Philosophizing cannot substitute for trials discuss Hoffman Singh Prakash This year

necessity determination to mitigate the current state where patients have unequal access to cancer procedures due to the location of residence and age.
Temporal patterns of stimulation represent a novel dimension for improving the efficacy of spinal cord stimulation to treat chronic neuropathic pain.
We hypothesized that nonregular temporal patterns of stimulation designed using a computational model would be superior to conventional stimulation at constant frequencies or completely random patterns of stimulation.
Using a computational model of the dorsal horn network and an optimization algorithm based on biological evolution, we designed an optimized pattern of spinal cord stimulation with comparable efficacy and increased efficiency relative to constant frequency (CF) stimulation. We evaluated the effect of different temporal patterns on individual neurons recorded in the dorsal horn of urethane-anesthetized rats.
The optimized pattern and 50Hz CF stimulation produced greater inhibition of spontaneously firing neurons recorded invivo than random 50Hz stimulation or a pattern designed intentionally with poor fitness. Spinal Cord Stimulation (SCS) led to significant changes in the firing patterns of recorded units, and stimulation patterns that generated significant inhibition also tended to reduce entropy and regularize the firing patterns of units, suggesting that patterns of dorsal horn neuron activity may be important for pain perception in addition to the firing rate.
These results demonstrate that the computational model can be used as a tool for optimizing stimulation parameters and suggest that optimized temporal patterns may increase the efficacy of spinal cord stimulation.
These results demonstrate that the computational model can be used as a tool for optimizing stimulation parameters and suggest that optimized temporal patterns may increase the efficacy of spinal cord stimulation.
To examine time trends in the use of NSAIDs and opioids for patients with osteoarthritis undergoing total hip arthroplasty (THA) during 1996-2018.
Using Danish population-based medical databases, we identified 103,209 THA patients. Prevalence rates of NSAID and opioid use among preoperative users and non-users were calculated in four quarters (Q1-Q4) after THA by calendar periods (1996-2000, 2001-2006, 2007-2012 and 2013-2018). Prevalence rate ratios (PRR) were adjusted for age and gender.
Among preoperative NSAID users and non-users, NSAID use in Q1 increased from 32.6% in 1996-2000 to 48.0% in 2013-2018 (PRR=1.49, 95% CI 1.42-1.55) and from 12.9% to 32.0% (PRR=2.49 (2.32-2.67)), respectively. Among preoperative opioid users and non-users, opioid use in Q1 increased from 42.7% in 1996-2000 to 76.9% in 2013-2018 (PRR=1.81 (1.73-1.89)) and from 15.2% to 58.2% (PRR=3.85 (3.65-4.05)), respectively. NSAID use in Q4 decreased from 24.5% in 1996-2000 to 21.4% in 2013-2018 (PRR=0.88 (0.83-0.93)) and from 6.9% to 5.6% (PRR=0.81 (0.73-0.91)) in preoperative NSAIDs users and non-users, respectively. Opioid use in Q4 increased from 26.6% in 1996-2000 to 28.6% (PRR=1.08 (1.02-1.15)) in 2013-2018 and from 4.1% to 5.0% (PRR=1.25 (1.11-1.40)) in preoperative opioid users and non-users, respectively.
We observed up to a 4-fold increase in NSAID and opioid use in Q1 during 1996-2018, while usage in Q4 did not change substantially. However, 5-6% of the preoperative non-users of NSAIDs and opioids were users in Q4, which might relate to inaccurate indication for or timing of THA and the post-surgical phasing out of analgesics use.
We observed up to a 4-fold increase in NSAID and opioid use in Q1 during 1996-2018, while usage in Q4 did not change substantially. However, 5-6% of the preoperative non-users of NSAIDs and opioids were users in Q4, which might relate to inaccurate indication for or timing of THA and the post-surgical phasing out of analgesics use.
The increase of quality of life, the improvement in the perioperative care programs, the use of the frailty index, and the surgical innovation has allowed to access of complex abdominal surgery for elderly patients like liver resection. Despite of this, in patients aged 70 or older there is a limitation for the implementation ERAS protocolos. The aim of this study is to evaluate the implementation ERAS protocol on elderly patients (≥70 years) undergoing liver resection.
A prospective cohort study of patients who underwent liver resection from December 2017 to December 2019 with an ERAS program. We compare the outcomes in patients ≥70 years (G ≥ 70) versus <70 years (G < 70). The frailty was measured with the Physical Frailty Phenotype score.
A total of 101 patients were included. 32 of these (31.6%) were patients ≥70 years. 90% of the both groups had performed >70% of the ERAS. Oral diet tolerance and mobilization on the first postoperative day were quicker in <70 years group. The hospital stay was similar in both groups (3.07days/2.7days). Morbidity and mortality were similar; Clavien I-II(G ≥ 7041% vs G < 7030,5%) and Clavien ≥ III (G ≥ 706% vs G < 708.5%), like hospital readmissions. Mortality was <1%. ERAS protocol compliance was associated with a decrease in complications (ERAS < 70%80% vs ERAS > 90%20%; p = 0.02) and decrease in severity of complications in both study groups. Frailty was found in 6% of the elderly group; the only patient who died had a frailty index of 4.
Implementation of ERAS protocol for elderly patients is possible, with major improvements in perioperative outcomes, without an increase in morbidity, mortality neither readmissions.
Implementation of ERAS protocol for elderly patients is possible, with major improvements in perioperative outcomes, without an increase in morbidity, mortality neither readmissions.Toxic aggregates of α-synuclein (αsyn) are considered key drivers of Parkinson's disease (PD) pathology. In early PD, αsyn induces synaptic dysfunction also modulating the glutamatergic neurotransmission. However, a more detailed understanding of the molecular mechanisms underlying αsyn-triggered synaptic failure is required to design novel therapeutic interventions. Here, we described the role of Rabphilin-3A (Rph3A) as novel target to counteract αsyn-induced synaptic loss in PD. Rph3A is a synaptic protein interacting with αsyn and involved in stabilizing dendritic spines and in promoting the synaptic retention of NMDA-type glutamate receptors. We found that in vivo intrastriatal injection of αsyn-preformed fibrils in mice induces the early loss of striatal synapses associated with decreased synaptic levels of Rph3A and impaired Rph3A/NMDA receptors interaction. Modulating Rph3A striatal expression or interfering with the Rph3A/αsyn complex with a small molecule prevented dendritic spine loss and rescued associated early motor defects in αsyn-injected mice. Notably, the same experimental approaches prevented αsyn-induced synaptic loss in vitro in primary hippocampal neurons. Overall, these findings indicate that approaches aimed at restoring Rph3A synaptic functions can slow down the early synaptic detrimental effects of αsyn aggregates in PD.Aberrant activation of the Hh pathway promotes cell proliferation and multi-drug resistance (MDR) in several cancers, including Acute Myeloid Leukemia (AML). Notably, only one Hh inhibitor, glasdegib, has been approved for AML treatment, and most patients eventually relapse, highlighting the urgent need to discover new therapeutic targets. Hh signal is transduced through the membrane of the primary cilium, a structure expressed by non-proliferating mammalian cells, whose stabilization depends on the activity of HDAC6. Here we describe a positive correlation between Hh, HDAC6, and MDR genes in a cohort of adult AML patients, human leukemic cell lines, and a zebrafish model of Hh overexpression. The hyper-activation of Hh or HDAC6 in zebrafish drove the increased proliferation of hematopoietic stem and progenitor cells (HSPCs). Interestingly, this phenotype was rescued by inhibition of HDAC6 but not of Hh. Also, in human leukemic cell lines, a reduction in vitality was obtained through HDAC6, but not Hh inhibition. Our data showed the presence of a cross-talk between Hh and HDAC6 mediated by stabilization of the primary cilium, which we detect for the first time in zebrafish HSPCs. Inhibition of HDAC6 activity alone or in combination therapy with the chemotherapeutic agent cytarabine, efficiently rescued the hematopoietic phenotype. Our results open the possibility to introduce HDAC6 as therapeutic target to reduce proliferation of leukemic blasts in AML patients.Age-related changes in the immune system increase susceptibility to infectious diseases. Vaccines are an important tool to prevent infection or boost immunological memory; however, vaccines are less effective in aged individuals. In order to protect our aging population from the threat of infectious diseases, we must gain a better understanding of age-related alterations in the immune response at the site of infection. The lung is one site of frequent infection in older individuals. In this study, we expanded on our previous work to study vaccine-induced immune responses in the local lung environment in a pilot study of aged rhesus macaques. To do this, we developed an in vivo model to probe recall responses to tuberculin challenge in the lungs 8 weeks and 16 weeks post-Mycobacterium bovis BCG vaccination by performing targeted bronchoalveolar lavages. In parallel, we determined peripheral blood responses in vaccinated animals to compare systemic and local tissue responses to tuberculin challenge. We found th vaccination and challenge are impaired with age. These findings expand on our previous work to show that in addition to the skin, age-related changes in the lung environment impact recall immune responses to vaccination and challenge. The impact of age on local tissue responses to infectious challenge should be accounted for in the development of therapeutics or medical interventions aimed at boosting immune recall responses of aged individuals.Due to the inflammatory nature of type 2 diabetes mellitus (T2DM) and the increased cardiovascular risk, there is a growing need for innovative strategies to change our identification and treatment approach to avoid clinical complications. One approach would be the use of circulating biomarkers to track disease progression and management. Thus, this study aimed to evaluate the concentrations of inflammatory biomarkers in patients diagnosed with type 2 diabetes mellitus and systemic arterial hypertension, correlating inflammatory cytokines and disease severity. Initially, 259 individuals were stratified into different degrees of disease low risk, moderate risk, high risk, and very high risk, according to the European Society of Cardiology, which correlates blood pressure values with the presence of cardiovascular risk factors. selleck kinase inhibitor For this stratification, analysis of body composition, blood pressure measurement, and questionnaires were applied. Blood was collected for biochemical measurements and for ELISA to deten the systems, and the dysregulation of just one of these systems is enough to generate consequences in all the other systems.