Aggressive pain treatment was advocated for ESRD patients, but new Centers for Disease Control and Prevention guidelines recommend cautious opioid prescription. Little is known regarding outcomes ...associated with ESRD opioid prescription. We assessed opioid prescriptions and associations between opioid prescription and dose and patient outcomes using 2006-2010 US Renal Data System information in patients on maintenance dialysis with Medicare Part A, B, and D coverage in each study year (
=671,281, of whom 271,285 were unique patients). Opioid prescription was confirmed from Part D prescription claims. In the 2010 prevalent cohort (
=153,758), we examined associations of opioid prescription with subsequent all-cause death, dialysis discontinuation, and hospitalization controlled for demographics, comorbidity, modality, and residence. Overall, >60% of dialysis patients had at least one opioid prescription every year. Approximately 20% of patients had a chronic (≥90-day supply) opioid prescription each year, in 2010 usually for hydrocodone, oxycodone, or tramadol. In the 2010 cohort, compared with patients without an opioid prescription, patients with short-term (1-89 days) and chronic opioid prescriptions had increased mortality, dialysis discontinuation, and hospitalization. All opioid drugs associated with mortality; most associated with worsened morbidity. Higher opioid doses correlated with death in a monotonically increasing fashion. We conclude that opioid drug prescription is associated with increased risk of death, dialysis discontinuation, and hospitalization in dialysis patients. Causal relationships cannot be inferred, and opioid prescription may be an illness marker. Efforts to treat pain effectively in patients on dialysis yet decrease opioid prescriptions and dose deserve consideration.
The Alzheimer's Disease Neuroimaging (ADNI) database is an expansive undertaking by government, academia, and industry to pool resources and data on subjects at various stage of symptomatic severity ...due to Alzheimer's disease. As expected, magnetic resonance imaging is a major component of the project. Full brain images are obtained at every 6-month visit. A range of cognitive tests studying executive function and memory are employed less frequently. Two blood draws (baseline, 6 months) provide samples to measure concentrations of approximately 145 plasma biomarkers. In addition, other diagnostic measurements are performed including PET imaging, cerebral spinal fluid measurements of amyloid-beta and tau peptides, as well as genetic tests, demographics, and vital signs. ADNI data is available upon review of an application. There have been numerous reports of how various processes evolve during AD progression, including alterations in metabolic and neuroendocrine activity, cell survival, and cognitive behavior. Lacking an analytic model at the onset, we leveraged recent advances in machine learning, which allow us to deal with large, non-linear systems with many variables. Of particular note was examining how well binary predictions of future disease states could be learned from simple, non-invasive measurements like those dependent on blood samples. Such measurements make relatively little demands on the time and effort of medical staff or patient. We report findings with recall/precision/area under the receiver operator curve after application of CART, Random Forest, Gradient Boosting, and Support Vector Machines, Our results show (i) Random Forests and Gradient Boosting work very well with such data, (ii) Prediction quality when applied to relatively easily obtained measurements (Cognitive scores, Genetic Risk and plasma biomarkers) achieve results that are competitive with magnetic resonance techniques. This is by no means an exhaustive study, but instead an exploration of the plausibility of defining a series of relatively inexpensive, broad population based tests.
In some settings, cancer cells responding to treatment undergo an immunogenic form of cell death that is associated with the abundant emission of danger signals in the form of damage-associated ...molecular patterns. Accumulating preclinical and clinical evidence indicates that danger signals play a crucial role in the (re-)activation of antitumor immune responses
, thus having a major impact on patient prognosis. We have previously demonstrated that the presence of calreticulin on the surface of malignant blasts is a positive prognostic biomarker for patients with acute myeloid leukemia (AML). Calreticulin exposure not only correlated with enhanced T-cell-dependent antitumor immunity in this setting but also affected the number of circulating natural killer (NK) cells upon restoration of normal hematopoiesis. Here, we report that calreticulin exposure on malignant blasts is associated with enhanced NK cell cytotoxic and secretory functions, both in AML patients and
in mice. The ability of calreticulin to stimulate NK-cells relies on CD11c
CD14
cells that, upon exposure to CRT, express higher levels of IL-15Rα, maturation markers (CD86 and HLA-DR) and CCR7. CRT exposure on malignant blasts also correlates with the upregulation of genes coding for type I interferon. This suggests that CD11c
CD14
cells have increased capacity to migrate to secondary lymphoid organs, where can efficiently deliver stimulatory signals (IL-15Rα/IL-15) to NK cells. These findings delineate a multipronged, clinically relevant mechanism whereby surface-exposed calreticulin favors NK-cell activation in AML patients.
Centers for Disease Control and Prevention guidelines recommend caution in prescribing opioids for chronic pain. The characteristics of opioid prescription (OpRx) among kidney transplant (KTx) ...recipients have not been described in a national population.
We assessed OpRx prevalence among prevalent KTx recipients, and associated duration (long-term, defined as ≥90 days in a year) and dosing (in morphine milligram equivalents per day of <50, 50-89, and ≥90) with outcomes, death and graft loss, among incident KTx recipients using 2006-2010 US Renal Data System files, including Medicare Part D for medication ascertainment. Cox models controlled for recipient factors.
Of 36,486 KTx recipients in the 2010 prevalent cohort, approximately 14.6% had long-term OpRx. The strongest association with long-term OpRx after KTx was long-term OpRx before KTx (64%; adjusted odds ratio, 95% confidence interval, 95.2, 74.2-122.1). Incident KTx recipients with long-term OpRx had increased risk of mortality and graft loss compared with those without OpRx or short-term OpRx after KTx. This risk was highest among recipients with long-term OpRx doses of ≥90 morphine milligram equivalents or higher per day (adjusted hazard ratio, 95% confidence interval, 1.61, 1.24-2.10 for death, and 1.33, 1.05-1.67 for graft loss, respectively).
In contrast to either no or short-term OpRx, long-term, and especially long-term high-dose OpRx, is associated with increased risk of death and graft loss in US KTx recipients. Causal relationships cannot be inferred, and OpRx may be an illness marker. Nevertheless, efforts to treat pain effectively in KTx recipients with less toxic interventions and decrease OpRx deserve consideration.
Although intermittent hypoxia training (IHT) has proven effective against various clinical disorders, its impact on mild cognitive impairment (MCI) is unknown. This pilot study examined IHT’s safety ...and therapeutic efficacy in elderly patients with amnestic MCI (aMCI). Seven patients with aMCI (age 69 ± 3 years) alternately breathed 10% O2 and room-air, each 5 minutes, for 8 cycles/session, 3 sessions/wk for 8 weeks. The patients’ resting arterial pressures fell by 5 to 7 mm Hg (P < .05) and cerebral tissue oxygenation increased (P < .05) following IHT. Intermittent hypoxia training enhanced hypoxemia-induced cerebral vasodilation (P < .05) and improved mini-mental state examination and digit span scores from 25.7 ± 0.4 to 27.7 ± 0.6 (P = .038) and from 24.7 ± 1.2 to 26.1 ± 1.3 (P = .047), respectively. California verbal learning test score tended to increase (P = .102), but trail making test-B and controlled oral word association test scores were unchanged. Adaptation to moderate IHT may enhance cerebral oxygenation and hypoxia-induced cerebrovasodilation while improving short-term memory and attention in elderly patients with aMCI.
Calreticulin (CALR) exposed on the surface of cancer cells succumbing to therapy delivers robust phagocytic signals that support the activation of adaptive anticancer immune responses. Recent data ...from our group demonstrate that spontaneous CARL exposure on leukemic blasts also supports innate anticancer immunity by natural killer (NK) cells via an indirect mechanism relying on myeloid CD11c
+
CD14
+
cells.
Brief hypoxic exposures are increasingly applied as interventions for aging-related conditions. To optimize the therapeutic impact of hypoxia, knowledge of the sex-related differences in ...physiological responses to hypoxia is essential. This study compared hypoxia-induced hypoxemic responses in elderly men and women.
: Seven elderly men (70.3 ± 6.0 years old) and nine women (69.4 ± 5.5 years old) breathed 10% O
for 5 min while arterial (SaO
; transcutaneous photoplethysmography) and cerebral tissue O
saturation (ScO
; near-infrared spectroscopy), ventilatory frequency, tidal volume, minute-ventilation, and partial pressures of end-tidal O
(P
O
) and CO
(mass spectrometry) were continuously monitored. Cerebral tissue oxygen extraction fraction (OEF) equaled (SaO
-ScO
)/SaO
.
During 5 min hypoxia SaO
fell from 97.0 ± 0.8% to 80.6 ± 4.6% in the men and from 96.3 ± 1.4% to 72.6 ± 4.0% in the women. The slope ΔSaO
/min was steeper in the women than the men (-4.71 ± 0.96 vs. -3.24 ± 0.76%/min;
= 0.005). Although SaO
fell twice as sharply per unit decrease in P
O
in the women than the men (-1.13 ± 0.11 vs. -0.54 ± 0.06%/mmHg;
= 0.003), minute-ventilation per unit hypoxemia increased less appreciably in the women (-0.092 ± 0.014 vs. -0.160 ± 0.021 L/min/%;
= 0.023). OEF fell with hypoxia duration in the women, but remained stable in the men.
During 5 min hypoxic breathing, elderly women experience more intense hypoxemia and reduced chemoreflex sensitivity vs. their male counterparts, which may lower OEF stability in women despite augmented O
dissociation from hemoglobin during hypoxia. These sex-related differences merit attention when implementing brief hypoxic exposures for therapeutic purposes.
•Pelvis and trunk gait kinematics in people with multiple sclerosis are impaired.•Pelvis kinematics were associated with muscle function and gait performance.•Rehabilitation may consider addressing ...proximal compensations to improve gait.
Problems with gait are common in people with multiple sclerosis (MS), but little is known about pelvis and trunk kinematics, especially in the frontal plane.
Are pelvis and trunk kinematics in people with MS related to muscle function, spatiotemporal parameters, and gait performance?
In this cross-sectional study, 20 people with MS (Expanded Disability Status Scale 1.5–5.5) and 10 people with comparable age and sex (CTL) underwent threedimensional gait analysis, muscle function assessments (hip and trunk strength and endurance), and gait performance measures (Timed 25-Foot Walk – T25FW, 2-Minute Walk Test – 2MWT). Frontal and sagittal plane pelvis and trunk excursion during the stance period of walking were compared between groups; and in the MS group, associations were determined between kinematic variables, muscle function, spatiotemporal parameters, and gait performance.
Compared to the CTL group, the MS group had significantly greater sagittal plane trunk and pelvis excursion for both the stronger (p = 0.031) and weaker (p = 0.042) sides; less frontal plane trunk and pelvis excursion for both the stronger (p = 0.008) and weaker (p = 0.024) sides; and more sagittal plane trunk excursion for the stronger side (p = 0.047) during stance phase. There were low-to-moderate correlations in the MS group for sagittal plane pelvis excursion with muscle function (p = 0.019 to 0.030), spatiotemporal parameters (p < 0.001 to 0.005), and gait performance (p = < 0.001 to 0.001). Using linear regression, frontal and sagittal plane pelvis excursion were significant predictors of both T25FW and 2MWT, explaining 34 % and 46 % of the variance of each gait performance measure, respectively.
Rehabilitation interventions may consider addressing pelvis movement compensations in order to improve spatiotemporal parameters and gait performance in people with MS.
Accumulating evidence indicates that immune checkpoint inhibitors (ICIs) can restore CD8
+
cytotoxic T lymphocyte (CTL) functions in preclinical models of acute myeloid leukemia (AML). However, ICIs ...targeting programmed cell death 1 (PDCD1, best known as PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) have limited clinical efficacy in patients with AML. Natural killer (NK) cells are central players in AML-targeting immune responses. However, little is known on the relationship between co-inhibitory receptors expressed by NK cells and the ability of the latter to control AML. Here, we show that hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM-3) is highly expressed by NK cells from AML patients, correlating with improved functional licensing and superior effector functions. Altogether, our data indicate that NK cell frequency as well as TIM-3 expression levels constitute prognostically relevant biomarkers of active immunity against AML.
Disruption of pathways leading to programmed cell death plays a major role in most malignancies, including multiple myeloma (MM). ABT-737 is a BH3 mimetic small-molecule inhibitor that binds with ...high affinity to Bcl-2 and Bcl-xL, preventing the sequestration of proapoptotic molecules and shifting the cell survival/apoptosis balance toward apoptosis induction. In this study, we show that ABT-737 is cytotoxic to MM cell lines, including those resistant to conventional therapies, and primary tumor cells. Flow cytometric analysis of intracellular levels of Bcl-2 family proteins demonstrates a clear inversion of the Bax/Bcl-2 ratio leading to induction of apoptosis. Activation of the mitochondrial apoptosis pathway was indicated by mitochondrial membrane depolarization and caspase cleavage. Additionally, several signaling pathways known to be important for MM cell survival are disrupted following treatment with ABT-737. The impact of ABT-737 on survival could not be overcome by the addition of interleukin-6, vascular endothelial growth factor or insulin-like growth factor, suggesting that ABT-737 may be effective in preventing the growth and survival signals provided by the microenvironment. These data indicate that therapies targeting apoptotic pathways may be effective in MM treatment and warrant clinical evaluation of ABT-737 and similar drugs alone or in combination with other agents in the setting of MM.
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