Klebsiella pneumoniae carrying New Delhi metallo-β-lactamase and oxacillinase-48 genes among 19 screened contacts of an index case after 14 months of routine practices in a long-term care facility.Infection prevention and control measures are used to contain outbreaks of carbapenemase-producing Enterobacteriaceae. We report the absence of transmission of  The emergence of carbapenem resistance among Gram negative bacteria heralds a future of potentially untreatable infections due to extreme antimicrobial resistance . The hydCanadian rates of CPE colonisation increased nearly five-fold from 2014 to 2017; however, an increase in the rate of CPE infection has not yet been documented in Canada . The impCombined control measures are typically required to prevent and control outbreaks with CPE. These measures include routine practices and additional precautions such as contact precautions, hand hygiene, staff education, patient isolation, enhanced environmental cleaning and disinfection, and active surveillance . ConsideHere, we report the findings of a programme of active contact surveillance for a CPE positive index case who had been residing in the chronic care unit of a long-term care facility (LTCF) for 14 months following the isolation of CPE during a brief hospital admission. The patient’s status as an individual infected or colonised with a CPE was not known to the chronic care unit. As a result, only routine practices were implemented during this time.KPC, NDM, VIM, OXA-48, IMP and GES genes. Phenotypic susceptibility testing was performed on all CPE isolates using the Vitek 2 N208 or N391 cards  and disk diffusion and interpreted according to current Clinical and Laboratory Standards Institute (CLSI) and US Food and Drug Administration (FDA) breakpoints (for tigecycline). Whole genome sequencing of carbapenemase-producing Enterobacteriaceae was performed with the Illumina MiSeq platform . Sequencing data have been deposited in NCBI as BioProject PRJNA511988 and BioSamples SAMN13659125 (Klebsiella pneumoniae) and SAMN13659126 (Escherichia coli). Contigs were generated using the assembly and annotation pipeline of the rapid infectious disease analysis platform (IRIDA v19.09), which combines SPAdes-based de novo assembly with Prokka-based annotation. Carbapenemase-producing genes were characterised using ResFinder 3.2  and CARD .This study was performed at the chronic care unit of a LTCF within Winnipeg, Manitoba, Canada. Subjects were patients who were in contact with a CPE colonised individual prior to the initiation of specific infection prevention and control (IPC) measures. Subjects were screened for CPE colonisation via rectal swabs collected on days 0, 7 and 21 after exposure was identified. Swabs were cultured on CHROMagar mSuperCARBA agar , and Gram negative, carbapenem-resistant organisms were identified to species level using matrix-assisted laser desorption/ionisation-time of flight mass spectrometry . Phenotypic confirmation of carbapenemase production by Enterobacteriaceae isolates was performed using the Neo-Rapid CARB kit , a chromogenic assay based on the hydrolysis of imipenem. The carbapenemase type was initially determined by a polymerase chain reaction (PCR) screen capable of detecting Research ethics approval for retrospective chart review was approved as well as institutional approval at the LTCF.K. pneumoniae from a urine sample obtained in May 2017 during an acute care hospitalisation. As per regional practice, this patient’s CPE status was identified in the electronic patient record (EPR) to ensure that staff are aware of the need for additional infection control measures. This organism demonstrated phenotypic antimicrobial susceptibility only to tigecycline  without additional precautions or enhanced environmental disinfection.E. coli which was of intermediate susceptibility to meropenem  and K. aerogenes blood isolate (August 2019) as well as the positive CPE contact’s E. coli rectal isolate (June 2019). Analyses revealed that the contact’s E. coli isolate harbored OXA-181, not the OXA-48 or NDM of the index case’s isolates. This established a lack of CPE transmission between the index case and contact. The OXA-181 enzyme shares 94% nucleotide identify with OXA-48 and cross-reacts with primers for PCR-based detection of OXA-48.Whole genome sequencing (WGS) was undertaken of the index case’s Once the patient’s CPE status was known to the LTFC, specific IPC precautions were immediately initiated. Staff were required to glove and gown prior to entry into the patient environment and to use dedicated equipment. If this was not possible, shared equipment was disinfected after use. Enhanced cleaning and disinfection was implemented on the unit. Education about CPE pathogens was provided to staff, residents and families. Admission screening policies were enhanced so that similar situations do not occur in the future.Our findings call into question the efficiency of CPE transmission. In our case, routine practices appear to have prevented CPE plasmid and/or clonal spread, a surprising result for a chronic care unit in a LTCF facility where residents share common spaces with other occupants.Institutional control of CPE typically involves bundled interventions. Thus, it is difficult to tease apart the relative effect of each intervention. It has been noted that routine practices are insufficient in controlling CPE transmission considering previous documented failures of CPE control with the implementation of contact precautions and isolation .The spontaneous decolonisation of CPE colonised patients may provide an explanation for our results . ConsideRepeat hospitalisation is known to prolong CPE colonization . ConsideNDM and OXA-48 genes from a CPE index case on a chronic care unit of a LTCF after 14 months of routine practices with no additional precautions. Our findings suggest that CPE transmissibility may differ between institutional settings. Further studies involving genotypic CPE analysis, institutional antimicrobial prevalence and prolonged surveillance sampling of contacts are required to inform whether infection control measures should be tailored to the specific CPE type and institutional context.While bundled interventions are typically required to control the spread of CPE, we report the absence of transmission of Click here for additional data file.Supplemental material, sj-pdf-1-bji-10.1177_17571774211012443 for Absence of transmission of NDM and OXA-48 carbapenemase genes in a chronic care unit of a long-term care facility by Carl Boodman, Natalie Gibson, Davenna Conrod, Christine Y Turenne, David C Alexander, Tatyana Taubes, Ana Lucha, David A Boyd, Laura F Mataseje, Michael Mulvey, James A Karlowsky, Molly Blake and John M Embil in Journal of Infection Prevention


The use of blood biomarkers after mild traumatic brain injury (mTBI) has been widely studied. We have identified eight unresolved issues related to the use of five commonly investigated blood biomarkers: neurofilament light chain, ubiquitin carboxy-terminal hydrolase-L1, tau, S100B, and glial acidic fibrillary protein. We conducted a focused literature review of unresolved issues in three areas: mode of entry into and exit from the blood, kinetics of blood biomarkers in the blood, and predictive capacity of the blood biomarkers after mTBI.Although a disruption of the blood brain barrier has been demonstrated in mild and severe traumatic brain injury, biomarkers can enter the blood through pathways that do not require a breach in this barrier. A definitive accounting for the pathways that biomarkers follow from the brain to the blood after mTBI has not been performed. Although preliminary investigations of blood biomarkers kinetics after TBI are available, our current knowledge is incomplete and definitive studies are needed. Optimal sampling times for biomarkers after mTBI have not been established. Kinetic models of blood biomarkers can be informative, but more precise estimates of kinetic parameters are needed. Confounding factors for blood biomarker levels have been identified, but corrections for these factors are not routinely made. Little evidence has emerged to date to suggest that blood biomarker levels correlate with clinical measures of mTBI severity. The significance of elevated biomarker levels thirty or more days following mTBI is uncertain. Blood biomarkers have shown a modest but not definitive ability to distinguish concussed from non-concussed subjects, to detect sub-concussive hits to the head, and to predict recovery from mTBI. Blood biomarkers have performed best at distinguishing CT scan positive from CT scan negative subjects after mTBI. Mild traumatic brain injury (mTBI), also known as concussion, has been defined as a minor head injury with a Glasgow Coma Scale score of 13 to 15. Loss of consciousness and post traumatic amnesia occur variably. The CT scan and MRI may be normal or show minor abnormalities. A variety of protein macromolecules and smaller molecules detectable in the blood and cerebrospinal fluid have been investigated as biomarkers for mTBI , 15. GFAβ) is a low-molecular weight 10 kDa calcium-binding protein expressed in glia and Schwann cells. Blood levels of S100B may be elevated after trauma without head injury [Tau is a protein involved in the stabilization of microtubules in the axons of neurons in both the central and peripheral nervous system. In the central nervous system, tau has six isoforms (A-F) with molecular weights ranging from 33 kDa to 46 kDa . Tau hasd injury . Immediad injury . Eliminad injury –28. Afted injury .How do biomarkers enter and exit the blood?What are the kinetics of blood biomarkers?What is the optimal sampling time for blood biomarkers?How long do the blood biomarker levels remain elevated?What are the confounding factors for blood biomarker levels?Can blood biomarkers differentiate between subjects with concussions or sub-concussive hits to the head from healthy controls?Can blood biomarkers predict CT scan positivity?Can blood biomarkers predict outcome or severity of mTBI?Despite much investigation of blood biomarkers in the settings of mild, moderate, and severe brain injury, some issues regarding their use remain unresolved –12. McDoOvid MEDLINE and Epub Ahead of Print  for the keyword traumatic brain injuries  and the search terms UCH-L1 OR GFAP OR tau proteins OR S100 proteins OR neurofilament proteins  which yielded 406 articles. We added 202 articles with the search terms glymphatic system OR periarterial drainage. We added 195 articles from ad hoc searches. We reviewed the titles and abstracts of 803 full-text publications to select the 140 articles retained for this review.This list of unresolved issues is selective and is not comprehensive. Most of the literature discussed in this paper stems from the intersection of the searches in After mTBI, axonal shearing and cellular disruption cause the release of biomarkers from neurons and astrocytes , 8. NF-LWith a volume of approximately 1200 ml, the human brain is tightly packed with cellular elements . About 20% of the brain is extracellular space ; filled After mTBI, biomarkers can potential diffuse through the extracellular space of the brain to penetrating blood vessels and enter the blood if the blood brain barrier is disrupted. Disruption of the blood brain barrier occurs with moderate or severe brain injury in about 40% of the cases , 39. It After TBI, levels of biomarkers in the cerebrospinal fluid rise rapidly, suggesting that these biomarkers have easy access to the cerebrospinal fluid from the interstitial fluid. Biomarkers can reach the cerebrospinal fluid by trans-ependymal flow into the ventricles or trans-pial flow into the subarachnoid space . Once inThe cerebrospinal fluid volume (150 ml) turns over four times per day . Some ceIt has been recognized for more than 25 years that radioactively labeled albumin injected into the interstitial fluid of the brain can be recovered from cervical lymph nodes draining the head . Since aOnce in the blood, biomarkers must have a mode of exit. Little is known with certainty about the mode of elimination of biomarkers from the blood. Elimination could occur by redistribution to other compartments, renal excretion, hepatic metabolism, or intravascular proteolysis . Dadas eTmax), maximum concentration (Cmax), and half-life  and ke (the elimination rate constant) determine the blood biomarker level at any time t after a mTBI  if estimates are available for amount of biomarker released (D0), the fractional absorption rate (F), and the volume of distribution (Vd) as illustrated in Fig. When the blood levels of biomarkers are sampled repeatedly after a mTBI, time-concentration curves can be created . The desentclass1pt{minimaentclass1pt{minimamentclasspt{minimaentclass1pt{minimamTBI Eq. . Based oentclass1pt{minimaentclass1pt{minimaD0) could serve as a more reliable marker for TBI severity than an isolated blood biomarker level (Cp) at a random time t. McDonald et al. [Tmax and decreasing the absorption rate constant (ka) while keeping the amount of biomarker released constant (D0) [Azizi et al.  have sugd et al.  have empant (D0) . FurtherTmax, important elevations may be missed. Based on their approximate Tmax (Table 2), it is predicted that S100B is best sampled between 0-4 hrs, UCH-L1 and tau between 4-12 hrs, GFAP between 12-36 hrs, and NF-L between 100-300 hrs. Estimates for the Tmax of NF-L are not reliable and the actual value of the Tmax could be much longer [For some neurological diseases such as fronto-temporal dementia, Alzheimer disease, and multiple sclerosis, blood sample timing for biomarkers is unlikely to be critical –77. Withh longer . BogosloEmpirical studies are needed to confirm the best sampling times for blood biomarkers after mTBI depending on the intended context of use. In general, the best test performance, as measured by AUROC (area under the receiver operator curve), for S100B, UCH-L1, and tau occurs with early sampling times of 0-6 hrs Table . Note thOne confounding factor for biomarker blood levels is total blood volume (TBV). Individuals with higher blood volumes have lower blood biomarker levels. Manouchehrinia et al.  studied Another confounding factor is renal function. Since some elimination of blood biomarker is likely renal, impaired renal function can lengthen biomarker half-life in the blood and elevate biomarker blood levels. Akamine et al.  investigEndogenous levels of plasma neurofilament protein, tau, and GFAP are known to rise with age –93. In tAβ40, or Aβ42. McDonald et al. [β42, tau, and GFAP at 0, 30, and 90 days after TBI in 34 subjects entered into the COBRIT trial. Subjects were of mixed TBI severity; none had simple concussions. They found elevated levels of three biomarkers compared to controls, although levels of tau and GFAP were dropping. Currently, explanation for persistently elevated biomarker levels after mTBI in some subjects remains uncertain. Persistent elevations of NF-L after mTBI could reflect ongoing release of biomarker from original injury or re-injury [A few studies have examined biomarker levels months or years after mTBI. Blood half-lives of most biomarkers UCH-L1, S100B, GFAP) are short (less than 48 hrs) . With thB, GFAP ad et al.  found eld et al.  measurede-injury . The proe-injury .Studies have shown that blood biomarkers have a modest capability to distinguish healthy controls from concussed subjects Table . Most ofSome studies have shown that sub-concussive hits to the head can elevate biomarker levels. For example, Kawata et al.  studied Concussed patients with abnormalities on either MRI or CT scan are termed complicated mTBI . In the Cost savings are possible if patients with mild head injuries who are unlikely to benefit from CT scanning are excluded from neuroimaging. In Europe, S100B has been extensively studied as a biomarker that could reduce the use of CT scanning for minor head injuries , 114. IfIn the United States, the FDA has approved the Banyan BTI™(Brain Trauma Indicator) to predict CT scan abnormalities after mTBI. Blood is sampled within 12 hrs of head injury. Test sensitivity is 97.5% and specificity is 36.5% on the FDA application . The FDAGill et al.  studied Several clinical measures have been used to assess the clinical severity of mTBI including the SAC (Standardized Assessment of Concussion), the SCAT (Sports Concussion Assessment Tool), the BESS , BSI-18 (Brief Symptom Inventory-18), and the ImPACT (Immediate Post-Concussion Assessment and Cognitive Test (ImPACT). In general, few correlations have been found between these clinical measures and blood biomarker levels after mild TBI , 79, 83.The prediction of outcome after mTBI has been difficult, whether the outcome is measured by the time to recovery, the persistence of symptoms, or the development of a post-concussion syndrome (PCS). Accurate models to predict outcome from mTBI are not available . As asseThis review examined eight unresolved issues related to the use of blood biomarkers for the diagnosis and management of mTBI. A number of review limitations should be emphasized. We focused on the five most commonly investigated blood biomarkers after mTBI and did not address other blood biomarkers such as neuron specific enolase (NSE), myelin basic protein, inflammatory biomarkers, or microRNA . Our revEvidence from the clinical setting and from animal models indicates a disruption of the blood brain barrier occurs after moderate to severe traumatic brain injury , 136–139Tmax and half-life provide important information about the behavior of mTBI biomarkers in the blood. Current estimates of these kinetic parameters are imprecise [max, but it is likely later than the other commonly measured biomarkers for mTBI. Several confounding factors for blood biomarker levels have been identified including increasing age, renal failure, and increased blood volume. However, corrections in biomarker levels are not routinely made for these confounding factors. Elevated levels of both tau and NF-L have been observed months or years after traumatic brain injury. The significance of these persistent elevations in blood biomarker levels is uncertain.Kinetic parameters such as mprecise . Better Blood biomarkers have a modest ability to detect sub-concussive head injuries and a modest ability to discriminate between concussed and non-concussed subjects. Some subjects with verified concussions may have minimal increases in blood biomarker levels which overlap with the levels found in control subjects. None of the studied blood biomarkers have been shown to reliably correlate with repetitive sub-concussive hits or cumulative concussive hits to the head. Blood biomarkers have had some success in predicting CT scan positivity after mild traumatic brain injury. S100B is widely used in Europe, and the GFAP/UCH-L1 tandem test has been approved for use in the United States. Despite impressive levels of sensitivity, these tests lack high levels of specificity. Correlations between blood biomarker levels and mTBI severity have been disappointing to date. Evidence is inconclusive as to whether any blood biomarker predicts recovery time, post-concussion syndrome, or return to sport after mild traumatic brain injury. Both tau and neurofilament light chain protein have shown limited promise for this application. Return to sport and return to work decisions are influenced by complex educational, sociological, and psychological factors not captured in a blood biomarker test .


The risk of AMR and allograft loss in sensitized patients is increased due to preformed DSA detected at time of transplant or the reactivation of HLA memory after transplantation, causing acute and chronic AMR. Alternatively, de novo DSA that develops post-transplant due to inadequate immunosuppression and again may lead to acute and chronic AMR or even allograft loss. Circulating antibody, the final product of the humoral immune response, has been the primary target of desensitization and AMR treatment. However, in many cases these protocols fail to achieve efficient removal of all DSA and long-term outcomes of patients with persistent DSA are far worse when compared to non-sensitized patients. We believe that targeting multiple components of humoral immunity will lead to improved outcomes for such patients. In this review, we will briefly discuss conventional desensitization methods targeting antibody or B cell removal and then present a mechanistically designed desensitization regimen targeting plasma cells and the humoral response.There is an urgent need for therapeutic interventions for desensitization and antibody-mediated rejection (AMR) in sensitized patients with preformed or  Desensitization treatment within the field of transplantation refers to the process of antibody removal , specifiFor many patients awaiting transplantation, blood transfusion, prior transplantation, and pregnancy are the sources of sensitization , 5. TherFor sensitized patients with an incompatible living kidney donor, to whom they have DSA, the decision is whether to use a kidney paired donation (KPD) program to obtain a compatible match, await a compatible deceased donor offer, or proceed with a HLA-incompatible, positive cross match transplant (HLA-i) which requires desensitization prior to transplantation. Simulation of how KPD programs might run were initially optimistic , but oveIn the USA, multicenter data demonstrates a clear survival benefit  in proceIn highly sensitized patients removal of circulating anti-HLA antibody or lowering cPRA is an important and fundamental strategy for expanding donor options and successfully transplanting across DSA barriers. However, durable inhibition of HLA antibody production is the “holy grail” for successful kidney transplantation (KT) in sensitized patients.Plasmapheresis (PP) has been used for several decades as a method for lowering circulating antibody in various immune diseases , 21. PlaIVIG has been widely used in inflammatory and autoimmune conditions . IVIG alAlthough various combinations of IVIG or PP with rituximab have been proposed, two protocols have been widely accepted and used .Using PP with low-dose IVIG, many centers report transplant outcomes with acute AMR rates of 12-43% when used in combination with various induction agents, anti-thymocyte globulin, anti-IL-2Rc antibody or OTK3 –43. The via antibody-dependent cytotoxicity, complement-dependent cytotoxicity or direct apoptosis. Originally, anti-CD 20 antibody was used to treat B-cell lymphoma. In transplantation, rituximab was introduced to deplete B cells with the goal of reducing donor-specific antibody (DSA) production  have emerged as a viable alternative to heart transplant, it is not without significant risks and complications that limit access to therapy. As such, thoracic transplantation faces a greater urgency and waitlist mortality, and desensitization regimens must take into account these temporal challenges of sensitized patients. 1 in 7 adult heart transplant candidates are sensitized, a number that has doubled in the past two decades . A risinA common sequela of AMR in heart transplantation is cardiac allograft vasculopathy (CAV), and in lungs, chronic lung allograft dysfunction (CLAD), both of which result in significant mortality and morbidity within 5 years of transplantation –63. The via cytokines and costimulation to T cells. During this aberrant state of T cell activation, LVAD patients are believed to develop B cell hyper-reactivity with subsequent allosensitization. By way of a CD95-dependent pathway, these activated T cells then undergo apoptosis  & F (c) fragments, thus inhibiting both complement-dependent cytotoxicity and antibody-dependent cytotoxicity  which is a bacterial enzyme produced by toxicity . IdeS hatoxicity . Jordan toxicity . All patFcRn)] effectively blocked the IgG-FcRn interaction when repeated injections of ZFcRn and ZFcRn fused to an albumin binding domain (ABD) in mouse models led to a 40% reduction of IgG in serum . Additional studies in animal models that inhibit IgG-FcRn binding include an anti-FcRn directed mAb, 1G3, that accelerated endogenous serum IgG clearance and reduced the severity of myasthenia gravis in rat models (manuscript in submission). Treatment with aFcRn prior to transplantation significantly reduced the levels of total and donor-specific alloantibody. However, in the context of renal transplantation, anti-FcRn treatment did not block the synthesis of DSA, such that transient reduction in DSA was followed by robust DSA increase and antibody-mediated rejection (manuscript in submission). The anti-FcRn approach demonstrated promising applications in lowering alloantibody levels in transplantation; however potential limitations and complexity of using the agent require further investigation in transplantation.Brambell et al. identified FcRn, a neonatal IgG receptor that is closely related to the MHC Class I receptor, which is involved in a variety of critical biological and immunological functions, most notably regulating serum IgG levels and the recycling and transcytosis process that results in an increased half-life of IgG and albumin in human serum –80. Strain serum . ABY-039t models . Abdegs,t models . Synthett models . Our gro+CD20  in the bone marrow compartment, along with the identification of these cells as being CD138+CD20 , bortezo+CD20 . Bortezo+CD20 . Now sev®) is a 1st generation, reversible inhibitor of the 26S proteasomal subunit. This drug is a potent inhibitor of plasma cells, which rely on rapid protein turnover to continually secrete antibodies, and succumb to oxidative stress and apoptosis when cellular recycling mechanisms are rendered nonfunctional. For this reason, bortezomib is approved for usage in multiple myeloma, a malignancy of plasma cells  is a 2nd generation, irreversible inhibitor of the 20S proteasomal subunit. Studies in patients with multiple myeloma suggest that this drug may be more efficacious and better tolerated than its predecessor bortezomib , also known as CD319, which is highly expressed on MM, NK and other immune cells  is a pleiotropic cytokine produced by many different cell lineages. The membrane-bound IL-6 receptor (IL-6R) is expressed only on hepatocytes and some immune cells , but a s®) is a humanized monoclonal antibody with activity against both the membrane and soluble forms of IL-6R approved to treat moderate to severe rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, and Castleman’s disease (Tocilizumab (Actemra disease . Pharmac disease . Vo et a disease . This re®), was the first targeted biologic approved for the treatment of systemic lupus erythematosus (B cell activating factor (BAFF) is a homotrimer and member of the tumor necrosis factor (TNF) family that is found on the cell surface as a transmembrane protein or released in soluble form after cleavage . BAFF isematosus . Belimumematosus , NCT0116The concept of desensitization has been expanded from only targeting alloantibody (IVIG/IA/plasmapheresis) to instead targeting the upstream sources of antibody such as B cells (Rituximab) and PC (proteasome inhibitor). The conventional desensitization concept, removal of preformed antibody, may prevent hyperacute rejection or acute AMR but without long-lasting impact on humoral alloimmunity. While many desensitization therapies have been tried alone or in combination in animal models and human trials, none yet have solved the barriers to transplantation faced by highly sensitized patients with high titer HLA antibodies. The answer to desensitization may lie in novel therapies not yet tested or those outside the field of transplantation. Therefore, upcoming therapies targeting plasma cells are potentially very attractive. However, considering the previous sensitization events to HLA, allograft could trigger the memory response in sensitized patients. For this reason, targeting each component of humoral response such as alloantibody, B cells, or PC, would tentatively reduce the steady state level of DSA, this would not promote long-term control of humoral response after transplantation. Due to its compensatory mechanism, it would more logical that we develop strategies to desensitizing patients that target multiple steps of DSA production. Fortunately, there are many agents targeting each step of the humoral response as shown in AC, MM, and DO participated in literature search and wrote the manuscript. BE, JP, and KF participated in writing the manuscript. AJ critically reviewed the manuscript. JK and SK participated in writing and reviewing the manuscript. All authors contributed to the article and approved the submitted version.This work was partially supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health as part of the Nonhuman Primate Transplantation Tolerance Cooperative Study Group under U19AI131471 (awarded to SK) and Opportunities Pool Round 13 (awarded to JK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cognitive impairment is a frequent and disabling sequela of stroke. There is however incomplete understanding of how lesion topographies in the left and right cerebral hemisphere brain interact to cause distinct cognitive deficits. We integrated machine learning and Bayesian hierarchical modelling to enable a hemisphere-aware analysis of 1080 acute ischaemic stroke patients with deep profiling ∼3 months after stroke. We show the relevance of the left hemisphere in the prediction of language and memory assessments and relevance of the right hemisphere in the prediction of visuospatial functioning. Global cognitive impairments were equally well predicted by lesion topographies from both sides. Damage to the hippocampal and occipital regions on the left was particularly informative about lost naming and memory functions, while damage to these regions on the right was linked to lost visuospatial functioning. Global cognitive impairment was predominantly linked to lesioned tissue in the supramarginal and angular gyrus, the post-central gyrus as well as the lateral occipital and opercular cortices of the left hemisphere. Hence, our analysis strategy uncovered that lesion patterns with unique hemispheric distributions are characteristic of how cognitive capacity is lost due to ischaemic brain tissue damage. Bonkhoff et al. integrate machine learning and Bayesian hierarchical modelling to enable hemisphere-aware analysis of 1080 stroke patients. They quantify lateralization effects of cortical and subcortical regions, such as the pallidum and hippocampus, of middle and posterior cerebral artery vascular territories to the left for naming/memory and to the right for visuospatial functions.  In the USA, somebody experiences a stroke every 40 s.,Many brain functions involve various lower and higher cognitive processes and are supported by regions spread across the brain’s grey matter. A key aspect of the spatial distribution of neurocognitive processes is the preferential lateralization to one hemisphere,,ipsilateral to the dominant hand. As such, many existing brain-imaging studies on stroke have studied only a single brain hemisphere.Previous stroke lesion studies have oftentimes been conducted under some anatomical constraint or deliberate topographical focus to tame the amount of information in lesion volume and distribution.Examples of lesion-symptom mapping studies, that have embraced the full complexity of lesion topographies and investigated left- and right-hemispheric stroke concurrently, exist.Therefore, in this proof-of-principle study, we sought to integrate machine learning and Bayesian hierarchical modelling to enable a hemisphere-aware analysis of 1080 ischaemic stroke patients. By bringing to bear this novel statistical framework, we investigated lesion associations to cognitive outcomes obtained on average 3 months after stroke and sought to disentangle lateralization effects on the level of entire hemispheres, specific lesion patterns and individual brain regions. We concentrated on four key cognitive outcomes that captured global cognitive abilities, as well as more language- and visuospatial-attention-related functions. We hypothesized to find a left-hemispheric dominance for language-centred tests, and right-hemispheric dominance for tests more heavily relying on attention and visuospatial abilities.,Using a prospective stroke registry database,Stroke subjects provided informed written consent in accordance with the Declaration of Helsinki. The local institutional review boards approved the study protocol and gave waived consent requirements based on the retrospective nature of this study and minimal risk to participants.Stroke patients underwent a comprehensive battery of neuropsychological tests ∼3 months after the onset of acute stroke (median time post-stroke: 98 days).The cognitive performance prior to stroke onset was captured by the Informant Questionnaire on Cognitive Decline in the Elderly.http://lsm.isi.uu.nl/).Brain-imaging acquisition was typically performed within the first week after stroke. Brain scanning included structural axial T1, T2-weighted spin echo, fluid-attenuated inversion recovery and DWI sequences  unsupervised dimensionality reduction of lesion maps and (ii) Bayesian hierarchical modelling to predict the outcome in cognitive performance tests. We here focused on quantitative analyses of the 3-months outcomes measured on the MMSE, Korean short versions of the BN and the SVL, as well as the RC.3 in grey matter. We sought to explore coherent topographical patterns that may be hidden in these high-dimensional brain scans and to represent each patient’s lesion fingerprint in a simpler and more directly interpretable form. To this end, we initially computed the lesion load within 54 parcels (108 for both hemispheres), composed of the Harvard-Oxford cortical atlas with 47 regions and subcortical atlas with 7 regions in each hemisphere.lesion atoms in the following. The number of 10 lesion atoms per hemisphere was chosen to achieve a balance between capturing a substantial amount of lesion variability, on the one hand, and keeping the number of quantities low for neuroscientific domain interpretation, on the other hand.Each to-be-analysed lesion map featured 435 642 total voxels of 1 mmW. These hidden topographical representations link the emerging spatial lesion pattern topography to each of the original anatomical brain regions. The matrix of latent factor loadings H indicates how relevant each emerging spatial lesion pattern is to describe a specific patient’s overall lesion distribution. The atomic representations hence decompose the actual lesion constellation in a given patient given by V = WH, with V being the local lesion summaries of p × n dimensions (p = number of brain regions and n = number of subjects). Accordingly, W and H have p × k and k × n dimensions, respectively, with k representing the number of latent spatial patterns.NMF achieved a low-rank approximation of the anatomical lesion data by partitioning the lesion maps into a matrix of latent factor representations W to varying degrees. In this way, each location could contribute to the prediction of cognitive outcome through relative contributions of multiple components, each of which reflected extracted lesion archetypes distributed across the whole brain. In this way, it was more similar to multivariate-lesion symptom mapping approaches,,,aW represented a unique and directly interpretable aspect of the overall topographical lesion pattern variation. The neurobiologically interpretable sum-of-parts representation enabled by NMF is in contrast to latent representations learned by alternative matrix factorization algorithms. For instance, in principal component analysis, individual lesions would be recovered through convoluted additions and subtractions of several components with positive and negative weights. For this reason, the overall effect of all principal components, yet not the effect of ensuing individual components, would have been as easily and intuitively interpretable to draw neuroscientific conclusions.NMF provided at least two key advantages in our modelling scenario: In contrast to classical lesion-symptom mapping,The NMF-derived expressions of topographical lesion atoms provided the neurobiological input into our Bayesian hierarchical modelTo directly examine possible differences in hemispheric predictive relevance in our data, the modelled generative process assumed a joint dispersion prior for all lesion atoms of each hemisphere. Therefore, the standard deviation priors for the left and right hemispheres could capture the hemisphere-specific predictive contributions tiled across all candidate lesion atoms. Priors of left- and right-hemispheric standard deviations were additionally combined through a joint hyperprior to complement the hierarchical model structure. Furthermore, the model took into account several covariates, including age, ageR2-based explained variance). That is, we empirically assessed the simulated outcome predictions generated by our model solution to approximate external validation based on our patient sample.Samples from the joint posterior distribution of the model parameters were drawn by the No U-Turn Sampler, a kind of Monte Carlo Markov Chain algorithm (setting: draws = 3500).Our Bayesian hierarchical approach facilitated the careful dissection of predictive relevance allocated to different levels of the model. For all outcome models, we first evaluated lateralization effects that were inferred from the left and right hemisphere posterior dispersion distributions. In analogy to ANOVA applications, where the total variance of a specific outcome variable is partitioned into several sources of variance, we thus here focused on the proportion of the variance that was attributable to variation in all lesion atoms linked to one brain hemisphere. In this way, we capitalized on the general hemispheric importance in predicting the outcome, yet de-emphasized the directionality of these associations: ‘Did regional effects from either one hemisphere, the left or right one, contribute more substantially to the accurate prediction of the outcome of interest?’ Therefore, predictive relevance could originate from predictors of more (‘more impaired’) or less deteriorated (‘less impaired’) cognitive impairment observed in our patient sample. Subsequently, we considered lateralization effects of specific lesion atoms and lastly reverted back the predictive relevance of lesion atomshttps://github.com/banilo/BrainCommunications2021/Analyses were conducted in a Python 3.7 environment and predominantly relied on the packages nilearn and pymc3. Full code is available here: Anonymized data that support the findings of this study are available from the corresponding author upon reasonable request.We relied on structural MRI data of 1080 ischaemic stroke patients, typically obtained within one week after symptom onset, to predict cognitive outcomes ∼3 months post-stroke. Analyses were focused on the Korean MMSE ,t-test: P = 0.81).Voxel-wise topographical overlap of the lesion distributions demonstrated an excellent whole-brain coverage across patients . In the lesion atoms, in a data-driven fashion based on NMF.r = 0.9.We summarized the initial high-dimensional lesion information at the voxel level in 108 cortical and subcortical brain regions for the exploration of coherent hidden patterns of lesion topography. We then uncovered a set of distinct topographical lesion configurations, After extracting this set of coherent atomic patterns that together underlie stroke topographies, we investigated the differential effects of (i) hemispheres, (ii) lesion atoms and (iii) anatomical regions on the cognitive outcome after stroke.We first examined possible hemisphere-specific effects on cognitive impairment in our stroke patients. We specifically investigated whether lateralized relevance varied across the four outcome scores. We relied on the posterior distribution of variance parameters at the hemisphere level that had inferred the magnitude of hemisphere-specific relevance for a given cognitive dimension. In the case of MMSE, similarly distributed hemisphere posteriors suggested that the combination of all lesion atoms of one hemisphere were equally relevant for predicting global cognitive outcome  = 0.0117–0.078; right posterior mean = 0.0513, HPDI = 0.0126–0.0901, Furthermore, we observed characteristic inter-relations between these hemisphere-specific effects and important covariates, i.e., lesion volume, education attainment and pre-stroke cognitive performance, in the prediction of cognitive outcome . We founentire hemispheres, but specific lesion topographies within a hemisphere in the prediction of cognitive outcome. We thus direct our attention to the examination of individual lesion atoms that combined several brain regions. We inferred lateralization effects from non-overlapping posterior parameter distributions of left and right lesion atoms. Such non-overlapping distributions implied that a specific lesion atom in either the left or right hemisphere was reliably more predictive of a given cognitive impairment than the same lesion atom of the other hemisphere. Hemisphere-specific predictions showed relevant differences for a total of 4 out of 10 lesion atoms considering all four target scores.The level of lesion atoms in our hierarchical Bayesian model offered yet another opportunity to gain rich insights on lateralization effects linked to not only The first lesion atom was characterized by a pronounced left-lateralization of predictive relevance for BN and SVL . While the posterior distributions for the right-hemispheric first lesion atom did not meaningfully differ from zero, the left-hemispheric lesion atom distributions featured a pronounced deviation in the negative direction: Signalling that only lesions in the left lesion atom 1 regions were predictive of lost function in the BN and SVL , while lesioned regions on the right were more predictive of preserved global cognitive functions (positive parameter weights). Explained variance, as determined via predictive posterior checks, for the MMSE model was Among the 108 total regions for both hemispheres, top regions informative for the prediction of lost MMSE function were the supramarginal and angular gyrus, the pre- and post-central gyrus as well as the lateral occipital and opercular cortices. To a lesser degree, the insular cortex and superior and middle temporal gyri contributed to the prediction of lost function as well R2-based explained variances from a minimum of 39.7% (SVL) to 55.8% (MMSE). Conceivable, these differences may originate from a multitude of different sources, such as differences in the variability of outcome scores related to the lesion anatomy and more or less extractable brain-behaviour associations. Altogether, our current levels of explained variance may also motivate the inclusion of even more biomarkers of stroke impairment and recovery in addition to the ones considered here.Lastly, such more prediction-focused studies could also further investigate differences in explained variances. We here observed We have introduced a probabilistic analytical framework that pools information across the entire brain and can therefore simultaneously integrate lesion facets on varying types and forms. Our results highlight strong lateralization effects to the left for naming and memory functions, and the right for visuospatial functions. These asymmetry effects were related to cortical and also subcortical regions, such as the pallidum and hippocampus, supplied by the middle and posterior cerebral artery vascular territories. Future studies, that employ the probabilistic multi-level approach as showcased here, are warranted to further elucidate hemispheric inter-relations for complex cognitive functions, such as spatial and verbal memory, and eventually finesse the probabilistic prediction of cognitive impairment at the single patient level.fcab110_Supplementary_DataClick here for additional data file.


The timing for heart surgery following cerebral embolization after cardiac valve vegetation is vital to postoperative recovery being uneventful, additionally Covid-19 may negatively affect the outcome. Minimally invasive methods and upgraded surgical instruments maximize the benefits of surgery also in complex cardiac revision cases with substantial perioperative risk.A 68 y.o. patient, 10 years after previous sternotomy for OPCAB was referred to cardiac surgery on the 10th postoperative day after neurosurgical intervention for intracerebral bleeding with suspected mitral valve endocarditis. Mitral valve vegetation, tricuspid valve insufficiency and coronary stenosis were diagnosed and treated by minimally invasive revision cardiac surgery on the 14th postoperative day after neurosurgery.The present clinical case demonstrates for the first time that the minimally invasive approach via right anterior mini-thoracotomy can be safely used for concomitant complex mitral valve reconstruction, tricuspid valve repair and aorto-coronary bypass surgery, even as a revision procedure in the presence of florid endocarditis after recent neurosurgical intervention. The Covid-19 pandemic and prophylactic patient isolation slow down the efficacy of pulmonary weaning and mobilisation and prolong the need for ICU treatment, without adversely affecting long-term outcome. The beginnings of minimally invasive thoracic surgery are attributed to Hans Christian Jacobaeus  and the After decades of slow development of minimal-invasive surgical technologies in the twentieth century, significant innovations in the field of cardiac surgical procedures were marked in the 1990s by Carpentier’s first video-assisted minimally invasive mitral valve surgery via mini-thoracotomy  and ChitAlthough double atrioventricular valve procedures are successfully performed via right mini thoracotomy , the suiHerein, we describe a complex case of successful double valve repair and coronary bypass implantation using minimal-invasive approach in a patient aged 68 with mitral valve endocarditis after having received a sternotomy treating CABG 20 years ago, and complicated by recent neurosurgical intervention for cerebral septic embolism. The postoperative course was impeded by fungal pneumonia and suspicion of Covid-19 infection.A 68-year-old diabetic male patient was urgently admitted to our hospital due to progressive changes in consciousness, ten years after having had OPCAB surgery (LIMA-LAD Bypass) via full sternotomy. The cranio-CT revealed a hemorrhagic metastasis-suspicious mass 8 × 15 × 12 mm) in the right superior temporal gyrus on the posterior wall of the Sylvian fissure .The mitral valve was exposed and inspected through a left atrial incision. The vegetation was removed. An annulus dilatation, endocarditic destruction and flail of the P3 segment were assessed and treated by quadrangular P2-P3 resection, sliding plasty and ring-annuloplasty  could be initiated in the early postoperative phase. After the operation, the patient came in contact with a later COVID-19-positive tested ICU nurse and a routine thoracic RTG examination Fig. a on the Cerebral embolisation with underlying left heart valve endocarditis remains an indication for urgent cardiac repair. Nonetheless, open heart surgery early after neurosurgery in a patient with sepsis and multiorgan dysfunction  is challenging. In addition, revision surgery after sternotomy increases the risk for surgical complications and anticoagulation. Also, prolonged major surgery  under sepsis may further increase the risk for postoperative cerebral and thoracic bleeding, systemic inflammatory response and multiorgan failure.Nonetheless, minimally invasive approaches have been shown to reduce the risk of major cardiac surgery,  althoughThe present case demonstrates the suitability of a right lateral mini thoracotomy for the first time. It allows adequate exposure and handling of both atrioventricular valves and of the right coronary artery in a revision setting.As previously described , the patTherefore, the present case reveals not only the advantages of minimal access surgery such as limited adhesion preparation, reduced risk of hemodynamic instability, better wound healing and feasibility for tracheostomy, but also a safer outcome due to reduced surgical trauma, less bleeding and need for transfusion, lower risk for wound infections, less pain and favorable cosmesis. Additionally, faster recovery of pulmonary function, early mobilization, shorter hospital stays and decreased healthcare costs, make this a preferred approach for the surgeons.The present clinical case demonstrates that the advantages arising from the procedural features enable the minimally invasive performance to generate a good outcome in complicated high-risk cardiac revision surgery.The COVID-19 pandemic and prophylactic patient isolation significantly slowed down the efficacy of pulmonary weaning and mobilisation, and prolonged the demand for ICU treatment, did not however heighten postoperative morbidity by increasing dysfunction of other organs and systems.In conclusion, the present case demonstrates that the minimally invasive approach can safely be used in complicated cases of mitral valve endocarditis with associated tricuspid and right coronary disease. Multimorbidity and previous coronary revascularisation are not contraindications, and a minimally invasive approach might minimize the risk for intracranial bleeding after recent neurosurgery. Aspects of minimal access surgery such as limited adhesion preparation, better wound healing, preservation of pulmonary function and feasibility for tracheostomy are advantageous. Efforts should be made to further develop these procedures, making their application available and safe for a larger population of patients.


Coronavirus disease 2019 (COVID-19) has been shown to have extensive effects on the cardiovascular system. Its long-term cardiac manifestations, however, remain unclear.We report the case of a Caucasian patient with a mild and self-limited presentation of COVID-19, with subsequent development, months later, of exertional dyspnea and non-sustained ventricular tachycardia, long after resolution of his illness and after returning to aerobic exercise. The patient had normal screening tests including electrocardiogram (ECG) and echocardiogram 4 months after his illness. Cardiac magnetic resonance imaging demonstrated epicardial and pericardial fibrosis of the right ventricle free wall and outflow tract and the pericardium over the anterior wall, 6 months following the initial infection. First abnormal ECG was recorded at month 7 following illness.This case suggests an insidious and possible long-term cardiac involvement and reflects the challenges in traditional workups and screening modalities in identifying cardiac involvement in COVID-19. Coronavirus disease 2019 (COVID-19) has been shown to have a wide variety of clinical manifestations. It typically presents with a spectrum of symptoms ranging from no symptoms to an array of mild symptoms such as cough, headache, fever, or anosmia. Less common is a rapid progression of pneumonia, hypoxemia, and acute respiratory distress syndrome and/or death. Recent emerging evidence suggests a significant impact on the cardiovascular system. Proposed mechanisms involve direct viral- or inflammatory-mediated myocardial damage, endothelial dysfunction or plaque instability, arterial or venous thrombosis, and indirect hypoxic cell injury . HoweverCardiovascular magnetic resonance imaging (CMR) is an advanced cardiac imaging modality that can directly visualize the cardiovascular system in any dimensional plane. It has excellent spatial and temporal resolution and is used to characterize myocardial tissues. It is considered the gold standard for assessing myocardial function. Clinically, it is utilized to aid in the assessment of various cardiomyopathies, myocarditis, and/or pericardial disease , 13. FurThe following is a case report of a mild and self-limited presentation of COVID-19 with the subsequent development of cardiac symptoms months after its clinical resolution and CMR demonstrating epicardial and pericardial fibrosis.A 46-year-old athletic and otherwise healthy Caucasian male with a past medical history of mild hyperlipidemia was diagnosed with COVID-19 on March 17, 2020. He had symptoms of malaise, dry cough, anosmia, and a low-grade fever for 2 days prior to his test. His symptoms were self-limited and fully abated on day 5 after onset. He did not require supportive oxygen or hospitalization. Due to his self-limited illness, there were no laboratory data acquired such as cardiac biomarkers. He did not warrant nor was he treated with any pharmacotherapies or antibiotics. His baseline electrocardiogram (ECG) was reported normal including the QT interval. He resumed normal activity after resolution of his illness that month including vigorous aerobic exercise for the following 2–3 months and felt very close to his normal baseline functional status.Approximately 3 months after resolution of illness June 2020), he began having frequent palpitations and exertional dyspnea. He attributed his symptoms to anxiety and some deconditioning from prior quarantine. He had COVID-19 antibodies checked at that time, which showed high titers. On month 4 after his diagnosis (July 2020), he had a chest x-ray, electrocardiogram, and echocardiogram which were all unremarkable. He underwent continuous Holter monitoring which showed frequent premature ventricular beats and multiple brief paroxysms of non-sustained ventricular tachycardia. His baseline ECG remained normal, as shown . Findings showed normal left and right ventricular systolic function with mild left ventricular hypertrophy, with prominent LGE involving epicardial and pericardial fibrosis of the basal to apical anterior wall and at the basal to mid anterior septum and right ventricular free wall with a trivial pericardial effusion Figs. , 5.Emerging evidence has shown myocardial involvement in patients with covid-19. In one prospective, observational cohort study, 100 patients who had COVID-19 underwent CMR which revealed cardiac involvement in 78 percent of patients with the average follow-up time of 71 days. More than half of the patients had ongoing myocardial inflammation, which was independent of preexisting conditions and their severity of illness et al., demonstrated 58% of patients had abnormal CMR findings, 54% with myocardial edema and LGE in 31% of patients in a retrospective study with an average patient age of 38-years-of age and follow-up time from illness to scan of 47 days [In another study, 26 competitive athletes who were diagnosed with the COVID-19 infection, all of which were either asymptomatic or presented with mild symptoms  had CMR findings suggestive of myocarditis. Pericardial effusion was present in only 2 patients [ 47 days . DespiteOur patient appears to have developed symptoms of palpitations and dyspnea 3 months after his clinical resolution of covid-19, which is markedly unusual in the timing of his presenting cardiac symptoms. It is unclear if he had underlying inflammation or subclinical myocarditis, however, his echocardiogram and ECG were both notably normal, even on month 4 after illness. He also had high covid-19 antibody titers at that time, which suggested immunity. Furthermore, his CMR (6 months after illness) showed LGE with the absence of T2 weighted myocardial edema, which may reflect less of an acute myocardial injury response and more so a chronic process of fibrosis or scar remodeling –24. It iet al. for cardiac involvement during active covid-19 infection [Our patient may have also had insidious or subclinical cardiac involvement that may have been exacerbated by returning to heavy aerobic exercise once he felt recovered. This may explain the large time gap between his recovery of covid-19 and the development of cardiac symptoms and findings. There is emerging evidence that myocarditis in covid-19 can be detected in athletes via CMR despite a normal ECG, echocardiogram and/or other laboratory or imaging parameters. This manfection . This waThe patient is to undergo further ambulatory telemetry monitoring. Pharmacotherapy with beta blockade has been initiated with improvement in his palpitations. Electrophysiological testing with electrical mapping may be considered on his course if persistent ventricular tachycardia is detected or based on the development of other high-risk clinical features, and it may help to correlate electrical or ectopic origins with LGE patterns. Cardiac ablation and/or an implantable defibrillator may also be indicated in the future depending on his clinical course, although not warranted at this time. Finally, a follow-up CMR may also be considered to reassess fibrosis patterns or further myocardial involvement.This case suggests an insidious and atypical presentation of the cardiac manifestations of COVID-19 and may suggest possible long-term cardiac involvement, with demonstrated LGE on CMR 6 months following illness and new ECG findings at month 7. Furthermore, it illustrates the challenges in traditional workups and screening modalities in identifying patients with potential cardiac involvement and highlights the clinical utility of CMR in such patients. Clinicians should have a high index of clinical suspicion regardless of normal screening tests such as ECG or even echocardiogram and should consider close follow-up or monitoring in patients returning to heavy exercise after COVID-19 recovery. Future long-term and larger studies are recommended to better understand the long-term cardiac manifestations in COVID-19.


Major salivary gland  and lacrimal gland (dacryoadenitis) involvement can be a common feature of IgG4-related disease. There can be involvement of lacrimal and parotid gland which was previously called as Mikulicz disease and/or submandibular gland enlargement which was previously called Küttner tumour. These were previously mistakenly considered to be subcategories of Sjogren’s syndrome, but are now classified as IgG4-related disease. Here we discuss a case report of a patient who presented with bilateral dacryoadenitis and unilateral submandibular gland enlargement which initially was thought to be IgG4-related disease but turned out to be low-grade lymphoma.A 15-year-old boy presented with 6-month history of bilateral eyelid swelling. The swelling was more on the lateral side of the eyelids and was painless. It had come on suddenly over a couple of days. No history of weight loss, dry eyes, dry mouth, joint issues or skin rashes or any other symptoms. Physical examination revealed bilateral ptosis, no visual impairment and systemic examination revealed an enlarged right submandibular gland. He had initially been to a local hospital where he had investigations which included autoimmune screen including ANA, ENA, ANCA, dsDNA, serum ace and complement levels which were all negative. C1 esterase inhibitor was normal. Routine bloods including complete blood count, urea and electrolytes, thyroid stimulating hormone and erythrocyte sedimentation rate were within normal limits. Urine albumin to creatinine ratio was not raised. Hepatitis serology including Hepatitis B & C and HIV was negative. Ultrasound abdomen was unremarkable. CT scan of orbits showed bilateral enlarged lacrimal glands with patchy post contrast enhancement and the glands extending up to insertion of lateral rectus muscle. CT chest some enlarged axillary lymph nodes and nodes in lung query infective etiology. CT abdomen and pelvis was unremarkable. Ultrasound neck showed right submandibular node enlargement with colour doppler showing increased vascularity. Fine needle aspirate of the submandibular gland showed reactive lymphoid hyperplasia. He was given two short courses of steroids and each time the swelling rapidly responded to the steroids but recurred on cessation of the steroids. IgG subset analyses revealed elevated IgG4 levels of 1152mg/dl. The differential here was IgG4-related disease but as there was no clear tissue diagnosis a core biopsy of the right submandibular gland was done. This revealed tissue suspicious of low grade  lymphoma and excision biopsy was performed for definitive diagnosis.IgG4-related disease is an immune mediated fibroinflammatory condition which can affect a variety of organs and can present as tumour-like enlargement and/or organ dysfunction. The pathological findings in IgG4-related disease are lymphoplasmocytic infiltrates of IgG4-positive cells along with increased levels of serum IgG4 levels. Salivary and lacrimal glands can be commonly affected and present as enlargement, which is usually painless and bilateral. The combination of lacrimal gland enlargement with both parotid and submandibular gland enlargement is called IgG4-related Mikulicz disease.Apart from salivary glands, another commonly affected organ is the pancreas which can present as a pancreatic mass and painless jaundice, sclerosing cholangitis, retroperitoneal fibrosis, aortitis and periaortitis. Less commonly it can affect thyroid, kidney and lungs.Early recognition, diagnoses and treatment is important due to the fibroinflammatory nature of the disease. Malignancy is always in the differential and should be excluded. Steroids are the mainstay of treatment. If patients experience flare, rituximab can be added.Diagnosis should be confirmed with biopsy but histopathological findings are never alone diagnostic of IgG4-related disease and should be interpreted with clinical, serological and radiological findings.Although this patient had typical presentation of IgG4-related disease with painless enlargement of salivary and lacrimal glands and elevated IgG4 serum levels, biopsy was imperative to get to the diagnoses of low-grade lymphoma and fine needle aspirate was not adequate. As mentioned above, biopsy in IgG4-related disease will confirm the diagnosis provided there are other supporting features . However, it is imperative for excluding other important diseases like lymphoproliferative disorders.


A diabetic 20-year-old male patient, not previously vaccinated against SARS-CoV-2, was referred to our emergency department for rapid bilateral visual loss with left periorbital pain, proptosis, palpebral edema and swelling.He had been admitted one week before in a primary Covid-19 center for COVID-19 respiratory distress syndrome and treated with corticosteroids.Upon ophthalmic examination, both eyes had a fixed dilated pupil with no light perception. The left eye showed features of orbital cellulitis Fig.  with comBrain CT complemented with cerebral MRI disclosed endocranial extension of the disease and thrombosis of both left cavernous sinus and left internal carotid artery Fig. .The patient underwent emergency endoscopic sinus examination and removal of a blackish necrotic tissues from paranasal sinuses. Histopathological examination confirmed the diagnosis of mucormycosis.The patient was started on intra-venous liposomal amphotericin B and clavulanic-acid-amoxicillin. Dexamethasone was discontinued. Debridement of the involved sinuses and adjacent structures was attempted together with diluted amphotericin B irrigation. Orbital exenteration was discussed but it was not retained due to poor prognosis and lack of the patient’s consent.Over the following days, the patient’s ocular and general conditions worsened due to bilateral extensive eyelid and facial necrosis with purulent melting of the left eyeball and central nervous system involvement Fig. . He passWith the onset of COVID-19 pandemic, clinicians have seen a sudden surge of cases of mucormycosis. Although all ocular structures may be involved in patients with COVID-19 infection, orbital mucormycosis seems to be the most aggressive and so far fatal complication .To the best of our knowledge very few cases of severe bilateral blindness in Covid-19 patient have been reported –6. They The presentation of our patient suggests a left cavernous sinus and internal carotid thrombosis together with a right CRAO. From the ophthalmic and other orbital arteries, fungal infection advanced into the left cavernous sinus, ipsilateral carotid artery and right central retinal artery. This resulted in acute onset of bilateral vision loss and left ophthalmoplegia.Successful treatment of ROCM highly depends on the early diagnosis of the infection, the control of the underlying predisposing factors and aggressive surgery .Hence, Ophthalmologists should have a high index of suspicion for mucormycosis development in diabetic patients with COVID-19 illness, treated with corticosteroids. Vaccination against SARS-COv2 seems to be the best treatment to prevent COVID-19 and related blinding and fatal diseases.


In the last year, the global outbreak of COVID-19 and the sharply rising price of Bitcoin greatly influence the financial market. Such influences include but are not limited to the trading strategies between different cryptocurrencies, portfolio diversification, foreign exchange markets, and macroeconomic policy. In this 26th issue of Financial Innovation (FIN), Volume 7, No. 2(2021), 22 researchers from 7 countries have used both traditional statistical methods and the newly developed machine learning techniques to analyze how COVID-19 affects the global financial market and how cryptocurrencies affect portfolio diversification. The research results could be beneficial to governments in making macroeconomic policies and financial investors for making better investment decisions.The first paper, titled “Forecasting and trading cryptocurrencies with machine learning under changing market conditions”, uses machine learning techniques to predict three major cryptocurrencies. The empirical results indicate that the machine learning tools can be used to devise trading strategies for cryptocurrencies.The second paper, titled “Portfolio diversification benefits of alternative currency investment in Bitcoin and foreign exchange markets”, examines the portfolio diversification benefits of alternative currency trading in Bitcoin and foreign exchange markets. Using the spillover index method, the spillover asymmetry measures, and the frequency connectedness method, this study investigats the dynamics of volatility spillover from Bitcoin to the foreign exchange pairs of major trading currencies. The findings could have significant implications for portfolio diversification and risk minimization.The third paper, titled “The explosion in cryptocurrencies: a black hole analogy”, uses an analogy between finance and astrophysics to investigate the existence of a mechanism that can describe the explosive increase in the number of traded cryptocurrencies and the cryptocurrency market. The study shows that the changes in the traded cryptocurrencies are a positive function of the number of traded cryptocurrencies in the previous period.The fourth paper, titled “Regime specific spillover across cryptocurrencies and the role of COVID‑19”, examines the daily return spillover among 18 cryptocurrencies under low and high volatility regimes considering the effect of the COVID-19 outbreak. The analysis reveals that much higher spillovers exist in the high volatility regime during the COVID-19 outbreak.The fifth paper, titled “Discovering interlinkages between major cryptocurrencies using high‑frequency data: new evidence from COVID‑19 pandemic”, examines the return and volatility spillover between three cryptocurrencies during the pre-COVID-19 period and the COVID-19 period. The findings could be helpful to portfolio managers and policymakers regarding portfolio diversification, hedging, forecasting, and risk management.The sixth paper, titled “Dynamic connectedness between stock markets in the presence of the COVID‑19 pandemic: does economic policy uncertainty matter?”, investigates the dynamic connectedness between stock indices and the effect of economic policy uncertainty (EPU) in eight countries where COVID-19 was most widespread. The results have important implications for individual investors, portfolio managers, policymakers, investment banks, and central banks.The seventh paper, titled “The Impact of the COVID-19 Outbreak on Chinese-listed Tourism Stocks”, uses an event study method to analyze the effects of COVID-19 outbreak on stock price movements of China’s tourism industry. The study shows a negative impact exists, and the government’s responses could minimize its impact.The eighth paper, titled “The macroeconomic effects of COVID‑19 in Montenegro: a Bayesian VARX approach”, examines and assesses appropriate macroeconomic policy responses of the Montenegrin Government to the outbreak of COVID-19. The study shows that the current government’s response is efficient and suggests some useful methods for developing the anti-pandemic and overall development strategy.


Body homeostasis is predominantly controlled by hormones secreted by endocrine organs. The central nervous system contains several important endocrine structures, including the hypothalamic-pituitary axis. Conventionally, neurohormones released by the hypothalamus and the pituitary gland (hypophysis) have received much attention owing to the unique functions of the end hormones released by their target peripheral organs . Recent advances in mouse genetics have revealed several important metabolic functions of hypothalamic neurohormone-expressing cells, many of which are not readily explained by the action of the corresponding classical downstream hormones. Notably, the newly identified functions are better explained by the action of conventional neurotransmitters  that constitute a neuronal circuit. In this review, we discuss the regulation of appetite and metabolism by hypothalamic neurohormone-expressing cells, with a focus on the distinct contributions of neurohormones and neurotransmitters released by these neurons. Signaling molecules produced by the brain’s hypothalamus function both as neurotransmitters  and hormones (throughout the rest of the body) to regulate appetite and metabolism. Jong-Woo Sohn and colleagues from the Korea Advanced Institute of Science and Technology in Daejeon, South Korea, summarize the well-established ways in which certain hypothalamic cells interact with parts of the pituitary gland in the brain to control the activity of hormones involved in feeding behaviors and energy balances.The same cells can also impact appetite and metabolism in non-hormonal ways. New research has shown that neurohormone-producing cells in the hypothalamus can form connections with appetite-associated neurons and communicate via neurotransmitters. A deeper understanding of this process could lead to new therapies for obesity, diabetes and other metabolic disorders. Similar to other endocrine organs, some hypothalamic neuroendocrine cells secrete end hormones , which are delivered to their target organs, where they produce specific effects. Other types of hypothalamic neuroendocrine cells secrete releasing hormones, such as corticotropin-releasing hormone (CRH). Releasing hormones are secreted into the hypophyseal portal system and consequently excite a second population of neuroendocrine cells in the anterior pituitary gland (adenohypophysis) to secrete stimulating hormones, such as adrenocorticotropic hormone (ACTH). This type of functional connection between hypothalamic and pituitary neuroendocrine cells is referred to as the hypothalamic-pituitary (HP) axis, which constitutes a major component of the hypothalamic neuroendocrine system.The hypothalamus is a vital region of the brain that regulates whole-body homeostasis. Hypothalamic neuroendocrine cells control homeostasis through the production and secretion of neurohormones into the general circulation3. Hormones released by the HPA and HPT axes were also shown to regulate appetite and metabolism. Glucocorticoids were shown to increase appetite and affect glucose homeostasis4, and thyroid hormones tend to promote appetite, increase heat generation, and reduce body weight5. Human diseases associated with dysfunction of the HPA axis  and the HPT axis  are characterized by abnormal feeding behavior and/or perturbed metabolism, which confirms the above-mentioned effects of these hormones7. Additionally, CRH and thyrotropin-releasing hormone (TRH) are reported to control appetite and metabolism10. These findings highlight the potential importance of hypothalamic CRH and TRH neurons as well as the HPA and HPT axes in the regulation of energy homeostasis and metabolism.The HP axis provides important humoral responses to challenges such as stress and cold. The HP-adrenal (HPA) axis releases glucocorticoids from the adrenal cortex in response to stress, and the HP-thyroid (HPT) axis releases thyroid hormones from the thyroid gland in response to cold12. Therefore, neurohormone-expressing cells comprise neuroendocrine and non-neuroendocrine cells, and the term “neuroendocrine cells” may only be used to refer to neurons that project to the median eminence and release neurohormones. However, a subset of CRH neurons located in the paraventricular nucleus of the hypothalamus (PVH) labeled with peripherally injected fluorogold also showed retrograde labeling of fluorescent beads injected into the lateral hypothalamic area (LHA)13. These results suggest that neuroendocrine and non-neuroendocrine cells are not always completely segregated within a single population of neurohormone-expressing cells. However, throughout this review, we use the expression “neuroendocrine cells” only to refer to neuroendocrine neurohormone-expressing cells.All neurons that express neurohormones are not “neuroendocrine” cells; some neurohormone-expressing neurons  do not project to the median eminence14. Moreover, PVH CRH neurons send glutamatergic fibers to neurons of the LHA, which is reportedly involved in stress behaviors13. OXT neurons within the PVH were also shown to transmit glutamatergic projections to the lateral parabrachial nucleus (PBN) to regulate fluid intake15. Therefore, it is important to consider the neural (non-neuroendocrine) circuitry collectively with the neuroendocrine axis to gain a deeper and complete understanding of the role of hypothalamic neurohormone-expressing cells.The non-neuroendocrine neurohormone-expressing cells of the hypothalamus constitute a neural circuitry that utilizes conventional neurotransmitters. For example, previous studies have reported that TRH neurons within the PVH form glutamatergic synapses on orexigenic (appetite-promoting) agouti-related peptide (AgRP) neurons within the arcuate nucleus of the hypothalamus (ARH), the stimulation of which increases appetiteIn this review, we summarize the endocrine function of selected hypothalamic neurohormone-expressing cells and the relevant HP axis that regulates appetite and metabolism. We also discuss recent studies that investigated the role of conventional neurotransmitters released by these neurons.16. OXT causes contraction of the smooth muscles of the uterus and mammary gland, and VP acts on the kidneys to promote water reabsorption17. These posterior pituitary hormones and the OXT and VP neurons are also known to control appetite and metabolism. For example, OXT administration causes anorexia18, and hypothalamic lesions of OXT neurons result in hyperphagia and obesity19. OXT neurons within the PVH were shown to be inhibited by AgRP neurons within the ARH20. OXT also produces several beneficial metabolic effects, such as an increase in energy expenditure and promotion of lipolysis18. On the other hand, experimental evidence suggests that VP suppresses food intake21. Recent studies in mouse models have reported that chemogenetic activation of VP neurons within the PVH induced anorexia, whereas chemogenetic inhibition of these neurons partially reversed anorexia induced by MTII, a melanocortin-4 receptor (MC4R) agonist22. Reportedly, chemogenetic activation of VP neurons located in the PVH, SON, and suprachiasmatic nucleus reduces food intake in rats23, further supporting the anorexigenic (appetite-suppressing) property of VP neurons.Hypothalamic neuroendocrine cells release neurohormones that regulate the homeostatic function of the pituitary gland (hypophysis) Fig. . Usually1  axis is bidirectionally controlled by hypothalamic neuroendocrine cells with opposite functions. This axis is upregulated by GHRH neurons in the ARH, which initiates the release of growth hormone (GH) from the adenohypophysis and insulin-like growth factor-1 (IGF-1) from the liver25. Conversely, SST neurons in the periventricular nucleus (PeV) and PVH downregulate the HPS axis by inhibiting GH secretion26. The HP-gonadal (HPG) axis is stimulated by GnRH neurons in the preoptic area (POA), which causes secretion of follicle-stimulating hormone (FSH)/luteinizing hormone (LH) and sex hormones1. DAergic neurons in the PeV and ARH downregulate prolactin (PRL) release27, whereas several neurohormones including TRH and GnRH trigger PRL release29. In contrast to DA, which is an amine, hypothalamic neurohormones are peptide hormones.Another class of hypothalamic neuroendocrine cells regulates the secretion of hormones from the adenohypophysis via the hypophyseal portal system. These anterior pituitary hormones include CRH, TRH, growth hormone-releasing hormone (GHRH), somatostatin (SST), gonadotropin-releasing hormone (GnRH), and dopamine (DA)30. Later, investigators attributed the anti-obesity effects of estradiol to estrogen receptor-α expressed by pro-opiomelanocortin (POMC) neurons within the ARH and steroidogenic factor-1 neurons within the ventromedial nucleus of the hypothalamus (VMH)31. As mentioned earlier, hormones controlled by the HPA and HPT axes are known to regulate appetite and metabolism9. Compared with the functions of hormones released by the neurohypophysis and the other HP axes, the “classical” function of glucocorticoids and thyroid hormones is more relevant to the regulation of energy balance and glucose homeostasis. Interestingly, glucocorticoids and thyroid hormones promote food intake5, whereas CRH and TRH produce anorexigenic effects9. These findings suggest a complex nature of appetite and metabolism regulation by the HPA and HPT axes. Recent studies have observed that both CRH and TRH neurons within the PVH release glutamate to regulate homeostasis14, which highlights the non-neuroendocrine function of these neurohormone-expressing cells. Therefore, investigators believe that the “neuroendocrine” subsets of CRH and TRH neurons utilize the HPA and HPT axes, whereas other “non-neuroendocrine” cell populations affect appetite and metabolism via neural circuitry. In the following sections, we review the available literature to discuss the role of CRH neurons/the HPA axis and TRH neurons/the HPT axis in the regulation of appetite and metabolism, with a focus on the differences in the functions of each hormone and distinctions between neural and endocrine regulation.Hormones of the HP axes are associated with multiple metabolic functions. For example, estradiol is a gonadal steroid hormone released by stimulation of the HPG axis. Studies have shown that food intake is reduced close to the time of ovulation and that postmenopausal women gain body weight; therefore, estradiol was proposed to exert anti-obesity effects33. Available evidence suggests that in addition to playing a pivotal role in stress-related responses34, CRH actively participates in the regulation of energy metabolism35. Most CRH neurons that control the HPA axis are located within the PVH, particularly in the lateral part36. CRH neurons within the PVH may affect appetite and metabolism either intrinsically or via HPA axis stimulation38. Additionally, CRH neurons located outside the hypothalamus may function independent of the HPA axis. We discuss the control of appetite and metabolism by the HPA axis and the CRH neurons expressed throughout the brain.CRH is a 41-amino acid peptide that is widely expressed throughout the body, including the brain42 , which is associated with downregulation of uncoupling protein-1 (UCP-1) expression, as well as expansion of white adipose tissue (WAT)42. CORT administration was shown to elevate plasma triglyceride (TG) levels and increase the liver TG content42, which was associated with increased expression of genes involved in hepatic fatty acid metabolism. CORT injections also tended to increase the blood free fatty acid (FFA) level, although the difference was not statistically significant42. However, energy expenditure was unchanged in mice after CORT administration, regardless of whether the mice were fed a HFD or a chow diet43. Locomotive activity remained unchanged43 or was decreased39 after exogenous CORT administration. These results suggest that CORT-induced obesity is largely due to increased appetite rather than changes in energy consumption. Studies suggest that the orexigenic effects of glucocorticoids are at least partially mediated by modulation of POMC and AgRP neurons within the ARH45.Glucocorticoids are secreted from the adrenal cortex following HPA axis activation. Corticosterone (CORT), which is the major glucocorticoid in rodents, induces hyperphagia and increases fat mass and body weight42 Table . Chronic38. Dexamethasone  has been reported to reduce insulin secretion from the isolated pancreas46. However, the effects of glucocorticoids on whole-body glucose homeostasis are equivocal. It was shown that CORT administration for 1 to 2 weeks did not affect glucose homeostasis42; however, CORT administration for 4 weeks caused hyperglycemia with increased insulin levels39, although glucose homeostasis was unaffected after 22 weeks of CORT treatment43. These findings suggest that although glucocorticoids may cause hyperglycemia, they appear to produce variable effects on long-term glucose homeostasis depending on the experimental conditions.Previous studies have also reported the effects of exogenous CORT on glucose metabolism. It is well known that glucocorticoid-induced gluconeogenesis and glycogenolysis result in increased blood glucose levels47. In addition, treatment of primary cultures of BAT and WAT with ACTH led to elevated UCP-1 levels48. The effects of ACTH on lipid and glucose metabolism were also different from those produced by glucocorticoids. ACTH was shown to cause a transient increase in insulin secretion from the isolated pancreas49 and release of FFAs from isolated epididymal fat tissue50 under ex vivo conditions. However, ACTH injections administered in vivo for 3 consecutive days did not affect blood glucose, TG and FFA levels51. Blood levels of total cholesterol and high-density lipoprotein (HDL) cholesterol were also unchanged by in vivo ACTH injections, although this treatment increased plasma CORT and low-density lipoprotein (LDL) cholesterol levels51. Currently, no plausible explanation is available for the disparate observations; however, these results could be attributed to the possibility that exogenous ACTH affects the HPA axis and glucocorticoid secretion under some experimental conditions. Further studies utilizing knockout or knockdown of endogenous ACTH, as described below for CRH, are required to resolve this issue.Interestingly, the effects of ACTH on appetite and energy consumption contrasted with those induced by glucocorticoids Table . For exa53. Another study demonstrated that i.c.v. injections of CRH increased oxygen consumption (VO2) and locomotion concomitant with a decrease in the respiratory exchange ratio (RER)35. CRH injections into the PVH reduced food intake in rats54, and CRH injections into the lateral septal area (LS) caused anorexia in food-deprived mice with no effects on body weight55. However, CRH-deficient mice did not show any defects in feeding behavior57 or even showed anorexigenic phenotypes59, which suggests that experiments using exogenous CRH may not accurately predict the metabolic effects of endogenous CRH. These results also emphasize the necessity of loss-of-function experiments to corroborate the findings of experiments using exogenous hormones to investigate the role of the HPA axis in the regulation of appetite and metabolism.The effects of exogenous CRH on energy homeostasis are also markedly different from those of CORT, although these effects are consistent with those of exogenous ACTH administration Table . For exa61 -induced hyperphagia63. It was recently reported that fasting-induced activation of AMP-activated kinase (AMPK) causes increased activity of PVH CRH neurons, which contributes to a preference for a high-carbohydrate diet (nutrition) over a HFD  under fasting conditions64. A more recent study demonstrated that HFD feeding blunted the responsiveness of PVH CRH neurons and that mice with blunted PVH CRH neuronal responsiveness were more likely to develop HFD-induced obesity65. Overall, these studies suggest that PVH CRH neurons may participate in the fine tuning of food intake rather than control food intake per se. It is currently unknown whether appetite modulation by PVH CRH neurons occurs via the action of hormones or neurotransmitters. Considering the conflicting reports on the role of endogenous CRH in appetite regulation59, it can be inferred that the observed alterations in food intake are largely mediated by glutamate, which is a classical neurotransmitter released by PVH CRH neurons. Notably, defective glutamatergic neurotransmission from single-minded-1 neurons, which constitute the largest proportion of PVH neurons, was shown to cause obesity66. PVH CRH neurons send monosynaptic projections to various brain regions67 and polysynaptic projections to peripheral tissues and organs that regulate metabolism, such as WAT and the liver68. Therefore, defective glutamatergic neurotransmission from PVH CRH neurons is also likely to play a role in the pathophysiology of obesity.Studies in mice showed that chemogenetic inhibition or toxin-induced ablation of PVH CRH neurons did not alter acute or chronic food intake or body weight61 Table . Interes69. Conventionally, CRH neurons in the CeA and BNST have received considerable attention for their roles in the development of fear and anxiety71. Available evidence suggests that CRH neurons in these regions also participate in the control of appetite and metabolism. A recent study demonstrated that lentiviral knockdown of CRH in the CeA resulted in elevation of the basal but not the stress-induced CORT level72, which suggests that CeA CRH neurons downregulate the basal (non-stress) activity of the HPA axis. These neurons do not directly project to the median eminence; therefore, it is possible that CRH neurons in the CeA inhibit PVH CRH neurons via an unidentified neural circuitry. A previous study reported that photostimulation of CeA CRH neurons did not change food consumption under either fed or fasting conditions73  and the bed nucleus of the stria terminalis (BNST)78, similar to the findings associated with CeA CRH neurons (Table BNST neurons) to LHA projections induced food consumption in fed mice, whereas optogenetic inhibition of this circuit diminished food consumption in fasted mice79. Similarly, food consumption was increased by optogenetic stimulation of axon terminals of VgatBNST neurons innervating PBN neurons in sated mice80. Notably, this manipulation increased the consumption of salty and bitter-tasting food80. BNST CRH neurons are primarily GABAergic; however, it is unclear whether stimulation and inhibition of BNST CRH neuronal projections to the above-mentioned brain areas also affect feeding behavior under comparable experimental conditions.Chemogenetic activation of BNST CRH neurons did not change body weight or food intakens Table . However81, but they may also affect feeding behavior via their actions on specific areas of the brain82. TRH neurons reportedly regulate appetite and metabolism directly via neural circuitry within the brain83. Currently, there is little direct evidence that TRH neurons control appetite and metabolism indirectly through the HPT axis. Below, we discuss the metabolic function of thyroid hormones, TSH, TRH, and TRH neurons in the brain.Thyroid hormones released from the thyroid gland include thyroxine (T4), which is converted by the action of deiodinase enzymes into the bioactive form triiodothyronine (T3). Thyroid hormones affect the metabolic rate and synthesis of proteins essential for thermogenesis in cold environments predominantly via peripheral mechanisms85. Fasting is reported to cause a significant increase in hypothalamic T3 and D2 mRNA levels/activity88. Conversely, D2-null mice showed reduced food intake in response to a fast-refeeding paradigm, but normal food intake was restored after exogenous T3 injections89. Therefore, increased production of hypothalamic T3 secondary to D2 activity is important for increased food intake in response to acute food deprivation.Type 2 deiodinase (D2) is an important enzyme that catalyzes the conversion of endogenous T4 to T3. Local production of T3 in the hypothalamus is controlled by tanycytes, which are glial cells that express D290, increased food intake secondary to the action of thyroid hormones was previously considered a compensatory mechanism for the increased energy consumption in these patients. However, a direct action of T3 on hypothalamic neurons was suggested in a study in which exogenous T3 significantly increased food intake whether it was injected subcutaneously or directly into the VMH, whereas T3 injections into the ARH did not alter food intake86  or VMH but not into the LHA101. It is possible that exogenous TRH injected into a specific brain area can spread to adjacent brain sites; therefore, these findings should be confirmed using more sophisticated methods, such as studies in genetically engineered mice and neuron-specific viral injections.A previous study showed that subcutaneous injections of exogenous TRH decreased food intake and increased body temperature in rats98 Table . Additio106, which may explain the anorexigenic effects of i.c.v. TRH100. In another study, i.c.v. injections of TRH increased histamine turnover in the tuberomammillary nucleus, PVH, and VMH in rats, and the anorexigenic effects of i.c.v. TRH were attenuated in histamine-depleted rats and histamine H1 receptor-null mice107. TRH was also shown to suppress the activity of melanin-concentrating hormone (MCH) neurons in the LHA indirectly by increasing synaptic inhibition through activation of local GABAergic neurons108, which suggests that the metabolic effects of TRH can be attributed to inhibition of MCH neuronal activity. In this study, TRH was shown to excite the hypocretin/orexin neurons in the LHA, although it produced no effect on the activity of POMC or NPY neurons within the ARH108. Therefore, multiple cellular and synaptic mechanisms are implicated in the in vivo phenotypes resulting from exogenous TRH injections. Considering the TRH-induced alterations in the activity of multiple neuronal populations, future experiments should focus on assigning specific neuronal populations to distinct phenotypes of TRH administration.Studies have investigated the cellular and circuit-level mechanisms underlying the development of in vivo phenotypes after exogenous TRH injections. Earlier research showed that TRH administration stimulated glucose-responsive neurons within the VMH109. It was previously shown that chemogenetic activation of PVH TRH neurons stimulates feeding via their excitatory glutamatergic projections to the orexigenic AgRP neurons within the ARH14 (Table 83. PVH TRH neurons are reported to function as targets of major metabolic signals, such as leptin and melanocortin110. In rat models, leptin was shown to regulate TRH production via a combination of a direct action on PVH TRH neurons and an indirect mechanism by which leptin first modulates the activity of ARH neurons, which consequently project to PVH TRH neurons111. Leptin was also reported to directly activate PVH TRH neurons and increase serum T4 levels in fasted mice112. However, a recent study reported that only a few PVH TRH neurons express leptin receptors and that PVH TRH neurons receive few axon fibers originating from ARH POMC neurons in mice113. It is, therefore, reasonable to infer that leptin-induced regulation of PVH TRH neurons shows species-specific differences. MC4R is expressed by most TRH neurons within the PVH114. PVH TRH neurons were shown to receive synaptic input from the POMC and NPY/AgRP neurons within the ARH, constituting the central melanocortin pathway117. In vivo studies have also confirmed that i.c.v. injections of α-melanocyte-stimulating hormone can prevent the reduction in Trh gene expression that occurs during fasting118. Therefore, the central melanocortin pathway originating from the ARH appears to control PVH TRH neurons via MC4Rs, although the physiological significance of MC4Rs expressed by TRH neurons remains to be determined.TRH neurons are located in multiple hypothalamic areas, including the PVH, DMH, VMH, and LHA14 Table . Additio119. However, no studies have investigated the metabolic functions of TRH neurons in the LHA. Further studies are warranted to accurately delineate the functions of TRH neurons located in the above-mentioned hypothalamic areas.Currently, little is known regarding the function of TRH neurons located outside the PVH. TRH neurons in the LHA were shown to receive input from the POMC and NPY/AgRP neurons within the ARH, which suggests that the activity of TRH neurons in the LHA is affected by the metabolic state of the organism2+ imaging techniques. In fact, these cutting-edge techniques have revealed several previously unknown mechanisms underlying homeostatic regulation by hypothalamic neurohormone-expressing cells at the molecular, cellular, and circuit levels. To date, these techniques have been applied primarily to understand the contribution of non-neuroendocrine or neural mechanisms to feeding behavior and metabolism. Currently available data regarding the contribution of endocrine mechanisms are derived mainly from experiments using more conventional methods, such as fluorogold labeling, immunostaining, and hormone measurements. Notably, the neuroendocrine effects of these cells are potentially more powerful and long-lasting than the non-neuroendocrine effects; therefore, it is necessary to address this issue using novel techniques with the understanding that these techniques could lead to major scientific breakthroughs. Therefore, further research is warranted to develop effective strategies to evaluate the endocrine and neural functions of hypothalamic neurohormone-expressing cells of interest to determine the relative importance of each aspect in the regulation of feeding behavior and metabolism. This information will enable scientists to gain a deeper understanding of the functions of neurohormone-expressing cells and facilitate the development of novel therapeutic strategies for obesity and metabolic diseases.Hypothalamic neurohormone-expressing cells control appetite and metabolism via hormones and neurotransmitters. Therefore, the mechanisms underlying their physiological functions are significantly more complicated than those underlying humoral or neural regulation. Various genetic tools are currently available to investigate the neural circuitry associated with various animal behaviors; these tools include genetically engineered mouse models and optogenetic, chemogenetic, and in vivo Ca


Only around 200 cases have been described in the literature, so little is known about incidence, prevalence, patient management and outcomes. This differs and should not be confused with post-viral myalgia which bears neither the histological changes nor chronicity of focal myositis. Treatment options are centred on immunomodulation and in severe cases surgical management of contractures.Focal myositis is a rare immune-mediated pseudotumour of a single skeletal muscle groupCase 1A systemically well 7-year-old girl presented with 5-weeks of right calf tenderness and swelling following a short episode of pharyngitis and generalised maculopapular rash. There was no gait abnormality, focal neurology or restriction in activity aside from fatigability on walking distances. There were no skin rashes, joint involvement, eye changes or involvement of other muscles. She had a raised creatine kinase, plasma viscosity and lactate dehydrogenase. Her other blood results were normal including an extended autoimmune screen, immunoglobulins, complement levels, ASOT and titres of mycoplasma, EBV and CMV. MRI showed evidence of extensive inflammation of the gastrocnemius and soleus. A muscle biopsy showed heavy interstitial inflammatory cell infiltrate of predominantly lymphocytes, features of fibre necrosis including phagocytosis and hyalinisation with concurrent fibre regeneration. Case 2o on abduction and external rotation with bilateral mild swelling of the proximal interphalangeal (PIP) joints on both upper limbs. Otherwise, there was a full range of movement in all joints, with no rashes or other joint swelling or inflammation. Her blood tests were ANA positive 1:6000 and MRI of her hips demonstrated high T2 signal intensity in the left gluteus minimis and medius, obturator internus, obturator externus in keeping with myositis.A systemically well 14-year-old presented with 6-months of left-sided hip pain, weight loss and inability to weight-bear without crutches. On examination there was painful fixed limitation of the left hip to 45Case 1She was initially managed with physiotherapy and anti-inflammatory medications but then developed intermittent right calf pain, restriction in activity and tiptoe walking due to gastrocnemius contractures. She was commenced on an 8-week tapering course of oral steroids and is improving with weekly methotrexate.Case 2She received a pulse of corticosteroids followed by a course of methotrexate. There was immediate improvement in her PIP joint swellings and within a few weeks she was able to walk without crutches for the first time in 6 months; a surveillance MRI confirmed complete radiographical resolution of myositis. Unfortunately, 18 months after her diagnosis, she had developed anterior uveitis of her left eye with posterior synechiae; this responded well to steroid and cyclopentolate eye drops.We emphasise that clinicians should bear this rare differential diagnosis for in mind for consideration of early conservative management, assessment for uveitis, immunomodulation and possibly surgical correction to improve patient outcome.