Sepsis remains a major therapeutic challenge and is associated with a high rate of morbidity and mortality. It is a dynamic condition in which multiple parameters change over time, rendering it ...difficult to overcome the various injurious responses, which worsen the prognosis in these patients. The prognosis of sepsis is associated with a disbalance of compensatory responses to infectious triggers, part of which can be deleterious. Marked inter- and intra-patient variability characterizes the mechanisms that underlie sepsis progression and determine the response to therapy. In this paper, we review some of the data on the use of chronopharmacological approaches for the treatment of patients with sepsis and discuss the role of the autonomic nervous system in the mechanisms associated with immune response and chronotherapy in these patients. We describe the implementation of an individualized platform that is based on the personalized autonomic nervous system, immune, and chronobiology-derived parameters for generating a patient-tailored therapeutic regimen. The notion of overcoming the deleterious compensatory response in a highly dynamic system in sepsis is presented to ensure an improved response to current therapies.
Microtubules (MTs) are highly dynamic polymers that constitute the cellular cytoskeleton and play a role in multiple cellular functions. Variability characterizes biological systems and is considered ...a part of the normal function of cells and organs. Variability contributes to cell plasticity and is a mechanism for overcoming errors in cellular level assembly and function, and potentially the whole organ level. Dynamic instability is a feature of biological variability that characterizes the function of MTs. The dynamic behavior of MTs constitutes the basis for multiple biological processes that contribute to cellular plasticity and the timing of cell signaling. Colchicine is a MT‐modifying drug that exerts anti‐inflammatory and anti‐cancer effects. This review discusses some of the functions of colchicine and presents a platform for introducing variability while targeting MTs in intestinal cells, the microbiome, the gut, and the systemic immune system. This platform can be used for implementing novel therapies, improving response to chronic MT‐based therapies, overcoming drug resistance, exerting gut‐based systemic immune responses, and generating patient‐tailored dynamic therapeutic regimens.
We investigated the clinical implications of the practice in our emergency department (ED) of discharging patients with pending blood cultures. We reviewed the medical records of adults discharged ...with positive blood cultures from the ED of a 330-bed university hospital during a five-year period. Clinical characteristics, laboratory data, and antibiotic treatment prescribed in the ED and at discharge were accessed. Antimicrobial susceptibility profiles were used to determine whether antibiotic treatment was adequate. The outcomes assessed for 90 days following discharge were return to the ED, hospitalization, modified diagnosis, and death. Of 220,681 visits to the ED, 1362 showed positive blood cultures; of these, 307 (22.5%) were from discharged patients. More than half the isolates (56.3%) were considered contaminants. Of 124 visits with true bacteremia, Enterobacteriaceae were the most common pathogens (67.0%). This is concordant with urinary tract infection (UTI) being the most common diagnosis (52.4%). With antibiotic treatment, 69.4% had been discharged with antibiotic treatment, which was adequate in two-thirds of them. Among the 77 who returned to the ED, 27.5% had persistent bacteremia. The diagnosis was changed in 44.2% of them, mostly with brucellosis or bone and joint infections, and 84.4% were subsequently hospitalized. Within three months, 5.6% of bacteremic patients died, all after hospitalization. Bacteremia in discharged patients occurred mainly in association with UTI. Outcomes were generally favorable, although only about half received appropriate antibiotic treatment. Diagnoses were changed in a relatively high proportion of patients following culture results.
Heart failure is a major public health problem, which is associated with significant mortality, morbidity, and healthcare expenditures. A substantial amount of the morbidity is attributed to volume ...overload, for which loop diuretics are a mandatory treatment. However, the variability in response to diuretics and development of diuretic resistance adversely affect the clinical outcomes. Morevoer, there exists a marked intra- and inter-patient variability in response to diuretics that affects the clinical course and related adverse outcomes. In the present article, we review the mechanisms underlying the development of diuretic resistance. The role of the autonomic nervous system and chronobiology in the pathogenesis of congestive heart failure and response to therapy are also discussed. Establishing a novel model for overcoming diuretic resistance is presented based on a patient-tailored variability and chronotherapy-guided machine learning algorithm that comprises clinical, laboratory, and sensor-derived inputs, including inputs from pulmonary artery measurements. Inter- and intra-patient signatures of variabilities, alterations of biological clock, and autonomic nervous system responses are embedded into the algorithm; thus, it may enable a tailored dose regimen in a continuous manner that accommodates the highly dynamic complex system.
The association between infectious diseases and autoimmunity has long been reported. Specifically, during the coronavirus disease 2019 (COVID-19) pandemic, this relation was further emphasized. The ...interplay between the two disease processes remains interesting, yet incompletely defined. Herein, we report a case series of six patients presenting with autoimmune phenomena first developed or exacerbated following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We describe the disease course and discuss the possible mechanisms underlying the association between autoimmunity and COVID-19.
Secondary hyperparathyroidism is characterized by increased serum parathyroid hormone (PTH) level and parathyroid cell proliferation. However, the molecular pathways mediating the increased ...parathyroid cell proliferation remain undefined. Here, we found that the mTOR pathway was activated in the parathyroid of rats with secondary hyperparathyroidism induced by either chronic hypocalcemia or uremia, which was measured by increased phosphorylation of ribosomal protein S6 (rpS6), a downstream target of the mTOR pathway. This activation correlated with increased parathyroid cell proliferation. Inhibition of mTOR complex 1 by rapamycin decreased or prevented parathyroid cell proliferation in secondary hyperparathyroidism rats and in vitro in uremic rat parathyroid glands in organ culture. Knockin rpS6(p-/-) mice, in which rpS6 cannot be phosphorylated because of substitution of all five phosphorylatable serines with alanines, had impaired PTH secretion after experimental uremia- or folic acid-induced AKI. Uremic rpS6(p-/-) mice had no increase in parathyroid cell proliferation compared with a marked increase in uremic wild-type mice. These results underscore the importance of mTOR activation and rpS6 phosphorylation for the pathogenesis of secondary hyperparathyroidism and indicate that mTORC1 is a significant regulator of parathyroid cell proliferation through rpS6.
A Unique Case of Myositis Hurvitz, Noa; Kenig, Ariel; Kessler, Asa ...
Rambam Maimonides medical journal,
10/2022, Volume:
13, Issue:
4
Journal Article
Peer reviewed
Open access
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare systemic small-vessel disease, with heterogeneous clinical manifestations. While arthralgia and myalgia are common in ...the disease course, frank myositis is exceedingly rare. Immune-mediated necrotizing myopathy (IMNM) is a subtype of idiopathic inflammatory myopathies (IIMs), characterized by severe myositis. We report herein a case of prominent diffuse myositis with shared features of AAV and IMNM.
We report the case of a 29-year-old adult presenting with severe IgA vasculitis, with cutaneous, urologic, and renal manifestations. The late appearance of severe gastrointestinal bleeding dominated ...the clinical picture, necessitating the administration of tens of units of packed cells and the augmentation of the immunosuppressive protocol. It was not until therapy with intravenous immunoglobulin (IVIG) was introduced that the massive bleeding was controlled. We herein discuss the patient’s presentation, the gastrointestinal manifestations of IgA vasculitis, the recommended treatments, and the existent evidence about IVIG therapy.
•Hospital Onset and Community Onset Invasive Pneumococcal Disease (HO/CO-IPD), differ.•HO-IPD affects mainly patients with comorbidities.•HO-IPD results in increased morbidity and mortality compared ...to CO-IPD.•HO-IPD is more often caused by serotypes that are not within pneumococci vaccines.•Pneumococci isolates from HO-IPD are more often antibiotic resistant.
Invasive pneumococcal disease (IPD) usually has its onset in the community (CO-IPD), but it can commence following hospitalization (HO-IPD). This study compared HO-IPD and CO-IPD cases during the implementation of the pneumococcal conjugate vaccine (PCV) program for children in Israel.
This was a nationwide retrospective cohort study of adult (age >18 years) IPD patients covering the period from the implementation of the PCV7/13 program in 2009/2010 through 2015. HO-IPD and CO-IPD were defined as IPD with onset ≥4 and ≤2 days from admission, respectively. Patient characteristics, outcome measures, serotypes, and antimicrobial susceptibility were compared for the entire cohort, followed by a matched case–control analysis.
The study included 114 patients with HO-IPD and 2180 with CO-IPD. After matching HO-IPD to CO-IPD patients by age, sex, and comorbidities, the mortality rate and discharge to long-term care facility rate were significantly higher for HO-IPD patients than for CO-IPD patients (44.6% vs. 26.3% and 26.5% vs. 8.2%, respectively). HO-IPD isolates were less often covered by PCV13 (39.6% vs. 49.0%) and pneumococcal polysaccharide vaccine PPSV23 (56.6% vs. 71.3%) and more often resistant to penicillin (9.3% vs. 3.6%), ceftriaxone (3.8% vs. 0.75%), and levofloxacin (9.3% vs. 0.8%).
HO-IPD was associated with higher morbidity and mortality than CO-IPD and was more often caused by non-vaccine serotypes (primarily non-PCV13 types) and antibiotic-resistant strains.
Severe acute respiratory syndrome coronavirus 2 infected patients, receiving background anti-CD20 therapy, were treated with convalescent plasma or plasma-based products. Eight patients were included ...in the study, presenting with prolonged disease course and delayed viral clearance. CP/plasma-based products were offered as an add-on therapy to standard medical treatment. All patients showed remarkable clinical and laboratory improvement. In addition, polymerase chain reaction from nasopharyngeal swabs rapidly converted to negative following plasma administration. This study emphasizes the therapeutic efficacy of convalescent plasma and plasma-based products in a subgroup of immunocompromised patients with iatrogenic B-cell depletion.
•B cell depleted patients infected with COVID19 displayed a protracted disease course.•COVID19 convalescent plasma therapy proved to be efficient and safe in B cell depleted patients.
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