Offloading of Diabetic Neuropathic Plantar Ulcers: Secondary Analysis of Step Activity and Ulcer Healing.

OBJECTIVE: Although it is well-known that offloading devices facilitate healing in people with diabetes and neuropathic plantar ulcers, little is known about how step activity affects healing. The purposes of this study were to compare: (1) healing outcomes (time to healing, percentage of ulcers healed); (2) healing rates by ulcer location; and (3) step activity (daily step count, daily peak mean cadence) among patients using either total contact casts (TCCs) or removable cast walker boots (RCWs). METHODS: The study included 55 participants (TCC, 29; RCW, 26) with diabetes mellitus, peripheral neuropathy, and a Wagner grade 1 or 2 neuropathic plantar ulcer. Each participant wore an activity monitor for 14 consecutive days. Step activity and healing variables were assessed using independent t tests, Kruskal-Wallis, Kaplan-Meier, and Mantel-Cox log-rank tests. RESULTS: Mean participant age was 55 (SD, 11) years. The percentage of ulcers healed was lower in the RCW group versus the TCC group (65% vs 93%). If healed, average healing rate was 77 (SD, 48) days in the TCC group and 138 (SD, 143) days in the RCW group. Survival distribution by ulcer location was different for RCW forefoot than other locations (132 ± 13 days vs 91 ± 15, 75 ± 11, and 102 ± 36 days for TCC forefoot, TCC-midfoot/hindfoot, and RCW-midfoot/hindfoot, respectively; χ2 = 10.69, P = .014). Average step count was 2,597 in the RCW group versus 1,813 steps in the TCC group (P = .07). The daily peak mean cadence for 20-, 30-, or 60-minute periods was greater with RCW use. CONCLUSIONS: Step activity in participants with RCWs was increased compared with those with TCCs. Because of their potential to be easily removable, RCWs may impair ulcer healing by allowing greater step activity.

Effects of Mindfulness Training and Exercise on Cognitive Function in Older Adults: A Randomized Clinical Trial.

Importance: Episodic memory and executive function are essential aspects of cognitive functioning that decline with aging. This decline may be ameliorable with lifestyle interventions. Objective: To determine whether mindfulness-based stress reduction (MBSR), exercise, or a combination of both improve cognitive function in older adults. Design, Setting, and Participants: This 2 × 2 factorial randomized clinical trial was conducted at 2 US sites (Washington University in St Louis and University of California, San Diego). A total of 585 older adults (aged 65-84 y) with subjective cognitive concerns, but not dementia, were randomized (enrollment from November 19, 2015, to January 23, 2019; final follow-up on March 16, 2020). Interventions: Participants were randomized to undergo the following interventions: MBSR with a target of 60 minutes daily of meditation (n = 150); exercise with aerobic, strength, and functional components with a target of at least 300 minutes weekly (n = 138); combined MBSR and exercise (n = 144); or a health education control group (n = 153). Interventions lasted 18 months and consisted of group-based classes and home practice. Main Outcomes and Measures: The 2 primary outcomes were composites of episodic memory and executive function (standardized to a mean [SD] of 0 [1]; higher composite scores indicate better cognitive performance) from neuropsychological testing; the primary end point was 6 months and the secondary end point was 18 months. There were 5 reported secondary outcomes: hippocampal volume and dorsolateral prefrontal cortex thickness and surface area from structural magnetic resonance imaging and functional cognitive capacity and self-reported cognitive concerns. Results: Among 585 randomized participants (mean age, 71.5 years; 424 [72.5%] women), 568 (97.1%) completed 6 months in the trial and 475 (81.2%) completed 18 months. At 6 months, there was no significant effect of mindfulness training or exercise on episodic memory (MBSR vs no MBSR: 0.44 vs 0.48; mean difference, -0.04 points [95% CI, -0.15 to 0.07]; P = .50; exercise vs no exercise: 0.49 vs 0.42; difference, 0.07 [95% CI, -0.04 to 0.17]; P = .23) or executive function (MBSR vs no MBSR: 0.39 vs 0.31; mean difference, 0.08 points [95% CI, -0.02 to 0.19]; P = .12; exercise vs no exercise: 0.39 vs 0.32; difference, 0.07 [95% CI, -0.03 to 0.18]; P = .17) and there were no intervention effects at the secondary end point of 18 months. There was no significant interaction between mindfulness training and exercise (P = .93 for memory and P = .29 for executive function) at 6 months. Of the 5 prespecified secondary outcomes, none showed a significant improvement with either intervention compared with those not receiving the intervention. Conclusions and Relevance: Among older adults with subjective cognitive concerns, mindfulness training, exercise, or both did not result in significant differences in improvement in episodic memory or executive function at 6 months. The findings do not support the use of these interventions for improving cognition in older adults with subjective cognitive concerns. Trial Registration: ClinicalTrials.gov Identifier: NCT02665481.

Aerobic or Resistance Exercise, or Both, in Dieting Obese Older Adults.

BACKGROUND: Obesity causes frailty in older adults; however, weight loss might accelerate age-related loss of muscle and bone mass and resultant sarcopenia and osteopenia. METHODS: In this clinical trial involving 160 obese older adults, we evaluated the effectiveness of several exercise modes in reversing frailty and preventing reduction in muscle and bone mass induced by weight loss. Participants were randomly assigned to a weight-management program plus one of three exercise programs - aerobic training, resistance training, or combined aerobic and resistance training - or to a control group (no weight-management or exercise program). The primary outcome was the change in Physical Performance Test score from baseline to 6 months (scores range from 0 to 36 points; higher scores indicate better performance). Secondary outcomes included changes in other frailty measures, body composition, bone mineral density, and physical functions. RESULTS: A total of 141 participants completed the study. The Physical Performance Test score increased more in the combination group than in the aerobic and resistance groups (27.9 to 33.4 points [21% increase] vs. 29.3 to 33.2 points [14% increase] and 28.8 to 32.7 points [14% increase], respectively; P=0.01 and P=0.02 after Bonferroni correction); the scores increased more in all exercise groups than in the control group (P<0.001 for between-group comparisons). Peak oxygen consumption (milliliters per kilogram of body weight per minute) increased more in the combination and aerobic groups (17.2 to 20.3 [17% increase] and 17.6 to 20.9 [18% increase], respectively) than in the resistance group (17.0 to 18.3 [8% increase]) (P<0.001 for both comparisons). Strength increased more in the combination and resistance groups (272 to 320 kg [18% increase] and 288 to 337 kg [19% increase], respectively) than in the aerobic group (265 to 270 kg [4% increase]) (P<0.001 for both comparisons). Body weight decreased by 9% in all exercise groups but did not change significantly in the control group. Lean mass decreased less in the combination and resistance groups than in the aerobic group (56.5 to 54.8 kg [3% decrease] and 58.1 to 57.1 kg [2% decrease], respectively, vs. 55.0 to 52.3 kg [5% decrease]), as did bone mineral density at the total hip (grams per square centimeter; 1.010 to 0.996 [1% decrease] and 1.047 to 1.041 [0.5% decrease], respectively, vs. 1.018 to 0.991 [3% decrease]) (P<0.05 for all comparisons). Exercise-related adverse events included musculoskeletal injuries. CONCLUSIONS: Of the methods tested, weight loss plus combined aerobic and resistance exercise was the most effective in improving functional status of obese older adults. (Funded by the National Institutes of Health; LITOE ClinicalTrials.gov number, NCT01065636 .).

A Candidate Imaging Marker for Early Detection of Charcot Neuroarthropathy.

Inflammation-mediated foot osteopenia may play a pivotal role in the etiogenesis, pathogenesis, and therapeutic outcomes in individuals with diabetes mellitus (DM), peripheral neuropathy (PN), and Charcot neuroarthropathy (CN). Our objective was to establish a volumetric quantitative computed tomography-derived foot bone measurement as a candidate prognostic imaging marker to identify individuals with DMPN who were at risk of developing CN. We studied 3 groups: 16 young controls (27 ± 5 years), 20 with DMPN (57 ± 11 years), and 20 with DMPN and CN (55 ± 9 years). Computed tomography image analysis was used to measure metatarsal and tarsal bone mineral density in both feet. The mean of 12 right (7 tarsals and 5 metatarsals) and 12 left foot bone mineral densities, maximum percent difference in bone mineral density between paired bones of the right and the left feet, and the mean difference of the 12 right and the 12 left bone mineral density measurements were used as input variables in different classification analysis methods to determine the best classifier. Classification tree analysis produced no misclassification of the young controls and individuals with DMPN and CN. The tree classifier found 7 of 20 (35%) individuals with DMPN to be classified as CN (1 participant developed CN during follow-up) and 13 (65%) to be classified as healthy. These results indicate that a decision tree employing 3 measurements derived from volumetric quantitative computed tomography foot bone mineral density defines a candidate prognostic imaging marker to identify individuals with diabetes and PN who are at risk of developing CN.

Weight loss, exercise, or both and physical function in obese older adults.

BACKGROUND: Obesity exacerbates the age-related decline in physical function and causes frailty in older adults; however, the appropriate treatment for obese older adults is controversial. METHODS: In this 1-year, randomized, controlled trial, we evaluated the independent and combined effects of weight loss and exercise in 107 adults who were 65 years of age or older and obese. Participants were randomly assigned to a control group, a weight-management (diet) group, an exercise group, or a weight-management-plus-exercise (diet-exercise) group. The primary outcome was the change in score on the modified Physical Performance Test. Secondary outcomes included other measures of frailty, body composition, bone mineral density, specific physical functions, and quality of life. RESULTS: A total of 93 participants (87%) completed the study. In the intention-to-treat analysis, the score on the Physical Performance Test, in which higher scores indicate better physical status, increased more in the diet-exercise group than in the diet group or the exercise group (increases from baseline of 21% vs. 12% and 15%, respectively); the scores in all three of those groups increased more than the scores in the control group (in which the score increased by 1%) (P<0.001 for the between-group differences). Moreover, the peak oxygen consumption improved more in the diet-exercise group than in the diet group or the exercise group (increases of 17% vs. 10% and 8%, respectively; P<0.001); the score on the Functional Status Questionnaire, in which higher scores indicate better physical function, increased more in the diet-exercise group than in the diet group (increase of 10% vs. 4%, P<0.001). Body weight decreased by 10% in the diet group and by 9% in the diet-exercise group, but did not decrease in the exercise group or the control group (P<0.001). Lean body mass and bone mineral density at the hip decreased less in the diet-exercise group than in the diet group (reductions of 3% and 1%, respectively, in the diet-exercise group vs. reductions of 5% and 3%, respectively, in the diet group; P<0.05 for both comparisons). Strength, balance, and gait improved consistently in the diet-exercise group (P<0.05 for all comparisons). Adverse events included a small number of exercise-associated musculoskeletal injuries. CONCLUSIONS: These findings suggest that a combination of weight loss and exercise provides greater improvement in physical function than either intervention alone. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00146107.).

Major adverse foot events and functional mobility deficits associated with diabetic neuropathy and nephropathy.

Aim: The purpose is to determine the risk ratios (RR) for both major adverse foot events (MAFEs) and the presence of moderate and severe functional mobility deficits in participants with diabetic peripheral neuropathy across the stages of chronic kidney disease (CKD). Methods: We studied 284 participants with diabetes mellitus, peripheral neuropathy, and CKD. MAFEs including foot fracture, ulcerations, Charcot neuropathic arthropathy (CN), osteomyelitis, and minor foot amputations were collected from foot x-ray reports in the medical records of 152 participants; functional mobility deficits were assessed in 132 participants using the modified physical performance test (mPPT). Moderate mobility deficit was categorized as mPPT scores 22-29 and severe mobility deficit as < 22. Unadjusted and adjusted (age, body weight, race, HbA1c) RR were calculated across each stage of CKD, with stage 1 CKD used as the reference group. Results: The RR for neuropathic foot fracture, CN, and diabetic foot ulceration remained consistent across CKD stages. The RR of minor amputation is greater in CKD stages 4 and 5. The RR of moderate or severe mobility deficit is greater in CKD stages 3 and 5 and in CKD stages 3, 4, and 5, respectively. An inverse association was observed between MAFE prevalence and mPPT scores across CKD stages. Conclusion: Major adverse foot events and functional mobility deficits are prevalent in individuals with DPN and diabetic kidney disease. The risks for minor foot amputation and functional mobility deficits increase as early as stage 3 CKD and increase further in stages 4 and 5.

Weight-bearing versus nonweight-bearing exercise for persons with diabetes and peripheral neuropathy: a randomized controlled trial.

OBJECTIVE: To determine the effects of weight-bearing (WB) versus nonweight-bearing (NWB) exercise for persons with diabetes mellitus (DM) and peripheral neuropathy (PN). DESIGN: Randomized controlled trial with evaluations at baseline and after intervention. SETTING: University-based physical therapy research clinic. PARTICIPANTS: Participants with DM and PN (N=29) (mean age ± SD, 64.5±12.5y; mean body mass index [kg/m(2)] ± SD, 35.5±7.3) were randomly assigned to WB (n=15) and NWB (n=14) exercise groups. All participants (100%) completed the intervention and follow-up evaluations. INTERVENTIONS: Group-specific progressive balance, flexibility, strengthening, and aerobic exercise conducted sitting or lying (NWB) or standing and walking (WB) occurred 3 times a week for 12 weeks. MAIN OUTCOME MEASURES: Measures included the 6-minute walk distance (6MWD) and daily step counts. Secondary outcome measures represented domains across the International Classification of Functioning, Disability and Health. RESULTS: The WB group showed greater gains than the NWB group over time on the 6MWD and average daily step count (P<.05). The mean and 95% confidence intervals (CIs) between-group difference over time was 29m (95% CI, 6-51) for the 6MWD and 1178 (95% CI, 150-2205) steps for the average daily step count. The NWB group showed greater improvements than the WB group over time in hemoglobin A1c values (P<.05). CONCLUSIONS: The results of this study indicate the ability of this population with chronic disease to increase 6MWD and daily step count with a WB exercise program compared with an NWB exercise program.

The effect of exercise, physical activity, stepping characteristics, and loading on diabetic foot ulcer healing: a systematic review.

The aim of this review was to investigate the effect of exercise, physical activity, stepping characteristics, and loading on DFU healing. A systematic review using proprietary software and a PRISMA 2020 checklist was performed by searching MEDLINE, ProQuest, Scopus, CINAHL, Ovid, and the Cochrane Library for eligible articles from 1960 to December 2020. The primary outcome was time to wound closure. Other outcomes included percentage of DFU healed and time to percentage reduction in DFU. Of the 9 articles included, 6 addressed step activity during the off-loading phase of healing and 3 investigated the addition of NWB exercise on wound healing. Reduced loading via lower daily step activity, less standing duration, and shorter walking bouts in combination with wearing an off-loading device facilitated more rapid wound healing. Exercise seemed to facilitate more rapid healing, as well. Reduced limb loading via daily activity and use of offloading devices improved DFU healing rates. Additional research is necessary to determine the optimal thresholds for exercise, activity, step characteristics, and loading to improve healing outcomes in persons with DFU.

Prematriculation Predictors of Academic Difficulties During the First Year of a Doctor of Physical Therapy Program.

PURPOSE: To analyze the ability of pre-matriculation metrics to predict difficulties during the first year of a Doctor of Physical Therapy (DPT) program with a pass-fail grading system. METHODS: Undergraduate cumulative, science, and pre-requisite grade point averages (GPAs) and verbal and quantitative Graduate Record Examination (GRE) percentiles were collected during the admissions process of 190 students in an accredited DPT program at a southeastern US private university between 2019-2021. Students were dichotomized to groups with and without academic difficulties in coursework and a first-year comprehensive assessment (CA). Independent t-tests identified differences between groups, and logistic regression analyses identified predictors of academic difficulties. Receiver operating characteristic (ROC) curve analyses were performed to identify cut-off scores and risk ratios were calculated. RESULTS: Students with coursework difficulties had lower verbal (d=0.36, p=0.009) and quantitative (d=0.31, p=0.02) GRE scores. Verbal GRE scores were also lower in students who failed the CA (p=0.049). Students who scored less than the 47th percentile on the verbal GRE were 53% more likely to have academic difficulties and 4.2 times more likely to fail the CA than those who scored in the 70th percentile or higher. CONCLUSION: Verbal GRE percentile best predicted academic difficulty in the first year of a DPT program.

Botulinum toxin effects on gasatrocnemius strength and plantar pressure in diabetics with peripheral neuropathy and forefoot ulceration.

BACKGROUND: High forefoot plantar pressure is associated with plantar ulcers in people with diabetes and peripheral neuropathy. The purpose of this pilot study was to determine the safety and efficacy of botulinum toxin A injected into the gastrocnemius-soleus muscles to reduce muscle strength and plantar pressure. METHODS: This double blind, randomized clinical trial studied 17 people with diabetes mellitus, peripheral neuropathy and a forefoot plantar ulcer. Subjects were randomized into one of three groups receiving gastrocnemius-soleus muscle injections on the involved side with; 1) Saline (n = 5, weight =99± 21 kg), 2) 200-units of Botox® (n = 7, weight = 101± 5 kg), or 3) 300-units of Botox® (n = 5, weight = 129± 22 kg). Botox® dose was converted to units/kg, the majority received between 1.9 and 2.4 units/kg (n = 11) and one 3.2 units/kg. Plantarflexor peak torque and forefoot peak plantar pressure were quantified prior and 2 weeks post-injection. RESULTS: There were no complications from the injections. Plantarflexor peak torque on the involved side increased in the placebo and 300 groups (3± 4 Nm and 6± 10 Nm, respectively) and decreased -8± 11 Nm in the 200 group. There was no relationship between units/kg of Botox® for each subject and change in plantarflexor peak torque. Forefoot peak plantar pressure did not change in the placebo and 300 groups (0± 11 and 0± 5 N/cm(2), respectively) and decreased -4± 16 N/cm2 (4%) for the 200 group. CONCLUSION: There were no adverse events associated with the Botox® injections. This study was unable to determine the dose to consistently reduce plantarflexor strength and forefoot plantar pressure. Additional research is needed to investigate diabetes mellitus specific physiological changes and their impact of BoNT-A effectiveness in order to guide appropriate dosing.

Biomarkers of chronic kidney disease-mineral bone disorder (CKD-MBD) in the diabetic foot: A medical record review.

AIMS: Determine the prevalence and relative risk of having single and combinations of biomarkers of chronic kidney disease-mineral bone disorder (CKD-MBD) syndrome in the diabetic foot from an electronic medical record (EMR) review. METHODS: Review of 152 patients with one foot radiograph and diagnoses of both diabetes mellitus (DM) and chronic kidney disease (CKD) stages 1-5. Presence/absence of peripheral neuropathy (PN), targeted serum markers, and both pedal vessel calcification (PVC) and buckling ratio (BR) of 2nd and 5th metatarsals from radiographs were recorded. Prevalence of single and combinations of foot biomarkers are reported as count and percentage. Risk ratios (RR) with 95% confidence intervals (95% CI) were calculated to assess risk of foot biomarkers in each stage of CKD-MBD. RESULTS: Prevalence and RR of PVC, PN, and BR ≥ 3.5 biomarkers, both single and in combination, all increase with progression of CKD. The RR increases to 9.6 (95 % CI: 3, 26; p < 0.001) when all 3 biomarkers present in stage 5. CONCLUSIONS: PVC, PN, and BR ≥ 3.5 are prognostic biomarkers of CKD-MBD syndrome in the diabetic foot. Recognition of these foot biomarkers may allow earlier interventions to help reduce nontraumatic lower extremity amputation in individuals with diabetic CKD-MBD.

Effect of Aerobic or Resistance Exercise, or Both, on Intermuscular and Visceral Fat and Physical and Metabolic Function in Older Adults With Obesity While Dieting.

BACKGROUND: Obesity exacerbates age-related effects on body composition and physical and metabolic function. Which exercise mode is most effective in mitigating these deleterious changes in dieting older adults with obesity is unknown. METHODS: In a randomized controlled trial, we performed a head-to-head comparison of aerobic (AEX), resistance (REX), or combination (COMB) exercise during matched ~10% weight loss in 160 obese older adults. Prespecified analyses compared 6-month changes in intermuscular adipose tissue (IMAT) and visceral adipose tissue (VAT) assessed using MRI, insulin sensitivity index (ISI) by oral glucose tolerance test, physical function using Modified Physical Performance Test (PPT), VO2peak, gait speed, and knee strength by dynamometry. RESULTS: IMAT and VAT decreased more in COMB than AEX and REX groups (IMAT; -41% vs -28% and -23% and VAT: -36% vs -19% and -21%; p = .003 to .01); IMAT and VAT decreased in all groups more than control (between-group p < .001). ISI increased more in COMB than AEX and REX groups (86% vs 50% and 39%; p = .005 to .03). PPT improved more in COMB than AEX and REX groups, while VO2peak improved more in COMB and AEX than REX group (all p < .05). Knee strength improved more in COMB and REX than AEX group (all p < .05). Changes in IMAT and VAT correlated with PPT (r = -0.28 and -0.39), VO2peak (r = -0.49 and -0.52), gait speed (r = -0.25 and -0.36), and ISI (r = -0.49 and -0.52; all p < .05). CONCLUSIONS: Weight loss plus combination aerobic and resistance exercise was most effective in improving ectopic fat deposition and physical and metabolic function in older adults with obesity.

Worksite-based intensive lifestyle therapy has profound cardiometabolic benefits in people with obesity and type 2 diabetes.

Lifestyle therapy (energy restriction and exercise) is the cornerstone of therapy for people with type 2 diabetes (T2D) but is difficult to implement. We conducted an 8-month randomized controlled trial in persons with obesity and T2D (17 women and 1 man) to determine the therapeutic effects and potential mechanisms of intensive lifestyle therapy on cardiometabolic function. Intensive lifestyle therapy was conducted at the worksite to enhance compliance and resulted in marked (17%) weight loss and beneficial changes in body fat mass, intrahepatic triglyceride content, cardiorespiratory fitness, muscle strength, glycemic control, ß cell function, and multi-organ insulin sensitivity, which were associated with changes in muscle NAD+ biosynthesis, sirtuin signaling, and mitochondrial function and in adipose tissue remodeling. These findings demonstrate that intensive lifestyle therapy provided at the worksite has profound therapeutic clinical and physiological effects in people with T2D, which are likely mediated by specific alterations in skeletal muscle and adipose tissue biology.

Volumetric quantitative computed tomography measurement precision for volumes and densities of tarsal and metatarsal bones.

Diabetic foot diseases, such as ulcerations, infections, and neuropathic (Charcot's) arthropathy, are major complications of diabetes mellitus (DM) and peripheral neuropathy (PN) and may cause osteolysis (bone loss) in foot bones. The purposes of our study were to make computed tomography (CT) measurements of foot-bone volumes and densities and to determine measurement precision (percent coefficients of variation for root-mean-square standard deviations) and least significant changes (LSCs) in these percentages that could be considered biologically real with 95% confidence. Volumetric quantitative CT scans were performed and repeated on 10 young healthy subjects and 13 subjects with DM and PN. Two raters used the original- and repeat-scan data sets to make measurements of volumes and bone mineral densities (BMDs) of the tarsal and metatarsal bones of the 2 feet (24 bones). Precisions for the bones ranged from 0.1% to 0.9% for volume measurements and from 0.6% to 1.9% for BMD measurements. The LSCs ranged from 0.4% to 2.5% for volume measurements and from 1.5% to 5.4% for BMD measurements. Volumetric quantitative CT provides precise measurements of volume and BMD for metatarsal and tarsal bones, where diabetic foot diseases commonly occur.

Precision of foot alignment measures in Charcot arthropathy.

BACKGROUND: Foot deformity associated with diabetes mellitus (DM) and peripheral neuropathy (PN) contributes to joint instability, ulceration and amputation. This study reports the intrarater and inter-rater measurement precision and least significant change (LSC) of radiological measures of foot deformity in subjects with DM, PN, and foot related complications. METHODS: Cuboid height, Meary's angle, calcaneal pitch and hindfoot-forefoot angle were measured from plain-film radiographs on 15 subjects with DM, PN, and foot-related complications. A foot and ankle fellowship-trained orthopedic surgeon with 23 years of experience (Rater 1) measured radiographs twice. A foot and ankle fellowship-trained orthopedic surgeon with 2 years of experience (Rater 2) and a radiologist in residency training (Rater 3) measured radiographs once. Root mean square standard deviation and LSC were calculated to determine measurement precision and the smallest change considered biologically real, not the result of chance. RESULTS: Intrarater measurement precision was: 0.9 mm for cuboid height, 3 degrees for Meary's angle, and 2 degrees for calcaneal pitch and hindfoot-forefoot angle. Inter-rater measurement precision for rater 1 versus 2 and 1 versus 3 were: 1.7 and 1.6 mm for cuboid height, 4 degrees for Meary's angle, 2 degrees for calcaneal pitch, and 3 degrees for the hindfoot-forefoot angle. The LSC was less than or equal to: 4.7 mm for cuboid, 12 degrees for Meary's angle, 6 degrees for calcaneal pitch, and 8 degrees for hindfoot-forefoot angle. CONCLUSION: Cuboid height, calcaneal pitch, and hindfoot-forefoot angle measures can be completed with relatively good measurement precision.

Deficits in the Skeletal Muscle Transcriptome and Mitochondrial Coupling in Progressive Diabetes-Induced CKD Relate to Functional Decline.

Two-thirds of people with type 2 diabetes mellitus (T2DM) have or will develop chronic kidney disease (CKD), which is characterized by rapid renal decline that, together with superimposed T2DM-related metabolic sequelae, synergistically promotes early frailty and mobility deficits that increase the risk of mortality. Distinguishing the mechanisms linking renal decline to mobility deficits in CKD progression and/or increasing severity in T2DM is instrumental both in identifying those at high risk for functional decline and in formulating effective treatment strategies to prevent renal failure. While evidence suggests that skeletal muscle energetics may relate to the development of these comorbidities in advanced CKD, this has never been assessed across the spectrum of CKD progression, especially in T2DM-induced CKD. Here, using next-generation sequencing, we first report significant downregulation in transcriptional networks governing oxidative phosphorylation, coupled electron transport, electron transport chain (ETC) complex assembly, and mitochondrial organization in both middle- and late-stage CKD in T2DM. Furthermore, muscle mitochondrial coupling is impaired as early as stage 3 CKD, with additional deficits in ETC respiration, enzymatic activity, and increased redox leak. Moreover, mitochondrial ETC function and coupling strongly relate to muscle performance and physical function. Our results indicate that T2DM-induced CKD progression impairs physical function, with implications for altered metabolic transcriptional networks and mitochondrial functional deficits as primary mechanistic factors early in CKD progression in T2DM.

Qualitative study of musculoskeletal tissues and their radiographic correlates in diabetic neuropathic foot deformity.

BACKGROUND: Diabetes mellitus (DM) with peripheral neuropathy (PN) results in foot deformity increasing ulceration, joint dislocation, and amputation risk. This study describes the frequency and severity of foot and ankle musculoskeletal abnormalities and their relationship to radiographic alignment in people with DMPN with (DMPN + MCD) and without (DMPN - MCD) medial column deformity (MCD) compared to age- and body mass index-matched controls without DMPN or MDC. METHODS: DMPN + MCD (n = 11), DMPN - MCD (n = 12), and controls (n = 12) were studied. A radiologist scored foot and ankle magnetic resonance images (MRI) for abnormalities in tendons/fascia, ligaments, muscles, joints, and bones. Higher scores represent greater abnormalities. Foot alignment was measured from lateral weightbearing radiographs. Frequency of abnormalities between groups and relationships between abnormalities and foot alignment in the combined group (n = 35) were examined. RESULTS: DMPN + MCD had higher total muscle, joint, and bone scores compared to controls and higher total joint scores than DMPN - MCD. DMPN - MCD had higher total muscle scores than controls. DMPN + MCD higher bone and joint scores were driven by increased frequency of osteophytes, cartilage damage, focal bone marrow edema, new bone formation, and subchondral cysts. Significant correlations included cuboid height and total bone and joint scores (ρ = -0.37 and ρ = -0.40, respectively) and talar declination angle and total joint score (ρ = 0.38). CONCLUSION: High contrast resolution MRI allowed identification of structural lesions of the foot affecting the cartilage surfaces, bone marrow, and soft tissue supports in patients with DMPN + MCD. As expected, the presence of bone and joint lesions on MRI were strongly associated with DMPN + MCD; surprisingly, although the sample is small, lesions of the soft tissue supports were not associated with MCD. While MRI is not done routinely to investigate MCD, opportunistic use of the information from MRI done for the common clinical indications may allow early identification of the structural lesions associated with MCD and facilitate early, aggressive therapy. LEVEL OF EVIDENCE: III.

A multi-center trial of exercise and testosterone therapy in women after hip fracture: Design, methods and impact of the COVID-19 pandemic.

BACKGROUND: Up to 75% of hip fracture patients never recover to their pre-fracture functional status. Supervised exercise that includes strength training can improve functional recovery after hip fracture. The role of testosterone replacement for augmenting the effects of exercise in older women after hip fracture is unknown. METHODS: The Starting Testosterone and Exercise after Hip Injury (STEP-HI) Study is a 6-month Phase 3 multicenter randomized placebo-controlled trial designed to compare supervised exercise (EX) plus 1% testosterone topical gel, with EX plus placebo gel, and with enhanced usual care (EUC). Female hip fracture patients age ≥ 65 years are being recruited from clinical centers across the United States. Participants are community dwelling and enrolled within 24 weeks after surgical repair of the fracture. The EX intervention is a center-based program of progressive resistance training. The EUC group receives a home exercise program and health education. Participants receive dietary counseling, calcium and vitamin D. The primary outcome is the Six Minute Walk Distance. Secondary outcomes include physical performance measures, self-reported function and quality of life, and dual energy x-ray absorptiometry measures of body composition and bone mineral density. RESULTS: Enrollment, interventions, and follow-up are ongoing. We describe the impact of the coronavirus disease 2019 pandemic on the trial, including modifications made to allow continuation of the interventions and outcome data collection using remote video and audio technology. CONCLUSIONS: Results from the STEP-HI study are expected to have important clinical and public health implications for management of the growing population of hip fracture patients.

Skeletal Muscle Regeneration in Advanced Diabetic Peripheral Neuropathy.

BACKGROUND: Decreased lean muscle mass in the lower extremity in diabetic peripheral neuropathy (DPN) is thought to contribute to altered joint loading, immobility, and disability. However, the mechanism behind this loss is unknown and could derive from a reduction in size of myofibers (atrophy), destruction of myofibers (degeneration), or both. Degenerative changes require participation of muscle stem (satellite) cells to regenerate lost myofibers and restore lean mass. Determining the degenerative state and residual regenerative capacity of DPN muscle will inform the utility of regeneration-targeted therapeutic strategies. METHODS: Biopsies were acquired from 2 muscles in 12 individuals with and without diabetic neuropathy undergoing below-knee amputation surgery. Biopsies were subdivided for histological analysis, transcriptional profiling, and satellite cell isolation and culture. RESULTS: Histological analysis revealed evidence of ongoing degeneration and regeneration in DPN muscles. Transcriptional profiling supports these findings, indicating significant upregulation of regeneration-related pathways. However, regeneration appeared to be limited in samples exhibiting the most severe structural pathology as only extremely small, immature regenerated myofibers were found. Immunostaining for satellite cells revealed a significant decrease in their relative frequency only in the subset with severe pathology. Similarly, a reduction in fusion in cultured satellite cells in this group suggests impairment in regenerative capacity in severe DPN pathology. CONCLUSION: DPN muscle exhibited features of degeneration with attempted regeneration. In the most severely pathological muscle samples, regeneration appeared to be stymied and our data suggest that this may be partly due to intrinsic dysfunction of the satellite cell pool in addition to extrinsic structural pathology (eg, nerve damage). CLINICAL RELEVANCE: Restoration of DPN muscle function for improved mobility and physical activity is a goal of surgical and rehabilitation clinicians. Identifying myofiber degeneration and compromised regeneration as contributors to dysfunction suggests that adjuvant cell-based therapies may improve clinical outcomes.

Tarsal and metatarsal bone mineral density measurement using volumetric quantitative computed tomography.

A new method for measuring bone mineral density (BMD) of the tarsal and metatarsals is described using volumetric quantitative computed tomography (VQCT) in subjects with diabetes mellitus and peripheral neuropathy. VQCT images of a single foot were acquired twice from eight subjects (mean age 51 [11 SD], seven males, one female). The cortical shells of the seven tarsal and five metatarsal bones were identified and semiautomatically segmented from adjacent bones. Volume and BMD of each bone were measured separately from the two acquired scans for each subject. Whole-bone semiautomatic segmentation measurement errors were determined as the root mean square coefficient of variation for the volume and BMD of 0.8% and 0.9%, respectively. In addition to the whole-bone segmentation methods, we performed atlas-based partitioning of subregions within the second metatarsal for all subjects, from which the volumes and BMDs were obtained for each subregion. The subregion measurement BMD errors (root mean square coefficient of variation) within the shaft, proximal end, and distal end were shown to vary by approximately 1% between the two scans of each subject. The new methods demonstrated large variations in BMDs between the 12 bones of the foot within a subject and between subjects, and between subregions within the second metatarsal. These methods can provide an important outcome measure for clinical research trials investigating the effects of interventions, aging, or disease progression on bone loss, or gain, in individual foot bones.