Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed nonpolypoid lesions. Seven (88%) showed multifocal GI disease, including 5 with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single system), with the remaining 14 (36%) exhibiting multisystem disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multisystem LCH more frequently presented with GI symptoms (92%, P < .001), noncolorectal GI site involvement (50%, P = .02), multifocal GI lesions (43%, P = .005), nonpolypoid lesions (71%, P < .001), infiltrative histologic growth pattern (78%, P = .04), and persistent disease (57%, P < .001). Adult patients with multisystem LCH appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrated that adults with single-system LCH involving the GI tract have an excellent prognosis, whereas multisystem LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, noncolorectal GI involvement, multifocal GI disease, nonpolypoid lesions, and infiltrative growth pattern.

Rare cardiac inflammatory pseudotumor in a toddler: Complementary roles of cardiac magnetic resonance and positron emission tomography.

We present a rare pediatric case of cardiac inflammatory pseudotumor (IPT) with a unique presentation of fever of unknown origin with markedly elevated inflammatory markers. A right atrial mass was discovered incidentally by echocardiography. The cardiac magnetic resonance (CMR) signal characteristics and mass location were not consistent with any of the common benign cardiac tumors of childhood. The presence of high signal intensity on T2 imaging and late gadolinium enhancement, in conjunction with intense metabolic activity at the mass site on positron emission tomography (PET), raised the possibility of an inflammatory or malignant mass. The diagnosis of IPT was confirmed by biopsy. Our case highlights the utility of PET imaging to confirm the inflammatory nature and extent of an IPT.

Clinical applications of contactless photoplethysmography for vital signs monitoring in pediatrics: A systematic review and meta-analysis.

Background: Contactless photoplethysmography (PPG) potentially affords the ability to obtain vital signs in pediatric populations without disturbing the child. Most validity studies have been conducted in laboratory settings or with healthy adult volunteers. This review aims to evaluate the current literature on contactless vital signs monitoring in pediatric populations and within a clinical setting. Methods: OVID, Webofscience, Cochrane library, and clinicaltrials.org were systematically searched by two authors for research studies which used contactless PPG to assess vital signs in children and within a clinical setting. Results: Fifteen studies were included with a total of 170 individuals. Ten studies were included in a meta-analysis for neonatal heart rate (HR), which demonstrated a pooled mean bias of -0.25 (95% limits of agreement (LOA), -1.83 to 1.32). Four studies assessed respiratory rate (RR) in neonates, and meta-analysis demonstrated a pooled mean bias of 0.65 (95% LOA, -3.08 to 4.37). All studies were small, and there were variations in the methods used and risk of bias. Conclusion: Contactless PPG is a promising tool for vital signs monitoring in children and accurately measures neonatal HR and RR. Further research is needed to assess children of different age groups, the effects of skin type variation, and the addition of other vital signs.

Clinical applications of contactless photoplethysmography for monitoring in adults: A systematic review and meta-analysis.

Contactless photoplethysmography (cPPG) is a method of physiological monitoring. It differs from conventional monitoring methods (e.g., saturation probe) by ensuring no contact with the subject by use of a camera. The majority of research on cPPG is conducted in a laboratory setting or in healthy populations. This review aims to evaluate the current literature on monitoring using cPPG in adults within a clinical setting. Adhering to the Preferred Items for Systematic Reviews and Meta-analysis (PRISMA, 2020) guidelines, OVID, Webofscience, Cochrane library, and clinicaltrials.org were systematically searched by two researchers. Research articles using cPPG for monitoring purposes in adults within a clinical setting were selected. Twelve studies with a total of 654 individuals were included. Heart rate (HR) was the most investigated vital sign (n = 8) followed by respiratory rate ((n = 2), Sp02 (n = 2), and HR variability (n = 2). Four studies were included in a meta-analysis of HR compared to ECG data which demonstrated a mean bias of -0.13 (95% CI, -1.22-0.96). This study demonstrates cPPG can be a useful tool in the remote monitoring of patients and has demonstrated accuracy for HR. However, further research is needed into the clinical applications of this method.

Cardiac output monitoring in children: a review.

Cardiac output monitoring enables physiology-directed management of critically ill children and aids in the early detection of clinical deterioration. Multiple invasive techniques have been developed and have demonstrated ability to improve clinical outcomes. However, all require invasive arterial or venous catheters, with associated risks of infection, thrombosis and vascular injury. Non-invasive monitoring of cardiac output and fluid responsiveness in infants and children is an active area of interest and several proven techniques are available. Novel non-invasive cardiac output monitors offer a promising alternative to echocardiography and have proven their ability to influence clinical practice. Assessment of perfusion remains a challenge; however, technologies such as near-infrared spectroscopy and photoplethysmography may prove valuable clinical adjuncts in the future.

ASPECT Score and Its Application to Vasospasm in Aneurysmal Subarachnoid Haemorrhage: a Case-Control Study.

Delayed cerebral ischaemia (DCI) is a significant complication of aneurysmal subarachnoid haemorrhage (aSAH) and is strongly associated with poorer outcome. The Alberta Stroke Program Early Computer Tomography (ASPECT) score is an established scoring tool, used in acute ischaemic stroke, to quantify early ischaemic changes on CT head scans. We aim to identify if ASPECT scoring correlates with functional outcome in DCI following aSAH. Retrospective case-control study. Inclusion criteria: admission to the Department of Neurosurgery at Leeds Teaching Hospitals NHS Trust (a tertiary neurosurgical centre in the United Kingdom) between 2014 and 2018, with a diagnosis of anterior circulation aneurysmal subarachnoid haemorrhage; as confirmed by initial CT scan and subsequent CT angiography or catheter digital subtraction angiography. Cases were those who developed DCI (n = 43) and controls were randomly selected from those who did not develop DCI (n = 46) but otherwise met the same inclusion criteria. The primary outcome measure was Glasgow Outcome Score (GOS): assessed at discharge and 3 months. ASPECT scores were calculated from non-contrast CT head scans by three researchers blinded to each other and clinical outcome. Spearman's rank correlation was used to calculate correlation between ASPECT scores and GOS. ASPECT score positively correlated with GOS in the cases both at discharge (Spearman rho 0.436, p = 0.003) and at 3 months (Spearman rho 0.431, p = 0.004). When corrected for Fisher grading, the adjusted odds ratio of having a high GOS with a low ASPECT score at discharge was OR 0.74 (95% CI 0.61-0.94, p = 0.003), and 3 months OR 0.73 (95% CI 0.59-0.91, p = 0.005). ASPECT score significantly correlates with clinical outcome in DCI post aSAH, even after correcting for Fisher grade. ASPECT scoring may identify patients at risk of poor outcome following DCI and represents a quick and reliable tool that aids in clinical decision-making and prognostication.

Unaccounted for enteral volume loss linked to delayed cerebral ischemia after subarachnoid hemorrhage.

OBJECTIVE: Delayed ischemic neurological deficit (DIND) is seen as a clinical manifestation of cerebral vasospasm and is a significant cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH). Currently, the standard of care for DIND prevention in patients who have sustained aSAH is prophylactic nimodipine therapy and ensuring adequate fluid intake, alongside other treatments such as bowel care. Osmotic laxatives trap water within the bowel lumen to accelerate the transport of the gut contents through the bowel. Given the potential for DIND secondary to cerebral vasospasm, it is perhaps counterintuitive that gastrointestinal fluid loss and use of osmotic laxatives are not commonly considered in many aSAH management protocols. METHODS: A retrospective case note analysis was performed for all adult patients (aged > 16 years) admitted to the Department of Neurosurgery at Leeds General Infirmary with a diagnosis of aSAH between August 2019 and September 2020. RESULTS: A total of 105 patients were included, 62% of whom were female, with a mean and median age of 54 years (range 24-84 years). Diarrhea was noted in 12 patients (11.4%), 58% of whom subsequently developed DIND (OR 15.30, CI 3.92-59.14; p = 0.0001). All patients received osmotic laxatives (97% having received ≥ 2 laxative agents). CONCLUSIONS: Patients with aSAH who subsequently developed diarrhea had significantly increased odds of developing DIND. Enteral volume loss due to osmotic laxative use is a potential risk factor for DIND after aSAH.

Uterine Leiomyosarcoma Associated With Leiomyoma With Bizarre Nuclei: Histology and Genomic Analysis of 2 Cases.

Leiomyoma with bizarre nuclei (LM-BN) is a rare variant of leiomyoma with overall benign clinical course. It has histologic features showing focal or diffuse nuclear atypia surrounded by usual type leiomyoma. Uterine leiomyosarcomas (LMS) are a group of rare and aggressive malignancies with limited treatment options available. The potential association between LM-BN with LMS is largely unknown. In this study, we report 2 cases of uterine smooth muscle tumor with typical histologic and molecular evidence of LM-BN, which are associated with its progression to the malignant counterpart of LMS. We summarize the detailed histologic, morphologic, and genomic characteristics of these 2 sets of cases. Our findings suggest that LMS progressing from preexisting LM-BN can be one of the tumor pathogenesis pathways in uterine leiomyosarcomas.

Solitary fibrous tumor of thoracic cavity, extra-thoracic sites and central nervous system: Clinicopathologic features and association with local recurrence and metastasis.

Published risk stratification models of solitary fibrous tumor (SFT) have been associated with distant metastases outside the central nervous system (CNS), but have not been studied for tumors occurring in the CNS. In a retrospective review, we identified 72 cases of solitary fibrous tumor or hemangiopericytoma (HPC) diagnosed between January 2011 and December 2020 at our institution. The tumors involved the central nervous system (N = 17), thoracic cavity (N = 28), and extrathoracic sites (N = 27). The risk of local recurrence, distant metastasis, or death at 5 years was 57% (95% CI 23%, 76%) in the CNS, 24% (95% CI 2%, 41%) in the thoracic cavity, and 13% (95% CI 0%, 25%) in extrathoracic sites. By contrast, the risk of distant metastasis or death at 5 years was 13% (95% CI 0%, 29%) in CNS primaries, 5% (95% CI 0%, 14%) in thoracic primaries, and 14% (95% CI 0%, 27%) in extrathoracic primaries. Using the published 3- and 4-variable risk stratification models by Demicco et al., we retrospectively assessed our cases for risk of local recurrence, distant metastasis, and death. For tumors outside the CNS, we show that three- and four-variable risk stratification models were associated with recurrence-free survival in addition to the previously known association with distant metastasis (all P < 0.05). In contrast, inside the CNS, we show that neither risk model is a significantly associated with clinical behavior, and that WHO grade is likely the best available prognostic tool, though none of the differences were significant. The lack of significant differences can be likely explained by the younger median age (47 years vs 61 years) and smaller median tumor size (3.5 cm vs 5.6 cm), downgrading the risk stratification scores in CNS compared to non-CNS primaries. In conclusion, existing risk stratification models of SFT are not associated with clinical behavior for tumors arising inside the CNS, but are associated with local recurrence in addition to distant metastasis outside the CNS.

Liver Pathology and SARS-CoV-2 Detection in Formalin-Fixed Tissue of Patients With COVID-19.

OBJECTIVES: The novel coronavirus, severe acute respiratory syndrome coronavirus 2, causing coronavirus disease 2019 (COVID-19) remains a global health threat and a significant source of human morbidity and mortality. While the virus primarily induces lung injury, it also has been reported to cause hepatic sequelae. METHODS: We aimed to detect the virus in formalin-fixed tissue blocks and document the liver injury patterns in patients with COVID-19 compared with a control group. RESULTS: We were able to detect viral RNA in the bronchioalveolar cell blocks (12/12, 100%) and formalin-fixed, paraffin-embedded tissue of the lung (8/8, 100%) and liver (4/9, 44%) of patients with COVID-19. Although the peak values of the main liver enzymes and bilirubin were higher in the patients with COVID-19 compared with the control group, the differences were not significant. The main histologic findings were minimal to focal mild portal tract chronic inflammation (7/8, 88%, P < .05) and mild focal lobular activity (6/8, 75%, P = .06). CONCLUSIONS: We found that most patients who died of COVID-19 had evidence of mild focal hepatitis clinically and histologically; however, the virus was detected in less than half of the cases.

Current and novel non-invasive imaging modalities in vascular neurosurgical practice.

Radiological investigations are a powerful tool in the assessment of patients with intracranial vascular anomalies. 'Visual' assessment of neurovascular lesions is central to their diagnosis, monitoring, prognostication and management. Computed tomography and magnetic resonance imaging are the two principal non-invasive imaging modalities used in clinical practice for the assessment of the cerebral vasculature, but these techniques continue to evolve, enabling clinicians to gain greater insights into neurovascular pathology and pathophysiology. This review outlines both established and novel imaging modalities used in modern neurovascular practice and their clinical applications.

PedsQL Score Post Encephalo-duro-arterio-myo-synangiosis Procedure for Moyamoya Disease: A Single Center Experience.

BACKGROUND: Moyamoya disease is a progressive, occlusive arteriopathy of the intracranial vessels causing an increased risk of stroke. It often results in functional impairment and decrease in quality of life, both in the presence and absence of stroke. Revascularization is the accepted treatment for patients with symptomatic moyamoya disease, preventing further stroke. At Leeds Children's Hospital we use the encephalo-duro-arterio-myo-synangiosis (EDAMS) technique to facilitate revascularization. We aim to assess the quality of life outcomes of patients who have undergone operative intervention at our unit for moyamoya disease. METHODS: Pediatric patients with operated moyamoya disease from Leeds Children Hospital between February 2009 and January 2019 were included. Patients awaiting primary surgery were excluded. Patients were contacted via telephone and the Pediatric Quality of Life Inventory 4.0 (PedsQL) questionnaire administered via parent proxy. Quality of life outcomes were assessed using the PedsQL questionnaire score, which measures physical, emotional social and school functioning domains. This score was then converted to a health-related quality of life score. Scores in each domain and mean scores were compared with normative data. RESULTS: This study included 11 children (5 boys), median age 6.8 years (range: 22 months to 15.5 years), and 9 children underwent bilateral operations. Mean parent proxy PedsQL score was 66 (range: 12.5-98.4), with a mean score of 61.9 in physical function, 88.9 in emotional function, 70.9 in social function, and 58.7 in school function. This was lower than healthy controls overall and in each individual domain except emotional function, which was similar to normative data. CONCLUSIONS: Children with moyamoya disease have a lower quality of life than healthy controls within this series. This suggests that children with moyamoya should be offered additional psychosocial support within the community.

Epidemiology of isolated adult lower limb burns over 15 years with a focus on preventable work-related injuries.

Our aim was to describe the epidemiology of isolated adult lower limb burns presenting to the Pinderfields Regional Burns Centre, Wakefield, United Kingdom between 2003 and 2018. Data was obtained using our local records of the international Burn Injury Database (iBID). 6059 patients were treated in our department during this period. 18.7% presented with isolated lower limb burns (n = 1133). 65.4% of patients were male (n = 741). Scald was the most common mechanism of injury. Work-related burns accounted for 23.4% of the injuries (n = 265). 36% of patients were admitted (n = 408), and 11.7% underwent surgical intervention (n = 133). Isolated lower limb burns are common in patients in the working age group. Work-related injuries are preventable. Targeted education to highlight the risks, reduce the incidence, and improve awareness of first aid measures are recommended.

Interconnected microbiomes and resistomes in low-income human habitats.

Antibiotic-resistant infections annually claim hundreds of thousands of lives worldwide. This problem is exacerbated by exchange of resistance genes between pathogens and benign microbes from diverse habitats. Mapping resistance gene dissemination between humans and their environment is a public health priority. Here we characterized the bacterial community structure and resistance exchange networks of hundreds of interconnected human faecal and environmental samples from two low-income Latin American communities. We found that resistomes across habitats are generally structured by bacterial phylogeny along ecological gradients, but identified key resistance genes that cross habitat boundaries and determined their association with mobile genetic elements. We also assessed the effectiveness of widely used excreta management strategies in reducing faecal bacteria and resistance genes in these settings representative of low- and middle-income countries. Our results lay the foundation for quantitative risk assessment and surveillance of resistance gene dissemination across interconnected habitats in settings representing over two-thirds of the world's population.

Enhancement of in vitro and in vivo function of agarose-encapsulated porcine islets by changes in the islet microenvironment.

The transplantation of porcine islets of Langerhans to treat type 1 diabetes may provide a solution to the demand for insulin-producing cells. Porcine islets encapsulated in agarose-agarose macrobeads have been shown to function in nonimmunosuppressed xenogeneic models of both streptozotocin-induced and autoimmune type 1 diabetes. One advantage of agarose encapsulation is the ability to culture macrobeads for extended periods, permitting microbiological and functional assessment. Herein we describe optimization of the agarose matrix that results in improved islet function. Porcine islets (500 IEQs) from retired breeding sows were encapsulated in 1.5% SeaKem Gold (SG), 0.8% SG, or 0.8% Litex (Li) agarose, followed by an outer capsule of 5% SG agarose. Insulin production by the encapsulated islets exhibited an agarose-specific effect with 20% (0.8% SG) to 50% (0.8% Li) higher initial insulin production relative to 1.5% SG macrobeads. Insulin production was further increased by 40-50% from week 2 to week 12 in both agarose types at the 0.8% concentration, whereas islets encapsulated in 1.5% SG agarose increased insulin production by approximately 20%. Correspondingly, fewer macrobeads were required to restore normoglycemia in streptozotocin-induced diabetic female CD(SD) rats that received 0.8% Li (15 macrobeads) or 0.8% SG (17 macrobeads) as compared to 1.5% SG (19 macrobeads). Islet cell proliferation was also observed during the first 2 months postencapsulation, peaking at 4 weeks, where approximately 50% of islets contained proliferative cells, including ß-cells, regardless of agarose type. These results illustrate the importance of optimizing the microenvironment of encapsulated islets to improve islet performance and advance the potential of islet xenotransplantation for the treatment of type 1 diabetes.

Treatment of agarose-agarose RENCA macrobeads with docetaxel selects for OCT4(+) cells with tumor-initiating capability.

The cancer stem cell (CSC) theory depicts such cells as having the capacity to produce both identical CSCs (symmetrical division) and tumor-amplifying daughter cells (asymmetric division). CSCs are thought to reside in niches similar to those of normal stem cells as described for neural, intestinal, and epidermal tissue, are resistant to chemotherapy, and are responsible for tumor recurrence. We recently described the niche-like nature of mouse renal adenocarcinoma (RENCA) cells following encapsulation in agarose macrobeads. In this paper we tested the hypothesis that encapsulated RENCA colonies function as an in vitro model of a CSC niche and that the majority of cells would undergo chemotherapy-induced death, followed by tumor recurrence. After exposure to docetaxel (5 µg/ml), 50% of cells were lost one week post-treatment while only one or two cells remained in each colony by 6 weeks. Surviving cells expressed OCT4 and reformed tumors at 16 weeks post-treatment. Docetaxel-resistant cells also grew as monolayers in cell culture (16-17 weeks post-exposure) or as primary tumors following transplantation to Balb/c mice (6 of 10 mice) or NOD.CB17-Prkdc(scid)/J mice (9 of 9 mice; 10 weeks post-transplantation or 28 weeks post-exposure). These data support the hypothesis that a rare subpopulation of OCT4(+) cells are resistant to docetaxel and these cells are sufficient for tumor recurrence. The reported methodology can be used to obtain purified populations of tumor-initiating cells, to screen for anti-tumor-initiating cell agents, and to investigate the in vitro correlate of a CSC niche, especially as it relates to chemo-resistance and tumor recurrence.

Differences in glycinergic mIPSCs in the auditory brain stem of normal and congenitally deaf neonatal mice.

We have investigated the fundamental properties of central auditory glycinergic synapses in early postnatal development in normal and congenitally deaf (dn/dn) mice. Glycinergic miniature inhibitory postsynaptic currents (mIPSCs) were recorded using patch-clamp methods in neurons from a brain slice preparation of the medial nucleus of the trapezoid body (MNTB), at 12-14 days postnatal age. Our results show a number of significant differences between normal and deaf mice. The frequency of mIPSCs is greater (50%) in deaf versus normal mice. Mean mIPSC amplitude is smaller in deaf mice than in normal mice (mean mIPSC amplitude: deaf, 64 pA; normal, 106 pA). Peak-scaled fluctuation analysis of mIPSCs showed that mean single channel conductance is greater in the deaf mice (deaf, 64 pS; normal, 45 pS). The mean decay time course of mIPSCs is slower in MNTB neurons from deaf mice (mean half-width: deaf, 2.9 ms; normal, 2.3 ms). Light- and electron-microscopic immunolabeling results showed that MNTB neurons from deaf mice have more (30%) inhibitory synaptic sites (postsynaptic gephyrin clusters) than MNTB neurons in normal mice. Our results demonstrate substantial differences in glycinergic transmission in normal and congenitally deaf mice, supporting a role for activity during development in regulating both synaptic structure (connectivity) and the fundamental (quantal) properties of mIPSCs at central glycinergic synapses.