What Are Culturally Relevant Activities of Daily Living in the Asian-Indian Population? A Survey of 402 Patients With Knee Pain.

BACKGROUND: Patient-reported outcome measures are essential tools in assessing clinical outcomes. Although several patient-reported outcome measures such as the Oxford Knee Score and Knee Injury and Osteoarthritis Outcome Score have been developed and validated, their applicability in the Asian-Indian population may be limited; key cultural differences including varying functional demands, ethnicity-specific necessities, and social expectations represent a unique collection of needs. Such differences include preferences toward ground-level activities and those favoring the manual completion of tasks. QUESTIONS/PURPOSES: (1) Which activities of daily living (ADLs) do patients in an Asian-Indian population consider the most important? (2) How do the categories of ADLs (personal care, household, work, travel, and recreation) vary among patients of different gender (men and women) and age (< 60 and > 60 years) groups? METHODS: A cross-sectional study was conducted in October 2019 at a hospital in Mumbai, India. We developed a questionnaire with five domains for physical activity (personal care, household, work, travel, and recreation) formulated from a review and modification of existing categories identified by the WHO and the American Heart Association. Forty key ADLs were identified according to input obtained from detailed interviews of healthcare providers involved in the care of patients with orthopaedic illness, based on established domains. Respondents were instructed to identify the ADLs that were the most relevant to their lifestyle and culture. Responses from 402 patients (mean age 60 ± 12 years; 51% [206 of 402] were women) were analyzed to identify the most commonly selected ADLs. Responses were further evaluated to understand the impact of gender and age on these preferences by comparing men and women, as well as younger (age < 60 years) and older (age > 60 years) patients. RESULTS: The three most frequently reported ADLs in each domain, representing the ADLs that were the most important to the Asian-Indian population, were standing without assistance (82% [331 of 402]), getting up with support (81% [324 of 402]), and toilet use (74% [298 of 402]) in the personal activity category; climbing stairs (80% [322 of 402]), sitting cross-legged (80% [320 of 402]), and praying (79% [319 of 402]) in the household activity category; going to the market (72% [291 of 402]), long-distance walking (62% [250 of 402]), and carrying a shopping bag (60% [242 of 402]) in the work activity category; walking on an uneven surface (66% [266 of 402]), using a taxi (61% [247 of 402]), and traveling by train (59% [239 of 402]) in the travel activity category; and yoga (67% [269 of 402]), playing with children (66% [264 of 402]), and indoor games (63% [252 of 402]) in the recreational activity category. The order of importance of ADL domains was identical in the men versus women groups as well as in the younger age versus older age groups; ADL domains with the highest number of selected ADLs in order of decreasing importance were household care, personal care, work, travel, and recreation when analyzed by individual gender and age groups. Women were more likely than men to report the following ADLs as being important: climbing stairs (84% [172 of 206] of women and 77% [150 of 196] of men), getting up without support (83% [171 of 206] of women and 78% [153 of 196] of men), going to the market (74% [152 of 206] of women and 71% [139 of 196] of men), walking on uneven surfaces (67% [139 of 206] of women and 65% [127 of 196] of men), and playing with children (72% [148 of 206] of women and 59% [116 of 196] of men). CONCLUSION: The findings of this study aim to help providers engage in personalized and socioculturally relevant discussions about knee arthritis. Highlighted areas of importance may facilitate a more comprehensive preoperative discussion of total joint arthroplasty expectations in the context of the needs and demands of Asian-Indian patients. The findings of this study could establish the groundwork for the development of ethnicity-specific patient-reported outcome measures by incorporating the identified ADLs in novel metrics with validation of face and content validity.Level of Evidence Level III, prognostic study.

Efficacy of Periarticular Local Infiltrative Analgesic Injection on Postoperative Pain Control and Functional Outcome in Sequential Bilateral Total Knee Replacement: A Prospective Controlled Trial in 120 Consecutive Patients.

Background: One of the drawbacks of total knee replacements (TKR) is the early postoperative pain, which affects patient satisfaction and increases the duration of rehabilitation. The present study analyzes the potency of local infiltrative analgesia and its effect on rehabilitation in bilateral sequential TKRs. Materials and Methods: The present prospective observational study was conducted on 120 patients undergoing bilateral sequential TKR performed by a single surgeon using an anterior midline incision with a standard medial parapatellar approach. At the end of the surgery, a periarticular cocktail injection was administered to one knee, whereas the other knee served as the control. Postoperatively, patients were assessed for the pain level in each knee based on the visual analog scale (VAS) score and improvement in the range of motion (ROM). Intergroup and intragroup analyses were performed using the unpaired t test and analysis of variance, respectively. A p value of < 0.05 was considered significant. Results: Of the 120 patients, 58% were women and 42% were men with a mean age of 62.14 ± 8.58 years. The postoperative mean VAS score was significantly lower in the test knee group than in the control knee group (p < 0.05). The postoperative mean ROM was more in the test group as compared to the control group on days 3 and 7 (p < 0.05), whereas it was comparable on day 14 (p > 0.05). Conclusion: Periarticular injection of a drug combination in patients managed with bilateral TKRs that are done simultaneously reduces the early postoperative pain and improves rehabilitation during the first week after surgery.

Opposing roles for sMAdCAM and IL-15 in COVID-19 associated cellular immune pathology.

Immune cell dysregulation and lymphopenia characterize COVID-19 pathology in moderate to severe disease. While underlying inflammatory factors have been extensively studied, homeostatic and mucosal migratory signatures remain largely unexplored as causative factors. In this study, we evaluated the association of circulating IL-6, soluble mucosal addressin cell adhesion molecule (sMAdCAM), and IL-15 with cellular dysfunction characterizing mild and hypoxemic stages of COVID-19. A cohort of SARS-CoV-2 infected individuals (n = 130) at various stages of disease progression together with healthy controls (n = 16) were recruited from COVID Care Centres (CCCs) across Mumbai, India. Multiparametric flow cytometry was used to perform in-depth immune subset characterization and to measure plasma IL-6 levels. sMAdCAM, IL-15 levels were quantified using ELISA. Distinct depletion profiles, with relative sparing of CD8 effector memory and CD4+ regulatory T cells, were observed in hypoxemic disease within the lymphocyte compartment. An apparent increase in the frequency of intermediate monocytes characterized both mild as well as hypoxemic disease. IL-6 levels inversely correlated with those of sMAdCAM and both markers showed converse associations with observed lympho-depletion suggesting opposing roles in pathogenesis. Interestingly, IL-15, a key cytokine involved in lymphocyte activation and homeostasis, was detected in symptomatic individuals but not in healthy controls or asymptomatic cases. Further, plasma IL-15 levels negatively correlated with T, B, and NK count suggesting a compensatory production of this cytokine in response to the profound lymphopenia. Finally, higher levels of plasma IL-15 and IL-6, but not sMAdCAM, were associated with a longer duration of hospitalization.

Varus Knee Deformity Classification Based on Degree and Extra- or Intra-Articular Location of Coronal Deformity and Osteoarthritis Grade.

BACKGROUND: Medial coronal plane malalignment, also known as varus alignment, is commonly reported in osteoarthritic knees. Although the degree of deformity provides some insight regarding the severity of the disease, it does not always reflect the potential complexity of the surgical treatment. METHODS: This prospective observational study was conducted by analyzing the radiographs of 100 consecutive knees in patients undergoing total knee arthroplasty. For each knee, coronal alignment, expressed as the hip-knee-ankle angle, was measured on a full-leg standing radiograph and classified in 3 stages. The primary location of the varus deformity was identified as intra-articular and/or extra-articular. Additionally, knees were evaluated to assess for 10 radiographic features of varus deformity and then classified in 3 grades of osteoarthritis severity. RESULTS: The mean (and standard deviation) preoperative varus deformity was 11° ± 6° of varus (hip-knee-ankle, 169°), as measured on standardized full-leg radiographs. Extra-articular varus deformity was observed in 14% of patients. A higher number of radiographic features of varus severity corresponded with higher degrees of deformity. Varus grade correlated strongly with stage of varus deformity. Twenty-three (100%) of 23 stage-III deformities had grade-C features; however, 13 (48%) of 27 stage-I patients also had grade-C disease. CONCLUSIONS: One of every 7 osteoarthritis patients with varus deformity had an extra-articular deformity, and 1 of 2 of these patients had severe intra-articular disease (grade C) despite limited coronal deformity (stage I). These findings reconfirm the need for individual deformity analysis that accounts for the degree, location, and severity of the varus deformity. This insight may help to formulate an algorithmic treatment approach specific to the epiphyseal knee anatomy of the patient and according to the surgical preferences of the surgeon. CLINICAL RELEVANCE: Knee surgeons tend to consider knees with higher degrees of coronal deformity as more technically difficult, but the present study shows that knees with less deformity can still present with severe grades of osteoarthritis inside the knee, leading to more challenging joint reconstruction.

The feasibility of direct adductor canal block (DACB) as a part of periarticular injection in total knee arthroplasty.

BACKGROUND: Adductor canal block (ACB) is one of the preferred methods of analgesia in total knee arthroplasty (TKA). However, conventionally its use is time-consuming, requires ultrasound guidance, a trained anaesthesia team and adherence to strict asepsis by members of the allied teams. This study was done to assess the feasibility and safety of direct adductor canal block (DACB) as a part of surgeon-administered periarticular infiltration. MATERIALS AND METHODS: Thirty computed tomography (CT) angiography films of the patients were retrospectively reviewed. The trajectory of the needle placement for a DACB in relation to the target region of the adductor block was determined. Fourteen knees in seven cadavers, were dissected through a medial parapatellar approach to perform TKA. After administering the DACB using the technique based on CT data, dissection was carried out to ascertain the correct placement of the dye by visualising the stained areas. RESULTS: The angle of approach in the coronal plane from the entry point to the medial high point and to the adductor hiatus was 10.2° (8-14°) and 6° (3.8-11°), respectively. The angle of approach in the sagittal plane from the entry point to the medial high point and to the adductor hiatus was 7° (5-10.5°) and 29° (19-43°), respectively. In all the 14 cadaveric knees, we confirmed the correct placement of the methylene blue dye as demonstrated by the staining of the adductor canal. CONCLUSION: The study demonstrates the feasibility of the DACB. This surgeon-driven technique is likely to reduce the cost of the procedure, reduce operating room time and also eliminate the risks of surgical-site contamination.

Anthropometry of Nonarthritic Asian Knees: Is It Time for a Race-Specific Knee Implant?

BACKGROUND: This study was done to study the anthropometry of nonarthritic Asian knees; to determine the differences in morphology between knees of different ethnicities and to compare the knee anthropometry values with sizes of available knee implants. METHODS: Magnetic resonance imaging scans of 100 nonarthritic Indian knees were analyzed. Anteroposterior (AP) length, mediolateral (ML) length, and aspect ratio of the distal femur and proximal tibia, patellar length, and patellar tendon length were measured. These values were compared with values of other ethnicities from literature. The values were also compared with sizes of available knee implants and evaluated for mismatch. RESULTS: All the parameters of female knees were significantly smaller than those of male knees (p < 0.05). The distal femur of Indian knees resembled that of Chinese knees with similar AP and ML lengths and aspect ratio. The distal femur of Indian knees had a significantly smaller AP, ML, and aspect ratio than those of Hispanic knees did. In comparison to Caucasian distal femur, Indian knees had smaller AP and ML lengths and larger aspect ratio. In terms of the proximal tibia, the Indian knees were smaller than Chinese (only ML), Caucasian (AP and ML) and Hispanic (AP and ML) knees. On comparison with implant sizes, there was a mismatch between the distal femur morphology and the dimensions of all implants. For a given AP length, the ML dimensions of all implants were smaller than the measured ML length of the knee. However, the tibial components of all the studied implants correlated well with the tibial morphology. CONCLUSIONS: Distinct anthropometric differences exist between knees of different ethnicities. The knees of females were smaller than the knees of males. In Indian knees, the ML-AP aspect ratio of the distal femur was higher than that of the currently available femoral components. These results suggest the need for race-specific knee implants.

Novel, non-nitrocatechol catechol-O-methyltransferase inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility.

RATIONALE: Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. OBJECTIVES: To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel compounds in a set of preclinical in vivo efficacy assays in rats to determine their ability to inhibit COMT function and viability as potential clinical candidates. METHODS: We measured the change in concentration of dopamine (DA) metabolites in cerebrospinal fluid (CSF) from the cisterna magna and extracellular fluid (ECF) from the frontal cortex produced by our novel compounds. Additionally, we tested the effects of our brain-penetrant COMT inhibitors in an attentional set-shifting assay (ASST). We benchmarked the performance of the novel COMT inhibitors to the effects produced by the known COMT inhibitor tolcapone. RESULTS: We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two DA metabolites, in CSF and the frontal cortex. Additionally, we found that LIBD-1 significantly improved cognitive flexibility in the ASST, an effect previously reported following tolcapone administration. CONCLUSIONS: These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment.

The effects in rats of lisdexamfetamine in combination with olanzapine on mesocorticolimbic dopamine efflux, striatal dopamine D2 receptor occupancy and stimulus generalization to a D-amphetamine cue.

The etiology of schizophrenia is poorly understood and two principle hypotheses have dominated the field. Firstly, that subcortical dopamine function is enhanced while cortical dopamine function is reduced and secondly, that cortical glutamate systems are dysfunctional. It is also widely accepted that currently used antipsychotics have essentially no impact on cognitive deficits and persistent negative symptoms in schizophrenia. Reduced dopamine transmission via dopamine D1 receptors in the prefrontal cortex has been hypothesized to be involved in the aetiology of these symptom domains and enhancing cortical dopamine transmission within an optimal window has been suggested to be potentially beneficial. In these pre-clinical studies we have determined that combined administration of the d-amphetamine pro-drug, lisdexamfetamine and the atypical antipsychotic olanzapine increased dopamine efflux in the rat prefrontal cortex and nucleus accumbens to an extent greater than either drug given separately without affecting olanzapine's ability to block striatal dopamine D2 receptors which is important for its antipsychotic activity. Furthermore, in an established rodent model used to compare the subjective effects of novel compounds the ability of lisdexamfetamine to generalize to a d-amphetamine cue was dose-dependently attenuated when co-administered with olanzapine suggesting that lisdexamfetamine may produce less marked subjective effects when administered adjunctively with olanzapine.

A sustained release formulation of novel quininib-hyaluronan microneedles inhibits angiogenesis and retinal vascular permeability in vivo.

Pathologic neovascularisation and ocular permeability are hallmarks of proliferative diabetic retinopathy and age-related macular degeneration. Current pharmacologic interventions targeting VEGF are effective in only 30-60% of patients and require multiple intraocular injections associated with iatrogenic infection. Thus, our goal is to develop novel small molecule drugs that are VEGF-independent are amenable to sustained ocular-release, and which reduce retinal angiogenesis and retinal vascular permeability. Here, the anti-angiogenic drug quininib was formulated into hyaluronan (HA) microneedles whose safety and efficacy was evaluated in vivo. Quininib-HA microneedles were formulated via desolvation from quininib-HA solution and subsequent cross-linking with 4-arm-PEG-amine prior to freeze-drying. Scanning electron microscopy revealed hollow needle-shaped particle ultrastructure, with a zeta potential of -35.5mV determined by electrophoretic light scattering. The incorporation efficiency and pharmacokinetic profile of quininib released in vitro from the microneedles was quantified by HPLC. Quininib incorporation into these microneedles was 90%. In vitro, 20% quininib was released over 4months; or in the presence of increasing concentrations of hyaluronidase, 60% incorporated quininib was released over 4months. Zebrafish hyaloid vasculature assays demonstrated quininib released from these microneedles significantly (p<0.0001) inhibited ocular developmental angiogenesis compared to control. Sustained amelioration of retinal vascular permeability (RVP) was demonstrated using a bespoke cysteinyl leukotriene induced rodent model. Quininib-HA microparticles significantly inhibited RVP in Brown Norway rats one month after administration compared to neat quininib control (p=0.0071). In summary, quininib-HA microneedles allow for sustained release of quininib; are safe in vivo and quininib released from these microneedles effectively inhibits angiogenesis and RVP in vivo.

DNA Polymorphisms in Lentinula edodes, the Shiitake Mushroom.

DNA restriction fragment length polymorphisms (RFLPs) were examined in Lentinula edodes strains. Genomic DNA from strain 70 was cloned in plasmid vector pUC19, and 18 random clones containing low-copy DNA sequences were used to probe seven strains in Southern DNA-DNA hybridizations. Each cloned fragment revealed DNA polymorphism. An RFLP genotype was determined for each strain and the genetic relatedness was assessed. The coefficients of genetic similarity among the seven strains ranged from 0.43 to 0.90. The inheritance of RFLP markers was examined in single spore isolates. Homokaryons displayed a loss of polymorphic bands compared with the parent dikaryon. Hybrids constructed by crossing compatible homokaryons displayed the inheritance of RFLP markers from each parent homokaryon.

Differences in the neurochemical and behavioural profiles of lisdexamfetamine methylphenidate and modafinil revealed by simultaneous dual-probe microdialysis and locomotor activity measurements in freely-moving rats.

Lisdexamfetamine dimesylate is a novel prodrug approved in North America, Europe and Brazil for treating attention deficit hyperactivity disorder (ADHD). It undergoes rate-limited hydrolysis by red blood cells to yield d-amphetamine. Following our previous work comparing lisdexamfetamine with d-amphetamine, the neurochemical and behavioural profiles of lisdexamfetamine, methylphenidate and modafinil were compared by dual-probe microdialysis in the prefrontal cortex (PFC) and striatum of conscious rats with simultaneous locomotor activity measurement. We employed pharmacologically equivalent doses of all compounds and those that spanned the therapeutically relevant and psychostimulant range. Lisdexamfetamine (0.5, 1.5, 4.5 mg/kg d-amphetamine base, per os (po)), methylphenidate (3, 10, 30 mg/kg base, po) and modafinil (100, 300, 600 mg/kg base, po) increased efflux of dopamine and noradrenaline in PFC, and dopamine in striatum. Only lisdexamfetamine increased 5-hydroxytryptamine (5-HT) efflux in PFC and striatum. Lisdexamfetamine had larger and more sustained effects on catecholaminergic neurotransmission than methylphenidate or modafinil. Linear correlations were observed between striatal dopamine efflux and locomotor activity for lisdexamfetamine and methylphenidate, but not modafinil. Regression slopes revealed greater increases in extracellular dopamine could be elicited without producing locomotor activation by lisdexamfetamine than methylphenidate. These results are consistent with clinical findings showing that lisdexamfetamine is an effective ADHD medication with prolonged duration of action and good separation between its therapeutic actions and stimulant side-effects.