Pancreatitis-Associated Medication Use in Hospitalized Pediatric and Young Adult Patients With Acute Pancreatitis.

OBJECTIVE: The objective of this study is (1) to describe the prevalence of pancreatitis-associated medication (PAM) use at admission and discharge in pediatric and young adult patients hospitalized with acute pancreatitis (AP) and (2) to describe the prevalence of PAM use at admission in patients classified as having idiopathic AP. STUDY DESIGN: A single-center retrospective study of patients <21 years who were hospitalized with AP or acute recurrent pancreatitis from March 2015 to July 2017 was performed. Charts were reviewed for demographic data, etiology of pancreatitis, comorbidities, and use of PAMs at admission and discharge. PAMs were defined and scored based on an evidence-based classification system, with class I PAMs having strongest evidence for causation. Standard descriptive statistics were used to report prevalence data. RESULTS: Our cohort was comprised of 119 patients; 50% of patients were using a PAM at admission and 67% were taking a PAM at discharge, reflecting a significant change (P = 0.0009); 44% of patients classified as having idiopathic pancreatitis were taking a PAM on admission, reflecting a possibly missed role of medication in their presentation. Comorbidities significantly associated with PAM use included seizure disorder (P = 0.005) and oncologic disease (P = 0.005). The most commonly used class I PAMs were omeprazole, trimethoprim-sulfamethazole, valproic acid, and 6-mercaptopurine. The increase in prevalence of PAM use at discharge compared to admission was partially driven by addition of omeprazole to the outpatient medication regimen during the hospital stay (P = 0.07). CONCLUSION: Medications likely play an under-recognized role in pediatric AP. The practice of using proton pump inhibitors in management of AP warrants further study.

Small Gene Networks Delineate Immune Cell States and Characterize Immunotherapy Response in Melanoma.

Single-cell technologies have elucidated mechanisms responsible for immune checkpoint inhibitor (ICI) response, but are not amenable to a clinical diagnostic setting. In contrast, bulk RNA sequencing (RNA-seq) is now routine for research and clinical applications. Our workflow uses transcription factor (TF)-directed coexpression networks (regulons) inferred from single-cell RNA-seq data to deconvolute immune functional states from bulk RNA-seq data. Regulons preserve the phenotypic variation in CD45+ immune cells from metastatic melanoma samples (n = 19, discovery dataset) treated with ICIs, despite reducing dimensionality by >100-fold. Four cell states, termed exhausted T cells, monocyte lineage cells, memory T cells, and B cells were associated with therapy response, and were characterized by differentially active and cell state-specific regulons. Clustering of bulk RNA-seq melanoma samples from four independent studies (n = 209, validation dataset) according to regulon-inferred scores identified four groups with significantly different response outcomes (P < 0.001). An intercellular link was established between exhausted T cells and monocyte lineage cells, whereby their cell numbers were correlated, and exhausted T cells predicted prognosis as a function of monocyte lineage cell number. The ligand-receptor expression analysis suggested that monocyte lineage cells drive exhausted T cells into terminal exhaustion through programs that regulate antigen presentation, chronic inflammation, and negative costimulation. Together, our results demonstrate how regulon-based characterization of cell states provide robust and functionally informative markers that can deconvolve bulk RNA-seq data to identify ICI responders.

Urine Proteomics Reveals Sex-Specific Response to Total Pancreatectomy With Islet Autotransplantation.

OBJECTIVES: Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical option for refractory chronic pancreatitis-related pain. Despite the known clinical implications of TPIAT, the molecular effects remain poorly investigated. We performed the first hypothesis-generating study of the urinary proteome before and after TPIAT. METHODS: Twenty-two patients eligible for TPIAT were prospectively enrolled. Urine samples were collected the week before and 12 to 18 months after TPIAT. The urine samples were prepared for bottom-up label-free quantitative proteomics using the "MStern" protocol. RESULTS: Using 17 paired samples, we identified 2477 urinary proteins, of which 301 were significantly changed post-TPIAT versus pre-TPIAT. Our quantitative analysis revealed that the molecular response to TPIAT was highly sex-specific, with pronounced sex differences pre-TPIAT but minimal differences afterward. Comparing post-TPIAT versus pre-TPIAT, we found changes in cell-cell adhesion, intracellular vacuoles, and immune response proteins. After surgery, immunoglobulins, complement proteins, and cathepsins were increased, findings that may reflect glomerular damage. Finally, we identified both known and novel markers for immunoglobulin A nephropathy after 1 patient developed the disease 2 years after TPIAT. CONCLUSIONS: We found distinct changes in the urinary proteomic profile after TPIAT and the response to TPIAT is highly sex-specific.

Triple gallbladder with heterotopic gastric mucosa: a case report.

BACKGROUND: Triple gallbladder is a rare congenital anomaly of the biliary tract that can be associated with heterotopic tissue. Gallbladder triplication results from the failure of rudimentary bile ducts to regress during embryological development, and can be difficult to distinguish from Todani type II choledochal cysts and biliary duplication cysts. CASE PRESENTATION: A 2-year-old patient presented to our institution with intermittent abdominal pain for 1 year. She had elevated transaminases with imaging concerning for a choledochal cyst. After assessment with magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography, she was diagnosed with a gallbladder multiplication and a common bile duct stricture. She underwent laparoscopic cholecystectomy, which confirmed the diagnosis of triple gallbladder. One of the three gallbladders demonstrated heterotopic gastric mucosa on final pathology, including at the cystic duct margin. Follow up testing with a technetium 99 m scan demonstrated a subtle focus of increased activity in the right upper abdomen at the expected location of the common bile duct, concerning for the presence of residual gastric mucosa. The patient remains well without abdominal pain. CONCLUSIONS: We describe the first case of heterotopic gastric mucosa in a triple gallbladder in a young patient presenting with chronic abdominal pain. We also demonstrate the safety and feasibility of laparoscopic cholecystectomy in young children with triple gallbladder. Finally, we propose an interdisciplinary approach to the management of common bile duct strictures in the setting of ectopic acid secretion, involving a combination of medical management, endoscopic intervention, and possible salvage laparoscopic Roux-en-Y hepaticojejunostomy.

Prevalence of dyspnoea and usage of opioids in managing dyspnoea in advanced cancer patients: a longitudinal observational multi-centre study from India.

Context: Breathlessness is one of the devastating symptoms experienced by patients with advanced cancer and can be very challenging to manage. Objectives: To find the point prevalence of dyspnoea in advanced cancer patients presenting to palliative care out-patient clinics, and the usage of opioids in palliation of dyspnoea. Methods: We conducted a prospective observational study among all consecutive patients presenting to the outpatient clinics of six cancer centres in India from different parts of the country. In addition to routinely documented demographic and clinical data from patient charts, study investigators collected information on the Edmonton Symptom Assessment System, Cancer Dyspnoea Scale (CDS) and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 15 Palliative Care. We calculated the prevalence of dyspnoea and documented the usage of opioids in palliation of dyspnoea using tests of differences across patient characteristics. Results: Between May 1, 2019, and April 30, 2020, 5,541 patients were screened for eligibility, and 288 were enrolled (48 patients from each of the six centres). We analysed the data of 288 patients, of which 36.4% had dyspnoea, with 28.5% with moderate to a severe degree (>4/10). Tiredness and loss of appetite were found to have associations with dyspnoea which were statistically significant on multivariate analysis. Standard palliative care management and routine usage of opioids preceded improvement in dyspnoea scores, CDS scores and quality of life scores throughout 7 days. Conclusion: Dyspnoea is a common symptom in advanced cancer patients, presenting to outpatient clinics, and routine documentation of dyspnoea with appropriate usage of opioids helps in mitigation. Key message: The article suggests that breathlessness is a common problem in advanced cancer patients and opioid prescription preceded symptom improvements in such patients.

Clinical Characteristics and Short-Term Outcomes of Children With Asparaginase-Associated Pancreatitis.

OBJECTIVES: Acute pancreatitis is a significant toxicity of l-asparaginase, a chemotherapeutic agent used to treat acute lymphoblastic leukemia. This case series describes the short-term clinical course and disposition of patients who developed asparaginase-associated pancreatitis (AAP) at one quaternary pediatric center. METHODS: Clinical data, including laboratory data, inpatient and intensive care unit (ICU) days, imaging findings, presence of complications such as need for ventilation, dialysis, and the development of pleural effusions, and mode of nutrition were abstracted from the medical record of patients with AAP. Pediatric criteria were used to classify episode severity based on the development of organ failure and local complications, such as pancreatic necrosis. RESULTS: Between 2005 and 2015, 34 patients had AAP with 43 distinct episodes of pancreatitis. The median inpatient length of stay was 10 days (range 2-65). Seven episodes (16.3%) required intensive care unit (ICU)-level care. Seventeen episodes (39.5%) were severe based on the development of organ failure or presence of pancreatic necrosis. Total parenteral nutrition (TPN) was used in 17 episodes (39.5%); for 34 episodes (79.1%), patients were discharged on entirely oral feeds. Antibiotics were administered in 20 episodes (46.5%). Pancreatic necrosis was identified within the first week in 12 episodes (27.9%). There were no deaths due to AAP. CONCLUSIONS: The clinical course varies widely among patients with AAP. Over one-third of the patients in this series developed severe pancreatitis. Although the prognosis of AAP is generally good, many patients develop systemic complications of AAP, requiring TPN or ICU-level care.

Myeloid-Derived Suppressor Cells: A Propitious Road to Clinic.

Myeloid-derived suppressor cells (MDSC) are important regulators of immune responses in cancer. They represent a relatively stable form of pathologic activation of neutrophils and monocytes and are characterized by distinct transcriptional, biochemical, functional, and phenotypical features. The close association of MDSCs with clinical outcomes in cancer suggests that these cells can be an attractive target for therapeutic intervention. However, the complex nature of MDSC biology represents a substantial challenge for the development of selective therapies. Here, we discuss the mechanisms regulating MDSC development and fate and recent research advances that have demonstrated opportunities for therapeutic regulation of these cells. SIGNIFICANCE: MDSCs are attractive therapeutic targets because of their close association with negative clinical outcomes in cancer and established biology as potent immunosuppressive cells. However, the complex nature of MDSC biology presents a substantial challenge for therapeutic targeting. In this review, we discuss those challenges and possible solutions.

C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor.

Acute erythroid leukemia (AEL) commonly involves both myeloid and erythroid lineage transformation. However, the mutations that cause AEL and the cell(s) that sustain the bilineage leukemia phenotype remain unknown. We here show that combined biallelic Cebpa and Gata2 zinc finger-1 (ZnF1) mutations cooperatively induce bilineage AEL, and that the major leukemia-initiating cell (LIC) population has a neutrophil-monocyte progenitor (NMP) phenotype. In pre-leukemic NMPs Cebpa and Gata2 mutations synergize by increasing erythroid transcription factor (TF) expression and erythroid TF chromatin access, respectively, thereby installing ectopic erythroid potential. This erythroid-permissive chromatin conformation is retained in bilineage LICs. These results demonstrate that synergistic transcriptional and epigenetic reprogramming by leukemia-initiating mutations can generate neomorphic pre-leukemic progenitors, defining the lineage identity of the resulting leukemia.

Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells.

Rare multipotent haematopoietic stem cells (HSCs) in adult bone marrow with extensive self-renewal potential can efficiently replenish all myeloid and lymphoid blood cells, securing long-term multilineage reconstitution after physiological and clinical challenges such as chemotherapy and haematopoietic transplantations. HSC transplantation remains the only curative treatment for many haematological malignancies, but inefficient blood-lineage replenishment remains a major cause of morbidity and mortality. Single-cell transplantation has uncovered considerable heterogeneity among reconstituting HSCs, a finding that is supported by studies of unperturbed haematopoiesis and may reflect different propensities for lineage-fate decisions by distinct myeloid-, lymphoid- and platelet-biased HSCs. Other studies suggested that such lineage bias might reflect generation of unipotent or oligopotent self-renewing progenitors within the phenotypic HSC compartment, and implicated uncoupling of the defining HSC properties of self-renewal and multipotency. Here we use highly sensitive tracking of progenitors and mature cells of the megakaryocyte/platelet, erythroid, myeloid and B and T cell lineages, produced from singly transplanted HSCs, to reveal a highly organized, predictable and stable framework for lineage-restricted fates of long-term self-renewing HSCs. Most notably, a distinct class of HSCs adopts a fate towards effective and stable replenishment of a megakaryocyte/platelet-lineage tree but not of other blood cell lineages, despite sustained multipotency. No HSCs contribute exclusively to any other single blood-cell lineage. Single multipotent HSCs can also fully restrict towards simultaneous replenishment of megakaryocyte, erythroid and myeloid lineages without executing their sustained lymphoid lineage potential. Genetic lineage-tracing analysis also provides evidence for an important role of platelet-biased HSCs in unperturbed adult haematopoiesis. These findings uncover a limited repertoire of distinct HSC subsets, defined by a predictable and hierarchical propensity to adopt a fate towards replenishment of a restricted set of blood lineages, before loss of self-renewal and multipotency.

Unusual Presentation of Mycetoma of the Foot: A Rare Case Report.

INTRODUCTION: Mycetoma is a chronic granulomatous infection. It is caused by actinomycetes or fungi. It is common in tropical countries and males. Predisposing conditions include malnutrition, poor hygiene, history of trauma, wounds on barefeet, and systemic infections. Eumycotic mycetoma commonly involves lower extremities whereas actinomycosis affects the cervicofacial, thoracic, and abdominal regions. Mycetoma presents with a chronic indurated ulcerated plague with swelling and yellowish discharge of sulfur granules. CASE REPORT: We report a rare case of a 40-year-old male with a left foot plantar swelling of 4 months duration with no discharging sinuses, fever, and pain. There was no history of trauma or barefoot walking. Clinical and magnetic resonance imaging (MRI) findings were suggestive of a soft-tissue malignancy. The mass was excised and sent for histopathology. Histopathology reported it as a mycetoma. Complete resolution was seen after 3 months of antifungal treatment and excision of the mass. This was unusual since there were no discharging sinuses, nodules, and even MRI reported as a fibrous or muscular mass. The diagnosis was made only after a histopathological examination. CONCLUSION: Mycetoma is a rare infection caused by fungal or bacterial organisms. In the absence of ulceration and sinuses, diagnosis can be difficult. Diagnosis requires a high degree of suspicion in the absence of such clinical signs. Definitive diagnosis should be made on histopathological examination. Once diagnosis is made, surgical excision with appropriate antifungals can result in complete cure without recurrence.

A transit-amplifying population underpins the efficient regenerative capacity of the testis.

The spermatogonial stem cell (SSC) that supports spermatogenesis throughout adult life resides within the GFRα1-expressing A type undifferentiated spermatogonia. The decision to commit to spermatogenic differentiation coincides with the loss of GFRα1 and reciprocal gain of Ngn3 (Neurog3) expression. Through the analysis of the piRNA factor Miwi2 (Piwil4), we identify a novel population of Ngn3-expressing spermatogonia that are essential for efficient testicular regeneration after injury. Depletion of Miwi2-expressing cells results in a transient impact on testicular homeostasis, with this population behaving strictly as transit amplifying cells under homeostatic conditions. However, upon injury, Miwi2-expressing cells are essential for the efficient regenerative capacity of the testis, and also display facultative stem activity in transplantation assays. In summary, the mouse testis has adopted a regenerative strategy to expand stem cell activity by incorporating a transit-amplifying population to the effective stem cell pool, thus ensuring rapid and efficient tissue repair.

Distinct myeloid progenitor-differentiation pathways identified through single-cell RNA sequencing.

According to current models of hematopoiesis, lymphoid-primed multi-potent progenitors (LMPPs) (Lin(-)Sca-1(+)c-Kit(+)CD34(+)Flt3(hi)) and common myeloid progenitors (CMPs) (Lin(-)Sca-1(+)c-Kit(+)CD34(+)CD41(hi)) establish an early branch point for separate lineage-commitment pathways from hematopoietic stem cells, with the notable exception that both pathways are proposed to generate all myeloid innate immune cell types through the same myeloid-restricted pre-granulocyte-macrophage progenitor (pre-GM) (Lin(-)Sca-1(-)c-Kit(+)CD41(-)FcγRII/III(-)CD150(-)CD105(-)). By single-cell transcriptome profiling of pre-GMs, we identified distinct myeloid differentiation pathways: a pathway expressing the gene encoding the transcription factor GATA-1 generated mast cells, eosinophils, megakaryocytes and erythroid cells, and a pathway lacking expression of that gene generated monocytes, neutrophils and lymphocytes. These results identify an early hematopoietic-lineage bifurcation that separates the myeloid lineages before their segregation from other hematopoietic-lineage potential.

Single-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells.

Aged haematopoietic stem cells (HSCs) generate more myeloid cells and fewer lymphoid cells compared with young HSCs, contributing to decreased adaptive immunity in aged individuals. However, it is not known how intrinsic changes to HSCs and shifts in the balance between biased HSC subsets each contribute to the altered lineage output. Here, by analysing HSC transcriptomes and HSC function at the single-cell level, we identify increased molecular platelet priming and functional platelet bias as the predominant age-dependent change to HSCs, including a significant increase in a previously unrecognized class of HSCs that exclusively produce platelets. Depletion of HSC platelet programming through loss of the FOG-1 transcription factor is accompanied by increased lymphoid output. Therefore, increased platelet bias may contribute to the age-associated decrease in lymphopoiesis.

Functional Outcome Following Arthroscopic ACL Reconstruction with Rigid Fix: A Retrospective Observational Study.

BACKGROUND: No uniform consensus exists to decide type of fixation for arthroscopic anterior cruciate ligament reconstruction. Hypothsis: There is similar functional outcome after rigid fix compared to other methods of fixation which has been published. STUDY DESIGN: Retrospective observational study. METHODS: A total of 50 patients underwent arthroscopic anterior cruciate ligament reconstruction with hamstring tendons using femoral Rigid fix cross-pin and interference screw tibial fixation. The evaluation methods were clinical examination, IKDC scores, Lysholm and pre injury and post reconstruction Tegner score. Patients were followed up from minimum of 6 months to 4 year seven months. RESULTS: C In our study of sample size 50 we found that mean age of patients was 30.8 Years with male preponderance. Mean post operative IKDC and Lysholm score has been 75.6 and 84.4 respectively. Mean Tegner pre-injury score and post reconstruction score has been 5.4 and 4.26. Box plot comparison of pre injury and post operativeTegner score reveals a statistically significant difference with respect to paired t test P<0.001. CONCLUSIONS: Arthroscopic anterior cruciate ligament reconstruction with femoral rigid fix cross pins and tibial interference screws results in comparable short term to midterm functional results compared to other types of fixation.

Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia.

The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-α (C/EBPα) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBPα p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) histone-methyltransferase complexes. Accordingly, p30-bound genomic regions were enriched for MLL-dependent H3K4me3 marks. The p30-dependent increase in self-renewal and inhibition of myeloid differentiation required Wdr5, as downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a new small-molecule antagonist of the Wdr5-MLL interaction. This compound selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells. Our data reveal the mechanism of p30-dependent transformation and establish the essential p30 cofactor Wdr5 as a therapeutic target in CEBPA-mutant AML.

To analyze the impact of intracavitary brachytherapy as boost radiation after external beam radiotherapy in carcinoma of the external auditory canal and middle ear: a retrospective analysis.

PURPOSE: The purpose of this study was to analyze the impact of intra-cavitary brachytherapy (ICBT) as boost radiation after external beam radiotherapy (EBRT) in carcinoma of the external auditory canal and middle ear (EACMA): A retrospective analysis. MATERIALS AND METHODS: A retrospective study of 18 patients with carcinoma of the EACMA who were treated with a curative intent from the year 1998 to 2010 was carried out. The age of the patients ranged from 25 years to 67 years. There were 11 male patients (61.1%) and 7 female patients (38.9%). A total of 15 (88.2%) patients were treated with curative radiation alone after a biopsy and two patients received post-operative radiation therapy. The patients were initially treated with EBRT with cobalt 60 machine up to 60-64 Gy. In our department, all the patients who were technically suitable for ICBT received an ICBT boost. RESULTS: The overall survival (OS) in these patients ranged from 7 months to 151 months (9 out of 17 patients, no evidence of disease 53%). The OS in patients treated with a combination of EBRT with ICBT was (8 out of 11) 72.7%, P value statistically significant (P value: 0.0024). The multivariate analysis shows statistically significant difference only for patients who got an ICBT boost (P Value: 0.020). CONCLUSION: ICBT as a boost after EBRT has got a positive impact on the OS. In conclusion, our results demonstrate that radical radiation therapy (EBRT and ICBT) is the treatment of choice for stage T2, carcinoma of EACMA.

Erythropoietin guides multipotent hematopoietic progenitor cells toward an erythroid fate.

The erythroid stress cytokine erythropoietin (Epo) supports the development of committed erythroid progenitors, but its ability to act on upstream, multipotent cells remains to be established. We observe that high systemic levels of Epo reprogram the transcriptomes of multi- and bipotent hematopoietic stem/progenitor cells in vivo. This induces erythroid lineage bias at all lineage bifurcations known to exist between hematopoietic stem cells (HSCs) and committed erythroid progenitors, leading to increased erythroid and decreased myeloid HSC output. Epo, therefore, has a lineage instructive role in vivo, through suppression of non-erythroid fate options, demonstrating the ability of a cytokine to systematically bias successive lineage choices in favor of the generation of a specific cell type.

Bilateral neck femur fracture following a generalized seizure- a rare case report.

Hip fractures are one of the most common injuries which present to an orthopaedic surgeon. Most of these cases are unilateral .Bilateral simultaneous femur neck fracture is a rare occurrence. We report a case of a bilateral neck femur fracture in a 30 year male following a generalized tonic clonic seizure in view of its rarity and also to increase the awareness of such rare injuries. The patient was operated within 3 hours. At 5 months, the patient had good radiological and functional outcome. During a convulsion, there is a powerful and forceful contraction of muscles which may lead to fracture or dislocation. The incidence of fractures following a convulsion is 1.1%. A delay in diagnosis can lead to complications like avascular necrosis, osteoarthritis, non union, functional disability and legal consequences. All orthopaedic surgeons and emergency physicians should be aware of such uncommon injuries to ensure early diagnosis and treatment.