Cost-effectiveness of a second opinion program on spine surgeries: an economic analysis.

BACKGROUND: In this study we proposed a new strategy to measure cost-effectiveness of second opinion program on spine surgery, using as measure of effectiveness the minimal important change (MIC) in the quality of life reported by patients, including the satisfaction questionnaire regarding the treatment and direct medical costs. METHODS: Retrospective analysis of patients with prior indication for spine surgery included in a second opinion program during May 2011 to May 2019. Treatment costs and outcomes were compared considering each patients' recommended treatment before and after the second opinion. Costs were measured under the perspective of the hospital, including hospital stay, surgical room, physician and staff fees and other costs related to hospitalization when surgery was performed and physiotherapy or injection costs when a conservative treatment was recommended. Reoperation costs were also included. For comparison analysis, we used data based on our clinical practice, using data from patients who underwent the same type of surgical procedure as recommended by the first referral. The measure of effectiveness was the percentage of patients who achieved the MIC in quality of life measured by the EQ-5D-3 L 2 years after starting treatment. An incremental cost-effectiveness ratio (ICER) was calculated. RESULTS: Based upon the assessment of 1,088 patients that completed the entire second opinion process, conservative management was recommended for 662 (60.8%) patients; 49 (4.5%) were recommended to injection and 377 (34.7%) to surgery. Complex spine surgery, as arthrodesis, was recommended by second opinion in only 3.7% of cases. The program resulted in financial savings of -$6,705 per patient associated with appropriate treatment indication, with an incremental effectiveness of 0.077 patients achieving MIC when compared to the first referral, resulting in an ICER of $-87,066 per additional patient achieving the MIC, ranging between $-273,016 and $-41,832. CONCLUSION: After 2 years of treatment, the second opinion program demonstrated the potential for cost-offsets associated with improved quality of life.

Eight weeks of a lower limb resistance training protocol and gait performance in patients with symptomatic mild to moderate knee osteoarthritis.

BACKGROUND: The role of strengthening the lower limbs to optimize the biomechanics of the hip, knee and ankle during walking in patients with knee osteoarthritis, is still unclear. This study aimed to analyse the walking biomechanics of individuals with symptomatic mild to moderate knee osteoarthritis before and after a simplified lower limb resistance training protocol, focused on knee joint exercises with individualized load. METHODS: Forty-one patients with symptomatic and radiographic mild to moderate knee osteoarthritis underwent 3D gait analysis pre-post 8 weeks lower limb resistance training protocol performed 3 times a week. Parameters investigated were spatiotemporal, sagittal range of motion, flexion and extension minimum and maximum values, power and moment of hip, knee and ankle, as well as self-reported pain and physical function by the Western Ontario MacMaster University Osteoarthritis Index. Paired t test, Wilcoxon, Spearman's correlation and a logistic model were used for statistical analysis, with p < 0.05. Pain improvement more than 2 points was considered clinically relevant. The effect size (ES) was calculated using Cohen's d. RESULTS: Post protocol walking speed increased 6.7% (ES: 0.711), cadence 3.7% (ES: 0.655), stride length 2.6% (ES: 0.542), and double support time reduced 6.9% (ES:0.459). It was also observed a significant increase in one maximum repetition test for legpress 46%, knee extension 23% and knee flexion chair 27% (p < 0.001). Patients reported a 62.5% reduction in pain (ES:1.518) and 64.9% improvement in physical function (ES:1.376). 82% of the patients presented more than 2 points improvement in pain. No evidence of strong correlations between pain, strength gains and gait parameters were found. CONCLUSIONS: There was a significant and clinical improvement of spatiotemporal gait parameters, pain, physical function, and strength after 8-week lower limb resistance training protocol. Patients who had a clinically relevant pain improvement presented better gait performance.

Comparative Effects of Intra-Articular versus Intravenous Mesenchymal Stromal Cells Therapy in a Rat Model of Osteoarthritis by Destabilization of Medial Meniscus.

Transplanted mesenchymal stromal cells (MSCs) exhibit a robust anti-inflammatory and homing capacity in response to high inflammatory signals, as observed in studies focused on rheumatic diseases that target articular cartilage (AC) health. However, AC degradation in osteoarthritis (OA) does not necessarily coincide with a highly inflammatory joint profile. Often, by the time patients seek medical attention, they already have damaged AC. In this study, we examined the therapeutic potential of a single bone marrow MSC transplant (2 × 106 cells/kgbw) through two different routes: intra-articular (MSCs-IAt) and intravenous (MSCs-IVt) in a preclinical model of low-grade inflammatory OA with an established AC degeneration. OA was induced through the destabilization of the medial meniscus (DMM) in female Wistar Kyoto rats. The animals received MSCs 9 weeks after surgery and were euthanized 4 and 12 weeks post-transplant. In vivo and ex vivo tracking of MSCs were analyzed via bioluminescence and imaging flow cytometry, respectively. Cytokine/chemokine modulation in serum and synovial fluid was measured using a multiplex panel. AC degeneration was quantified through histology, and hindlimb muscle balance was assessed with precision weighing. To our knowledge, we are the first group to show the in vivo (8 h) and ex vivo (12 h) homing of cells to the DMM-OA joint following MSCs-IVt. In the case of MSCs-IAt, the detection of cellular bioluminescence at the knee joint persisted for up to 1 week. Intriguingly, intra-articular saline injection (placebo-IAt) resulted in a worse prognosis of OA when compared to a non-invasive control (placebo-IVt) without joint injection. The systemic cytokines/chemokines profile exhibited a time-dependent variation between transplant routes, displaying a transient anti-inflammatory systemic response for both MSCs-IVt and MSCs-IAt. A single injection of MSCs, whether administered via the intra-articular or intravenous route, performed 9 weeks after DMM surgery, did not effectively inhibit AC degeneration when compared to a non-invasive control.

FAM3B/PANDER inhibits cell death and increases prostate tumor growth by modulating the expression of Bcl-2 and Bcl-XL cell survival genes.

BACKGROUND: FAM3B/PANDER is a novel cytokine-like protein that induces apoptosis in insulin-secreting beta-cells. Since in silico data revealed that FAM3B can be expressed in prostate tumors, we evaluated the putative role of this cytokine in prostate tumor progression. METHODS: FAM3B expression was analyzed by quantitative PCR in tumor tissue clinical samples and prostate tumor cell lines. Culture growth and viability of DU145 cell line were evaluated after treatment with either exogenous FAM3B protein obtained from conditioned media (CM) of 293 T cells overexpressing FAM3B or a recombinant FAM3B protein produced in a bacterial host. DU145 cells overexpressing FAM3B protein were produced by lentiviral-mediated transduction of full-length FAM3B cDNA. Cell viability and apoptosis were analyzed in DU145/FAM3B cells after treatment with several cell death inducers, such as TNF-alpha, staurosporine, etoposide, camptothecin, and serum starvation conditions. Anchorage-independent growth in soft agarose assay was used to evaluate in vitro tumorigenicity. In vivo tumorigenicity and invasiveness were evaluated by tumor xenograft growth in nude mice. RESULTS: We observed an increase in FAM3B expression in prostate tumor samples when compared to normal tissues. DU145 cell viability and survival increased after exogenous treatment with recombinant FAM3B protein or FAM3B-secreted protein. Overexpression of FAM3B in DU145 cells promoted inhibition of DNA fragmentation and phosphatidylserine externalization in a time and dose-dependent fashion, upon apoptosis triggered by TNF-alpha. These events were accompanied by increased gene expression of anti-apoptotic Bcl-2 and Bcl-XL, decreased expression of pro-apoptotic Bax and diminished caspase-3, -8 and -9 proteolytic activities. Furthermore, inhibition of Bcl-2 anti-apoptotic family proteins with small molecules antagonists decreases protective effects of FAM3B in DU145 cells. When compared to the respective controls, cells overexpressing FAM3B displayed a decreased anchorage- independent growth in vitro and increased tumor growth in xenografted nude mice. The immunohistochemistry analysis of tumor xenografts revealed a similar anti-apoptotic phenotype displayed by FAM3B-overexpressing tumor cells. CONCLUSIONS: Taken together, by activating pro-survival mechanisms FAM3B overexpression contributes to increased resistance to cell death and tumor growth in nude mice, highlighting a putative role for this cytokine in prostate cancer progression.

Effect of Human Adipose Tissue Mesenchymal Stem Cells on the Regeneration of Ovine Articular Cartilage.

Cell therapy is a promising approach to improve cartilage healing. Adipose tissue is an abundant and readily accessible cell source. Previous studies have demonstrated good cartilage repair results with adipose tissue mesenchymal stem cells in small animal experiments. This study aimed to examine these cells in a large animal model. Thirty knees of adult sheep were randomly allocated to three treatment groups: CELLS (scaffold seeded with human adipose tissue mesenchymal stem cells), SCAFFOLD (scaffold without cells), or EMPTY (untreated lesions). A partial thickness defect was created in the medial femoral condyle. After six months, the knees were examined according to an adaptation of the International Cartilage Repair Society (ICRS 1) score, in addition to a new Partial Thickness Model scale and the ICRS macroscopic score. All of the animals completed the follow-up period. The CELLS group presented with the highest ICRS 1 score (8.3 ± 3.1), followed by the SCAFFOLD group (5.6 ± 2.2) and the EMPTY group (5.2 ± 2.4) (p = 0.033). Other scores were not significantly different. These results suggest that human adipose tissue mesenchymal stem cells promoted satisfactory cartilage repair in the ovine model.

Prospective Study of the Assessment of Anxiety Symptoms after Minimally Invasive Lumbar Decompression.

Objective To analyze associations between anxiety and postsurgical clinical outcomes in patients who underwent minimally invasive lumbar decompression surgery in addition to comparing symptoms of anxiety and depression before and after surgery. Methods This prospective cohort study of patients who underwent minimally invasive lumbar decompression surgery. Clinical outcomes were measured before and 6 months after surgery using the Visual Analog Scale (VAS), Global Perceived Effect of Change (GPE), Hospital Anxiety and Depression Scale (HADS), and Oswestry Disability Index (ODI). Based on the presurgical anxiety score, patients were categorized into anxious and non-anxious patients, and the outcomes were compared. Results The patients of both groups obtained similar results concerning the clinical outcomes evaluated. Preoperative HADS scores decreased significantly 6 months after surgery in both anxiety (8.70 ± 3.48 vs. 5.75 ± 3.91) and depression (6.95 ± 3.54 vs. 5.50 ± 2.99). The VAS scale for the back (-2.8 ± 3.64) and legs (-5.5 ± 3.5) showed a reduction in pain. Conclusion Minimally invasive lumbar decompression surgery promoted clinical and functional improvement, not being affected by preoperative anxiety symptoms. Mental health indicators showed a significant reduction in symptoms 6 months after surgery.

Robot-assisted knee arthroplasty: Analyzing the learning curve and initial institutional experience.

Robot-assisted total knee arthroplasty (rTKA) involves a learning curve for orthopedic surgeons. The aim of the present study was to assess the surgical times of rTKA procedures performed by initial stage and proficiency stage surgeons in comparison with times of conventional total knee arthroplasty (cTKA). The results reveal that the learning curve for rTKA varies considerable between surgeons, suggesting that the skill and aptitude of the individual to adapt to the robotic system play key roles in the learning process. Proficiency stage surgeons were able to reduce rTKA surgical times to levels comparable with those of conventional surgeries after performing approximately 30 to 40 robotic procedures. Ongoing research has shown promising outcomes in terms of improved clinical results and reduced complications following the application of advanced robotic technology to total knee arthroplasty.

The American College of Surgeons National Surgical Quality Improvement Program surgical risk calculator is not reliable in predicting complications and length of stay after primary total hip arthroplasty at an institution implementing clinical pathways.

INTRODUCTION: The authors aimed to: (1) determine how length of stay (LOS) and complication rates changed over the past 10 years, in comparison to values estimated by the ACS-NSQIP surgical risk calculator, at a single private institution open to external surgeons; and (2) determine preoperative patient factors associated with complications. METHODS: We retrospectively assessed 1018 consecutive patients who underwent primary elective THA over 10 years. We excluded 87 with tumours and 52 with incomplete records. Clinical data of the remaining 879 were used to determine real LOS and rate of 9 adverse events over time, as well as to estimate these values using the risk calculator. Its predictive reliability was represented on receiver operating characteristic curves. Multivariable analyses were performed to determine associations of complications with age, sex, ASA score, diabetes, hypertension, heart disease, smoking and BMI. RESULTS: Over the 10-year period, real LOS and real complication rates decreased considerably, while LOS and complication rates estimated by the surgical risk calculator had little or no change. The difference between real and estimated LOS decreased over time. The overall estimated and real rates of any complication were respectively 3.3% and 2.8%. The risk calculator had fair reliability for predicting any complications (AUC 0.72). Overall estimated LOS was shorter than the real LOS in 764 (86.9%) patients. Multivariable analysis revealed risks of any complication to be greater in patients aged ⩾75 (OR = 4.36, p = 0.002), and with hypertension (OR = 3.13, p = 0.016). CONCLUSIONS: Since the implementation of clinical pathways at our institution, real LOS and complication rates decreased considerably, while LOS and complication rates estimated by the surgical risk calculator had little or no change. The difference between real and estimated LOS decreased over time, which could lead some clinicians to reconsider their discharge criteria, knowing that advanced age and hypertension increased risks of encountering complications.

TOTAL HIP ARTHROPLASTY IN THE PUBLIC HEALTH SYSTEM OF SÃO PAULO: COMPARING TYPES OF FIXATION.

Brazil lacks registries on the prevalence of primary total hip arthroplasty (THA) fixation methods. Objective: (i) to describe the demographic profile of patients who underwent THA in the public health system of the municipality of São Paulo during the last 12 years and (ii) to compare fixation methods regarding costs, hospital stay length, and death rates. Methods: This is an ecological study conducted with data available on TabNet, a platform belonging to DATASUS. Public data (from the government health system) on THA procedures performed in São Paulo from 2008 to 2019 were extracted. Gender, age, city region, THA fixation method, number of surgeries, costs, hospital stay length, and death rates were analyzed. Results: We analyzed 7,673 THA, of which 6220 (81%) were performed via cementless/hybrid fixation and 1453 (19%), via the cemented technique. Cementless/hybrid fixation had a higher cost (US$ 495.27) than the cemented one (p < 0.001). Nevertheless, hospital stay length was 0.87 days longer for cemented fixation than the cementless/hybrid one. We found no significant difference in death rates between THA fixation methods. Conclusion: THA cementless/hybrid fixation is prevalent in the municipality of São Paulo, which had higher total costs and shorter hospitalizations than cemented fixation. We found no difference between THA fixation methods and death rates. Level of Evidence IV, Case Series.

No Brasil, não há registros da prevalência do tipo de fixação da artroplastia total de quadril (ATQ). Objetivo: (i) Descrever perfil demográfico de pacientes submetidos à ATQ no Sistema Único de Saúde de São Paulo durante os últimos doze anos; e (ii) comparar as técnicas de fixação de ATQ quanto aos custos, tempo de internação (TI) e taxa de óbito. Métodos: Estudo ecológico, com dados disponíveis na TabNet do DATASUS. Dados públicos de procedimentos de ATQ eletivos realizados em São Paulo de 2008 a 2019 foram extraídos. Foram analisados: sexo, idade, região municipal, método de fixação em ATQ, número de cirurgias, custo, tempo de internação e óbitos. Resultados: Foram analisadas 7.673 ATQs, sendo 6.220 (81%) não-cimentada/híbridas e 1.453 (19%) cimentadas. A fixação não-cimentada/híbrida teve custo maior em US$ 495,27 do que a cimentada (p < 0,001). Entretanto, TI foi 0,87 dia mais longo na fixação cimentada. Não houve diferença significativa nas taxas de óbito entre os métodos de fixação. Conclusão: A fixação não-cimentada/híbrida na ATQ é prevalente em São Paulo, e apresentou maior custo total, porém menor tempo de internação do que a fixação cimentada. Não houve diferença entre o método de fixação em ATQ e a taxa de óbito. Nível de Evidência IV, Série de Casos.

Clinical outcome analysis in surgical patients enrolled in a Second Opinion Program in spine surgery.

OBJECTIVE: To analyze pain, functional capacity, quality of life, anxiety and depression outcomes in patients undergoing lumbar spine surgery following use of the Second Opinion Program, and to present disagreements regarding diagnoses and therapeutic indications between the first and second opinions. METHODS: A prospective, observational cohort study with 100 patients enrolled in the Second Opinion Program who underwent lumbar spine surgery. Questionnaires addressing pain intensity, level of disability, quality of life, anxiety and depression were applied prior to and within 1, 3, 6 and 12 months of surgery. Descriptive and comparative statistical analyses were performed. The following clinical outcomes were analyzed: pain intensity, level of disability, quality of life, anxiety, and depression. RESULTS: In this sample, 88% and 12% out of 100 patients were submitted to lumbar decompression and arthrodesis, respectively. Patients reported improvements in function, pain intensity, and quality of life factors following surgery and were able to attain the minimal clinically important difference relative to the preoperative period. Agreement between the first and second opinions was observed in 44% of diagnoses, and in 27% of therapeutic indications. CONCLUSION: Patients had favorable postoperative outcomes regarding pain, disability, and quality of life. These findings and the high rates of diagnostic and therapeutic indication disagreements corroborate the need of a second opinion in cases of spine disease with surgical indications.

Impact of Hyaluronic Acid on the Viability of Mesenchymal Cells Derived from Adipose Tissue Grown in Collagen Type I/III Membrane.

Objective To evaluate in vitro the viability of mesenchymal stem cells derived from adipose tissue (AD-MSCs) in different commercial solutions of hyaluronic acid (HA) before and after being sowed in collagen I/III membrane. Methods In the first stage, the interaction between AD-MSCs was analyzed with seven different commercial products of HA, phosphate buffered saline (PBS), and bovine fetal serum (BFS), performed by counting living and dead cells after 24, 48 and 72 hours. Five products with a higher number of living cells were selected and the interaction between HA with AD-MSCs and type I/III collagen membrane was evaluated by counting living and dead cells in the same time interval (24, 48 and 72 hours). Results In both situations analyzed (HA + AD-MSCs and HA + AD-MSCs + membrane), BFS presented the highest percentage of living cells after 24, 48 and 72 hours, a result higher than that of HA. Conclusion The association of HA with AD-MSCs, with or without membrane, showed no superiority in cell viability when compared with BFS.

Matrix-assisted autologous chondrocyte transplantation for treatment of focal chondral lesions in the knee: the Hospital Israelita Albert Einstein experience.

OBJECTIVE: Phase 1 clinical trial to determine feasibility, safety, and efficacy of a new advanced cell therapy product for treatment of knee articular cartilage injuries. METHODS: Three participants with knee focal chondral lesions were included, with no signs of osteoarthritis. Chondrocytes were obtained through knee arthroscopy, cultured in collagen membrane for 3 weeks at the laboratory, subjected to tests to release the cell therapy product, and implanted. All patients underwent a specific 3-month rehabilitation protocol, followed by assessments using functional and imaging scales. The main outcome was the incidence of severe adverse events. RESULTS: Three participants were included and completed the 2-year follow-up. There was one severe adverse event, venous thrombosis of distal leg veins, which was no associated with therapy, was treated and left no sequelae. The clinical and radiological scales showed improvement in the three cases. CONCLUSION: The preliminary results, obtained with the described methodology, allow concluding that this product of advanced cell therapy is safe and feasible. ReBEC platform registration number: RBR-6fgy76.

Report of a clinical and laboratory management of cell therapy for knee cartilage in the face of mycoplasma contamination.

To describe a case of autologous chondrocyte implantation after cell culture contamination by Mycoplasma pneumoniae and the measures taken to successfully complete cell therapy in a patient with focal chondral lesion. A 45-year-old male patient, complaining of chronic pain on the knee and no history of trauma. He had a chondral lesion in the trochlear region of the femur and clinical tests compatible with pain in the anterior compartment of the knee. Conservative treatment failed to alleviate symptoms. Surgical treatment was indicated, but due to the size of the lesion, membrane-assisted autologous chondrocyte implantation was the technique of choice. Cartilage biopsies were collected from the intercondylar region of the distal femur. After isolation, chondrocytes were expanded ex vivo in a trained laboratory, for three weeks, and seeded onto a commercially available collagen membrane prior to implantation in the knee. Two days before surgery, a cell culture sample tested positive for Mycoplasma pneumoniae. The source of contamination was found to be autologous blood serum, extracted from the patient´s peripheral vein, and used to supplement the cell culture medium. After treating the patient with antibiotics, all procedures were repeated and the new final cell product, free from contaminants, was successfully implanted. We discuss the strategies available to deal with this situation, and describe the results of this particular case, which led to modifications in the autologous chondrocyte implant protocol.

ID1 inhibits USF2 and blocks TGF-ß-induced apoptosis in mesangial cells.

Mesangial cells (MC) play an essential role in normal function of the glomerulus. Phenotypic changes in MC lead to the development of glomerular diseases such as diabetic nephropathy and glomerulosclerosis. The late phase of diabetic glomerulopathy is characterized by MC death and fibrosis. Current data highlight the transforming growth factor (TGF)-ß as a trigger of the pathological changes observed in MC, including death by apoptosis. However, the mechanisms and mediators involved in this process are still poorly understood. Identification of novel elements involved in MC death may provide a better understanding of the pathophysiology of glomerular diseases. Here, we show that bone morphogenetic proteins (BMPs; known antagonists of the profibrotic effects of TGF-ß in the kidney) strongly induce inhibitor of DNA binding (ID1) mRNA transcription and protein expression in human MC. ID genes have been implicated in cell survival control and are constitutively expressed in MC. We show that BMPs and ID1 exert an anti-apoptotic effect in MC by inhibition of USF2 transcriptional activity. On the other hand, TGF-ß upregulates USF2, increasing BAX (proapoptotic gene) levels and apoptosis rates. Taken together, our results point to a novel molecular pathway that modulates MC apoptosis, which is potentially involved in the pathogenesis of glomerular diseases.

Lumbar Decompression Versus Spinal Fusion in a Private Outpatient Setting: A Retrospective Study with Three Years of Follow-up.

Objective To compare pain, function, quality of life and adverse events of lumbar decompression and spinal fusion in patients with degenerative spinal pathologies who participated in a second opinion program for spinal surgeries with a 36-month follow-up. Methods The data for this retrospective cohort were withdrawn from a private healthcare system between June 2011 and January 2014. The study sample consisted of 71 patients with a lumbar spine surgical referral. The outcomes for the comparisons between lumbar decompression and spinal fusion were quality of life (evaluated through the EuroQoL 5D), pain (measured by the Numerical Rating Scale) and function (assessed through the Roland Morris Disability Questionnaire) measured at baseline, and at 12 and 36 months after the surgical procedures. The definitions of recovery were established by the minimal clinically important difference (MCID). The baseline differences between the groups were analyzed by non-paired t -test, and the differences in instrument scores between time points, by generalized mixed models. The results were presented as mean values adjusted by the models and 95% confidence intervals. Results Concerning the surgical techniques, 22 patients were submitted to spinal fusion and 49 patients, to lumbar decompression. As for the comparisons of the findings before and after the surgical interventions, the MCID was achieved in all outcomes regarding quality of life, pain and function at both time points when compared to baseline scores Moreover, concerning the complication rates, only lumbar decompression presented a surgical rate of 4% ( n = 3) for recurrence of lumbar disc hernia. Conclusion Patients with degenerative spinal pathologies present improvements in long-term outcomes of pain, function and quality of life which are clinically significant, no matter the surgical intervention.

Clinical outcomes and cost-utility of rotator cuff repair surgery by open and arthroscopic techniques: study protocol for a randomised clinical trial.

INTRODUCTION: Rotator cuff injuries account for up to 70% of pain in the shoulder. However, there remains no consensus on the best surgical treatment for patients with rotator cuff injuries, in terms of the cost-effectiveness and cost-utility of open and arthroscopic methods for rotator cuff repair. The objective of this trial is to compare the efficacy, cost-effectiveness and cost-utility of open and arthroscopic procedures for rotator cuff repair. METHODS AND ANALYSIS: The trial is a two-group, parallel-design, randomised controlled trial. A total of 100 patients with symptomatic rotator cuff lesions will be allocated in either open or arthroscopic technique in a 1:1 ratio, considering smoking (yes or no), lesion size (≤3 cm or >3 cm) and diabetes (present or absent) as stratification factors. All patients will be included in the same rehabilitation programme after the intervention. The primary outcome measure will be the Constant-Murley Score and the EuroQol-5D-3L score at 48 weeks postsurgery. Secondary outcomes include cost-effectiveness, cost-utility, pain, complications and clinical analysis, using the Simple Shoulder Test, Visual Analogue Pain Scale (VAS), integrity of the repair evaluated through MRI, and complications and failures of the proposed methods. For the cost-effectiveness analysis, we will use the VAS and the Constant-Murley Score as measures of effectiveness. For the cost-utility analysis, we will use the EuroQol-5D-3L as a measure of utility in terms of incremental cost per quality-adjusted life-years. ETHICS AND DISSEMINATION: The study has been approved by the local research ethics committee of both institutions: Hospital Israelita Albert Einstein and Hospital Alvorada Moema/Hospital Pró-Cardíaco. The results will be published in a peer-reviewed, open access journal. TRIAL REGISTRATION NUMBER: NCT04146987.

Clinical pathway improves medical practice in total knee arthroplasty.

PURPOSE: Clinical pathways in total knee arthroplasty (TKA) consist of general guidelines, including several topics as early rehabilitation and antibiotic systematization, which are used to improve patient's management, decrease complication rates and enhance clinical outcomes. The primary purpose of this study was to assess whether the use of a clinical pathway for TKA can contribute to reduce LOS and healthcare costs in a private hospital, without an increase in the hospital readmission rate. We also aimed to assess whether care providers adhered to the recommendations mainly antibiotic use and physical therapy. METHODS: Retrospective cohort study of 485 patients who underwent TKA at private hospital. Patients were analyzed in two groups: Group I (GI), composed by 220 TKA patients, prior to the clinical pathway implementation, and Group 2 (GII), with 265 TKA patients post-clinical pathway. Several outcomes were analyzed: length of hospital stay, time from use of prophylactic antibiotic therapy, readmission within 30 days, physical therapy and costs associated to procedures and hospitalization rates. RESULTS: The implementation of the clinical pathway was related with the reduction of the length of hospital stay from 6.3 days to 4.9 days (p = 0.021) without increase in readmissions. The physical therapy on the first postoperative day was most frequent in GII than GI (96.2% vs 78.1%, p < 0.001). Prophylactic ATB 60 minutes prior the surgery was significantly more used in GII than GI (99.2% vs 87.4%, p < 0.001). In addition, ATB suspension within 48 hours was significantly more frequent in GII than GI (84.7% vs. 51.6%, p < 0.001). The cost procedure of TKA showed a reduction of US$1,252.00 in GII when compared with GI (p<0,001). CONCLUSION: The implementation of a clinical pathway, with focus on early rehabilitation, for patients underwent TKA, contributed to a reduction of LOS and costs during hospital stay, with no increase in the readmission rate. We also concluded that there was adherence to the clinical pathway by care providers in our institution.

Individual response to mTOR inhibition in delaying replicative senescence of mesenchymal stromal cells.

BACKGROUND AIMS: Delaying replicative senescence and extending lifespan of human mesenchymal stromal cells (MSCs) may enhance their potential for tissue engineering and cell based therapies. Accumulating evidence suggests that inhibitors of the mTOR signaling pathway, such as rapamycin, constitute promising pharmacological agents to retard senescence and extend stemness properties of various progenitor cell types. Here, we investigated whether the ability of rapamycin to postpone replicative senescence varies among bone marrow MSC samples (BM-MSCs) derived from different healthy donors, and explored the molecular mechanisms that drive rapamycin-mediated lifespan increment. METHODS: BM-MSCs at early passages were serially passaged either in absence or continuous presence of rapamycin and the number of cell population doublings until growth arrest was measured. The inhibition of mTOR signaling was assessed by the phosphorylation status of the downstream target RPS6. The expression levels of several senescence and pluripotency markers at early and late/senescent passages were analyzed by RT-qPCR, flow cytometry and western blot. RESULTS: We found that the lifespan extension in response to the continuous rapamycin treatment was highly variable among samples, but effective in most BM-MSCs. Despite all rapamycin-treated cells secreted significantly reduced levels of IL6, a major SASP cytokine, and expressed significantly higher levels of the pluripotency marker NANOG, the expression patterns of these markers were not correlated with the rapamycin-mediated increase in lifespan. Interestingly, rapamycin-mediated life-span extension was significantly associated only with repression of p16INK4A protein accumulation. CONCLUSIONS: Taken together, our results suggest that some, but not all, BM-MSC samples would benefit from using rapamycin to postpone replicative arrest and reinforce a critical role of p16INK4A protein downregulation in this process.

Cell Viability of Porous Poly(d,l-lactic acid)/Vertically Aligned Carbon Nanotubes/Nanohydroxyapatite Scaffolds for Osteochondral Tissue Engineering.

Treatment of articular cartilage lesions remains an important challenge. Frequently the bone located below the cartilage is also damaged, resulting in defects known as osteochondral lesions. Tissue engineering has emerged as a potential approach to treat cartilage and osteochondral defects. The principal challenge of osteochondral tissue engineering is to create a scaffold with potential to regenerate both cartilage and the subchondral bone involved, considering the intrinsic properties of each tissue. Recent nanocomposites based on the incorporation of nanoscale fillers into polymer matrix have shown promising results for the treatment of osteochondral defects. In this present study, it was performed using the recently developed methodologies (electrodeposition and immersion in simulated body fluid) to obtain porous superhydrophilic poly(d,l-lactic acid)/vertically aligned carbon nanotubes/nanohydroxyapatite (PDLLA/VACNT-O:nHAp) nanocomposite scaffolds, to analyze cell behavior and gene expression of chondrocytes, and then assess the applicability of this nanobiomaterial for osteochondral regenerative medicine. The results demonstrate that PDLLA/VACNT-O:nHAp nanocomposite supports chondrocytes adhesion and decreases type I Collagen mRNA expression. Therefore, these findings suggest the possibility of novel nanobiomaterial as a scaffold for osteochondral tissue engineering applications.