exogenous insulin requirements was 30±16% and was higher between nights than between any daytime period (56±29% overnight [2300-0459] compared with 41±21% in the morning [0500-1059], 39±15% in the afternoon [1100-1659] and 45±19% during the evening [1700-2259]; all p

Background: Primary cytotoxic T cell lymphomas are a heterogenous collection of ill-defined diseases with aggressive disease course and poor response to conventional therapy. Of these, primary cutaneous CD8+ aggressive epidermotropic T cell lymphoma and cutaneous T cell lymphoma, not otherwise specified, have undergone few to no systematic analyses of its genetic landscape. In this study, we classify these lymphomas based on their histological and clinical features and perform systematic genomic analyses to find novel therapeutic targets. Methods: We clinically characterize 35 patients from 10 institutions with cytotoxic T cell lymphoma and performed integrative clinical, pathological, and genetic analyses. We perform Archer™ Heme Fusion on an initial 24 FFPE samples. In addition, we perform DNA and/or RNA sequencing on 11 cases. We functionally validate our genetic findings by transducing alterations into Ba/F3 cells and subsequently performing biochemical assays. In this setting, we assess sensitivity to FDA-approved small molecule inhibitors. We provide orthogonal evidence of transcriptional upregulation by geneset enrichment analysis. Results: We find kinase fusions impacting JAK-STAT signaling in all primary cutaneous CD8+ aggressive epidermotropic T cell lymphomas in our cohort. Three of these fusions have not previously been described in cancer. Known fusions have been shown to upregulate JAK-STAT signaling. Upon each transduction, CAPRIN1-JAK2 and SELENOI-ABL1 cause increased phosphorylation and display IL-3-independent growth compared to control. Upon treatments to small molecule inhibitors, ruxolitinib and imatinib respectively, CAPRIN1-JAK2 and SELENOI-ABL1 expressing cells exhibit sensitivity. Cutaneous T cell lymphoma, not otherwise specified, harbor JAK-STAT hotspot mutations but not kinase fusions. Conclusions: All 9 primary cutaneous CD8+ aggressive epidermotropic T cell lymphomas in our series harbor kinase fusions, while the majority of the cutaneous T cell lymphoma, not otherwise specified, cases in our cohort harbor hotspot JAK/STAT mutations. We provide evidence that the of presence these alterations, which are associated with inhibitor response, depend on cytotoxic T cell lymphoma histology.

Aims/hypothesis The hyperinsulinaemic–hypoglycaemic glucose clamp technique has been developed and applied to assess effects of and responses to hypoglycaemia under standardised conditions. However, the degree to which the methodology of clamp studies is standardised is unclear. This systematic review examines how hyperinsulinaemic–hypoglycaemic clamps have been performed and elucidates potential important differences. Methods A literature search in PubMed and EMBASE was conducted. Articles in English published between 1980 and 2018, involving adults with or without diabetes, were included. Results A total of 383 articles were included. There was considerable variation in essential methodology of the hypoglycaemic clamp procedures, including the insulin dose used (49-fold difference between the lowest and the highest rate), the number of hypoglycaemic steps (range 1−6), the hypoglycaemic nadirs (range 2.0–4.3 mmol/l) and the duration (ranging from 5 to 660 min). Twenty-seven per cent of the articles reported whole blood glucose levels, most venous levels. In 70.8% of the studies, a dorsal hand vein was used for blood sampling, with some form of hand warming to arterialise venous blood in 78.8% of these. Key information was missing in 61.9% of the articles. Conclusions/interpretation Although the hyperinsulinaemic–hypoglycaemic clamp procedure is considered the gold standard to study experimental hypoglycaemia, a uniform standard with key elements on how to perform these experiments is lacking. Methodological differences should be considered when comparing results between hypoglycaemic clamp studies. PROSPERO registration This systematic review is registered in PROSPERO (CRD42019120083). Graphical abstract

Over 5 decades, Cesarean Delivery rates (CDR) have risen 6-fold while vaginal operative deliveries [VODs] decreased from >20% to ∼3%. Poor outcomes (HIE and cerebral palsy) haven’t improved. Potentiating the virtual abandonment of forceps (F), particularly midforceps (Mid), were allegations about various poor neonatal outcomes. Here, we evaluate VOD and CDR outcomes controlling for prior fetal risk metrics (PR) ascertained an hour before birth. Our 45-year-old database from a labor research unit of moderate/high risk laboring patients (288 NSVDs, 120 Lows, 30 Mids, and 32 CDs) had multiple fetal scalp samples for base excess (BE), pH, cord blood gases (CB), and umbilical artery bloods. ANOVA established relationships between birth methods and outcomes (Cord blood BE and pH and 1 and 5 min Apgar scores); correlations, and two-step multiple regression assessed PR for delivery method and neonatal outcomes. The main outcome measures were correlations of outcome measures with fetal scalp sample BE and pH up to an hour before delivery and fetal reserve index scores scored concurrently. NSVDs had the best immediate neonatal outcomes with significantly higher CB pH and BE as compared to forceps and CDs. However, controlling for PR revealed: (1) PR at 1 h before delivery correlated with delivery mode, i.e. the decrements in outcomes were already present before the delivery was performed; and (2) The presumed deleterious effects of interventional deliveries, per se, were significantly reduced, and (3) Fetal Reserve Index predicted neonatal outcomes better than fetal scalp sample BE, pH, or delivery mode. The historical belief that MF deliveries caused poorer outcomes than NSVDs seems mostly backwards. Appreciating PR’s impact on delivery routes, and when appropriate, properly performing VODs could safely reduce CDR. If our approach lowered CDR by only ∼2%, in the United States about 80,000 CDs might be avoided, saving ∼$750 Million yearly. In the post pandemic world, safely apportioning medical expenses will be even more critical than previously.

CamAPS FX (CamDiab, Cambridge, U.K.) is a hybrid closed-loop app hosting the Cambridge closed-loop algorithm on an Android smartphone, and it is approved in the European Union for use in children ≥1 year and adults (including during pregnancy) with type 1 diabetes (T1D). The interoperable CamAPS FX app receives glucose data from a compatible continuous glucose monitoring system (Dexcom G6; Dexcom, San Diego, CA), connects to a compatible insulin pump (Dana Diabecare RS and DANA-i; Sooil, Seoul, South Korea) to direct glucose-responsive insulin delivery every 8–12 min, includes a bolus calculator allowing discrete bolusing via the app, and streams data in real time to cloud-based diabetes data repositories (Diasend/Glooko, Gothenburg, Sweden). It is currently unknown how much time different user cohorts spend interacting with hybrid closed-loop systems. We aimed to investigate usage patterns of the CamAPS FX app across different populations by considering the amount of time a person spends using the app over a 24-h period. We noted time spent within the CamAPS FX app over an 11-week period from February to May 2020 in 134 individuals from six ongoing clinical studies. Each study involved a different demo graphic cohort: very young children (1–7 years) in which caregivers use the app (NCT03784027, ClinicalTrials.gov), children and adolescents (6–19 years) (NCT02925299), adolescents (10–17 years) using the closed-loop system from diagnosis of T1D (NCT02871089), adults (≥18 years) (NCT04055480), pregnant women (≥18 years) (ISRCTN56898625, www.isrctn.org), and older adults (≥60 years) (NCT04025762). All studies received regulatory and ethical approval; participants/guardians signed informed consent. User engagement is the duration of time that users have the application active and in the foreground, as calculated by an analytics cloud platform (Firebase; …

Cannabinoid CB1 and CB2 receptors are members of the G protein-coupled receptor family, which is the largest class of membrane proteins in the human genome. As part of the endocannabinoid system, they have many regulatory functions in the human body. Their malfunction therefore triggers a diverse set of undesired conditions, such as pain, neuropathy, nephropathy, pruritus, osteoporosis, cachexia and Alzheimer’s disease. Although drugs targeting the system exist, the molecular and functional mechanisms involved are still poorly understood, preventing the development of better therapeutics with fewer undesired effects. One path toward the development of better and safer medicines targeting cannabinoid receptors relies on the ability of some compounds to activate a subset of pathways engaged by the receptor while sparing or even inhibiting the others, a phenomenon known as biased signaling. To take advantage of this phenomenon for drug development, a better profiling of the pathways engaged by the receptors is required. Using a BRET-based signaling detection platform, we systematically analyzed the primary signaling cascades activated by CB1 and CB2 receptors, including 9 G protein and 2 β-arrestin subtypes. Given that biased signaling is driven by ligand-specific distinct active conformations of the receptor, establishing a link between the signaling profiles elicited by different drugs and their chemotypes may help designing compounds that selectively activate beneficial pathways while avoiding those leading to undesired effects. We screened a selection of 35 structurally diverse ligands, including endocannabinoids, phytocannabinoids and synthetic compounds structurally similar or significantly different from natural cannabinoids. Our data show that biased signaling is a prominent feature of the cannabinoid receptor system and that, as predicted, ligands with different chemotypes have distinct signaling profiles. The study therefore allows for better understanding of cannabinoid receptors signaling and provides the information about tool compounds that can now be used to link signaling pathways to biological outcomes, aiding the design of improved therapeutics.

Despite its known limitations, laboratory-based HbA1c level is widely used to assess medium- and long-term glycaemia in people with diabetes because of its well-established link with diabetes-related complications [1]. However, the recent increase in real-time and intermittently-scanned continuous glucose monitoring (CGM) sensor use over recent years has meant that sensor-based metrics are being increasingly used by healthcare professionals and people living with type 1 diabetes to assess glycaemia [2]. These devices also allow remote data sharing with the clinical team through various data-sharing web platforms such as Diasend/Glooko, Abbott Libreview, Dexcom Clarity and Medtronic Carelink. The ability to visualize glucose data remotely has been useful in supporting healthcare professionals look after people with type 1 diabetes during the current COVID-19 pandemic, as the capacity to perform face-to-face clinic visits and laboratory HbA1c measurements has been restricted.

Pulp canal calcification is 1 of the possible outcomes after certain types of dental trauma. This can make endodontic treatment more challenging should it become necessary. Because of the increased degree of difficulty, sometimes procedural incidents do occur during root canal treatment. This case report demonstrates an unusual clinical presentation of a root perforation and missed canal, which had undergone calcification as a result of trauma some years earlier. A contemporary approach to treatment involved a combination of treating the biological complication of the calcified canal combined with surgical repair of the iatrogenic complication of a perforation using modern imaging techniques and materials.

The use of pH and base excess (FSSPHBE) from fetal scalp sampling (FSS) was abandoned when cardiotocography (CTG) was believed to be sufficiently accurate to direct patient management. We sought to understand the fetus' tolerance to stress in the 1st stage of labor and to develop a better and earlier screening test for its risk for developing acidosis. To do so, we investigated sequential changes in fetal pH and BE obtained from FSS in the 1st stage of labor as part of a research protocol from the 1970s. We then examined the utility of multiple of the median (MoM's) conversion of BE and pH values, and the capacity of Fetal Reserve Index (FRI) scores to be a proxy for such changes. We then sought to examine the predictive capacity of 1st stage FRI and its change over the course of the first stage of labor for the subsequent development of acidosis risk in the 2nd stage of labor.Using a retrospective research database evaluation, we evaluated FSSPHBE data from 475 high-risk parturients monitored in labor and their neonates for 1 h postpartum.We categorized specimens according to cervical dilatation (CxD) at the time of FSSPHBE and developed non-parametric, multiples of the median (MOMs) assessments. FRI scores and their change over time were used as predictors of FSSPHBE. Our main outcome measures were the changes in BE and pH at different cervical dilatations (CxD) and acidosis risk in the early 2nd stage of labor.FSSPHBE worsens over the course of the 1st stage. The implications of any given BE are very different depending upon CxD. At 9 cm, -8 Mmol/L is 1.1 MOM; at 3 cm, it would be 2.0 MOM. The FRI level and its trajectory provide a 1st stage screening tool for acidosis risk in the second stage.Fetal acid-base balance ("reserve") deteriorates beginning early in the 1st stage of labor, irrespective of whether the fetus reaches a critical threshold of concern for actual acidosis. The use of MoM's logic improves appreciation of such information. The FRI and its trajectory reasonably approximate the trajectory of the FSSPHBE and appears to be a suitable screening test for early deterioration and for earlier interventions to keep the fetus out of trouble rather than wait until high risk status develops.

The last decade has seen significant advances in the management of type 1 diabetes. The usual management of type 1 diabetes involves ‘physiological’ basal bolus regimens with multiple daily insulin injections, but use of insulin pumps (continuous subcutaneous insulin infusion) is growing. Structured education programmes are of great importance in realizing the potential of the flexible insulin regimens that are now technically possible; these now offer patients with type 1 diabetes standardized support and education in counting carbohydrates (and perhaps fat and protein) and in adjusting doses for other behavioural factors. Evolution of continuous glucose monitors from being tools for ‘forensic’ retrospective monitoring to ‘real-time’ devices for continuous use has led to major interest in strategies for glycaemic control that involve insulin pumps linked to continuous glucose monitoring, with the hope that this will provide increasing automation of insulin delivery. Data from many devices – meters, pumps and continuous glucose monitors – are downloadable and can be analysed and/or shared with healthcare providers. In this chapter, we describe how modern glucose monitoring and insulin replacement can be used strategically together with education to manage glycaemia in type 1 diabetes.

An extramedullary plasmacytoma involving the gastrointestinal tract is extremely rare. We report an appendiceal extramedullary plasmacytoma in a 35-year-old man who presented to the emergency department because of upper abdominal pain. Computed tomography (CT) imaging revealed an incidental mass (3.7 × 1.9 × 1.6 cm) at the tip of the appendix. Microscopically, the appendix, periappendiceal soft tissue, and nearby lymph nodes were diffusely infiltrated by plasma cells that were kappa light chain restricted. Subsequent workup included an unremarkable bone marrow biopsy, as well as urine and serum electrophoresis. A diagnosis of kappa-restricted solitary extramedullary plasmacytoma was made. To our knowledge, this is the first case reported of an appendiceal extramedullary plasmacytoma in the medical literature.

Objective: The objective was to describe a novel composite continuous glucose monitoring index (COGI) and to evaluate its utility, in adults with type 1 diabetes, during hybrid closed-loop (HCL) therapy and multiple daily injections (MDI) therapy combined with real-time continuous glucose monitoring (CGM). Methods: COGI consists of three key components of glucose control as assessed by CGM: Time in range (TIR), time below range (TBR), and glucose variability (GV) (weighted by 50%, 35% and 15%). COGI ranges from 0 to 100, where 1% increase of time Results: Continuous subcutaneous insulin infusion (CSII) users with HbA1c >7.5-10%, had significantly higher COGI during 12 weeks of HCL compared to sensor-augmented pump therapy, mean (SD), 60.3 (8.6) versus 69.5 (6.9), P < .001. Similarly, in CSII users with HbA1c 7.5% to 9.9%, use of real-time CGM led to improved COGI, 49.8 (14.2) versus 58.2 (9.1), P < .0001. In MDI users with impaired awareness of hypoglycemia, use of real-time CGM led to improved COGI, 53.4 (12.2) versus 66.7 (11.1), P < .001. Conclusions: COGI summarizes three key aspects of CGM data into a concise metric that could be utilized to evaluate the quality of glucose control and to demonstrate the incremental benefit of a wide range of treatment modalities.

Since the first reported case in 1997, over 600 women with breast implant-associated anaplastic large cell lymphoma (BI ALCL) have been reported. BI ALCL is a CD30-positive T-cell lymphoma that carries clonal T-cell receptor gene rearrangements, and a subset of cases harbors mutations in the JAK-STAT signaling pathway. Rarely, other histologic types of lymphoma have been reported in association with breast implants, including fewer than 10 cases of B-cell origin. Here, we describe three additional patients with B-cell lymphoma occurring around breast implants. Two of these patients developed extranodal marginal zone lymphoma in the peri-implant capsule, one of which had a concurrent ALCL within the superficial lining of the capsule. The third patient presented with diffuse large B-cell lymphoma inside the breast parenchyma surrounding her implant. Determining the etiology and risk factors for the development of B-cell lymphomas associated with breast implants remains challenging, given the wide spectrum of histologic features and the rarity of these neoplasms. Ultimately, we document three new cases of B-cell lymphoma arising around breast implants and highlight their clinical and pathologic features in order to expand our understanding of this rare disease presentation.

Infertility treatments have allowed millions of couples to have their own children, but resultant multiple pregnancies with their increased morbidity and mortality have been a significant complication. Fetal reduction was developed to ameliorate this issue. Over 30 years of publications show that fetal reduction has been highly successful in substantially reducing both mortality and morbidity related to multiple pregnancies. As with most radically new techniques, initial cases were in the "nothing to lose" category. With experience, indications liberalize, and quality of life issues gain relevance. The overall risks of twin pregnancy are not twice that of singleton pregnancy; they are about 4 to 5 times higher. In experienced hands, the combination of genetic testing by chorionic villus sampling followed by fetal reduction has made the outcomes of most multiple pregnancies statistically equivalent to those of pregnancies with lower fetal numbers. Use of microarray analysis to better determine fetal genetic health before deciding on which fetus(es) to keep or reduce further improves pediatric outcomes. With increasing experience and lower average starting numbers, the proportion of fetal reductions to a singleton has increased considerably. Twins to a singleton fetal reductions now constitute an increasing proportion of cases performed. Data on such cases show improved outcomes, and we believe fetal reduction should be at least discussed and offered to all patients with a dichorionic twin pregnancy or higher. With the increasing reliance on elective single-embryo transfers, monochorionic twins, which have much higher complication rates than dichorionic twins, have increased substantially. Furthermore, monochorionic twins cannot be readily and safely reduced, so the adverse perinatal statistics of elective single-embryo transfer are a major setback for good outcomes. Although elective single-embryo transfer is appropriate for some, we believe that for many couples, the transfer of 2 embryos is generally a more rational approach.

171 Background: Mutational profiling is recommended for selecting targeted therapy for metastatic colorectal cancer (mCRC). Evidence suggests that among patients with mutations in one of three RAS genes who underwent resection of liver metastasis, those with early onset mCRC had worse outcomes compared to those with late onset mCRC. The goal of this study was to explore whether other mutated genes in mCRC exhibit an association between age and wild type versus mutant RAS status. Methods: Between October 2018 and October 2020, 974 tumor samples from patients with mCRC were identified. Samples meeting requirements were profiled with the Oncotype MAP Pan-Cancer Tissue test, which sequences 257 genes from tumor tissue, including all 3 RAS genes ( HRAS, KRAS, NRAS). Using the Oncotype MAP assay, single base variants, indels, copy number alterations and structural variants/fusions were identified. Tumor mutational burden (TMB) and microsatellite instability (MSI) were also determined. To identify genes for which there was an association between age group (patients ≤50 years vs >50 years) and RAS status we used Fisher’s Exact Test. Results: Of the 974 samples, 840 met minimum tumor tissue requirements for DNA sequencing (3mm2 and 15% tumor cellularity). Of these, 759 samples were successfully sequenced for NGS. Median turnaround time from the date of sample accessioning to the date of laboratory report was 5 days (interquartile range, IQR, 4-6 days). TMB varied from 0-227 mutations per megabase (median 6, IQR 4-8), and was high (≥10 mut/Mb) in 117 samples (15%). Of 775 specimens processed for MSI, 714 could be measured and approximately 7% were MSI-high. A total of 496 RAS variants were identified, of which 391 were pathogenic, likely pathogenic, or variants of unknown significance (349 KRAS, 34 NRAS, 8 HRAS). Of the 27 genes with at least 78 mutations in the data set, there was an association between RAS status and patient age for mutations at SMAD4, ABCC1, and RICTOR (Fisher’s Exact test, P < 0.05). For all three, mutations at these genes are relatively more prevalent in samples from young RAS wild type patients compared to young RAS mutant patients (Table). Conclusions: The Oncotype MAP Pan-Cancer Tissue test identified numerous genomic changes in mCRC samples. There appears to be an association between age group and RAS status for three mutated genes, SMAD4, ABCC1, and RICTOR. The clinical implication is unclear and warrants further investigation with outcomes data.[Table: see text]

471 Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is often diagnosed at an advanced stage with limited effective therapies. The advent of comprehensive genomic molecular profiling has the potential to identify novel therapeutic options in the treatment of HCC. In this descriptive clinical utility study, we evaluated the utility of the Oncotype MAP Pan-Cancer Tissue (MAP) test to identify potential therapeutic options, including clinical trials. Methods: Between October 2018 and October 2020, we identified 41 samples from patients with HCC submitted for MAP testing. The MAP test uses tumor tissue to identify single nucleotide variants, indels, copy number alterations, and select structural variants and fusions by next-generation sequencing (NGS) of a 257 gene panel. Tumor mutational burden and microsatellite instability are also determined. A custom immunohistochemical (IHC) panel is also performed. Results from NGS and IHC are run against a proprietary knowledgebase of genomic and proteomic data that includes FDA approvals, NCCN Recommendations and published biomarker data on potentially targetable alterations. Eligibility for ongoing clinical trials is determined using the NCI database. Results: Of the 41 samples, 37 (90%) met minimum tissue requirements (3mm2 and 15% tumor cellularity) for DNA sequencing. Of these 37 samples, 36 (97%) were successfully sequenced for NGS testing. Median turnaround time from the date of accessioning to the date of laboratory report was 5 days (interquartile range (IQR) 4-6 days). The most frequently identified genomic variants characterized as pathogenic, or unknown significance, were TP53, CTNNB1 and FAT1 genes. Thirty-two samples (86%) had a genomic alteration that could potentially direct treatment. Six samples (16%) had findings directing to an approved treatment for HCC, 4 (11%) had findings for an approved treatment of a different tumor type, and 22 (59%) had findings for one or more clinical trials. Conclusions: The Oncotype MAP Pan-Cancer Tissue test identified molecular variants that could be used to inform treatment decisions in 86% of HCC samples, including 16% to an approved HCC therapy. The Oncotype MAP test may be considered as another tool in the management of advanced HCC patients.

OBJECTIVE To assess the implications of increasing utilization of noninvasive prenatal screening (NIPS), which may reach 50% with the concomitant decrease in diagnostic procedures (DPs) for its impact on detection of chromosomal abnormalities. METHODS We studied our program's statistics over 5 years for DPs and utilization of array comparative genomic hybridization (aCGH). We then modeled the implications in our program if DP had not fallen and nationally of a 50% DP and aCGH testing rate using well-vetted expectations for the diagnosis of abnormal copy number variants (CNVs). RESULTS Our DP fell 40% from 2013-2017. Utilization of aCGH for DP nearly tripled. We detected 28 abnormal CNVs. If DP had not fallen, we likely would have detected 60. With 4 million US births per year, 2 million DPs would detect 30 000 abnormal CNVs and 4000 standard aneuploidies. At a 1/500 complication-pregnancy loss rate, the detection/complication ratio is 8.5/1. CONCLUSIONS Noninvasive prenatal screening has significantly changed the practice of prenatal screening. However, while increasing the detection of Down syndrome, the concomitant decrease in DP and lack of aCGH results in missing many more abnormalities than the increase in Down syndrome and complications of DP combined. From a public health perspective, such represents a missed opportunity for overall health care delivery.

Tanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse events requiring total joint replacements, resulting in a partial clinical hold on all NGF inhibitors. Three nonclinical toxicology studies were conducted to evaluate the effects of tanezumab or the murine precursor muMab911 on selected bone and joint endpoints and biomarkers in cynomolgus monkeys, Sprague-Dawley rats, and C57BL/6 mice. Joint and bone endpoints included histology, immunohistochemistry, microcomputed tomography (mCT) imaging, and serum biomarkers of bone physiology. Responses of bone endpoints to tanezumab were evaluated in monkeys at 4 to 30 mg/kg/week for 26 weeks and in rats at 0.2 to 10 mg/kg twice weekly for 28 days. The effects of muMab911 at 10 mg/kg/week for 12 weeks on selected bone endpoints were determined in mice. Tanezumab and muMab911 had no adverse effects on any bone or joint parameter. There were no test article–related effects on bone or joint histology, immunohistochemistry, or structure. Reversible, higher osteocalcin concentrations occurred only in the rat study. No deleterious effects were observed in joints or bones in monkeys, rats, or mice administered high doses of tanezumab or muMab911.

OBJECTIVE To compare the 6-month use rate of the etonogestrel implant placed immediately after dilation and evacuation (D&E) with placement 2-4 weeks postprocedure. METHODS This is a randomized controlled trial of women seeking abortion between 14 0/7 and 23 5/7 weeks of gestation and desiring the etonogestrel contraceptive implant at an urban family planning clinic. Participants were randomized to device insertion immediately after the D&E compared with delayed insertion in 2-4 weeks. The primary outcome was implant use rate at 6 months after insertion and was determined by follow-up phone interviews. Secondary outcomes included repeat pregnancy rates and method satisfaction. The sample size of 120 participants was calculated based on a power of 0.80 to demonstrate a 20% difference in implant use rates between groups assuming 40% of women overall are not using the device 6 months after the procedure. RESULTS Between November 2015 and October 2016, 148 participants were enrolled. Seventy-three participants (49.3%) were randomized to and underwent immediate implant insertion after D&E. The remaining 75 (50.6%) were randomized to delayed insertion. There were no significant differences in sociodemographic characteristics between the groups. Placement rate was 100% in the immediate group compared with 42.7% in the delayed group (P

OBJECTIVE Severe hypoglycemia is a feared complication of type 1 diabetes; yet, few trials have targeted prevention using optimized self-management (educational, therapeutic, and technological support). We aimed to investigate whether improved awareness and reduced severe hypoglycemia, achieved during an intensive randomized clinical trial (RCT), were sustained after return to routine care. RESEARCH DESIGN AND METHODS Ninety-six adults with type 1 diabetes (29 ± 12 years’ duration) and impaired awareness of hypoglycemia at five U.K. tertiary referral diabetes centers were recruited into a 24-week 2 × 2 factorial RCT (HypoCOMPaSS). Participants were randomized to pump (continuous subcutaneous insulin infusion [CSII]) or multiple daily injections (MDIs) and real-time continuous glucose monitoring (RT-CGM) or self-monitoring of blood glucose (SMBG), with equal education/attention to all groups. At 24 weeks, participants returned to routine care with follow-up until 24 months, including free choice of MDI/CSII; RT-CGM vs. SMBG comparison continued to 24 months. Primary outcome was mean difference (baseline to 24 months [between groups]) in hypoglycemia awareness. RESULTS Improvement in hypoglycemia awareness was sustained (Gold score at baseline 5.1 ± 1.1 vs. 24 months 3.7 ± 1.9; P < 0.0001). Severe hypoglycemia rate was reduced from 8.9 ± 12.8 episodes/person-year over the 12 months prestudy to 0.4 ± 0.8 over 24 months (P < 0.0001). HbA1c improved (baseline 8.2 ± 3.2% [66 ± 12 mmol/mol] vs. 24 months 7.7 ± 3.1% [61 ± 10 mmol/mol]; P = 0.003). Improvement in treatment satisfaction and reduced fear of hypoglycemia were sustained. There were no significant differences between interventions at 24 months. CONCLUSIONS Optimized insulin replacement and glucose monitoring underpinned by hypoglycemia-focused structured education should be provided to all with type 1 diabetes complicated by impaired awareness of hypoglycemia.

The near-ubiquitous use of electronic fetal monitoring has failed to lower the rates of both cerebral palsy and emergency operative deliveries (EODs). Its performance metrics have low sensitivity, specificity, and predictive values for both. There are many EODs, but the vast majority have normal outcomes. The EODs, however, cause serious disruption in the delivery suite routine with increased complications, anxiety, and concern for all.We developed the fetal reserve index (FRI) as multicomponent algorithm including 4 FHR components (analyzed individually), uterine activity, and maternal, obstetrical, and fetal risk factors to assess risk of cerebral palsy and EOD. Scores were categorized into green, yellow, and red zones. Here, we studied 300 patients by the FRI, all of whom had normal neonatal outcomes. We attempted to distinguish the clinical course of those cases which required an EOD versus controls which did not.51 cases with EOD had FRIs much lower than 249 non-EOD cases. The red zone was reached more frequently ( P.001) and lasted longer (1.06 vs 0.05 hours; P.001). Reaching the red zone had a sensitivity of 92% for EOD, with a positive predictive value of 64% and a false positive rate of 10.4%.Our data suggest the FRI can significantly lower the incidence of EODs by identifying the opportunity for intrauterine resuscitation. Our approach can reduce the disruptive effects of EODs and their concomitant increased risks of complications. The FRI may provide a metric that can refine labor management to reduce CP and EODs.

Tanezumab, a humanized monoclonal anti-NGF antibody, has demonstrated efficacy and safety profiles in Phase III clinical trials of chronic pain. In a 24-week study in non-human primates, morphological observations of sympathetic ganglia showed decreased ganglia volume, decreased neuronal size, and increased glial cell density compared with controls after 3 tanezumab treatments. Using stereological techniques to quantify glial cells, the present 26-week study found no significant difference after weekly treatments in total cervicothoracic ganglia satellite glial cell number between placebo- or tanezumab-treated cynomolgus monkeys. These findings suggest that tanezumab treatment does not result in a true gliosis in sympathetic ganglia.