Palliative Non-Operative Management in Geriatric Hip Fracture Patients: When Would Surgeons Abstain from Surgery?

Background: For hip fracture patients with a limited life expectancy, operative and palliative non-operative management (P-NOM) can yield similar quality of life outcomes. However, evidence on when to abstain from surgery is lacking. The aim of this study was to quantify the influence of patient characteristics on surgeons' decisions to recommend P-NOM. Methods: Dutch surgical residents and orthopaedic trauma surgeons were enrolled in a conjoint analysis and structured expert judgement (SEJ). The participants assessed 16 patient cases comprising 10 clinically relevant characteristics. For each case, they recommended either surgery or P-NOM and estimated the 30-day postoperative mortality risk. Treatment recommendations were analysed using Bayesian logistic regression, and perceived risks were pooled with equal and performance-based weights using Cooke's Classical Model. Results: The conjoint analysis and SEJ were completed by 14 and 9 participants, respectively. Participants were more likely to recommend P-NOM to patients with metastatic carcinomas (OR: 4.42, CrI: 2.14-8.95), severe heart failure (OR: 4.05, CrI: 1.89-8.29), end-stage renal failure (OR: 3.54, CrI: 1.76-7.35) and dementia (OR: 3.35, CrI: 1.70-7.06). The patient receiving the most P-NOM recommendations (12/14) had a pooled perceived risk of 30-day mortality between 50.8 and 62.7%. Conclusions: Overall, comorbidities had the strongest influence on participants' decisions to recommend P-NOM. Nevertheless, practice variation and heterogeneity in risk perceptions were substantial. Hence, more decision support for considering P-NOM is needed.

Systematic review and meta-analysis of preoperative predictors for early mortality following hip fracture surgery.

Hip fractures are a global health problem with a high postoperative mortality rate. Preoperative predictors for early mortality could be used to optimise and personalise healthcare strategies. This study aimed to identify predictors for early mortality following hip fracture surgery. Cohort studies examining independent preoperative predictors for mortality following hip fracture surgery were identified through a systematic search on Scopus and PubMed. Predictors for 30-day mortality were the primary outcome, and predictors for mortality within 1 year were secondary outcomes. Primary outcomes were analysed with random-effects meta-analyses. Confidence in the cumulative evidence was assessed using the GRADE criteria. Secondary outcomes were synthesised narratively. Thirty-three cohort studies involving 462,699 patients were meta-analysed. Five high-quality evidence predictors for 30-day mortality were identified: age per year (OR: 1.06, 95% CI: 1.04-1.07), ASA score ≥ 3 (OR: 2.69, 95% CI: 2.12-3.42), male gender (OR: 2.00, 95% CI: 1.85-2.18), institutional residence (OR: 1.81, 95% CI: 1.31-2.49), and metastatic cancer (OR: 2.83, 95% CI: 2.58-3.10). Additionally, six moderate-quality evidence predictors were identified: chronic renal failure, dementia, diabetes, low haemoglobin, heart failures, and a history of any malignancy. Weak evidence was found for non-metastatic cancer. This review found relevant preoperative predictors which could be used to identify patients who are at high risk of 30-day mortality following hip fracture surgery. For some predictors, the prognostic value could be increased by further subcategorising the conditions by severity.

Combining brain-computer interfaces with deep reinforcement learning for robot training: a feasibility study in a simulation environment.

Deep reinforcement learning (RL) is used as a strategy to teach robot agents how to autonomously learn complex tasks. While sparsity is a natural way to define a reward in realistic robot scenarios, it provides poor learning signals for the agent, thus making the design of good reward functions challenging. To overcome this challenge learning from human feedback through an implicit brain-computer interface (BCI) is used. We combined a BCI with deep RL for robot training in a 3-D physical realistic simulation environment. In a first study, we compared the feasibility of different electroencephalography (EEG) systems (wet- vs. dry-based electrodes) and its application for automatic classification of perceived errors during a robot task with different machine learning models. In a second study, we compared the performance of the BCI-based deep RL training to feedback explicitly given by participants. Our findings from the first study indicate the use of a high-quality dry-based EEG-system can provide a robust and fast method for automatically assessing robot behavior using a sophisticated convolutional neural network machine learning model. The results of our second study prove that the implicit BCI-based deep RL version in combination with the dry EEG-system can significantly accelerate the learning process in a realistic 3-D robot simulation environment. Performance of the BCI-based trained deep RL model was even comparable to that achieved by the approach with explicit human feedback. Our findings emphasize the usage of BCI-based deep RL methods as a valid alternative in those human-robot applications where no access to cognitive demanding explicit human feedback is available.

Brain Oscillation Entrainment by Perceptible and Non-perceptible Rhythmic Light Stimulation.

Objective and Background: Decades of research in the field of steady-state visual evoked potentials (SSVEPs) have revealed great potential of rhythmic light stimulation for brain-computer interfaces. Additionally, rhythmic light stimulation provides a non-invasive method for entrainment of oscillatory activity in the brain. Especially effective protocols enabling non-perceptible rhythmic stimulation and, thereby, reducing eye fatigue and user discomfort are favorable. Here, we investigate effects of (1) perceptible and (2) non-perceptible rhythmic light stimulation as well as attention-based effects of the stimulation by asking participants to focus (a) on the stimulation source directly in an overt attention condition or (b) on a cross-hair below the stimulation source in a covert attention condition. Method: SSVEPs at 10 Hz were evoked with a light-emitting diode (LED) driven by frequency-modulated signals and amplitudes of the current intensity either below or above a previously estimated individual threshold. Furthermore, we explored the effect of attention by asking participants to fixate on the LED directly in the overt attention condition and indirectly attend it in the covert attention condition. By measuring electroencephalography, we analyzed differences between conditions regarding the detection of reliable SSVEPs via the signal-to-noise ratio (SNR) and functional connectivity in occipito-frontal(-central) regions. Results: We could observe SSVEPs at 10 Hz for the perceptible and non-perceptible rhythmic light stimulation not only in the overt but also in the covert attention condition. The SNR and SSVEP amplitudes did not differ between the conditions and SNR values were in all except one participant above significance thresholds suggested by previous literature indicating reliable SSVEP responses. No difference between the conditions could be observed in the functional connectivity in occipito-frontal(-central) regions. Conclusion: The finding of robust SSVEPs even for non-intrusive rhythmic stimulation protocols below an individual perceptibility threshold and without direct fixation on the stimulation source reveals strong potential as a safe stimulation method for oscillatory entrainment in naturalistic applications.

Palmitoylated TMX and calnexin target to the mitochondria-associated membrane.

The mitochondria-associated membrane (MAM) is a domain of the endoplasmic reticulum (ER) that mediates the exchange of ions, lipids and metabolites between the ER and mitochondria. ER chaperones and oxidoreductases are critical components of the MAM. However, the localization motifs and mechanisms for most MAM proteins have remained elusive. Using two highly related ER oxidoreductases as a model system, we now show that palmitoylation enriches ER-localized proteins on the MAM. We demonstrate that palmitoylation of cysteine residue(s) adjacent to the membrane-spanning domain promotes MAM enrichment of the transmembrane thioredoxin family protein TMX. In addition to TMX, our results also show that calnexin shuttles between the rough ER and the MAM depending on its palmitoylation status. Mutation of the TMX and calnexin palmitoylation sites and chemical interference with palmitoylation disrupt their MAM enrichment. Since ER-localized heme oxygenase-1, but not cytosolic GRP75 require palmitoylation to reside on the MAM, our findings identify palmitoylation as key for MAM enrichment of ER membrane proteins.

Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress.

Increasing evidence indicates that endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response (UPR), but that beyond a certain degree of ER damage, this response triggers apoptotic pathways. The general mechanisms of the UPR and its apoptotic pathways are well characterized. However, the metabolic events that occur during the adaptive phase of ER stress, before the cell death response, remain unknown. Here, we show that, during the onset of ER stress, the reticular and mitochondrial networks are redistributed towards the perinuclear area and their points of connection are increased in a microtubule-dependent fashion. A localized increase in mitochondrial transmembrane potential is observed only in redistributed mitochondria, whereas mitochondria that remain in other subcellular zones display no significant changes. Spatial re-organization of these organelles correlates with an increase in ATP levels, oxygen consumption, reductive power and increased mitochondrial Ca²âº uptake. Accordingly, uncoupling of the organelles or blocking Ca²âº transfer impaired the metabolic response, rendering cells more vulnerable to ER stress. Overall, these data indicate that ER stress induces an early increase in mitochondrial metabolism that depends crucially upon organelle coupling and Ca²âº transfer, which, by enhancing cellular bioenergetics, establishes the metabolic basis for the adaptation to this response.

Rab32 modulates apoptosis onset and mitochondria-associated membrane (MAM) properties.

The mitochondria-associated membrane (MAM) has emerged as an endoplasmic reticulum (ER) signaling hub that accommodates ER chaperones, including the lectin calnexin. At the MAM, these chaperones control ER homeostasis but also play a role in the onset of ER stress-mediated apoptosis, likely through the modulation of ER calcium signaling. These opposing roles of MAM-localized chaperones suggest the existence of mechanisms that regulate the composition and the properties of ER membrane domains. Our results now show that the GTPase Rab32 localizes to the ER and mitochondria, and we identify this protein as a regulator of MAM properties. Consistent with such a role, Rab32 modulates ER calcium handling and disrupts the specific enrichment of calnexin on the MAM, while not affecting the ER distribution of protein-disulfide isomerase and mitofusin-2. Furthermore, Rab32 determines the targeting of PKA to mitochondrial and ER membranes and through its overexpression or inactivation increases the phosphorylation of Bad and of Drp1. Through a combination of its functions as a PKA-anchoring protein and a regulator of MAM properties, the activity and expression level of Rab32 determine the speed of apoptosis onset.

Ero1alpha requires oxidizing and normoxic conditions to localize to the mitochondria-associated membrane (MAM).

Protein secretion from the endoplasmic reticulum (ER) requires the enzymatic activity of chaperones and oxidoreductases that fold polypeptides and form disulfide bonds within newly synthesized proteins. The best-characterized ER redox relay depends on the transfer of oxidizing equivalents from molecular oxygen through ER oxidoreductin 1 (Ero1) and protein disulfide isomerase to nascent polypeptides. The formation of disulfide bonds is, however, not the sole function of ER oxidoreductases, which are also important regulators of ER calcium homeostasis. Given the role of human Ero1alpha in the regulation of the calcium release by inositol 1,4,5-trisphosphate receptors during the onset of apoptosis, we hypothesized that Ero1alpha may have a redox-sensitive localization to specific domains of the ER. Our results show that within the ER, Ero1alpha is almost exclusively found on the mitochondria-associated membrane (MAM). The localization of Ero1alpha on the MAM is dependent on oxidizing conditions within the ER. Chemical reduction of the ER environment, but not ER stress in general leads to release of Ero1alpha from the MAM. In addition, the correct localization of Ero1alpha to the MAM also requires normoxic conditions, but not ongoing oxidative phosphorylation.

Evaluation of gastric bypass patients 1 year after surgery: changes in quality of life and obesity-related conditions.

BACKGROUND: Obesity has recently been cited as the number one killer in the USA. This problem is both a national and regional epidemic. The health care costs of obesity and obesity-related illnesses are ever increasing, and gastric bypass surgery is becoming a popular treatment strategy. Recently, reports describe not only surgical outcomes, but also quality of life outcomes. The bigger issue of obesity-related illness resolution is still evolving. Our institution has performed well over 500 gastric bypasses since 2002. We evaluated over 100 patients prior to and 1 year after gastric bypass surgery. METHODS: A prospective study was designed in order to systematically examine quality of life in gastric bypass patients and couple the results with both objective and subjective assessment of bariatric surgery outcomes. One hundred nineteen patients undergoing gastric bypass at our institution from January 2005 to December of 2005 were enrolled in the study. In addition to routine preprocedural and postprocedural follow-up, completion of quality of life forms and anthropometric measurements were performed. Using these data, we then correlated the change in quality of life scores with social factors, weight loss success, and status of obesity-related conditions. We also examined the impact of alcohol intake and other demographic factors on both quality of life and obesity related conditions. RESULTS: A total of 119 patients were enrolled in the study during the calendar year 2005. Follow-up at approximately 1 year (average 12.86 months) postsurgery was obtained in 75 patients. A significant reduction in weight (144.4+/-34.4 vs. 91.5+/-28.8; p<0.0001), body mass index (52.4+/-12.2 vs. 32.3+/-8.6; p<0.0001), mean systolic blood pressure (140.4+/-14.7 vs. 130.0+/-21.7; p<0.001), and lipids (194.3+/-33.8 vs. 165.7+/-32.1; p<0.0001) was noted. Quality of life scores 1 year after gastric bypass surgery were also significantly improved (35.9+/-19.5 vs. 82.2+/-23.5; p<0.0001). There was also a significant reduction in the reported usage of medications for obesity related conditions. Various measures of success (change in BMI, change in quality of life scores, and follow up health ranking) were compared across demographic and social factors and no significant associations were identified. CONCLUSIONS: Gastric bypass is associated with a reduction in weight, BMI, mean systolic blood pressure, cholesterol, and the usage of medications for obesity-related conditions. A significant improvement in quality of life was also noted 1 year after surgery.