A Reconsideration of the Core and Matrix Classification of Thalamocortical Projections.

In 1998, Jones suggested a classification of thalamocortical projections into core and matrix divisions (Jones, 1998). In this classification, core projections are specific, topographical, innervate middle cortical layers, and serve to transmit specific information to the cortex for further analysis; matrix projections, in contrast, are diffuse, much less topographic, innervate upper layers, especially Layer 1, and serve a more global, modulatory function, such as affecting levels of arousal. This classification has proven especially influential in studies of thalamocortical relationships. Whereas it may be the case that a clear subset of thalamocortical connections fit the core motif, since they are specific, topographic, and innervate middle layers, we argue that there is no clear evidence for any single class that encompasses the remainder of thalamocortical connections as is claimed for matrix. Instead, there is great morphological variation in connections made by thalamocortical projections fitting neither a core nor matrix classification. We thus conclude that the core/matrix classification should be abandoned, because its application is not helpful in providing insights into thalamocortical interactions and can even be misleading. As one example of the latter, recent suggestions indicate that core projections are equivalent to first-order thalamic relays (i.e., those that relay subcortical information to the cortex) and matrix to higher-order relays (i.e., those that relay information from one cortical area to another), but available evidence does not support this relationship. All of this points to a need to replace the core/matrix grouping with a more complete classification of thalamocortical projections.

Conserved patterns of functional organization between cortex and thalamus in mice.

Higher-order thalamic nuclei contribute to sensory processing via projections to primary and higher cerebral cortical areas, but it is unknown which of their cortical and subcortical inputs contribute to their distinct output pathways. We used subpopulation specific viral strategies in mice to anatomically and physiologically dissect pathways of the higher-order thalamic nuclei of the somatosensory and visual systems (the posterior medial nucleus and pulvinar). Employing a complementary optogenetics and electrical stimulation strategy, we show that synapses in cortex from higher-order thalamus have functionally divergent properties in primary vs. higher cortical areas. Higher-order thalamic projections onto excitatory targets in S1 and V1 were weakly modulatory, while projections to S2 and higher visual areas were strong drivers of postsynaptic targets. Then, using transsynaptic tracing verified by optogenetics to map inputs to higher-order thalamus, we show that posterior medial nucleus cells projecting to S1 are driven by neurons in layer 5 of S1, S2, and M1 and that pulvinar cells projecting to V1 are driven by neurons in layer 5 of V1 and higher visual areas. Therefore, in both systems, layer 5 of primary and higher cortical areas drives transthalamic feedback modulation of primary sensory cortex through higher-order thalamus. These results highlight conserved organization that may be shared by other thalamocortical circuitry. They also support the hypothesis that direct corticocortical projections in the brain are paralleled by transthalamic pathways, even in the feedback direction, with feedforward transthalamic pathways acting as drivers, while feedback through thalamus is modulatory.

Layer 5 of cortex innervates the thalamic reticular nucleus in mice.

Neurons in the thalamic reticular nucleus (TRN) are a primary source of inhibition to the dorsal thalamus and, as they are innervated in part by the cortex, are a means of corticothalamic regulation. Previously, cortical inputs to the TRN were thought to originate solely from layer 6 (L6), but we recently reported the presence of putative synaptic terminals from layer 5 (L5) neurons in multiple cortical areas in the TRN [J. A. Prasad, B. J. Carroll, S. M. Sherman, J. Neurosci. 40, 5785-5796 (2020)]. Here, we demonstrate with electron microscopy that L5 terminals from multiple cortical regions make bona fide synapses in the TRN. We further use light microscopy to localize these synapses relative to recently described TRN subdivisions and show that L5 terminals target the edges of the somatosensory TRN, where neurons reciprocally connect to higher-order thalamus, and that L5 terminals are scarce in the core of the TRN, where neurons reciprocally connect to first-order thalamus. In contrast, L6 terminals densely innervate both edge and core subregions and are smaller than those from L5. These data suggest that a sparse but potent input from L5 neurons of multiple cortical regions to the TRN may yield transreticular inhibition targeted to higher-order thalamus.

Integration of signals from different cortical areas in higher order thalamic neurons.

Higher order thalamic neurons receive driving inputs from cortical layer 5 and project back to the cortex, reflecting a transthalamic route for corticocortical communication. To determine whether or not individual neurons integrate signals from different cortical populations, we combined electron microscopy "connectomics" in mice with genetic labeling to disambiguate layer 5 synapses from somatosensory and motor cortices to the higher order thalamic posterior medial nucleus. A significant convergence of these inputs was found on 19 of 33 reconstructed thalamic cells, and as a population, the layer 5 synapses were larger and located more proximally on dendrites than were unlabeled synapses. Thus, many or most of these thalamic neurons do not simply relay afferent information but instead integrate signals as disparate in this case as those emanating from sensory and motor cortices. These findings add further depth and complexity to the role of the higher order thalamus in overall cortical functioning.

Profile of and risk factors for early unplanned readmissions in patients with acute necrotizing pancreatitis.

INTRODUCTION: Acute necrotizing pancreatitis (ANP) complicates up to 15% of acute pancreatitis cases. ANP has historically been associated with a significant risk for readmission, but there are currently no studies exploring factors that associate with risk for unplanned, early (<30-day) readmissions in this patient population. METHODS: We performed a retrospective review of all consecutive patients presenting to hospitals in the Indiana University (IU) Health system with pancreatic necrosis between December 2016 and June 2020. Patients younger than 18 years of age, without confirmed pancreatic necrosis and those that suffered in-hospital mortality were excluded. Logistic regression was performed to identify potential predictors of early readmission in this group of patients. RESULTS: One hundred and sixty-two patients met study criteria. 27.7% of the cohort was readmitted within 30-days of index discharge. The median time to readmission was 10 days (IQR 5-17 days). The most frequent reason for readmission was abdominal pain (75.6%), followed by nausea and vomiting in (35.6%). Discharge to home was associated with 93% lower odds of readmission. We found no additional clinical factors that predicted early readmission. CONCLUSION: Patients with ANP have a significant risk for early (<30 days) readmission. Direct discharge to home, rather than short or long-term rehabilitation facilities, is associated with lower odds of early readmission. Analysis was otherwise negative for independent, clinical predictors of early unplanned readmissions in ANP.

COVID-19 vaccination acceptability in the UK at the start of the vaccination programme: a nationally representative cross-sectional survey (CoVAccS - wave 2).

OBJECTIVES: Investigate factors associated with the intention to have the COVID-19 vaccination following initiation of the UK national vaccination programme. STUDY DESIGN: An online cross-sectional survey completed by 1500 adults (13th-15th January 2021). METHODS: Linear regression analyses were used to investigate associations between intention to be vaccinated for COVID-19 and sociodemographic factors, previous influenza vaccination, attitudes and beliefs about COVID-19 and COVID-19 vaccination and vaccination in general. Participants' main reasons for likely vaccination (non-)uptake were also solicited. RESULTS: 73.5% of participants (95% CI 71.2%, 75.7%) reported being likely to be vaccinated against COVID-19, 17.3% (95% CI 15.4%, 19.3%) were unsure, and 9.3% (95% CI 7.9%, 10.8%) reported being unlikely to be vaccinated. The full regression model explained 69.8% of the variance in intention. Intention was associated with: having been/intending to be vaccinated for influenza last winter/this winter; stronger beliefs about social acceptability of a COVID-19 vaccine; the perceived need for vaccination; adequacy of information about the vaccine; and weaker beliefs that the vaccine is unsafe. Beliefs that only those at serious risk of illness should be vaccinated and that the vaccines are just a means for manufacturers to make money were negatively associated with vaccination intention. CONCLUSIONS: Most participants reported being likely to get the COVID-19 vaccination. COVID-19 vaccination attitudes and beliefs are a crucial factor underpinning vaccine intention. Continued engagement with the public with a focus on the importance and safety of vaccination is recommended.

Layer 5 Corticofugal Projections from Diverse Cortical Areas: Variations on a Pattern of Thalamic and Extrathalamic Targets.

The cerebral cortex, with all its computational power, can only influence behavior via corticofugal connections originating from layer 5 (L5) cells (Sherman and Guillery, 2013). To begin to establish the global pattern of these outputs, we examined L5 efferents originating from four cortical areas: somatosensory, visual, motor, and prefrontal (i.e., ventromedial orbitofrontal) cortex. We injected Cre-dependent adeno-associated virus in an Rbp4-Cre transgenic mouse line (both sexes) to label these L5 efferents selectively. Our study reveals that, across this diverse series of cortical regions, L5 commonly projects to multiple thalamic and extrathalamic sites. We also identified several novel corticofugal targets (i.e., the lateral dorsal nucleus, submedial nucleus) previously unidentified as L5 targets. We identified common patterns for these projections: all areas innervated both thalamus and the midbrain, and all areas innervated multiple thalamic targets, including those with core and matrix cell types (Jones, 1998). An examination of the terminal size within each of these targets suggests that terminal populations of L5 efferents are not consistently large but vary with cortical area and target; and in some cases, these include small terminals only. Overall, our data reveal more widespread and diverse L5 efferents than previously appreciated, suggesting a generalizable role for this cortical layer in influencing motor commands and cognitive processes.SIGNIFICANCE STATEMENT While the neocortex is responsible for coordination of complex behavior, it requires communication with subcortical regions to do so. It is specifically cortical layer 5 (L5) that is thought to underlie these behaviors, although it is unknown whether this holds true across functionally different cortical areas. Using a selective viral tracing method and transgenic mice, we examined the connectivity of four cortical regions (somatosensory, visual, motor and prefrontal cortex) to assess the generalizability of these L5 projections. All areas of cortex projected to overlapping as well as distinct thalamic and brainstem structures. Terminals within these regions varied in size, implicating that L5 has a broad and diverse impact on behavior.

An ultrastructural connectomic analysis of a higher-order thalamocortical circuit in the mouse.

Many studies exist of thalamocortical synapses in primary sensory cortex, but much less in known about higher-order thalamocortical projections to higher-order cortical areas. We begin to address this gap using genetic labeling combined with large volume serial electron microscopy (i.e., "connectomics") to study the projection from the thalamic posterior medial nucleus to the secondary somatosensory cortex in a mouse. We injected into this thalamic nucleus a cocktail combining a cre-expressing virus and one expressing cre-dependent ascorbate peroxidase that provides an electron dense cytoplasmic label. This "intersectional" viral approach specifically labeled thalamocortical axons and synapses, free of retrograde labeling, in all layers of cortex. Labeled thalamocortical synapses represented 14% of all synapses in the cortical volume, consistent with previous estimates of first-order thalamocortical inputs. We found that labeled thalamocortical terminals, relative to unlabeled ones: were larger, were more likely to contain a mitochondrion, more frequently targeted spiny dendrites and avoided aspiny dendrites, and often innervated larger spines with spine apparatuses, among other differences. Furthermore, labeled terminals were more prevalent in layers 2/3 and synaptic differences between labeled and unlabeled terminals were greatest in layers 2/3. The laminar differences reported here contrast with reports of first-order thalamocortical connections in primary sensory cortices where, for example, labeled terminals were larger in layer 4 than layers 2/3 (Viaene et al., 2011a). These data offer the first glimpse of higher-order thalamocortical synaptic ultrastructure and point to the need for more analyses, as such connectivity likely represents a majority of thalamocortical circuitry.

ASO Author Reflections: Indolent Growth and Small Bowel Neuroendocrine Tumor Management.

Surgical treatment is central to management of small bowel neuroendocrine tumors (SBNETs). Current controversies include whether to resect asymptomatic primary tumors in the setting of unresectable metastases, the role of minimally invasive surgery, and how best to incorporate/sequence medical treatments. Low SBNET incidence, long event-times, and variability in disease burden, surgical technique, and institutional treatment preferences remain obstacles to conducting randomized surgical trials for SBNETs. With increasing referral of these patients to high-volume centers, cooperation between experienced SBNET clinicians should allow design of high-quality randomized trials to test new treatments and answer key questions.

Should we be imaging lymph nodes at initial diagnosis of early-stage mycosis fungoides? Results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) international study.

BACKGROUND: Early-stage mycosis fungoides (MF) includes involvement of dermatopathic lymph nodes (LNs) or early lymphomatous LNs. There is a lack of unanimity among current guidelines regarding the indications for initial staging imaging in early-stage presentation of MF in the absence of enlarged palpable LNs. OBJECTIVES: To investigate how often imaging is performed in patients with early-stage presentation of MF, to assess the yield of LN imaging, and to determine what disease characteristics promoted imaging. METHODS: A review of clinicopathologically confirmed newly diagnosed patients with cutaneous patch/plaque (T1/T2) MF from PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) data. RESULTS: PROCLIPI enrolled 375 patients with stage T1/T2 MF: 304 with classical MF and 71 with folliculotropic MF. Imaging was performed in 169 patients (45%): 83 with computed tomography, 18 with positron emission tomography-computed tomography and 68 with ultrasound. Only nine of these (5%) had palpable enlarged (≥ 15 mm) LNs, with an over-representation of plaques, irrespectively of the 10% body surface area cutoff that distinguishes T1 from T2. Folliculotropic MF was not more frequently imaged than classical MF. Radiologically enlarged LNs (≥ 15 mm) were detected in 30 patients (18%); only seven had clinical lymphadenopathy. On multivariate analysis, plaque presentation was the sole parameter significantly associated with radiologically enlarged LNs. Imaging of only clinically enlarged LNs upstaged 4% of patients (seven of 169) to at least IIA, whereas nonselective imaging upstaged another 14% (24 of 169). LN biopsy, performed in eight of 30 patients, identified N3 (extensive lymphomatous involvement) in two and N1 (dermatopathic changes) in six. CONCLUSIONS: Physical examination was a poor determinant of LN enlargement or involvement. Presence of plaques was associated with a significant increase in identification of enlarged or involved LNs in patients with early-stage presentation of MF, which may be important when deciding who to image. Imaging increases the detection rate of stage IIA MF, and identifies rare cases of extensive lymphomatous nodes, upstaging them to advanced-stage IVA2.

The PEARL study: a prospective two-group pilot PrEP promotion intervention for cisgender female sex workers living in Baltimore, MD, U.S.

HIV remains elevated among female sex workers (FSW) globally, with a number of structural (e.g., poverty, access to care) factors driving these persistently high rates. Pre-exposure prophylaxis (PrEP), a user-controlled prevention method, is a promising means of empowering vulnerable populations to protect themselves and enhance agency. Yet there is a dearth of PrEP research and interventions targeting cisgender women in the United States, and even fewer aimed to reach FSW. We developed and implemented a multifaceted PrEP pilot intervention, the Promoting Empowerment And Risk Reduction (PEARL) study, to meet this gap. This paper describes the development process and nature of a community-informed intervention for tenofovir/emticitrabine (TDF/FTC) pre-exposure prophylaxis engagement among street-based cisgender FSW in Baltimore, Maryland, U.S. In the course of the study's implementation, structural, programmatic, and medical barriers have already posed significant barriers to full engagement. PEARL implemented a number of strategies in an effort to counter barriers and facilitate increased success of PrEP uptake and maintenance. The study will provide critical insights into the nature of intervention components that could help FSW to initiate PrEP and reduce PrEP care cascade gaps.

Complexation reduces nickel toxicity to purple sea urchin embryos (Strongylocentrotus purpuratus), a test of biotic ligand principles in seawater.

The potential for Ni toxicity in seawater is of concern because of mining and processing activities in coastal regions. Determining Ni speciation is vital to understanding and predicting Ni toxicity and for bioavailability-based nickel risk assessment. The goal of this study was to characterize the complexation of Ni in relation to toxicity using embryological development of purple sea urchin (S. purpuratus). It was predicted that free ion [Ni2+] would be a better predictor of toxicity than total dissolved Ni concentrations (NiD). Synthetic ligands with known logKf values (Ethylenediaminetetraacetic acid (EDTA), Nitrilotriacetic acid (NTA), tryptophan (TRP), glutamic acid (GA), histidine (HD), and citric acid (CA)) were used to test the assumptions of the biotic ligand model (BLM) for Ni in seawater. [NiD] was measured by graphite furnace atomic absorption spectroscopy (GFAAS) and Ni2+ was first quantified using the ion-exchange technique (IET) and then concentrations were measured by GFAAS; [Ni2+] was also estimated using aquatic geochemistry modelling software (Visual Minteq). The mean EC50 values for [NiD] in unmodified artificial seawater control was 3.6 µM (95% CI 3.0-4.5) [211 µg/L 95% CI 176-264] and the addition of ligands provided protection, up to 6.5-fold higher [NiD] EC50 for EDTA. Compared to the control, measured EC50 values based on total dissolved nickel were higher in the presence of ligands. As predicted by BLM theory, [Ni2+] was a better predictor of Ni toxicity with 17% variability in EDTA and CA media while there was 72% variability in the prediction of Ni toxicity with total dissolved Ni. The results of this research provide support for the application of BLM- based prediction models for estimating Ni impacts in seawater.

A Sensorimotor Pathway via Higher-Order Thalamus.

We now know that sensory processing in cortex occurs not only via direct communication between primary to secondary areas, but also via their parallel cortico-thalamo-cortical (i.e., trans-thalamic) pathways. Both corticocortical and trans-thalamic pathways mainly signal through glutamatergic class 1 (driver) synapses, which have robust and efficient synaptic dynamics suited for the transfer of information such as receptive field properties, suggesting the importance of class 1 synapses in feedforward, hierarchical processing. However, such a parallel arrangement has only been identified in sensory cortical areas: visual, somatosensory, and auditory. To test the generality of trans-thalamic pathways, we sought to establish its presence beyond purely sensory cortices to determine whether there is a trans-thalamic pathway parallel to the established primary somatosensory (S1) to primary motor (M1) pathway. We used trans-synaptic viral tracing, optogenetics in slice preparations, and bouton size analysis in the mouse (both sexes) to document that a circuit exists from layer 5 of S1 through the posterior medial nucleus of the thalamus to M1 with glutamatergic class 1 properties. This represents a hitherto unknown, robust sensorimotor linkage and suggests that the arrangement of parallel direct and trans-thalamic corticocortical circuits may be present as a general feature of cortical functioning.SIGNIFICANCE STATEMENT During sensory processing, feedforward pathways carry information such as receptive field properties via glutamatergic class 1 synapses, which have robust and efficient synaptic dynamics. As expected, class 1 synapses subserve the feedforward projection from primary to secondary sensory cortex, but also a route through specific higher-order thalamic nuclei, creating a parallel feedforward trans-thalamic pathway. We now extend the concept of cortical areas being connected via parallel, direct, and trans-thalamic circuits from purely sensory cortices to a sensorimotor cortical circuit (i.e., primary sensory cortex to primary motor cortex). This suggests a generalized arrangement for corticocortical communication.

Targeting the receptor for advanced glycation end products (RAGE) in type 1 diabetes.

Type 1 diabetes (T1D) is one of the most common chronic diseases manifesting in early life, with the prevalence increasing worldwide at a rate of approximately 3% per annum. The prolonged hyperglycaemia characteristic of T1D upregulates the receptor for advanced glycation end products (RAGE) and accelerates the formation of RAGE ligands, including advanced glycation end products, high-mobility group protein B1, S100 calcium-binding proteins, and amyloid-beta. Interestingly, changes in the expression of RAGE and these ligands are evident in patients before the onset of T1D. RAGE signals via various proinflammatory cascades, resulting in the production of reactive oxygen species and cytokines. A large number of proinflammatory ligands that can signal via RAGE have been implicated in several chronic diseases, including T1D. Therefore, it is unsurprising that RAGE has become a potential therapeutic target for the treatment and prevention of disease. In this review, we will explore how RAGE might be targeted to prevent the development of T1D.

Synaptic properties of the lemniscal and paralemniscal pathways to the mouse somatosensory thalamus.

Somatosensory information is thought to arrive in thalamus through two glutamatergic routes called the lemniscal and paralemniscal pathways via the ventral posterior medial (VPm) and posterior medial (POm) nuclei. Here we challenge the view that these pathways functionally represent parallel information routes. Using electrical stimulation and an optogenetic approach in brain slices from the mouse, we investigated the synaptic properties of the lemniscal and paralemniscal input to VPm and POm. Stimulation of the lemniscal pathway produced class 1, or "driver," responses in VPm relay cells, which is consistent with this being an information-bearing channel. However, stimulation of the paralemniscal pathway produced two distinct types of responses in POm relay cells: class 1 (driver) responses in 29% of the cells, and class 2, or "modulator," responses in the rest. Our data suggest that, unlike the lemniscal pathway, the paralemniscal one is not homogenous and that it is primarily modulatory. This finding requires major rethinking regarding the routes of somatosensory information to cortex and suggests that the paralemniscal route is chiefly involved in modulatory functions rather than simply being an information route parallel to the lemniscal channel.

My prolonged collaboration with Ray Guillery.

My active collaboration with Ray Guillery started in 1968, when he was a Full Professor at the University of Wisconsin and I was a graduate student at the University of Pennsylvania. The collaboration lasted almost 50 years with virtually no breaks. Among the ideas we proposed are that glutamatergic pathways in thalamus and cortex can be classified into drivers and modulators; that many thalamic nuclei could be classified as higher order, meaning that they receive driving input from layer 5 of cortex and participate in cortico-thalamocortical circuits; and that much of the information relayed by thalamus serves as an efference copy for motor commands initiated by cortex.

Convergent synaptic inputs to layer 1 cells of mouse cortex.

We used whole cell recordings from slice preparations of mouse cortex to identify various inputs to neurons of layer 1. Two sensory cortical areas were targeted: a primary somatosensory area, namely, the barrel cortex of S1, and a higher order visual area, namely, V2M. Results were similar from both areas. By activating local inputs using photostimulation with caged glutamate, we also identified glutamatergic (and possibly GABAergic) inputs from all lower layers plus GABAergic inputs from nearby layer 1 neurons. However, the patterns of such inputs to layer 1 neurons showed great variation among cells. In separate experiments, we found that electrical stimulation of axons running parallel to the cortical surface in layer 1 also evoked a variety of convergent input types to layer 1 neurons, including glutamatergic "drivers" and "modulators" plus classic modulatory inputs, including serotonergic, nicotinic, α- and ß-adrenergic, from subcortical sites. Given that these layer 1 cells significantly affect the responses of other cortical neurons, especially via affecting the apical dendrites of pyramidal cells so important to cortical functioning, their role in cortical processing is significant. We believe that the data presented here lead to better understanding of the functioning of layer 1 neurons in their role of influencing cortical processing.

Unilesional mycosis fungoides is associated with increased expression of microRNA-17~92 and T helper 1 skewing.

BACKGROUND: The molecular basis of unilesional mycosis fungoides (MF), characterized by a solitary lesion that is clinicopathologically indistinguishable from multifocal patch or plaque MF (early MF), is unknown. OBJECTIVES: To investigate the microRNA profile in unilesional MF distinguishing it from early MF. METHODS: Biopsy samples of unilesional MF and early MF were evaluated with the Affymetrix microRNA array, with further comparison with inflammatory dermatosis, using quantitative polymerase chain reaction. NanoString technology was applied to analyse the gene expression of T helper (Th)1 immune markers, and immunohistochemistry was used to evaluate CXCR3 and GATA-binding protein 3 (GATA3) markers for Th1 and Th2 cells, respectively. RESULTS: Unilesional MF had a significantly higher level of expression of all members of the microRNA miR-17~92 cluster than early MF. Specifically, unilesional MF had a higher miR-17 level than early MF and inflammatory dermatoses. There was downregulation of the expression of phosphatase and tensin homolog (PTEN) and CREB1, known targets of miR-17~92 members; higher gene expression of interleukin-2 and interferon-γ; and a statistically lower average percentage of GATA3+ dermal cells (6·7% vs. 42·3%), were detected in unilesional MF compared with early MF. High immunoreactivity of CXCR3 was noted in both unilesional and early MF. CONCLUSIONS: Unilesional MF exhibits a microRNA profile distinct from that of conventional early MF, with a higher level of miR-17~92 members along with Th1 skewing. These findings suggest a robust reactive T-cell immune response in unilesional MF and might account for the localized nature of this disease.

Grover disease and bullous pemphigoid: a clinicopathological study of six cases.

Grover disease (GD) is an idiopathic dermatosis that typically manifests as itchy papules over the trunk in middle-aged men. Bullous pemphigoid (BP) is an autoimmune bullous disease that affects older people. Not only are the two diseases easily distinguishable on clinical grounds, they are also characterized by differences in histopathology, pathogenesis and response to treatment Thus, the co-occurrence of these two conditions in the same patient is usually considered coincidental. In this report, we present a multicentre retrospective analysis of six patients who developed both GD and BP over a short period of time, and in all cases but one, GD preceded BP. We discuss the clinical and histopathological features of these patients, and the suggested mechanisms of the diseases. We conclude that GD might predispose to the development of BP.

No calcitonin change in a person taking dulaglutide diagnosed with pre-existing medullary thyroid cancer.

BACKGROUND: Glucagon-like peptide-1 receptor agonists, such as dulaglutide, exenatide and liraglutide, are approved to treat Type 2 diabetes mellitus. Although these drugs provide substantial glycaemic control, studies in rodents have prompted concerns about the development of medullary thyroid carcinoma. These data are reflected in the US package insert, with boxed warnings and product labelling noting the occurrence of these tumours after clinically relevant exposures in rodents, and contraindicating glucagon-like peptide-1 receptor agonist use in people with a personal or family history of medullary thyroid carcinoma, or in people with multiple endocrine neoplasia type 2. However, there are substantial differences between rodent and human responses to glucagon-like peptide-1 receptor agonists. This report presents the case of a woman with pre-existing medullary thyroid carcinoma who exhibited no significant changes in serum calcitonin levels despite treatment with dulaglutide 2.0 mg for 6 months in the Assessment of Weekly AdministRation of LY2189265 [dulaglutide] in Diabetes-5 clinical study (NCT00734474). CASE REPORT: Elevated serum calcitonin was noted in a 56-year-old woman with Type 2 diabetes mellitus at the 6-month discontinuation visit in a study of long-term dulaglutide therapy. Retroactive assessment of serum collected before study treatment yielded an elevated calcitonin level. At 3 months post-study, calcitonin level remained elevated; ultrasonography revealed multiple bilateral thyroid nodules. Eventually, medullary thyroid carcinoma was diagnosed; the woman was heterozygous positive for a germline RET proto-oncogene mutation. CONCLUSION: The tumour was not considered stimulated by dulaglutide therapy because calcitonin remained stable throughout.