The Mediterranean diet, but not time-restricted eating, mediates the effects of nesfatin on beta cell function among overweight, metabolically healthy individuals.

Nesfatin concentrations are positively correlated with beta cell function. However, it is unclear whether diet composition mediates this relationship. We recruited 27 overweight individuals who practiced Orthodox fasting (OF), a subset of the Mediterranean diet (MedDiet), for 7 weeks. Fourteen overweight people who practiced 16:8 time-restricted eating served as control group. Anthropometric parameters, biochemical data and adipokine levels were evaluated at baseline and after the end of the diet period (7 weeks from baseline). Subsequently, participants were asked to return to their usual eating plans, and an additional evaluation was performed 5 weeks after the end of the research diets (12 weeks from baseline). We observed a significant and negative correlation between HOMA-B and nesfatin values at 12 weeks, only in the OF group (r = -0.455, p = 0.01). In conclusion, returning to normal eating habits after 7 weeks of strict adherence to MedDiet affects the homeostatic balance between insulin secretion and nesfatin.

Infectious complications of transrectal prostate biopsy in patients receiving targeted antibiotic prophylaxis after urethral and rectal swab versus standard prophylaxis: A prospective comparative study.

Background: To evaluate the role of targeted antibiotic prophylaxis (TAP) after rectal and urethral swab cultures compared to empiric antibiotic prophylaxis (EAP) for the prevention of infectious complications after transrectal ultrasound-guided prostate biopsy (TRUS-Bx). Methods: We conducted a prospective comparative study on 141 patients who underwent TRUS-Bx and were allocated in two groups. The first group (n = 71) received EAP with ciprofloxacin and the second (n = 70) received TAP according to rectal and urethral cultures. Post-biopsy infectious complications rates were compared between the two groups. Fluoroquinolone resistance (FQ-R) in the urethral and rectal swabs was recorded. Baseline characteristics were analyzed to assess their relationship with infectious complications and antibiotic resistance. Results: A total of 8 infectious complications were observed, 7 of them in the EAP group (9.85%) and 1 in the TAP group (1.4%). There was a statistically significant difference in febrile UTIs between the two groups (6 vs 0, P = 0.028). FQ-R rate was 4.3% and 12.9% for rectal and urethral samples, respectively. Recent antibiotic exposure was associated with higher post-biopsy infection rates for EAP group and FQ-R rates for TAP group. Conclusion: Combination of rectal and urethral swab cultures for TAP was able to detect FQ-R bacteria carriers and was associated with fewer infectious complications compared to EAP.

Adaptation and validation of the Greek version of the Communication and Language Assessment questionnaire for persons with Multiple Sclerosis (CLAMS).

OBJECTIVE: The aim of the present study was to validate the Communication and Language Assessment questionnaire for persons with Multiple Sclerosis (CLAMS) into the Greek language. METHOD: 106 Persons with Multiple Sclerosis (PwMS) and 51 healthy controls (HCs) participated in this study. We evaluated patients' cognitive abilities with the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). All PwMS completed the CLAMS and three additional questionnaires (Speech Pathology-Specific Questionnaire for persons with Multiple Sclerosis, SMS; Stroke and Aphasia Quality of Life Scale-39, SAQOL-39; the Beck Depression Inventory Fast Screen, BDI-FS), and all HCs filled in the CLAMS. RESULTS: The internal consistency of the CLAMS was excellent (a = 0.933) for the PwMS and a significant difference was found between PwMS and HCs for the total CLAMS score. Statistical analyses showed a significant positive correlation between the CLAMS and the other questionnaires (SMS, BDI, and SAQOL-39) and a statistically significant negative correlation between the CLAMS and the three subtests of the BICAMS (Symbol Digit Modalities Test, Greek Verbal Learning Test-II, and Brief Visuospatial Memory Test-Revised). There was no correlation between the CLAMS and participants' age, disease duration, and disease type. CONCLUSION: The Greek version of the CLAMS is a valid self-reported questionnaire for the evaluation of language and communication symptoms in PwMS.

Different patterns of changes in free 25-hydroxyvitamin D concentrations during intermittent fasting among meat eaters and non-meat eaters and correlations with amino acid intake.

We prospectively assessed changes in free 25-hydroxyvitamin D [25(OH)D] and vitamin D binding protein (VDBP) among overweight adults who followed a pescatarian Orthodox intermittent fasting regimen (n = 59) and controls who followed a low-fat 12:12 diet (n = 46). Total and free 25(OH)D, parathyroid hormone, VDBP, anthropometric data, and amino acid intake were evaluated in both groups at three time points: at baseline, 7 weeks after diet implementation, and 5 weeks after participants returned to their usual eating habits (12 weeks from baseline). An increase in amino acid intake between baseline and 12 weeks was independently correlated with higher free 25(OH)D values at 12 weeks for both groups. Our findings suggest that diet can affect free 25(OH)D concentrations, through variations in amino acid intake, independently of exposure to sunlight, providing novel mechanistic insights into the future planning of vitamin D supplementation strategies. However, this hypothesis needs to be tested in larger studies.

Role of Kinesiotherapy in the Prevention of Heterotopic Ossification: A Systematic Review.

OBJECTIVE: The role of kinesiotherapy in heterotopic ossification remains unclear. The goal of this study was to revisit the literature on the preventive role of kinesiotherapy against heterotopic ossification formation and maturation. DESIGN: A systematic review was performed in MEDLINE, OVID, Scopus, and Cochrane databases. RESULTS: A high-quality clinical trial is missing from the literature. Of 9617 studies primarily identified, nine studies offered the proper data and were included. They infer that satisfactory results on neurogenic heterotopic ossification prevention were achieved with passive exercises, including continuous passive motion, that were initiated early and at a painless range of motion. On the contrary, for elbow posttraumatic heterotopic ossification and major joints burn-associated heterotopic ossification, active range of motion is indicated as early as possible. CONCLUSIONS: Because of the very low quality of the studies included in this review, firm conclusions cannot be drawn about the effectiveness of kinesiotherapy. Nevertheless, it is recommended that controlled passive range of motion exercises (especially continuous passive motion) be applied early and pain-free especially in the neurogenic heterotopic ossification patients while active range of motion in painless limits is beneficial in the heterotopic ossification prevention of traumatic elbows or burn joints.

Generalizability of randomized controlled trials in primary health care: Applying the PRECIS-2 tool on published protocols.

RATIONALE: Pragmatic design may facilitate the generalizability of effectiveness of randomized controlled trials (RCTs) in primary health care (PHC). AIMS AND OBJECTIVES: The aim of this study was to investigate whether published protocols in PHC were designed pragmatically and to explore whether specific trial characteristics may be related to a pragmatic design. METHODS: Using the Pragmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2), we assessed pragmatism for 123 published RCT protocols. For each domain, we calculated the mean score with the 95% confidence interval (95% CI). Interrater reliability was assessed by weighted κ-coefficient with 95% CI. We examined potential associations of published protocol characteristics with overall pragmatism by performing univariate and multivariate analyses. RESULTS: We observed the highest score for primary analysis (4.66, 95% CI: 4.51, 4.82). The eligibility score was intermediate (3.16, 95% CI: 3.01, 3.32). Domains with scores towards the explanatory side included organization (2.50, 95% CI: 2.36, 2.63), flexibility of delivery (2.74, 95% CI: 2.60, 2.88) and flexibility of adherence (3.00, 95% CI: 2.83, 3.17). Interrater agreement was good (κ = 0.61; 95% CI: 0.34, 0.80; p < 0.001). Higher sample sizes were correlated to a pragmatic design (odds ratio: 6.86, 95% CI: 1.64, 28.75; p = 0.04). CONCLUSION: Most RCT protocols were rated as intermediate in the pragmatic-explanatory continuum. Future research may guide all stakeholders on how best to incorporate the level of pragmatism in the interpretation of the results so that the trials are more likely to be applicable in real-world settings.

A Prospective Validation Study of the Functional Bedside Aspiration Screen with Endoscopy: Is It Clinically Applicable in Acute Stroke?

The purpose of this study was to investigate the reliability of the novel Functional Bedside Aspiration Screen (FBAS) to predict aspiration risk in acute stroke and to guide initial therapy needs. We conducted a prospective validation study of the FBAS 10-point scale in 101 acute ischemic stroke patients. Outcome measures were compared with the Penetration Aspiration Scale (PAS) via the Flexible Endoscopic Swallowing Study. Correlations with the Functional Oral Intake Scale (FOIS) and the Therapy Requirement Scale (TRS) were analyzed. We observed a 65.8% sensitivity and 70.2% specificity (p = 0.004) for predicting penetration risk (for PAS score ≥ 3) and a 73% sensitivity and 62% specificity for predicting aspiration risk (PAS score ≥ 6). For patients with a modified ranking scale 0-2 (n = 44) on admission, the predictive measurements of the FBAS yielded sensitivity and specificity values of 66.7% and 88.6% (p = 0.011). A significant negative correlation was found with PAS measurements, whereas a positive correlation was observed regarding FOIS. Significantly lower FBAS scores were observed in patients with high requirements for therapeutic interventions and dietary modification. FBAS may be regarded as an alternative time-efficient clinical support tool in settings in which instrumentation is not directly accessible. Further studies including a larger cohort of acute stroke patients with more severe neurological deficits are necessary.

Vitamin D Alleviates Anxiety and Depression in Elderly People with Prediabetes: A Randomized Controlled Study.

Older people are prone to frailness, present poor adherence to pharmacotherapy, and often have adverse drug effects. Therefore, it is important to develop effective and safe interventions to mitigate the burden of anxiety and depression disorders in this population. The aim of this study was to investigate the effect of vitamin D supplementation on the anxiety and depression status of elderly people with prediabetes. Participants were randomly assigned a weekly dose of vitamin D3 of 25,000 IU (n = 45, mean age 73.10 ± 7.16 years) or nothing (n = 45, mean age 74.03 ± 7.64 years), in addition to suggested lifestyle measures. The State-Trait Anxiety Inventory subscales (STAI-T and STAI-S) and the Patient Health Questionnaire-9 (PHQ-9) were used to evaluate anxiety and depression levels, respectively, at baseline, 6, and 12 months. A total of 92.68% of the participants in the vitamin D group and 97.14% of the controls exhibited vitamin D deficiency (<20 ng/mL) at baseline. Mean STAI-T scores were lower in supplemented individuals than in the control group at 6 (38.02 ± 9.03 vs. 43.91 ± 7.18, p = 0.003) and 12 months (32.35 ± 7.77 vs. 44.97 ± 7.78, p < 0.001). The same pattern was evident for STAI-S scores at 6 (37.11 ± 7.88 vs. 43.20 ± 9.33, p = 0.003) and 12 months (32.59 ± 6.45 vs. 44.60 ± 9.53, p < 0.001). Supplemented participants demonstrated lower mean PHQ-9 scores compared to controls at 6 (15.69 ± 6.15 vs. 19.77 ± 8.96, p = 0.021) and 12 months (13.52 ± 5.01 vs. 20.20 ± 8.67, p < 0.001). Participants with deficiency and insufficiency at baseline experienced equal benefits of supplementation in terms of anxiety and depression scores. In conclusion, in a high-risk population, a weekly vitamin D supplementation scheme was effective in alleviating anxiety and depression symptoms. More studies are needed to elucidate the relevant mechanisms.

The effect of vitamin D supplementation on glycemic status of elderly people with prediabetes: a 12-month open-label, randomized-controlled study.

BACKGROUND: Data on the efficacy of vitamin D in improving the glycemic status of elderly people with prediabetes are scarce. This open-label, randomized-controlled trial investigated the effect of vitamin D supplementation on glycemic markers of Greek people with prediabetes aged 60 years or above, over 12 months. RESEARCH DESIGN AND METHODS: Participants were randomized to a weekly vitamin D3 dose of 25,000 IU (n = 45) or nothing (n = 45), on top of lifestyle measures. Anthropometric and glycemic markers were assessed at baseline, 3, 6, and 12 months. RESULTS: Supplemented participants demonstrated a significant increase in 25(OH)D concentrations at 3,      6,      and 12 months     compared to baseline    . In the intervention group, fasting glucose was decreased at 6 months compared to baseline (96.12 ± 5.51 vs 103.40 ± 12.05 mg/dl, p < 0.01) and glycated hemoglobin was significantly lower at 6 and 12 months compared to baseline [5.82 ± 0.21% vs 5.87 ± 0.21%, p = 0.004 and 5.80 ± 0.23% vs 5.87 ± 0.21%, p < 0.001, respectively]. CONCLUSIONS: Vitamin D could be complementary to lifestyle change strategy for the management of prediabetes in the elderly. CLINICAL TRIAL REGISTRATION: ISRCTN51643592.

Implementation of Christian Orthodox fasting improves plasma adiponectin concentrations compared with time-restricted eating in overweight premenopausal women.

The exact mechanisms mediating the metabolic effects of Orthodox fasting remain unclear. Plasma adiponectin, biochemical and anthropometrical data were evaluated in 55 Orthodox fasters (OF) and 42 time-restricted eating controls (all women, mean age 47.8 years) at three time points: baseline, end of the dietary intervention (7 weeks) and 5 weeks after participants returned to their typical dietary habits (12 weeks from baseline). In the OF group, there was an increase in adiponectin values at 12 weeks compared with baseline (9815.99 vs 8983.52 mg/ml, p = 0.02) and a reduction in body fat mass between baseline and 12 weeks (35.44 vs 32.17%, p = 0.004) and between 7 and 12 weeks (35.33 vs 32.17%, p = 0.003). In the same group, an inverse correlation between adiponectin and waist circumference values was observed over the entire study period. Our results provide novel evidence that Orthodox fasting has favourable metabolic effects related to improved adiponectin concentrations.

The effectiveness of botulinum toxin on spasticity and gait of hemiplegic patients after stroke: A systematic review and meta-analysis.

The aim of the study is to evaluate the evidence supporting the efficacy of botulinum toxin type A (BTA) injections in lower limb of hemiplegic patients, after stroke or cerebrovascular accident, and their gait analysis. This study included: randomized controlled trials (RCTs), non-randomized or controlled clinical trials (CCTs) or cluster trials, clinical trials of various phases (I-III), interrupted time series (ITS) studies with at least three data points before and after the intervention, controlled before and after (CBA) studies, prospective and retrospective comparative cohort studies, case-control and multicentred studies. The patients included in these studies had similar characteristics: age over 18 years, history of stroke and following hemiplegia, minimum modified Ashworth scale (MAS) score of 2 and duration since stroke over 6 months. The number of studies included in this review was 21. A meta-analysis was performed on a fraction of them depending on the reported index and the methodology as reported in detail in the results section. MAS score, following BTA injections, was significantly improved (Hedges' g: -1.17; 95% CI: -1.66, 0.67; p < 0.001). The same applied for the 10 Meter Walk Test (MWT) (-0.35; 95% CI: -0.68, -0.02; p = 0.016). The gait velocity showed improvement, yet without statistical significance (0.27; 95% CI: -0.09, 0.63; p = 0.285). We concluded that botulinum toxin injections showed effectiveness on lower limb hypertonia reduction of hemiplegic patients after stroke. Apart from significantly reducing the MAS scores, 10 MWT was also improved. However, more research is required in order to determine the advancement in specific gait and posture parameters.

Vitamin D equilibrium affects sex-specific changes in lipid concentrations during Christian Orthodox fasting.

We aimed to evaluate sex differences in changes of lipid profiles in a cohort of metabolically healthy adults following Orthodox fasting (OF), as well as to assess a potential role of vitamin D status in mediating these variations. 45 individuals (24 premenopausal females, 53.3 %) with mean age 48.3 ± 9.1 years and mean Body Mass Index 28.7 ± 5.8 kg/m2 were prospectively followed for 12 weeks. Anthropometry, dietary and biochemical data regarding serum lipids, and vitamin D status were collected at baseline, 7 weeks after the implementation of OF, and 5 weeks after fasters returned to their standard dietary habits (12 weeks from baseline). According to 25-hydroxy-vitamin D [25(OH)D] measurements, participants were divided into two groups: those with concentrations above and below the median of values. Females with 25(OH)D concentrations below the median manifested a non-significant reduction by approximately 15 % in total and low-density lipoprotein cholesterol during the fasting period, followed by a significant increase 5 weeks after OF cessation (170.7 vs. 197.5 and 99.6 vs. 121.0 mg/dl respectively, p < 0.001). In contrast, males with 25(OH)D levels below the median demonstrated an inverse, non-significant trend of increase in lipid concentrations during the whole study period. Our findings suggest strikingly different inter-gender lipid responses to a dietary model of low-fat, mediated by vitamin D status. Further studies are necessary to reveal the underlying mechanisms and assess the importance of these differences with respect to cardiovascular health and the benefit of vitamin D supplementation strategies.

Effects of Christian Orthodox Fasting Versus Time-Restricted Eating on Plasma Irisin Concentrations Among Overweight Metabolically Healthy Individuals.

Irisin has been recently identified as an adipomyokine produced during physical activity and involved in the browning of adipose tissue. Despite the emerging evidence suggesting an inverse relationship between irisin plasma concentrations and adverse metabolic outcomes, the exact impact of diet on irisin levels remains obscure. Thus, we aimed to assess the effects of two dietary patterns, Christian Orthodox fasting (OF) and 16:8 time-restricted eating (TRE), on circulating irisin levels among overweight, metabolically healthy, adults. Plasma irisin, glucose and lipid parameters, calcium homeostasis, and anthropometry were evaluated in 29 Orthodox fasters and 14 age and body mass index (BMI)-matched TRE controls (mean age and BMI, 48.8 years and 28.7 kg/m2, respectively) at three, distinct time points-before the implementation of the energy-restricted diets (baseline), at the end of the dietary intervention (7 weeks) and 5 weeks after participants returned to their typical dietary habits (12 weeks from baseline). Repeated measures analysis was applied to assess differences between the two groups and the effect of several indices on irisin levels at all three time points. At 12 weeks, the OF group manifested higher irisin concentrations compared with both its baseline values (64.3 ± 54.4 vs. 43.6 ± 42.2 ng/mL, p = 0.01) and those of the TRE group at the same time point (64.3 ± 54.4 vs. 44.2 ± 26.6 ng/mL, p = 0.04). Glycemic, lipid, and anthropometric parameters were not found to correlate with irisin levels. In contrast, parathyroid hormone (PTH) concentrations at 12 weeks correlated with irisin concentrations (p = 0.04), indicating that lower values of irisin are expected for higher PTH measurements. The findings of this pilot study suggest favorable long-term effects of OF on irisin levels. The interplay between irisin, PTH, and diet warrants further investigation.

Predictive value of a novel pragmatic tool for post-stroke aspiration risk: The Functional Bedside Aspiration Screen.

BACKGROUND: There is still a strong need for an optimal clinician-friendly screening tool for the identification of aspiration risk in stroke patients. In this study, we present the development of a novel, context-specific screening tool for the prediction of aspiration risk on recent stroke survivors, the Functional Bedside Aspiration Screen (FBAS), and examine its construct validity, reliability with the predictive values toward pragmatic patients' outcomes. METHODS: We conducted a prospective validation study of 104 acute ischemic stroke patients admitted to clinical wards in a tertiary university hospital. A group of experts developed and administered the FBAS 10-point scale to all patients. Outcome measures were compared with those of the validated Yale Swallow Protocol (YSP, reference measure) and health indicators. KEY RESULTS: A strong association was found between the FBAS cutoff criterion and the YSP (Pearson χ2  = 54.92, P < .001). A score of ≤8 on the FBAS presented with 93.3% sensitivity and 83.3% specificity in deeming patient with reduced safety for oral nutrition (AUC = 0.934, CI = 0.884-0.985). An inverse relationship was found between performance on the FBAS and in-hospital and long-term outcome indicators. Patients who failed the FBAS were 1.82 times more likely to develop aspiration pneumonia (95% CI = 1.42-2.35) and 1.35 times more likely to develop pneumonia within 3 months postonset (95% CI = 1.15-1.59). CONCLUSIONS AND INFERENCES: The FBAS is a potentially useful tool for timely prediction of aspiration risk and health outcome in acute stroke.

Primary High-Grade Non-Muscle-Invasive Bladder Cancer: High NFκB Expression in Tumor Specimens Distinguishes Patients Who are at Risk for Disease Progression.

To investigate the potential prognostic role of NFκB expression in primary high-grade non-muscle-invasive bladder cancer. Patients with primary high-grade non-muscle-invasive bladder cancer who received induction and maintenance BCG therapy were retrospectively included. Recurrence and progression were histologically proven. Intensity and extent of immunochemistry were assessed. The final evaluation of the NFκB staining was done by combining intensity and extent as ΄΄product΄΄ and expressing it as ΄΄low NFκΒ expression΄΄ or ΄΄high NFκB expression΄΄. Epidemiological, pathological, clinical parameters and NFκB expression were statistically analyzed for recurrence (REC), progression (PR), recurrence-free survival (RFS) and progression-free survival (PFS). NFκB is significantly associated with disease progression (p < 0,001 in univariate analysis and p = 0,001, Odds Ratio = 14,484, 95% Confidence Interval = 3187-65,821 in multivariate analysis), but not with recurrence. The median value of NFκB expression as ΄΄product΄΄ is significantly higher for the patients with progression in comparison to patients with recurrence only (p = 0,003) and patients without recurrence or progression (p = 0,001). Patients' age is significantly associated (p = 0,001 in univariate analysis and p = 0,003, Odds Ratio = 1273, 95% Confidence Interval = 1086-1492 in multivariate analysis) with disease recurrence. High NFκB expression in primary high-grade non-muscle-invasive bladder cancer, treated with postoperative intravesical BCG immunotherapy, could represent an unfavorable prognostic factor.

Vascular endothelial growth factor for the treatment of femoral head osteonecrosis: An experimental study in canines.

AIM: To evaluate the treatment of osteonecrosis of the femoral head (ONFH) with the use of vascular endothelial growth factor (VEGF). METHODS: In 30 mature beagles (6 groups of 5 beagles) ONFH was induced cryosurgically and one of the following solutions was administered locally in the femoral head (FH) in each group: Single injection of 500 µg VEGF (t-VEGFµ group); single injection of 500 ng VEGF (t-VEGFn group); continuous delivery of 500 µg VEGF through osmotic micropump (t-VEGFpump-µ group); continuous delivery of 500 ng VEGF through osmotic micropump (t-VEGFpump-n group); single injection of 0.9% sodium chloride (t-NS group), while one group that served as control group did not receive any local solution (No-t group). FHs were retrieved 12 wk postoperatively, underwent decalcification and hematoxylin/eosin and toluidine blue staining. In two canines per group, one half of FH was processed without decalcification and stained with modified Masson Trichrome. Histological sections were observed by light microscopy and measured with a semi-automatized bone histomorphometry system and Bone Volume/Total Volume (BV/TV), Marrow Volume/Total Volume (MaV/TV), and Trabecular Thickness (TbTh) were assessed. Standard and robust tests (Welch, Brown Forsythe) of analysis of variance along with multiple comparisons, were carried out among the categories. RESULTS: The untreated (No-t) group had signs of osteonecrosis, whereas the VEGF groups revealed reversal of the osteonecrosis. Statistical analysis of the decalcified specimens revealed a significantly better BV/TV ratio and a higher TbTh between the VEGF treatment groups (except the t-VEGFn group) and the No-t group or the control t-NS group. Single dose 500 µgVEGF group had significantly better BV/TV ratio and higher TbTh when compared to the No-t group (50.45 ± 6.18 vs 29.50 ± 12.27, P = 0.002 and 151.44 ± 19.07 vs 107.77 ± 35.15, P = 0.161 respectively) and the control t-NS group (50.45 ± 6.18 vs 30.9 ± 6.67, P = 0.004 and 151.44 ± 19.07 vs 107.14 ± 35.71, P = 0.151 respectively). Similar differences were found for the prolonged VEGF delivery/pump groups of 500 µg and 500 ng. Analysis of the totality of specimens (decalcified/non-decalcified) enhanced the aforementioned differences and additionally revealed significant differences in the comparison of the TbTh. CONCLUSION: In an experimental model of ONFH in canines it was found that local treatment with VEGF leads to bone tissue remodeling and new bone formation.

Heterotopic ossification after the use of recombinant human bone morphogenetic protein-7.

AIM: To present the incidence of heterotopic ossification after the use of recombinant human bone morphogenetic protein-7 (rhBMP-7) for the treatment of nonunions. METHODS: Bone morphogenetic proteins (BMPs) promote bone formation by auto-induction. Recombinant human BMP-7 in combination with bone grafts was used in 84 patients for the treatment of long bone nonunions. All patients were evaluated radiographicaly for the development of heterotopic ossification during the standard assessment for the nonunion healing. In all patients (80.9%) with radiographic signs of heterotopic ossification, a CT scan was performed. Nonunion site palpation and ROM evaluation of the adjacent joints were also carried out. Factors related to the patient (age, gender), the nonunion (location, size, chronicity, number of previous procedures, infection, surrounding tissues condition) and the surgical procedure (graft and fixation type, amount of rhBMP-7) were correlated with the development of heterotopic ossification and statistical analysis with Pearsons χ 2 test was performed. RESULTS: Eighty point nine percent of the nonunions treated with rhBMP-7, healed with no need for further procedures. Heterotopic bone formation occurred in 15 of 84 patients (17.8%) and it was apparent in the routine radiological evaluation of the nonunion site, in a mean time of 5.5 mo after the rhBMP-7 application (range 3-12). The heterotopic ossification was located at the femur in 8 cases, at the tibia in 6, and at the humerus in οne patient. In 4 patients a palpable mass was present and only in one patient, with a para-articular knee nonunion treated with rhBMP-7, the size of heterotopic ossification affected the knee range of motion. All the patients with heterotopic ossification were male. Statistical analysis proved that patient's gender was the only important factor for the development of heterotopic ossification (P = 0.007). CONCLUSION: Heterotopic ossification after the use of rhBMP-7 in nonunions was common but it did not compromise the final clinical outcome in most cases, and affected only male patients.