Shear stress and microRNAs for better metastatic cancer management.

Metastasis is the process by which cancer cells move from the primary location to establish themselves in a new location in the human body. It is still a significant challenge in cancer management because it is responsible for 90% of cancer-related deaths. In this work, we present an idea to use shear stress encountered by all metastasizing cells as an elegant means to deactivate metastasizing cancer cells. Shear-induced ROS and cross-talk between ROS and miRNA play crucial roles in deactivating metastasizing cancer cells. In addition, there exists a vast therapeutic potential for miRNAs. Therefore, this study explores the effect of shear on miRNAs and reactive oxygen species (ROS), the two molecular mediators in the proposed {shear-stress}-{miRNA}-{metastasizing-cancer-cell-deactivation} approach. In this context, to understand the effect of defined shear on HCT116 colon cancer cells, they were cultivated in a defined shear environment provided by an appropriately designed and fabricated cone-and-plate device. Shear rate affected the culture growth characteristics and the specific intracellular reactive oxygen species level (si-ROS). HCT116 cell growth was observed at 0 and 0.63 s-1 but not at 1.57 s-1 or beyond. Shear rate induced upregulation of the hsa-miR-335-5p but induced downregulation of hsa-miR-34a-5p. Furthermore, the specific levels of hsa-miR-335-5p, hsa-miR-26b-5p, and hsa-miR-34a-5p negatively correlated with specific intracellular (si)-hydroxyl radical levels. In addition, some messenger RNAs (mRNAs) in HCT116 cells showed a differential expression under shear stress, notably the ROS-associated mRNA of PMAIP1. The above miRNAs (and possibly some mRNAs) could be targeted to manage colon cancer metastasis.

Use of POSSUM (Physiologic and Operative Severity Score for the Study of Mortality and Morbidity) and Portsmouth-POSSUM for Surgical Assessment in Patients Undergoing Emergency Abdominal Surgeries.

INTRODUCTION: The POSSUM (Physiologic and Operative Severity Score for the Study of Mortality and Morbidity) and Portsmouth-POSSUM (P-POSSUM) models have been popularly recommended as appropriate for predicting postoperative mortality and morbidity in surgical practice. This study aims to evaluate the efficacy and accuracy of both scoring systems for surgical risk assessment in predicting postoperative mortality and morbidity in patients undergoing emergency abdominal surgeries. METHODOLOGY: The study was conducted as a part of a post-doctoral fellowship program. A total of 150 patients, undergoing emergency abdominal surgery in a tertiary care hospital in Bhubaneswar, were evaluated using POSSUM and P-POSSUM. Physiological scoring was done prior to surgery and operative scoring was performed intra-operatively. Patients were followed up for 30 days after the operative period. The observed mortality rate was then compared with POSSUM and P-POSSUM predicted mortality rates. RESULTS: POSSUM predicted a morbidity rate of 116, whereas the actual morbidity rate was 92 (p < 0.05). P-POSSUM predicted a morbidity rate of 109, whereas the actual morbidity rate was 92 (p < 0.05). POSSUM predicted a mortality rate of 23, whereas the actual mortality rate was 21 (p < 0.05). P-POSSUM predicted a mortality rate of 25, whereas the actual mortality rate was 21 (p < 0.05). CONCLUSIONS: With a reasonably good prediction of morbidity and mortality rate, POSSUM and P-POSSUM scores are both effective scoring systems in clinical practice for use in abdominal surgery.

Multimodal imaging of the aging brain: Baseline findings of the LoCARPoN study.

We quantified and investigated multimodal brain MRI measures in the LoCARPoN Study due to lack of normative data among Indians. A total of 401 participants (aged 50-88 years) without stroke or dementia completed MRI investigation. We assessed 31 brain measures in total using four brain MRI modalities, including macrostructural (global & lobar volumes, white matter hyperintensities [WMHs]), microstructural (global and tract-specific white matter fractional anisotropy [WM-FA] and mean diffusivity [MD]) and perfusion measures (global and lobar cerebral blood flow [CBF]). The absolute brain volumes of males were significantly larger than those of females, but such differences were relatively small (<1.2% of intracranial volume). With increasing age, lower macrostructural brain volumes, lower WM-FA, greater WMHs, higher WM-MD were found (P = 0.00018, Bonferroni threshold). Perfusion measures did not show significant differences with increasing age. Hippocampal volume showed the greatest association with age, with a reduction of approximately 0.48%/year. This preliminary study augments and provides insight into multimodal brain measures during the nascent stages of aging among the Indian population (South Asian ethnicity). Our findings establish the groundwork for future hypothetical testing studies.

A Novel Plating System for First Metatarsophalangeal Joint Arthrodesis: A Retrospective Comparison of Hybrid and Traditional Locking Plate Constructs.

BACKGROUND: Dorsal plate fixation is commonly used for first metatarsophalangeal joint (1st MTPJ) arthrodesis and plate design continues to evolve. A new staple compression plate (SCP) design attempts to utilize the continuous compression of a nitinol staple across the fusion site while simultaneously providing the stability of a dorsal locked plate. Herein, we compare the radiographic, clinical, and patient-reported outcomes of 1st MTPJ joint arthrodesis using 2 dorsal locking plate constructs including a novel SCP construct. METHODS: Forty-four patients who underwent 1st MTPJ arthrodesis between 2016 and 2020 were retrospectively evaluated. There were 2 group cohorts. Group 1 cohort included 23 patients who received a CrossRoads Extremity SCP, and Group 2 cohort included 21 patients who received a Stryker dorsal locking precontoured titanium plate (LPP). All patients were evaluated with radiographs, Patient-Reported Outcomes Measures Information System (PROMIS) outcome scores, and Foot Function Index (FFI). RESULTS: The complication and union rates did not vary between groups with a fusion rate of 95.7% in the SCP group and 90.5 % in the LPP group. Similarly, we found no significant differences in PROMIS or FFI scores between the SCP and LPP plates. CONCLUSION: Use of either dorsal locking plate construct for 1st MTPJ arthrodesis was associated with high union rates and comparable functional outcomes. As locked plate technology continues to evolve for 1st MTPJ arthrodesis, it is important that clinical outcomes are reported. LEVELS OF EVIDENCE: Level IV.

Efficacy and Cost-Effectiveness of Laparoscopic Transversus Abdominis Plane (TAP) Block in Laparoscopic Cholecystectomy: A Comparison With the Non-TAP Group.

BACKGROUND: Postoperative pain caused by laparoscopic cholecystectomy can be controlled by different methods. The study aimed to observe the efficacy of laparoscopic transversus abdominis plane (TAP) block in laparoscopic cholecystectomy and to analyze the cost-effectiveness of the procedure in comparison to the non-TAP method. METHODS:  In this double-blinded randomized clinical trial, the subjects who had come for cholecystectomy were randomly divided into two groups (n = 43 in each group). Group A received laparoscopy-guided subcostal TAP block bilaterally (0.25% bupivacaine, 20 ml each) along with parenteral analgesics (100 mg tramadol injection in 100 ml normal saline IV) SOS as rescue analgesia, and group B received parenteral analgesics (injection paracetamol 1 gm IV) eight hourly and injection tramadol 100 mg in 100 ml normal saline IV SOS as rescue analgesia. RESULT:  A bulge was visualized by the surgeon through a laparoscope as a signature view for confirming the placement of local anesthetic in TAP. Based on the Visual Analog Scale (VAS) for assessment of postoperative pain and the Numeric Rating Scale (NRS) for assessment of pain at 30 minutes, four hours, eight hours, 12 hours, and 24 hours postoperatively, patients of both groups were assessed. According to the VAS, the pain assessment was better in the TAP block group at 30 minutes post-surgery than in the non-TAP group. As a primary outcome, 37% of TAP block group cases were recovered without any rescue analgesia. VAS score revealed a significant difference in postoperative nausea and vomiting (PONV) among the TAP block and non-TAP groups. PONV at four hours, eight hours, and 12 hours showed significantly lesser incidences in the TAP group as compared to the non-TAP group (p-value: 0.015, 0.028, and 0.055, respectively). CONCLUSION:  The cost-effectiveness of the TAP block method is 20 times lesser than the non-TAP method. Thus, a laparoscopic-guided TAP block could offer better postoperative analgesia at a low cost with a similar advantage to a USG-guided TAP block.

Carotid intima-media thickness and risk of mild cognitive impairment: A systematic review and meta-analysis.

Mild cognitive impairment (MCI) is an early phase of cognitive decline signalling the beginning of severe neurological diseases. Carotid intima-media thickness (cIMT) has shown some correlation with MCI development. This study was conducted to investigate the impact of elevated cIMT on the risk of MCI in adults. A literature search was conducted in PubMed, EMBASE, Cochrane Library, Scopus, Google Scholar and CINAHL databases till 30 July 2021, with keywords: ('Carotid Intima-Media Thickness' OR 'cIMT' OR 'IMT' AND 'Cognitive Impairment' OR 'Cognition' OR 'Cognitive Decline' AND 'Mild Cognitive Impairment' OR 'MCI'). Pooled standardized mean difference (SMD)/odds ratio (OR) and 95% confidence interval (CI) were determined for factor-disease association using either fixed (when I2 <50%) or random effect (when I2 >50%) models. Eight studies involving 1,585 MCI cases and 6,700 normal subjects were included in our meta-analysis which showed no significant association of increased cIMT with the risk of MCI [SMD 1.17, 95% CI -0.09 to 2.42]. However, sensitivity analysis revealed an outlier study significantly affecting the effect size. On omitting the outlier study, the re-evaluated meta-analysis revealed a significant association of cIMT with the risk of MCI [SMD 0.52, 95% CI 0.26 to 0.78]. This significant association was also observed during subgroup analysis in Caucasian population [SMD 0.65, 95% CI 0.13 to 1.18] but not in Asian population [SMD 0.39, 95% CI -0.01 to 0.79]. Elevated cIMT poses a potential risk for MCI. However, more population-based studies are required to corroborate these findings.

Epigenetics Mechanisms in Ischemic Stroke: A Promising Avenue?

Stroke has emerged as the second most common cause of mortality worldwide and is a major public health problem. It is a multi-factorial disease and genetics plays an important role in its pathophysiology, however, mechanisms of genome involvement in the disease remain unclear. Both genetic and epigenetic mechanisms could play a role in the development of stroke disease. Although epigenetic characteristics may also be heritable, they can be modified during the lifetime under different environmental exposure in response to lifestyle. Recent studies provide clear evidence that epigenetic factors play an important role in the pathological mechanisms leading to an elevated risk of cardiovascular diseases and stroke. Epigenetic changes are reversible therefore; studying epigenetic factors may serve as a marker for disease progression, biomarker for disease diagnosis, and development of novel targets for therapeutic intervention. Identifying the factors which predispose the risk of stroke provides information for the mechanism of stroke and the design of new drug targets where epigenetic modifications play a significant role. Epigenetic modifications play an essential role in a large variety of multifactorial diseases. This review will focus on the evidence that epigenetic mechanisms play a crucial role in the pathophysiology of ischemic stroke.

Cystatin C and Risk of Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

INTRODUCTION: Cystatin C (Cys C) has been found as a novel biomarker of neurodegenerative diseases, such as dementia and Alzheimer's disease. Published studies on the role of Cys C as a biomarker of mild cognitive impairment (MCI) have not been reviewed systematically. OBJECTIVE: Present meta-analysis was performed to elucidate the association between Cys C and risk of MCI. METHODS: A comprehensive search was performed in PubMed, EMBASE, Cochrane Library, Trip databases, Worldwide Science, and Google Scholar from January 1, 1950, to April 30, 2020. Standardized mean difference (SMD) with 95% confidence interval (CI) using fixed or random effect models were used to calculate summary estimates. Quality of evidence was also assessed using the Diagnostic Accuracy Quality Scale (DAQS) and grading quality of evidence and strength of recommendations approach. RESULTS: In our meta-analysis, 12 studies with a total of 2,433 MCI patients and 1,034 controls were included. Our findings suggest a strong association between increased levels of Cys C and risk of MCI as compared to control subjects (SMD = 2.39, 95% CI = 0.22-4.57). Subgroup analysis based on ethnicity, a significant association for the high level of Cys C with the risk of MCI was observed in the Asian population (SMD = 1.63, 95% CI = 0.44-2.82) but not in the Caucasian population (SMD = 2.80, 95% CI = [-0.66]-6.26). CONCLUSION: Cys C was associated with MCI, and it could be considered as a predictor for the risk of cognitive impairment.

CIMT as a risk factor for stroke subtype: A systematic review.

INTRODUCTION: An increase in the common carotid artery intima-media thickness (CCA-IMT) is generally considered an early marker of atherosclerosis and is a well-established predictor of cardiovascular disease (CVD). An association between changes in CCA-IMT and risk of stroke has been reported but has conflicting findings. OBJECTIVE: The present meta-analysis was aimed to clarify the association between CCA-IMT with the risk of stroke and its subtype by estimating pooled analysis of published literature. METHODS: Comprehensive search for all published articles was performed in electronic databases including PubMed, Embase, Cochrane Library, Trip Databases, Worldwide Science, CINAHL and Google Scholar from 01 January 1950 to 30 April 2020. RESULTS: In our meta-analysis, a total of 19 studies, of which sixteen studies involving 3475 ischaemic stroke (IS) cases and 11 826 controls; six studies with 902 large vessel disease (LVD) and 548 small vessel disease (SVD) of IS subtypes; five studies with 228 intracerebral haemorrhage (ICH) and 1032 IS cases, were included. Our findings suggest a strong association between increased CCA-IMT with risk of IS as compared to control subjects [SMD = 1.46, 95% CI = 0.90-2.02]. However, there is an increased risk of LVD as compared to the SVD subtype of IS [SMD = 0.36, 95% CI = 0.19-0.52] and more chance of occurrence of IS rather than ICH [SMD = 0.71, 95% CI = 0.28-1.41]. CONCLUSIONS: Carotid intima thickness measurements are found to be associated with the risk of stroke along with its subtypes and may be used as a diagnostic marker for predicting the risk of stroke events.

Mobile phone use and risk of brain tumours: a systematic review of association between study quality, source of funding, and research outcomes.

Mobile phones emit electromagnetic radiations that are classified as possibly carcinogenic to humans. Evidence for increased risk for brain tumours accumulated in parallel by epidemiologic investigations remains controversial. This paper aims to investigate whether methodological quality of studies and source of funding can explain the variation in results. PubMed and Cochrane CENTRAL searches were conducted from 1966 to December 2016, which was supplemented with relevant articles identified in the references. Twenty-two case control studies were included for systematic review. Meta-analysis of 14 case-control studies showed practically no increase in risk of brain tumour [OR 1.03 (95% CI 0.92-1.14)]. However, for mobile phone use of 10 years or longer (or >1640 h), the overall result of the meta-analysis showed a significant 1.33 times increase in risk. The summary estimate of government funded as well as phone industry funded studies showed 1.07 times increase in odds which was not significant, while mixed funded studies did not show any increase in risk of brain tumour. Metaregression analysis indicated that the association was significantly associated with methodological study quality (p < 0.019, 95% CI 0.009-0.09). Relationship between source of funding and log OR for each study was not statistically significant (p < 0.32, 95% CI 0.036-0.010). We found evidence linking mobile phone use and risk of brain tumours especially in long-term users (≥10 years). Studies with higher quality showed a trend towards high risk of brain tumour, while lower quality showed a trend towards lower risk/protection.

Prediction of Upper Limb Motor Recovery after Subacute Ischemic Stroke Using Diffusion Tensor Imaging: A Systematic Review and Meta-Analysis.

Early evaluation of the pyramidal tract using Diffusion Tensor Imaging (DTI) is a prerequisite to decide the optimal treatment or to assess appropriate rehabilitation. The early predictive value of DTI for assessing motor and functional recovery in ischemic stroke (IS) has yielded contradictory results. The purpose is to systematically review and summarize the current available literature on the value of Fractional Anisotropy (FA) parameter of the DTI in predicting upper limb motor recovery after sub-acute IS. MEDLINE, PubMed, EMBASE, Google Scholar and Cochrane CENTRAL searches were conducted from January 1, 1950, to July 31, 2015, which was supplemented with relevant articles identified in the references. Correlation between FA and upper limb motor recovery measure was done. Heterogeneity was examined using Higgins I-squared, Tau-squared. Summary of correlation coefficient was determined using Random Effects model. Out of 166 citations, only eleven studies met the criteria for inclusion in the systematic review and six studies were included in the meta-analysis. A random effects model revealed that DTI parameter FA is a significant predictor for upper limb motor recovery after sub-acute IS [Correlation Coefficient=0.82; 95% Confidence Interval-0.66 to 0.90, P value<0.001]. Moderate heterogeneity was observed (Tau-squared=0.12, I-squared=62.14). The studies reported so far on correlation between DTI and upper limb motor recovery are few with small sample sizes. This meta-analysis suggests strong correlation between DTI parameter FA and upper limb motor recovery. Well-designed prospective trials embedded with larger sample size are required to establish these findings.

Low socioeconomic status is an independent risk factor for ischemic stroke: a case-control study in North Indian population.

BACKGROUND: Stroke is a multifactorial disease and is influenced by complex environmental interactions. The contribution of various risk factors to the burden of stroke worldwide is not well known, particularly in developing countries. The present case-control study is aimed at exploring the association between a low socioeconomic status and the risk of ischemic stroke among the North Indian population. METHODS: The study design was a hospital-based, case-control study. Age- and sex-matched controls were included. The demographic characteristics and risk factor variables were documented by means of a personal interview through a standardized case record form. The household asset index for determining the socioeconomic status (HAISS) was used for the assessment of the socioeconomic status of the population. HAISS was validated with the widely used Kuppuswamy scale for measurement of socioeconomic status. The multivariable logistic regression model was used to estimate the odds ratio associated with stroke. RESULTS: In all, 224 ischemic stroke patients and 224 controls were recruited between February 2009 and February 2012. The mean age of cases and controls was 53.47 ± 14 and 52.92 ± 13.4, respectively. The low economic status was independently associated with the risk of ischemic stroke after adjustment for demographic and risk factor variables (OR 2.8; 95% CI 1.2-6.3). CONCLUSION: Our findings suggest that there is a significant association between a low socioeconomic status and the risk of ischemic stroke risk in North Indian population. Well-designed studies embedded with long-term prospective cohorts are required for confirming the results.

Outcomes of a Stepcut Lengthening Calcaneal Osteotomy for Adult-Acquired Flatfoot Deformity.

BACKGROUND: Lateral column lengthening is used to correct abduction deformity at the midfoot and improve talar head coverage in patients with flatfoot deformity. It was our hypothesis that following a stepcut lengthening calcaneal osteotomy (SLCO), patients would have adequate correction of the deformity, a high union rate of the osteotomy, and improvement in clinical outcome scores. METHODS: We retrospectively reviewed 37 consecutive patients who underwent SLCO for the treatment of stage IIB flatfoot deformity with a minimum 2-year follow-up. Deformity correction was assessed using preoperative and postoperative weight-bearing radiographs. Healing of the osteotomy was assessed by computed tomography. Clinical outcomes included the FAOS and SF-36 questionnaires. The Wilcoxon signed-rank test was used to compare clinical outcome scores. An alpha level of .05 was deemed statistically significant. RESULTS: Healing of the osteotomy occurred at a mean of 7.7 weeks postoperatively. The talonavicular (TN) coverage angle improved from 34.0 to 8.8 (P < .001), the percentage of TN uncoverage improved from 40.9% to 17.7% (P < .001), and the TN incongruency angle improved from 68.1 to 8.7 (P < .001). In addition, there was an improvement in FAOS pain (P < .001), daily activities (P < .001), sport activities (P = .006), and quality of life scores (P < .001). Overall SF-36 scores also showed improvement postoperatively (P < .001). There was no incidence of delayed union, nonunion, or graft collapse. CONCLUSION: Following SLCO, patients demonstrated excellent healing, good correction of the deformity, and improvement in clinical outcomes scores. The SLCO is an alternative to the Evans osteotomy for lateral column lengthening. LEVEL OF EVIDENCE: Level IV, retrospective case review.

Validation of the Foot and Ankle Outcome Score in adult acquired flatfoot deformity.

INTRODUCTION: The American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score has been under recent scrutiny. The Foot and Ankle Outcome Score (FAOS) is an alternative subjective survey, assessing outcomes in 5 subscales. It is validated for lateral ankle instability and hallux valgus patients. The aim of our study was to validate the FAOS for assessing outcomes in flexible adult acquired flatfoot deformity (AAFD). METHODS: Patients from the authors' institution diagnosed with flexible AAFD from 2006 to 2011 were eligible for the study. In all, 126 patients who completed the FAOS and the Short-Form 12 (SF-12) on the same visit were included in the construct validity component. Correlation was deemed moderate if the Spearman's correlation coefficient was .4 to .7. Content validity was assessed in 63 patients by a questionnaire that asked patients to rate the relevance of each FAOS question, with a score of 2 or greater considered acceptable. Reliability was measured using intraclass correlation coefficients (ICCs) in 41 patients who completed a second FAOS survey. In 49 patients, preoperative and postoperative FAOS scores were compared to determine responsiveness. RESULTS: All of the FAOS subscales demonstrated moderate correlation with 2 physical health related SF-12 domains. Mental health related domains showed poor correlation. Content validity was high for the Quality of Life (QoL; mean 2.26) and Sports/Recreation subscales (mean 2.12). All subscales exhibited very good test-retest reliability, with ICCs of .7 and above. Symptoms, QoL, pain, and daily activities (ADLs) were responsive to change in postoperative patients (P < .05). CONCLUSION: This study has validated the FAOS for AAFD with acceptable construct and content validity, reliability, and responsiveness. Given its previous validation for patients with ankle instability and hallux valgus, the additional findings in this study support its use as an alternative to less reliable outcome surveys. LEVEL OF EVIDENCE: Level II, prospective comparative study.

The contribution of medializing calcaneal osteotomy on hindfoot alignment in the reconstruction of the stage II adult acquired flatfoot deformity.

BACKGROUND: Successful correction of hindfoot alignment in adult acquired flatfoot deformity (AAFD) is likely influenced by the degree of medializing calcaneal osteotomy (MCO) performed, but it is not known if other reconstruction procedures significantly contribute as well. The purpose of this study was to evaluate the correlation between common preoperative and postoperative variables and hindfoot alignment. METHODS: Thirty patients with stage II AAFD undergoing flatfoot reconstruction were followed prospectively. Preoperative and postoperative radiographs were reviewed to assess for correction in hindfoot alignment as measured by the change in hindfoot moment arm. Nineteen variables were analyzed, including age, gender, height, weight, body mass index (BMI), medial cuneiform-fifth metatarsal height, anteroposterior (AP) talonavicular coverage, AP talus-first metatarsal, lateral talus-first metatarsal and calcaneal pitch angles as well as intraoperative use of the MCO, lateral column lengthening (LCL), Cotton osteotomy, first tarsometatarsal fusion, flexor digitorum longus transfer, spring ligament reconstruction, and gastrocnemius recession or Achilles lengthening. Mean age was 57.3 years (range, 22-77). Final radiographs were obtained at a mean of 47 weeks (range, 25-78) postoperatively. RESULTS: Seven variables were found to significantly affect hindfoot moment arm. These were gender (P < .05), the amount of MCO performed (P < .001), LCL (P < .01), first tarsometatarsal fusion (P < .01), spring ligament reconstruction (P < .01), medial cuneiform-fifth metatarsal height (P < .001), and calcaneal pitch angle (P < .05). Multivariate regression analysis revealed that MCO was the only significant predictor of hindfoot moment arm. The final regression model for MCO showed a good fit (R(2) = .93, P < .001). CONCLUSION: Correction of hindfoot valgus alignment obtained in flatfoot reconstruction is primarily determined by the MCO procedure and can be modeled linearly. We believe that the hindfoot alignment view can serve as a valuable preoperative measurement to help surgeons adjust the proper amount of correction intraoperatively. LEVEL OF EVIDENCE: Level IV, prospective case series.