The NtrC-like AAA+ ATPases control virulence and other important bacterial activities through delivering mechanical work to σ54-RNA polymerase to activate transcription from σ54-dependent genes. We ...report the first crystal structure for such an ATPase, NtrC1 of
Aquifex aeolicus, in which the catalytic arginine engages the γ-phosphate of ATP. Comparing the new structure with those previously known for apo and ADP-bound states supports a rigid-body displacement model that is consistent with large-scale conformational changes observed by low-resolution methods. First, the arginine finger induces rigid-body roll, extending surface loops above the plane of the ATPase ring to bind σ54. Second, ATP hydrolysis permits Pi release and retraction of the arginine with a reversed roll, remodeling σ54-RNAP. This model provides a fresh perspective on how ATPase subunits interact within the ring-ensemble to promote transcription, directing attention to structural changes on the arginine-finger side of an ATP-bound interface.
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► Crystal structure of NtrC1
C,E239A shows the engaged state of the arginine finger ► Conformational changes propagate from arginine finger to distant σ54-binding loops ► ATP binding at the interface affects both subunits forming the active site ► Resulting model: ATP directs rigid-body displacement to perform work on RNAP
Pancreatic ductal adenocarcinoma (PDAC) represents 3% of all cancer cases and 7% of all cancer deaths in the United States. Late diagnosis and inadequate response to standard chemotherapies ...contribute to an unfavorable prognosis and an overall 5-year survival rate of less than 10% in PDAC. Despite recent advances in tumor immunology, tumor-induced immunosuppression attenuates the immunotherapy response in PDAC. To date, studies have focused on IgG-based therapeutic strategies in PDAC. With the recent interest in IgE-based therapies in multiple solid tumors, we explored the MUC1-targeted IgE potential against pancreatic cancer. Our study demonstrates the notable expression of FceRI (receptor for IgE antibody) in tumors from PDAC patients. Our study showed that administration of MUC1 targeted-IgE (mouse/human chimeric anti-MUC1.IgE) antibody at intermittent levels in combination with checkpoint inhibitor (anti-PD-L1) and TLR3 agonist (PolyICLC) induces a robust antitumor response that is dependent on NK and CD8 T cells in pancreatic tumor-bearing mice. Subsequently, our study showed that the antigen specificity of the IgE antibody plays a vital role in executing the antitumor response as nonspecific IgE, induced by ovalbumin (OVA), failed to restrict tumor growth in pancreatic tumor-bearing mice. Utilizing the OVA-induced allergic asthma-PDAC model, we demonstrate that allergic phenotype induced by OVA cannot restrain pancreatic tumor growth in orthotopic tumor-bearing mice. Together, our data demonstrate the novel tumor protective benefits of tumor antigen-specific IgE-based therapeutics in a preclinical model of pancreatic cancer, which can open new avenues for future clinical interventions.
With increasing use of the Medicare hospice benefit, policymakers recognize the need for quality measurement to assure that terminally ill patients receive high-quality care and have the information ...they need when selecting a hospice. Toward these goals, Centers for Medicare & Medicaid Services has been collecting standardized patient-level quality data via the Hospice Item Set (HIS) since July 1, 2014.
This article presents a first look at the national hospice HIS quality data.
We calculated seven quality measures using the HIS data. These measures are endorsed by the National Quality Forum and focus on important care processes hospice providers are required to perform at admission, including discussion of patient preferences regarding life-sustaining treatments, care for spiritual and existential concerns, and symptom management (pain, opioid-induced constipation, and dyspnea).
Our sample included 1,218,786 hospice patients discharged from 3922 hospices from October 1, 2014 to September 30, 2015. More than 90% of patients received screenings and assessments captured by six of the seven quality measures. The only exception was pain assessment, for which the national mean score was 78.2%. A small number of hospices (156, 4.0%) had perfect scores for all seven quality measures.
Most hospices conduct critical assessments and discuss treatment preferences with patients at admission, although few hospices have perfect scores.
Escherichia coli O26 and O157 have similar overall prevalences in cattle in Scotland, but in humans, Shiga toxin-producing E. coli O26 infections are fewer and clinically less severe than E. coli ...O157 infections. To investigate this discrepancy, we genotyped E. coli O26 isolates from cattle and humans in Scotland and continental Europe. The genetic background of some strains from Scotland was closely related to that of strains causing severe infections in Europe. Nonmetric multidimensional scaling found an association between hemolytic uremic syndrome (HUS) and multilocus sequence type 21 strains and confirmed the role of stx(2) in severe human disease. Although the prevalences of E. coli O26 and O157 on cattle farms in Scotland are equivalent, prevalence of more virulent strains is low, reducing human infection risk. However, new data on E. coli O26-associated HUS in humans highlight the need for surveillance of non-O157 enterohemorrhagic E. coli and for understanding stx(2) phage acquisition.
“Southern Resident” killer whales include three “pods” (J, K and L) that reside primarily in Puget Sound/Georgia Basin during the spring, summer and fall. This population was listed as “endangered” ...in the US and Canada following a 20% decline between 1996 and 2001. The current study, using blubber/epidermis biopsy samples, contributes contemporary information about potential factors (i.e., levels of pollutants or changes in diet) that could adversely affect Southern Residents. Carbon and nitrogen stable isotopes indicated J- and L-pod consumed prey from similar trophic levels in 2004/2006 and also showed no evidence for a large shift in the trophic level of prey consumed by L-pod between 1996 and 2004/2006. ∑PCBs decreased for Southern Residents biopsied in 2004/2006 compared to 1993–1995. Surprisingly, however, a three-year-old male whale (J39) had the highest concentrations of ∑PBDEs, ∑HCHs and HCB. POP ratio differences between J- and L-pod suggested that they occupy different ranges in winter.
To describe a single-center experience with the management of ileal pouch-urethral fistulas (IPUF) following restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA).
We retrospectively ...identified patients with documented IPUF managed at our institution from a urethral fistula cohort and analyzed their cases.
Thirteen patients who underwent surgeries for IPUF management from 2005-2022 were identified. Median age at IPAA was 29 years (range 11-53). Indications for IPAA included familial adenomatous polyposis (n=3) and ulcerative colitis (n=10). Median time from IPAA to fistula diagnosis was 15 years (range 0.5-38.5). Eleven patients were initially diverted with either loop (n=8) or end ileostomy (n=3). Overall, two patients had resolution of IPUF symptoms with a loop ileostomy alone and eight eventually underwent pouch excision with end ileostomy, one of which subsequently underwent redo IPAA. Seven patients were managed with primary closure of the urethral defect at the time of pouch excision, five of which also underwent gracilis muscle interposition. With a median follow-up of 4 years (range 0.3-13 years), all patients had resolution of their fistulae without any recurrences.
IPUFs are a rare complication after IPAA. In this cohort, all patients had their urinary tract preserved, but most ultimately had permanent fecal diversion. These results can help guide management of this complex issue.
Abstract
INTRODUCTION
Since 2009, inflammatory bowel disease (IBD) specialists have been utilizing “IBD Live,” a weekly live video conference with a global audience of 150-200 participants, to ...discuss the multidisciplinary management of their commonly seen and most challenging cases. While most cases presented were confirmed as IBD, a substantial number were mimics for which IBD was not the ultimate diagnosis. We previously categorized all IBD Live cases and identified the frequency of “IBD mimics.” Here, we examine the use of biologic medications for these cases which ultimately were determined to be something other than IBD.
METHODS
Cases have been recorded and archived since May 2018. 371 total cases from May 2018 through February 2023 were reviewed spanning 186 hours. 65 of those cases were determined to be IBD mimics, defined as those with features of IBD that ultimately resulted in a non-IBD diagnosis. IBD mimics were analysed and categorized in terms of their biologic usage.
RESULTS
25 of the 65 mimics (38.5%) were treated with biologics for presumed IBD. 14 were treated with one biologic, 5 with two biologics, and 6 with three or more biologics.
The biologics used in the management of these IBD mimics included infliximab (n=21), vedolizumab (n=12), adalimumab (n=11), ustekinumab (n=6), and certolizumab (n=1).
Of the 25 cases of biologic usage without definitive confirmation of IBD, 6 ended up with a diagnosis where biologics were an appropriate treatment for the mimic. These mimics included drug-induced colitis (n=3), Behcet’s disease (n=1), segmental colitis associated with diverticulosis (SCAD; n=1), and CTLA-4 haploinsufficiency with autoimmune infiltrates (CHAI; n=1).
Several of the IBD mimics were prescribed steroids, azathioprine, mercaptopurine, or methotrexate, and 3 were trialled on tofacitinib (for Sweet’s syndrome, PIK3cd, and SCAD).
There were 3 patients with confirmed IBD, in remission on a biologic, who subsequently had symptoms concerning for an IBD flare. In each of these cases, IBD was not the cause of their symptoms (e.g., cecal volvulus).
There were 4 patients with confirmed IBD, in remission off biologics, who later developed symptoms suspicious for an IBD flare. Each of these cases was trialled on biologics to treat the supposed flare; however, symptoms were ultimately found to be due to an IBD mimic (e.g., eosinophilic esophagitis).
33 of the 65 IBD mimics were never treated with biologics.
DISCUSSION
In a 5-year period at IBD Live, 17.5% of cases (65 of 371) were found to be IBD mimics. 38.5% (25 of 65) of these were treated with biologics. The diverse presentation of signs and symptoms of IBD and IBD mimics requires reassessment of the biologic therapy in patients without response. Often the biologic needs to be optimized for IBD, but in some cases, the diagnosis of IBD will need to be called into question.
Table 1 IBD mimics and biologics used
Abbreviations
BADAS = bowel-associated dermatosis-arthritis syndrome, BCL = B-cell lymphoma, CD = Crohn’s Disease, CHAI = CTLA-4 haploinsufficiency with autoimmune infiltrates, C-MUSE = cryptogenic multifocal ulcerous stenosing enteritis, CMV = cytomegalovirus, CVID = common variable immunodeficiency, EGPA = eosinophilic granulomatosis with polyangiitis, GABA = gamma-aminobutyric acid, IBD = inflammatory bowel disease, IMHMV = idiopathic myointimal hyperplasia of the mesenteric veins, PIK3cd = phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunit delta, PNH = paroxysmal nocturnal hemoglobinuria, SCAD = segmental colitis associated with diverticulosis, STI = sexually transmitted infection, UC = Ulcerative Colitis.
Image 1: Biologic usage in IBD mimics
Sodium polystyrene sulfonate (SPS) is one of the most commonly used treatments for mild hyperkalemia. Other treatments include insulin, sodium bicarbonate, and salbutamol, which may be given alone or ...in combination. The results of research examining treatment effectiveness for mild hyperkalemia (e.g., the ability of SPS to achieve normokalemia) thus far have been inconsistent. Given that the effectiveness of treatment for mild hyperkalemia is debatable, new research is needed.
To determine whether treatment of hospitalized patients with mild hyperkalemia (using SPS or another approach, relative to no treatment) was associated with achievement of normokalemia (serum potassium < 5.1 mmol/L).
For this retrospective, quasi-experimental study, hospitalized patients with index serum potassium level between 5.1 and 6.4 mmol/L were identified. Post-index serum potassium level within 24 hours was dichotomized (< 5.1 or ≥ 5.1 mmol/L). Pre-index serum creatinine and serum potassium levels were recorded as the average of the first 5 values immediately before the index potassium value. For each patient, treatment was categorized as no treatment, SPS treatment, or other treatment strategy.
Among the 1944 patients included in the analysis, the average age was 66.8 (standard deviation 13.5) years; 605 (31.1%) of the patients were women and 1339 (68.9%) were men. Logistic regression results indicated that patients who were female and/or had higher pre-index serum potassium were less likely to return to normokalemia within 24 hours after the time of the index serum potassium value. Treatment category was not a statistically significant predictor of the achievement of normokalemia. Most patients with mild hyperkalemia (> 74.5% in each treatment category) achieved normokalemia, whether or not they received treatment.
The findings of this study suggest that although follow-up is required for mild hyperkalemia in hospitalized patients, active treatment may be unnecessary.
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