Level Of Functional Improvement Research Articles

Assessment of Functional Outcome and Quality of Life in Patients after Total Hip Replacement in Indian Population: A Prospective Cohort Study

Introduction: Hip osteoarthritis is a major public health issue associated with a considerable loss of Health-related Quality of Life (HR-QoL). However, not all patients achieve the same level of functional improvement after Total Hip Arthroplasty (THA) and it is unclear which factors are associated with it. Aim: To determine the functional outcome and QoL in patients who underwent Total Hip Replacement (THR) in an Indian set-up. Materials and Methods: The present prospective cohort study was conducted in the Department of Orthopaedics, Eras Lucknow Medical College and Hospital, Uttar Pradesh, India, from March 2020 to September 2021. A total of 100 patients who underwent THA were included through convenience sampling. Demographic and clinical information, like name, age, gender, Body Mass Index (BMI), duration of symptoms, co-morbidity, Visual Analogue Scale (VAS) score and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores, were noted from the medical records. A single follow-up of all the patients who underwent THA was conducted to assess the complications, functional outcomes and QoL using VAS score (preoperative and postoperative), WOMAC score (preoperative and postoperative), Harris Hip Score (HHS) (postoperative), Short Form-36 (SF-36) health survey (postoperative) questionnaire. The data was analysed using Statistical Package for the Social Sciences (SPSS) software version 25.0. Continuous variables were analysed using the Wilcoxon signed-rank test for paired data. Correlation assessment was done using Pearson’s correlation coefficient for continuous factors and Spearman’s correlation coefficient for categorical factors. Results: The average age of the patients who underwent THR was 58.90±15.93 years, with a range of 17-95 years. There were 72 males and 28 females. The mean VAS score preoperatively was 7.41±1.20, which decreased significantly to 2.93±0.81 in the postoperative follow-up (p-value<0.001). The mean total WOMAC score improvement was 38.51±10.26 (p-value<0.001). The average postoperative HHS was 73.53±16.16, suggesting a good outcome. The average postoperative SF-36 score was 68.89±12.88. A correlation coefficient of 0.21 (p-value=0.033) suggested that the WOMAC score improvement became higher with an increase in follow-up duration. Patients with postoperative complications had a significantly lower WOMAC improvement (r-value=-0.26, p-value=0.0084). It was observed that the follow-up duration (p-value=0.047) and postoperative complications (p-value=0.016) were significant factors of WOMAC score improvement. Conclusion: Follow-up duration and the presence of postoperative complications were important factors in the functional outcome of patients who underwent THA. Knowledge of these factors can help the clinician to plan the management accordingly while counseling the patients and their relatives regarding any possible adverse outcomes.

Adaptation dynamics between copy-number and point mutations.

Together, copy-number and point mutations form the basis for most evolutionary novelty, through the process of gene duplication and divergence. While a plethora of genomic data reveals the long-term fate of diverging coding sequences and their cis-regulatory elements, little is known about the early dynamics around the duplication event itself. In microorganisms, selection for increased gene expression often drives the expansion of gene copy-number mutations, which serves as a crude adaptation, prior to divergence through refining point mutations. Using a simple synthetic genetic reporter system that can distinguish between copy-number and point mutations, we study their early and transient adaptive dynamics in real time in Escherichia coli. We find two qualitatively different routes of adaptation, depending on the level of functional improvement needed. In conditions of high gene expression demand, the two mutation types occur as a combination. However, under low gene expression demand, copy-number and point mutations are mutually exclusive; here, owing to their higher frequency, adaptation is dominated by copy-number mutations, in a process we term amplification hindrance. Ultimately, due to high reversal rates and pleiotropic cost, copy-number mutations may not only serve as a crude and transient adaptation, but also constrain sequence divergence over evolutionary time scales.

Red Cell Rheology Biomarkers to Assess Cure in Gene-Based Therapies

Introduction Red cell rheology is abnormal in sickle cell disease (SCD); red blood cells (RBC) are rigid, dense, and the sickle hemoglobin (HbS) polymerizes with deoxygenation. There are several devices commercially available and under development to assess RBC rheology. One is an oxygen gradient ektacytometer (Lorrca with Oxygenscan, RR Mechatronics) which measures RBC deformability under oxygenated conditions (EImax) and deoxygenated conditions (EImin), and the oxygen concentration at which deformability begins to worsen, point of sickling (PoS). A commercially available hematology analyzer, the ADVIA (Siemens), measures hemoglobin (Hb) by flow and colorimetric methods, permitting automated calculation of the percent dense red blood cells (%DRBC). Allogeneic hematopoietic stem cell transplant (alloHSCT) can provide a cure for SCD, and viable gene-based therapy options are under investigation to serve the many patients without a matched related donor. However, the level of HbS correction or functional Hb induction necessary to achieve a cure is still unknown. Clinical endpoints such as prevention of pain events are important, but it is possible to be pain free for several years while still experiencing organ damage. As gene-based therapy clinical trials move forward, we must assess the level of functional improvement beyond Hb profile and conventional clinical labs. We propose that the goal of any gene-based SCD therapy should be to normalize blood rheology to the level of an individual with sickle cell trait (HbAS), and that EImax, EImin, PoS, and %DRBC may be used to distinguish between HbAS and HbSS/Sβ0 genotypes. Methods Subjects: Blood samples were collected from 257 unique patients (17 HbAS, and 240 HbSS/Sβ0) under IRB-approved protocols at Texas Children's Hospital and University Medical Center Utrecht. Patients were 56% male, ages 9 months to 22 years. Some HbSS/Sβ0 subjects were on transfusion and hydroxyurea (HU) (Table 1). Fetal hemoglobin (HbF) levels ranged from 0-41%. Oxygen gradient ektacytometry: Blood collected in EDTA and standardized to a fixed RBC count was suspended in 5 mL polyvinylpyrrolidone at room temperature. 1.5 mL of the sample solution was injected into test cup. Each sample was run in duplicate. ADVIA: 250µL of blood collected in EDTA at room temperature was aspirated to measure the %DRBC, defined as the percentage of RBCs with a Hb concentration >1.11 mg/mL. Analysis: Patient characteristics were summarized using median with 25th and 75th percentiles, and frequency with percentage. Characteristics and labs were compared by group with t-test, Wilcoxon rank sum test, or Fisher's exact test. Receiver operating characteristics (ROC) analyses were performed to identify HbAS versus HbSS/Sβ0 for each biomarker. All analyses were performed using Stata 15. Results The EImin, EImax, PoS, and %DRBC differed significantly between the HbAS and HbSS/Sβ0 groups, despite including transfused, very young, and HU-treated samples in the HbSS/Sβ0 cohort (p<0.001, p=0.002, p<0.001, and p<0.001, respectively; Table 1). ROC analysis showed that a threshold Elmin greater than or equal to 0.453 identified HbAS with 94.12% sensitivity and 95.43% specificity. EImax greater or equal to 0.569 identified HbAS with 94.12% sensitivity and 81.57% specificity. PoS less than 21.38 mmHg identified HbAS with 93.87% sensitivity and 93.33% specificity. %DRBC less than 1.6% identified HbAS with 88.13% sensitivity and 88.00% specificity (Table 2). Conclusion Conventional laboratory testing may not be able to establish if gene-based therapy has achieved a cure. We propose to define a cure as achievement of an HbAS level of RBC quality in a gene-based therapy edited RBC population. We show that rheological biomarkers EImin, EImax, PoS, and %DRBC differ significantly between individuals with HbAS and HbSS/Sβ0 of all spectrums of severity and treatment regimens. Not only are the rheological biomarker values significantly different, but there is little to no overlap in ranges of values obtained from the different genotypes, even in heavily transfused HbSS patients, with HbS as low as 31%. EImin, EImax, PoS, and %DRBC functionally identify genotype with high sensitivity and specificity; we propose that they be used not to diagnose SCD, but to determine if a HbSS or HbSS/Sβ0 individual who has undergone successful gene-based therapy has achieved the RBC functionality of a HbAS individual. Disclosures van Beers: Novartis: Research Funding; Pfizer: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding; RR mechatronics: Research Funding. Wijk:Agios Pharmaceuticals Inc.: Research Funding; RR mechatronics: Research Funding. Rab:RR Mechatronics: Research Funding. Sheehan:Global Blood Therapeutics: Research Funding; Novartis: Research Funding; Emmaus: Research Funding.

Treating spinal cord injury via sustained drug delivery from calcium phosphate coatings.

Spinal cord injury (SCI) is a devastating trauma that leaves approximately 10,000 to 20,000 people paralyzed every year in the United States. The majority of these cases are young people that will live to almost a full life expectancy, however, their quality of life is significantly reduced. After SCI there is loss of both sensory and motor function below the level of injury. Due to this loss of function SCI patients are often unable to care for themselves and rely on friends and family to serve as their primary caregivers. The Christopher Reeve Foundation found that more than 50 million people each year provide this care in the U.S., the value of which is estimated to be $306 billion annually. Along with the financial burden, SCI patients have emotional stress and continued health care problems throughout their lives most predominately renal complications and pressure sores. These facts demonstrate the overwhelming need to restore function after SCI.

Addendum to 'Intraoperative CD133+ cell transplantation during coronary artery bypass grafting in ischemic cardiomyopathy'

In a recent article [1], we reported on a combination therapy of CABG, laser treatment and CD133+ cell transplantation, to treat chronic cardiac ischaemia, which has been examined for safety and feasibility in the multicentre INSTEM trial. In our previous publication, we have shown exemplary 2D echocardiographyderived left ventricular ejection fraction (LVEF) data from patients who had been included in the study early on in this trial. While this subset of patients presented an increase in LVEF from 25% preoperatively to 40% after 6 months, the final analysis after completion of the study, including all patients from all centres, resulted in an echocardiographic improvement from 27.7 ± 0.9% preoperatively to 37.6 ± 1.4% after 6 months (P < 0.001). While the endpoint-relevant evaluation assessed by magnetic resonance imaging (MRI) among all patients included in this trial did not reach the level of functional improvement as previously assessed by echocardiography in a smaller cohort, a significant increase in LVEF was confirmed (29.7 ± 1.9% after 6 months vs 24.6 ± 1.5% preoperatively; P = 0.004). The difference between the data in our previous publication and the final trial analysis can be explained by the different functional readout methods as well as by the larger number of patients finally included upon completion of the study. Since MRI is the gold standard for global and regional functional evaluation of ischaemic myocardium, we regard the data obtained by MRI as crucial to objectively assess the overall results in addition to the previous 2D echocardiography analysis.

The unusual properties of effective blood substitutes.

Blood substitutes or oxygen carrying plasma expanders were originally formulated to simulate the transport properties of blood, particularly oxygen carrying capacity, viscosity, p50, and colloid osmotic pressure, under the hypothesis that blood is the most desirable fluid in volume restitution. However, changes introduced into the organism during hemorrhage adversely affect microvascular function due to reflex vasoconstriction which causes the fall of functional capillary density, and lowers tissue oxygenation, conditions that are not universally reversed with retransfusion of blood. The restoration of microvascular function is seldom complete upon retransfusion of blood. New formulations of hemoglobin molecules in solutions whose oncotic pressure is in the range of 60-100 mmHg, p50 is about 5 mmHg, viscosity 3-4 cP, and oxygen carrying capacity in the range of 4-7 g/dl equivalent hemoglobin deliver better microvascular function after resuscitation when compared to whole blood and oxygen carrying plasma expanders with transport properties similar to those of blood. The improved performance is in part due to the increased plasma viscosity which increases capillary transmural pressure which reverses capillary collapse induced during low perfusion pressures. High oncotic pressure reinforces this effect, since it brings more fluid into the circulation. Microvascular transport studies of the effects of resuscitation in shock show that functional capillary density is the primary determinant of survival, thus maintenance of an open and fully perfused microcirculation is more critical than insuring oxygen supply, since closed capillaries lead to the accumulation of slowly diffusing byproducts of metabolism which ultimately become toxic. The required combination of properties can be achieved by conjugating hemoglobin and polyethylene glycol. Resuscitation fluids based on hemoglobin containing vesicles may provide the next level of functional improvement in the formulation of volume restitution fluids since their biophysical properties can be specifically controlled through the inclusion of specialized compounds into the vesicles, and the formulation of the suspending medium.