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Intro: A weekly-based service was hypothesized as feasible and usable for surveillance, to monitoring cases in Long-Term Care Facilities (LTCFs) in the SARS-CoV-2 emergency in Italy. Methods: A web-based platform was set-up at the Italian National Institute of Health (ISS) at mid-2020. Protocols were validated and people trained to guarantee the delivery of a reliable weekly report to the Reference person of each participating Region, including the most relevant SARS-CoV-2 data and criticalities, i.e. new infections and outbreaks, deaths, hospitalization, isolations, vaccination coverage (VC), personal protective equipment and swabs. Findings: The service has been working at regimen since October 2020, available 24/7, the ISS database being fed by 7 Regions. In the period January 2021 – June 2022, 852 LCTFs (with over 22.000 residents) contributed to the service, with high adherence rate (92% on average in January 2021, 82% in March 2022 - end of emergency in Italy - and 77% in June 2022). Reports are delivered on Thursdays to inform Regional Contacts. So far, weekly data inconsistencies ranged between 6% and 10%; they were all solved by variables cross-check, comparisons with previous information, and direct interviews with the LCTFs’ operators. Regularly, data are processed to monitor trends, with focus on waves of infections. In particular, prevalence of infections reached 1.4% and SARS-CoV-2 positive deaths 0.4% in January 2021 (vaccination campaign just started), 5.5% and 0.2% respectively in January 2022 (VC ≈ 97%), 4.0% and

Background: Diabetes-related foot ulcers are a leading cause of morbidity and mortality globally, in which the most significant contributing factor is peripheral neuropathy. The purpose of this research was to evaluate the influence of diabetic peripheral neuropathy and ulceration on lower limb and foot joint kinematics during gait., Research Question: Are there any significant alterations lower limb and foot joint kinematics during gait in the presence of active and history of diabetic neuropathic ulceration?, Methods: A prospective, cross-sectional study was conducted, recruiting eighty adult participants who were equally divided into four groups, namely, the diabetes (DM), diabetic peripheral neuropathy (DPN), active diabetic neuropathic ulceration (DNU) and history of diabetic neuropathic ulceration (DHNU) groups. Three-dimensional gait analysis was performed, and participants were instructed to walk barefoot over a 10-m walkway at self-selected speed. The acquired pelvic, hip, knee, ankle and foot joint segmental kinematic data was compared between individuals with and without active neuropathic ulceration., Results: Mean scores between the four independent groups was performed using the Kruskal-Wallis test. Participants within the DNU and DHNU groups demonstrated significantly reduced knee flexion, ankle dorsiflexion and first metatarsal dorsiflexion kinematics with resultant increased anterior pelvic tilt, hip flexion and midtarsal kinematics (all values p<0.01) when compared to participants within the DM and DPN groups., Significance: Through the integration of a more individualised, biomechanical approach, the findings in this study may provide improved preventative and management strategies of ulceration amongst the diabetic population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: As little is known about the burden of type 1 (T1DM) and type 2 diabetes (T2DM) in adolescents in Western Europe (WE), we aimed to explore their epidemiology among 10-24 year-olds. Methods: Estimates were retrieved from the Global Burden of Diseases Study (GBD) 2019. We reported counts, rates per 100,000 population, and percentage changes from 1990 to 2019 for prevalence, incidence and years lived with disability (YLDs) of T1DM and T2DM, and the burden of T2DM in YLDs attributable to high body mass index (HBMI), for 24 WE countries. Results: In 2019, prevalence and disability estimates were higher for T1DM than T2DM among 10-24 years old adolescents in WE. However, T2DM showed a greater increase in prevalence and disability than T1DM in the 30 years observation period in all WE countries. Prevalence increased with age, while only minor differences were observed between sexes. Conclusion: Our findings highlight the substantial burden posed by DM in WE among adolescents. Health system responses are needed for transition services, data collection systems, education, and obesity prevention., Competing Interests: The authors declare that they do not have any conflicts of interest., (Copyright © 2024 Armocida, Monasta, Sawyer, Bustreo, Onder, Castelpietra, Pricci, Minardi, Giacomozzi, Abbafati, Stafford, Pasovic, Hay, Ong, Perel, Beran and GBD 2019 Europe Adolescent Diabetes.)

Context: In 2005, a nationwide program of iodine prophylaxis on a voluntary basis was implemented in Italy by law. However, recent data on iodine status are lacking., Objective: The aim of this study was to evaluate efficiency, effectiveness, and possible adverse effects (increased occurrence of thyroid autoimmunity and hyperthyroidism) of the Italian iodine prophylaxis program., Methods: From 2015 to 2019, a nationwide survey was performed. The use of iodized salt was evaluated in a sample of 164 593 adults and in 998 school canteens. A sample of 4233 schoolchildren (aged 11-13 years) was recruited to assess urinary iodine concentration, prevalence of goiter, and thyroid hypoechogenicity on ultrasound, with the latter being an indirect indicator of thyroid autoimmunity. Neonatal TSH values of 197 677 infants screened in regions representative of Northern, Central, and Southern Italy were analyzed to investigate the percentage of TSH values >5.0 mIU/L. Data on methimazole prescriptions were analyzed as indirect indicators of new cases of hyperthyroidism., Results: The prevalence of the use of iodized salt was 71.5% in adult population and 78% in school canteens. A median urinary iodine concentration of 124 μg/L, a prevalence of goiter of 2.2%, and a prevalence of thyroid hypoechogenicity of 5.7% were observed in schoolchildren. The percentage of neonatal TSH values >5.0 mIU/L resulted still higher (5.1%) than the World Health Organization threshold of 3.0%, whereas the prescriptions of methimazole showed a reduction of 13.5%., Conclusion: Fifteen years of iodine prophylaxis have led to iodine sufficiency in Italy, although there still is concern about iodine nutritional status during pregnancy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: The percentage of smokers who develop COPD (Chronic Obstructive Pulmonary Disease) peaks at 40-50% in most recent publications., Summary: Tobacco smoke remains the main cause of COPD, though smoking-related limitation of the flow is rather subjective. For patients who keep on smoking, general practitioners (GPs) and pulmonologists should be able to offer smoking cessation programs as an important part of COPD treatment. This narrative article aims to provide the scientific basis to help healthcare professionals develop this therapy; with this aim in mind, the authors have analyzed the most recent literature., Key Messages: Only 3% of smokers who try to quit without availing themselves of any support succeed. Effective smoking cessation methods are counselling and pharmacotherapy, which, combined together, are credited with a 24% success rate. Although there are no therapeutic novelties with strong scientific evidence for smoking cessation, it is however advisable to keep the literature updated to new devices and new digital therapies.

Purpose: We aimed to investigate a cohort of female and male patients with idiopathic central precocious puberty (CPP), negative for Makorin Ring Finger Protein 3 (MKRN3) defect, by molecular screening for Delta-like 1 homolog (DLK1) defects. DLK1 is an imprinted gene, whose mutations have been described as a rare cause of CPP in girls and adult women with precocious menarche, obesity and metabolic derangement., Methods: We enrolled 14 girls with familial CPP and 13 boys with familial or sporadic CPP from multiple academic hospital centers. Gene sequencing of DLK1 gene was performed. Circulating levels of DLK1 were measured and clinical and biochemical characteristics were described in those with DLK1 defects., Results: A novel heterozygous mutation in DLK1, c.288&#95;289insC (p.Cys97Leufs*16), was identified in a male proband, his sister and their father. Age at onset of puberty was in line with previous reports in the girl and 8 years in the boy. The father with untreated CPP showed short stature. No metabolic derangement was present in the father except hypercholesterolemia. Undetectable Dlk1 serum levels indicated the complete lack of protein production in the three affected patients., Conclusion: A DLK1 defect has been identified for the first time in a boy, underscoring the importance of genetic testing in males with idiopathic or sporadic CPP. The short stature reported by his untreated father suggests the need for timely diagnosis and treatment of subjects with DLK1 defects., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Context: Insulin-like growth factor (IGF)1 gene mutations are extremely rare causes of pre- and postnatal growth retardation. Phenotype can be heterogenous with varying degrees of neurosensory deafness, cognitive defects, glucose metabolism impairment and short stature., Objective: This study describes a 12.6-year-old girl presenting with severe short stature and insulin resistance, but with normal hearing and neurological development at the lower limit of normal., Methods: DNA was obtained from the proband and both parents for whole exome sequencing (WES). In silico analysis was performed to predict the impact of the IGF1 variant on IGF1 and insulin receptors (IGF1R and IR) signaling. Phosphorylation of the IGF1R at activating Tyr residues and cell proliferation analyses were used to assess the ability of each subject's IGF1 to bind and activate IGF1R., Results: The proband had low immunoreactive IGF1 in serum and WES revealed a novel homozygous IGF1 missense variant (c.247A>T), causing a change of serine 83 for cysteine (p.Ser83Cys; p.Ser35Cys in mature peptide). The proband's parents were heterozygous for this mutation. In silico analyses indicated the pathogenic potential of the variant with electrostatic variations with the potential of hampering the interaction with the IGF1R but strengthening the binding to IR. The mutant IGF1 protein had a significantly reduced activity on in vitro bioassays., Conclusion: We describe a novel IGF1 mutation leading to severe loss of circulating IGF1 immunoreactivity and bioactivity. In silico modeling predicts that the mutant IGF1 could interfere with IR signaling, providing a possible explanation for the severe insulin resistance observed in the patient. The absence of significant hearing and neurodevelopmental involvement in the present case is unusual and broadens the clinical spectrum of IGF1 mutations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The purpose of this study was to evaluate plantar pressure dynamics in the occurrence of active diabetic neuropathic ulceration (DNU) and any changes in loadings occurring in individuals with a history of diabetic neuropathic ulceration (DHNU). Since current gold standard offloading strategies are not producing desirable healing outcomes and optimum ulcer prevention, this study aimed to better understand the effect of diabetic peripheral neuropathy (DPN) and ulceration on mean peak plantar pressure (MPPP) and pressure-time integral (PTI) changes., Research Question: Is there a redistribution of plantar pressure during gait in the presence of active and history of diabetic neuropathic ulceration?, Methods: A prospective, cross-sectional study was conducted, in which, eighty adult participants were divided into four groups, namely, the DM, DPN, DNU and DHNU groups. Participants were instructed to walk barefoot over a Tekscan HR Mat™ at self-selected speed. MPPP and PTI data were analysed under five forefoot anatomical landmarks and compared between individuals with and without active neuropathic ulceration., Results: Minimal MPPP significant changes were observed between ulcerated and non-ulcerated groups, however, PTI values were significantly increased in the ulcerated groups under all plantar ulceration regions. No significant plantar pressure differences were observed between the DNU and DHNU groups. Logistic regression tests demonstrated that as PTIs under the hallux increase, the likelihood of an individual living with DPN developing ulceration increases., Significance: A significant increase in PTI values in the presence of ulceration highlights the importance of evaluating the duration of loads under forefoot regions during gait rather than just focusing on the magnitude of pressures during ulcer management and prevention. Moreover, results show that PTI values remain high in the presence of a history of neuropathic ulceration, possibly demonstrating the value of PTI as a clinical tool over MPPP in the assessment of the high-risk diabetic foot., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: We aimed to evaluate the near-final height (nFHt) in a large cohort of pediatricpatients with growth hormone deficiency (GHD) and to elaborate a new predictive method of nFHt., Methods: We recruited GHD patients diagnosed between 1987 and 2014 and followed-up until nFHt. To predict the values of nFHt, each predictor was run in a univariable spline., Results: We enrolled 1051 patients. Pre-treatment height was -2.43 SDS, lower than parental height (THt) (-1.09 SDS, p < 0.001). The dose of recombinant human GH (rhGH) was 0.21mg/kg/week at start of treatment. nFHt was -1.08 SDS (height gain 1.27 SDS), higher than pre-treatment height (p < 0.001) and comparable to THt. 1.6% of the patients were shorter than -2 SDS from THt. The rhGH dose at nFHt was 0.19 mg/kg/week, lower than at the start (p < 0.001). The polynomial regression showed that nFHt was affected by gender, THt, age at puberty, height at puberty, age at the end of treatment (F = 325.37, p < 0.0001, R 2 87.2%)., Conclusion: This large national study shows that GHD children can reach their THt. The rhGH/kg/day dose significantly decreased from the start to the end of the treatment. Our model suggests the importance of a timely diagnosis, possibly before puberty, the beneficial effect of long-term treatment with rhGH, and the key-role of THt. Our prediction model has a very acceptable error compared to the majority of other published studies., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Background: The tibialis anterior tendon transfer (TATT) is the suggested surgical intervention in the Ponseti method for treatment of dynamic recurrent congenital talipes equinovarus (clubfoot) presenting as hindfoot varus and forefoot supination during the swing phase of gait. The indication for surgery, however, is typically based on visual assessment, which does not sufficiently examine the variability of foot motion in this cohort., Research Question: The aim of this research was to determine whether subgroups, based on foot model kinematics, existed within a clubfoot cohort being considered for TATT surgery., Methods: Sixteen children with recurrent clubfoot that had been previously treated with the Ponseti method and were being considered for tendon transfer surgery were prospectively recruited for this study and were required to attend a pre-surgery data collection session at the Queensland Children's Motion Analysis Service (QCMAS). Data collected included standard Plug-in-Gait (PiG) kinematics and kinetics, Oxford Foot Model (OFM) foot kinematics, and regional plantar loads based on anatomical masking using the integrated kinematic-pressure method., Results: Results of this study identified two clear subgroups within the cohort. One group presented with increased hindfoot inversion across 91 % of the gait cycle. The second group presented with increased hindfoot adduction across 100 % of the gait cycle. Hindfoot adduction was statistically significantly different between the two groups., Significance: The identification of these two groups propose a need for further classification of deformity within this cohort and query the appropriateness of this surgical intervention for both presentations., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Low compliance with drug therapy in patients with chronic respiratory diseases was a well-known issue even before the coronavirus pandemic, but its causes are not yet fully defined., Objective: To verify the adherence to drug therapy in patients with respiratory disease during the COVID-19 pandemic., Methods: From June to September 2020, about 700 patients of the Forlanini Hospital who had been unmonitored during the March-May 2020 lockdown in Italy received a questionnaire during the pneumological check-up based on self-reported information on compliance with therapy during lockdown., Results: 284 out of the 418 returned questionnaires could be used in this study: 179 patients (63.0%) responded positively to the continuation of therapy, 18 (6.3%) reduced the dosage of their medication and 82 (28.9%) interrupted the therapy., Conclusions: The low percentage of patients that reduced their drug dosage may be due to an increased awareness of drug treatment benefits, and may also be ascribed to the Government healthcare strategy during lockdown.

Background: The aim of this study was to analyse the effect of induced lower limb joint restriction on plantar pressures during gait. Focusing on restricting a single joint, without the effect of other co-morbidities, would provide better understanding as to the resultant plantar loadings during gait, which would be especially beneficial in patients requiring offloading procedures., Research Question: Does induced lower limb joint restriction affect plantar pressure distribution during gait?, Methods: A prospective, quasi-experimental study was conducted, recruiting ten healthy, adult participants who were instructed to walk barefoot over a Tekscan HR Mat™. This procedure was repeated after separately inducing restriction of the hip, knee and ankle joints. Mean peak plantar pressure (MPP) and pressure-time integral (PTI) data were analysed to compare between unrestricted and restricted data., Results: Significant plantar pressure changes were observed in the heel and first metatarsal regions. Rearfoot PTIs were increased with restriction of the contralateral hip (left p <0.001) (right p =0.02) and knee joints (left p =0.01) (right p =0.04). Both MPPs (left p =0.01; right p =0.01) and PTIs (left p =0.004; right p =0.03) were increased in the first metatarsal when restricting the hip joint of the same limb. MPP was decreased in the left first metatarsal with induced knee (left p =0.01; right p =0.04) and ankle (left and right p <0.001) joint restriction. Finally, MPP was decreased in the right first metatarsal with knee (left and right p =0.01) and ankle (left p =0.04; right p =0.01) joint restriction., Significance: Limited joint mobility may have a direct effect on plantar pressure, particularly with restriction in the hip and knee joints, hence careful attention should be given especially in patients with conditions involving plantar loadings. Results in this study also show that PTI changes during gait should be equally evaluated clinically along with peak plantar pressure analysis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Musculoskeletal injuries, a public health priority also in the military context, are ascribed to several risk factors, including: increased reaction forces; low/reduced muscle strength, endurance, body mass, Vitamin D level, and bone density; inadequate lifestyles and environment. The MOVIDA Project-funded by the Italian Ministry of Defence-aims at developing a transportable toolkit (assessment instrumentation, assessment protocols and reference/risk thresholds) which integrates motor function assessment with biological, environmental and behavioural factors to help characterizing the risk of stress fracture, stress injury or muscle fatigue due to mechanical overload. The MOVIDA study has been designed following the STROBE guidelines for observational cross-sectional studies addressing healthy adults, both militaries and civilians, with varying levels of physical fitness (sedentary people, recreational athletes, and competitive athletes). The protocol of the study has been designed and validated and is hereby reported. It allows to collect and analyse anamnestic, diagnostic and lifestyle-related data, environmental parameters, and functional parameters measured through portable and wearable instrumentation during adapted 6 minutes walking test. The t-test, one and two-way ANOVA with post-hoc corrections, and ANCOVA tests will be used to investigate relevant differences among the groups with respect to biomechanical parameters; non-parametric statistics will be rather used for non-normal continuous variables and for quantitative discrete variables. Generalized linear models will be used to account for risk and confounding factors., Competing Interests: The authors have declared that no competing interests exist.

Background: Typical gait is often considered to be highly symmetrical, with gait asymmetries typically associated with pathological gait. Whilst gait symmetry is often expressed in symmetry ratios, measures of symmetry do not provide insight into how these asymmetries affect gait variables. To fully understand changes caused by gait asymmetry, we must first develop a normative database for comparison. Therefore, the aim of this study was to describe normative reference values of regional plantar load and present comparisons with two pathological case studies., Methods: A descriptive study of the load transfer of plantar pressures in typically developed children was conducted to develop a baseline for comparison of the effects of gait asymmetry in paediatric clinical populations. Plantar load and 3D kinematic data was collected for 17 typically developed participants with a mean age of 9.4 ± 4.0 years. Two case studies were also included; a 10-year-old male with clubfoot and an 8-year-old female with a flatfoot deformity. Data was analysed using a kinematics-pressure integration technique for anatomical masking into 5 regions of interest; medial and lateral forefoot, midfoot, and medial and lateral hindfoot., Results: Clear differences between the two case studies and the typical dataset were seen for the load transfer phase of gait. For case study one, lateral bias was seen in the forefoot of the trailing foot across all variables, as well as increases in contact area, force and mean pressure in the lateral hindfoot of the leading foot. For case study two, the forefoot of the trailing foot produced results very similar to the typical dataset across all variables. In the hindfoot of the leading foot, medial bias presents most notably in the force and mean pressure graphs., Conclusions: This study highlights the clinical significance of the load transfer phase of gait, providing meaningful information for intervention planning.

Children born small for gestational age (SGA), and failing to catch-up growth in their early years, are a heterogeneous group, comprising both known and undefined congenital disorders. Care for these children must encompass specific approaches to ensure optimal growth. The use of recombinant human growth hormone (rhGH) is an established therapy, which improves adult height in a proportion of these children, but not with uniform magnitude and not in all of them. This situation is complicated as the underlying cause of growth failure is often diagnosed during or even after rhGH treatment discontinuation with unknown consequences on adult height and long-term safety. This review focuses on the current evidence supporting potential benefits from early genetic screening in short SGA children. The pivotal role that a Next Generation Sequencing panel might play in helping diagnosis and discriminating good responders to rhGH from poor responders is discussed. Information stemming from genetic screening might allow the tailoring of therapy, as well as improving specific follow-up and management of family expectations, especially for those children with increased long-term risks. Finally, the role of national registries in collecting data from the genetic screening and clinical follow-up is considered., Competing Interests: CG received honoraria from Novo Nordisk for consultancies as an expert board member; honoraria from Merck Serono as a medical advisor; honoraria from Ferring for article authorship. CG has no non-financial relationships (personal, political, or professional) that may potentially influence the writing of this manuscript., (Copyright © 2021 Giacomozzi.)

Overuse-related musculoskeletal injuries mostly affect athletes, especially if involved in preseason conditioning, and military populations; they may also occur, however, when pathological or biological conditions render the musculoskeletal system inadequate to cope with a mechanical load, even if moderate. Within the MOVIDA (Motor function and Vitamin D: toolkit for risk Assessment and prediction) Project, funded by the Italian Ministry of Defence, a systematic review of the literature was conducted to support the development of a transportable toolkit (instrumentation, protocols and reference/risk thresholds) to help characterize the risk of overuse-related musculoskeletal injury. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) approach was used to analyze Review papers indexed in PubMed and published in the period 2010 to 2020. The search focused on stress (overuse) fracture or injuries, and muscle fatigue in the lower limbs in association with functional (biomechanical) or biological biomarkers. A total of 225 Review papers were retrieved: 115 were found eligible for full text analysis and led to another 141 research papers derived from a second-level search. A total of 183 papers were finally chosen for analysis: 74 were classified as introductory to the topics, 109 were analyzed in depth. Qualitative and, wherever possible, quantitative syntheses were carried out with respect to the literature review process and quality, injury epidemiology (type and location of injuries, and investigated populations), risk factors, assessment techniques and assessment protocols.

Background: Measurements of plantar loading reveal foot-to-floor interaction during activity, but information on bone architecture cannot be derived. Recently, cone-beam computer tomography (CBCT) has given visual access to skeletal structures in weight-bearing. The combination of the two measures has the potential to improve clinical understanding and prevention of diabetic foot ulcers. This study explores the correlations between static 3D bone alignment and dynamic plantar loading., Methods: Sixteen patients with diabetes were enrolled (group ALL): 15 type 1 with (N, 7) and without (D, 8) diabetic neuropathy, and 1 with latent autoimmune diabetes. CBCT foot scans were taken in single-leg upright posture. 3D bone models were obtained by image segmentation and aligned in a foot anatomical reference frame. Absolute inclination and relative orientation angles and heights of the bones were calculated. Pressure patterns were also acquired during barefoot level walking at self-selected speed, from which regional peak pressure and absolute and normalised pressure-time integral were worked out at hallux and at first, central and fifth metatarsals (LOAD variables) as averaged over five trials. Correlations with 3D alignments were searched also with arch index, contact time, age, BMI, years of disease and a neuropathy-related variable., Results: Lateral and 3D angles showed the highest percentage of significant (p < 0.05) correlations with LOAD. These were weak-to-moderate in the ALL group, moderate-to-strong in N and D. LOAD under the central metatarsals showed moderate-to-strong correlation with plantarflexion of the 2nd and 3rd phalanxes in ALL and N. LOAD at the hallux increased with plantarflexion at the 3rd phalanx in ALL, at 1st phalanx in N and at 5th phalanx in D. Arch index correlated with 1st phalanx plantarflexion in ALL and D; contact time showed strong correlation with 2nd and 3rd metatarsals and with 4th phalanx dorsiflexion in D., Conclusion: These preliminary original measures reveal that alteration of plantar dynamic loading patterns can be accounted for peculiar structural changes of foot bones. Load under the central metatarsal heads were correlated more with inclination of the corresponding phalanxes than metatarsals. Further analyses shall detect to which extent variables play a role in the many group-specific correlations.

Improving healthy life years requires an effective understanding and management of the process of healthy ageing. Assessing the perceived health status and its determinants is a relevant step in this process. This study explored the potentialities of the Minimum European Health Module (MEHM) to cope with this critical issue. Investigation was conducted on 4798 Italian residents (49.7% women, aged 35-79 years), participating in the CUORE Project Health Examination Survey 2008-2012. The three MEHM questions-perceived health status, chronic morbidity and activity limitations-were examined also in association with living context, seasonality, marital status and level of education. A higher prevalence of health status negative perception was associated with older age (9% and 24% respectively in men and women aged 35-44 years; 46% and 61% respectively in men and women aged 75-79 years). In women, this negative perception was higher than in men in any age group, and reached 50% in the 65-69 age group, 10 years earlier than in men. For both sexes, the level of education had a strong impact on this negative perception (odds ratio 2.32 and 2.72 in men and women respectively), while "living alone" played a greater impact in women than in men. MEHM activity limitations subscale was as much as 30% higher for questionnaires answered during the hottest months. This study identified potential predictors of perceived health status in adults aged 35-79 years, which can be used to target interventions aimed at improving self-perceived health status.

Background: Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis., Methods: This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs)., Findings: The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1·1, 95% CI 0·9-1·3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1·5, CI 1·1-1·9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3·8, 3·3-4·4; and 17·1, 15·6-18·7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups., Interpretation: In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance., Funding: European Union., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Musculoskeletal radiology has been mostly limited by the option between imaging under load but in two dimensions (i.e., radiographs) and three-dimensional (3D) scans but in unloaded conditions (i.e., computed tomography [CT] and magnetic resonance imaging in a supine position). Cone-beam technology is now also a way to image the extremities with 3D and weight-bearing CT. This article discusses the initial experience over a few studies in progress at an orthopaedic center. The custom design of total ankle replacements, the patellofemoral alignment after medial ligament reconstruction, the overall architecture of the foot bones in the diabetic foot, and the radiographic assessment of the rearfoot after subtalar fusion for correction of severe flat foot have all taken advantage of the 3D and weight-bearing feature of relevant CT scans. To further support these novel assessments, techniques have been developed to obtain 3D models of the bones from the scans and to merge these with state-of-the-art gait analyses., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Plantar pressure is critical in the onset of neuropathic foot ulcers. However, risk classifications do not consider it as a stratification parameter. Whether plantar pressure distribution affects ulcer-risk was investigated. Patients from a research study (n. 134) and from a clinical environment (n. 83) were classified into ulcer-risk groups according to the International Working Group on the Diabetic Foot guidelines. Pressure distribution was acquired during gait (Pedar-X System), and assessed for hindfoot, midfoot, forefoot and toes (1way- and 2way-ANOVAs, p < 0.05). Pressure distribution changed with polyneuropathy even in the low-risk groups: median p = 0.048 (0.001-0.223). Risk classification correlated poorly with pressure distribution: median p = 0.686 (0.374-0.828). BMI, age and walking speed influenced most parameters and rendered the studies almost impossible to compare (2-way ANOVA factor A > 0.05). Pressure-time integral, the only comparable parameter between the two studies, may increase the predictive capacity of ulcer-risk stratification models.

Background and Aim: Food quality control techniques based on process control methods are increasingly adopted in livestock production systems to fulfill increasing market's expectations toward competitiveness and issues linked to One Health pillars (environment, animal, and human health). Control Charts allow monitoring and systematic investigation of sources of variability in dairy production parameters. These parameters, however, may be affected by seasonal variations that render impractical, biased or ineffective the use statistical control charts. A possible approach to this problem is to adapt seasonal adjustment methods used for the analysis of economic and demographic seasonal time series. The aim of the present work is to evaluate a seasonal decomposition technique called X-11 on milk parameters routinely collected also in small farms (fat, protein, and lactose content, solids-not-fat, freezing point, somatic cell count, total bacterial count) and to test the efficacy of different seasonal removal methods to improve the effectiveness of statistical control charting. Method: Data collection was carried out for 3 years on routinely monitored bulk tank milk parameters of a small farm. Seasonality presence was statistically assessed on milk parameters and, for those parameters showing seasonality, control charts for individuals were applied on raw data, on X-11 seasonally adjusted data, and on data smoothed with a symmetric moving average filter. Correlation of seasonally influenced parameters with daily mean temperature was investigated. Results: Presence of seasonality in milk parameters was statistically assessed for fat, protein, and solids-non-fat components. The X-11 seasonally-adjusted control charts showed a reduced number of violations (false alarms) with respect to non-seasonally adjusted control chart (from 5 to 1 violation for fat, from 17 to 1 violation for protein, and from 9 to none violation for solids-non-fat.). This result was achieved despite stricter control chart limits: with respect to raw data charts, the interval of control chart allowed variation (UCL-LCL) was reduced by 43% for fat, by 33.1% for protein, and by 14.3% for solids-not-fat. Conclusions: X-11 deseasonalization of routinely collected milk parameters was found to be an effective method to improve control chart application effectiveness in farms and milk collecting centers.

Introduction: During rowing, foot positioning on the foot stretcher is critical to optimise muscle force transmission and boat propulsion. Following the beneficial effects of textured insoles on gait and balance, this study aims at investigating whether passive stimulation of foot mechanoreceptors induced by these insoles may contribute to improving foot loading pattern and symmetry during indoor rowing., Methods: Eleven elite rowers were assessed during controlled training on a standard rowing machine while wearing control, low-density or high-density textured insoles. Plantar pressure and knee and trunk kinematics were measured; performance data were recorded from the machine. Insole effect on kinematic parameters, peak and average values of foot force, contact area and position of centre of pressure was assessed with ANOVA and Bonferroni correction for pair-wise comparisons., Results: A main effect was observed for force and contact area, with the high-density insoles providing greatest values (P<0.035). No interaction was observed between side and insole (P>0.190), even though symmetry was higher with high-density insoles. Kinematics (P = 0.800) and rowing performance were not affected by insole type; a consistent though not statistically significant increase in mean travelled distance was observed for denser insoles (P>0.21)., Conclusion: The high-density textured insoles affected foot loading distribution during indoor rowing. Rowers applied greater foot force and over a greater foot stretcher area with the high-density than the low-density and control insoles. These findings and the methodology applied may be relevant for the understanding and monitoring of rowing performance.

Introduction Despite the increased interest in telerehabilitation (TR), virtual reality (VR) and outcome measures for stroke rehabilitation, surprisingly little research has been done to map and identify the most common outcome measures used in TR. For this review, we conducted a systematic search of the literature that reports outcome measures used in TR or VR for stroke rehabilitation. Our specific objectives included: 1) to identify the outcome measures used in TR and VR studies; and 2) to describe which parts of the International Classification of Functioning are measured in the studies. Methods We conducted a comprehensive search of relevant electronic databases (e.g. PubMed, the Cumulative Index to Nursing and Allied Health Literature, Embase, PSYCOINFO, The Cochrane Central Register of Controlled Trial and the Physiotherapy Evidence Database). The scoping review included all study designs. Two reviewers conducted pilot testing of the data extraction forms and independently screened all the studies and extracted the data. Disagreements about inclusion or exclusion were resolved by consensus or by consulting a third reviewer. Results In total, 28 studies were included in this scoping review. The results were synthesized and reported considering the implications of the findings within the clinical practice and policy context. Discussion This scoping review identified a wide range of outcome measures used in VR and TR studies and helped identify gaps in current use of outcome measures in the literature. The review also informs researchers and end users (i.e. clinicians, policymakers and researchers) regarding the most appropriate outcome measures for TR or VR.

Context: Growth hormone (GH) is prescribed for an increasing range of indications, but there has been concern that it might raise cancer risk. Published data are limited., Objective: To examine cancer risks in relation to GH treatment., Design: Cohort study., Setting: Population-based., Patients: Cohort of 23,984 patients treated with recombinant human GH (r-hGH) in eight European countries since this treatment was first used in 1984. Cancer expectations from country-specific national population statistics., Main Outcome Measures: Cancer incidence and cancer mortality., Results: Incidence and mortality risks in the cohort were raised for several cancer sites, largely consequent on second primary malignancies in patients given r-hGH after cancer treatment. There was no clear raised risk in patients with growth failure without other major disease. Only for bone and bladder cancers was incidence significantly raised in GH-treated patients without previous cancer. Cancer risk was unrelated to duration or cumulative dose of r-hGH treatment, but for patients treated after previous cancer, cancer mortality risk increased significantly with increasing daily r-hGH dose (P trend < 0.001). Hodgkin lymphoma (HL) incidence increased significantly with longer follow-up (P trend = 0.001 for patients overall and 0.002 for patients without previous cancer)., Conclusions: Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and HL risks, need further investigation., (Copyright © 2017 Endocrine Society)

Plantar pressure analysis is widely used in the assessment of foot function. In order to assess regional loading, a mask is applied to the footprint to sub-divide it into regions of interest (ROIs). The most common masking method is based on geometric features of the footprint (GM). Footprint masking based on anatomical landmarks of the foot has been implemented more recently, and involves the integration of a 3D motion capture system, plantar pressure measurement device, and a multi-segment foot model. However, thorough validation of anatomical masking (AM) using pathological footprints has not yet been presented. In the present study, an AM method based on the Oxford Foot Model (OFM) was compared to an equivalent GM. Pressure footprints from 20 young healthy subjects (HG) and 20 patients with clubfoot (CF) were anatomically divided into 5 ROIs using a subset of the OFM markers. The same foot regions were also identified by using a standard GM method. Comparisons of intra-subject coefficient of variation (CV) showed that the OFM-based AM was at least as reliable as the GM for all investigated pressure parameters in all foot regions. Clinical relevance of AM was investigated by comparing footprints from HG and CF groups. Contact time, maximum force, force-time integral and contact area proved to be sensitive parameters that were able to distinguish HG and CF groups, using both AM and GM methods However, the AM method revealed statistically significant differences between groups in 75% of measured variables, compared to 62% using a standard GM method, indicating that the AM method is more sensitive for revealing differences between groups., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Plantar load can be considered as a measure of the foot ability to transmit forces at the foot/ground, or foot/footwear interface during ambulatory activities via the lower limb kinematic chain. While morphological and functional measures have been shown to be correlated with plantar load, no exhaustive data are currently available on the possible relationships between range of motion of foot joints and plantar load regional parameters. Joints' kinematics from a validated multi-segmental foot model were recorded together with plantar pressure parameters in 21 normal-arched healthy subjects during three barefoot walking trials. Plantar pressure maps were divided into six anatomically-based regions of interest associated to corresponding foot segments. A stepwise multiple regression analysis was performed to determine the relationships between pressure-based parameters, joints range of motion and normalized walking speed (speed/subject height). Sagittal- and frontal-plane joint motion were those most correlated to plantar load. Foot joints' range of motion and normalized walking speed explained between 6% and 43% of the model variance (adjusted R 2 ) for pressure-based parameters. In general, those joints' presenting lower mobility during stance were associated to lower vertical force at forefoot and to larger mean and peak pressure at hindfoot and forefoot. Normalized walking speed was always positively correlated to mean and peak pressure at hindfoot and forefoot. While a large variance in plantar pressure data is still not accounted for by the present models, this study provides statistical corroboration of the close relationship between joint mobility and plantar pressure during stance in the normal healthy foot., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: The increasing spread of software components in the healthcare context renders explanatory guides relevant and mandatory to interpret laws and standards, and to support safe management of software products in healthcare., Methodology: In 2012 a working group has been settled for the above purposes at Italian Electrotechnical Committee (CEI), made of experts from Italian National Institute of Health (ISS), representatives of industry, and representatives of the healthcare organizations., Results: As a first outcome of the group activity, Guide CEI 62-237 was published in February 2015. The Guide incorporates an innovative approach based on the proper contextualization of software products, either medical devices or not, to the specific healthcare scenario, and addresses the risk management of IT systems., Conclusions: The Guide provides operators and manufacturers with an interpretative support with many detailed examples to facilitate the proper contextualization and management of health software, in compliance with related European and international regulations and standards.

Objective: Measurement of urinary LH (uLH) and FSH (uFSH) may facilitate non-invasive pubertal assessment but there is a need for further validation by studying children and adolescents with disorders of puberty., Design: 65 cases (Male: 25) with a median age of 12 years (2.9-18.1) supplied at least one non-timed urine sample for uLH and uFSH measurement by immunoassay and corrected for creatinine excretion. 25 cases were receiving GnRH-agonist (GnRH-a) at the time of sample collection. In 41 cases, urine samples were collected prior to a LHRH test and in 12 cases matched serum samples for basal LH (sLH) and FSH (sFSH) were also available., Results: There was a significant correlation between sLH and uLH:uCr (r=0.82; p-value <0.001) and sFSH and uFSH:uCr (r=0.93; p-value <0.001). Based on receiver operator characteristics analysis, a uLH:uCr value of 0.05 IU/mmol as a cut-off would detect a LH peak >5U I/L with a sensitivity of 86% and a specificity of 72% with a positive predictive value of 93%. In pubertal boys (6) and girls (22) with a sLH peak >5UI/L, median uLH:uCr was 0.27 IU/mmol (0.27-0.28) and 0.17 IU/mmol (0.09-0.43), respectively. The median uFSH:uCr was 0.51 IU/mmol (0.41-0.60) for boys and 1.1 IU/mmol (0.21-2.44) for girls. In the 25 cases on GnRH-a, the median uLH:uCr for boys and girls was 0.02 IU/mmol (0.01-0.02) and 0.02 IU/mmol (0.004-0.07), respectively, and the median uFSH:uCr was 0.07 IU/mmol (0.05-0.09) and 0.27 IU/mmol (0.09-0.54), respectively., Conclusion: Urinary gonadotrophins reflect serum gonadotrophin concentration and may represent a reliable non-invasive method of assessing pubertal progress.

Aims: To evaluate the quality of systematic reviews on telemedicine applications in palliative care., Methods: A structured literature review was conducted to identify systematic reviews dealing with telemedicine in palliative care; the AMSTAR (Assessment of Multiple Systematic Reviews) checklist was used to appraise the evidence related to the systematic reviews., Results: 405 records were initially identified; of these 14 were eligible for full-text analysis. In summary, the research strategy allowed the identification of 6 reviews to be included which showed a medium quality (AMSTAR score in between 4 and 7). All the included systematic reviews considered telemedicine applications as a feasible means to be used in palliative care; however, the positive findings are counterbalanced by several critical issues mainly related to the evidence from the primary studies included in each single review., Conclusions: Results of this first attempt to appraise the evidence in the field of telemedicine applications in palliative care highlighted that there is still limited evidence related to this approach. Strengths and weaknesses that impact on the general quality of the reviews were identified and relevant points to be taken into account for future research were suggested.

Unlabelled: Despite the increased interest about tele-rehabilitation, virtual reality and outcome measures for stroke rehabilitation, surprisingly little research has been done to map and summarize the most common outcome measures used in tele-rehabilitation. For this review, we propose to conduct a systematic search of the literature that reports outcome measures used in tele-rehabilitation or virtual reality for stroke rehabilitation. Specific objectives include: 1) to identify the outcome measures used in tele-rehabilitation studies; 2) to describe the psychometric properties of the outcome measures in the included studies; 3) to describe which parts of the International Classification of Functioning are measured in the studies., Methods: we will conduct a comprehensive search of relevant electronic databases (e.g., PUBMED, CINAHL, EMBASE, PSYCOINFO, Cochrane Central Register of Controlled Trial and PEDRO). The scoping review will include all study designs. Two reviewers will pilot-test the data extraction forms and will independently screen all the studies and extract the data. Disagreements about inclusion or exclusion will be resolved by consensus or by consulting a third reviewer. The results will be synthesized and reported considering the implications of the findings within the clinical practice and policy context. Dissemination: we anticipate that this scoping review will contribute to inform researchers and end-users (ie, clinicians and policy-makers), regarding the most appropriate outcome measures for tele-rehabilitation or virtual reality as well as help to identify gaps in current measures. Results will be disseminated through reports and open access journals, conference presentations, as well as newsletters, podcasts and meetings targeting all the relevant stakeholders.

Background: Recombinant human growth hormone (rhGH) is being used to promote linear growth in short children with Noonan syndrome. However, its efficacy is still controversial., Aims: To systematically determine the impact of rhGH therapy on adult height in children with Noonan syndrome., Methods: We searched the Cochrane Central Register of Controlled Trials, ISI Web of Science, MEDLINE, and the bibliographic references from all retrieved articles published until April 2014. Studies reporting adult/near-adult height in children with Noonan syndrome treated with rhGH or reporting at least a 3-year follow-up were analysed. Quality and strength of recommendation were assessed according to the Endocrine Society criteria., Results: No controlled trials reporting adult height were available. Five studies were identified reporting adult height or near adult height. Data comparison showed inter-individual variability in the response to rhGH, mean height gain standard deviation score ranging between 0.6 and 1.4 according to national standards, and between 0.6 and 2 according to Noonan standards. Significant biases affected all the studies., Conclusions: High-quality controlled trials on the impact of rhGH therapy on adult height are lacking, and the robustness of available data is not sufficient to recommend such therapy in children with Noonan syndrome., (© 2015 S. Karger AG, Basel.)

Unlabelled: Extrauterine growth retardation (EUGR) seriously affects premature newborns and is related to the impairment of growth during childhood. There are very limited data available concerning the growth outcome of EUGR children. Our aim was to assess the growth outcome in a cohort of children born before 34 weeks of gestation with severe EUGR. This was a retrospective multicenter study, performed in outpatient endocrinology clinic. A total of 103 premature children with weight and/or length below -2 standard deviation score (SDS) of "intrauterine" growth expectation at the time of discharge from hospital (within 42 weeks of postmenstrual age) were included in the study. The study participants underwent a thorough anthropometric assessment at a mean age of 3.9 years ± 1.7 SD. Of the EUGR children, 12.6 % showed a height below -2 SDS and 7.7 % even below -2.5 SDS. Growth impairment was more common in males than in females (17 vs. 8 %). The prevalence of subnormal weight (below -2 SDS) was 13.6 %, being higher in males than in females (17 vs. 10 %). BMI values below -2 SDS were found in 18.4 % of our study population (22.7 % in males and 12 % in females). The 19.6 % of EUGR children did not catch up in head circumference during early childhood. Length at term was the major predictor of height in childhood (P < 0.001)., Conclusion: A significant proportion of children born prematurely with severe EUGR show growth retardation in childhood thus suggesting the need for a close clinical follow-up to determine their growth potential and implement effective intervention strategies.

Aims: To evaluate the quality of systematic reviews on telerehabilitation., Methods: The AMSTAR--Assessment of Multiple Systematic Reviews--checklist was used to appraise the evidence related to the systematic reviews., Results: Among the 477 records initially identified, 10 systematic reviews matched the inclusion criteria. Fifty percent were of high quality; anyway the majority of them did not report the following aspects: i) analysis of the grey literature; ii) a list of the excluded studies and their characteristics; iii) the identification of possible source of bias and the assessment of its likehood; iv) an appropriate method to combine the findings of the included studies addressing the heterogeneity as well. From the main findings of the high-scored systematic reviews telerehabilitation resulted at least as effective as usual care: 1) in the short term treatment of mental health related to people affected by spinal cord injury; 2) in rural communities for treating patients affected by chronic conditions; 3) in treating common pathologies (mainly asthma) affecting children and adolescents. As for stroke, evidence is currently insufficient to reach conclusions about its effectiveness. As for costs, there is insufficient evidence to confirm that telerehabilitation is a cost-saving or cost-effective solution., Conclusions: In the authors' knowledge this is the first attempt to evaluate the quality of systematic reviews on telerehabilitation. This work also identified the main findings related to the high-scored systematic reviews; the analysis confirms that there is a mounting evidence concerning the effectiveness of telerehabilitation, at least for some pathologies.

Background: The long-term safety of growth hormone treatment is uncertain. Raised risks of death and certain cancers have been reported inconsistently, based on limited data or short-term follow-up by pharmaceutical companies., Patients and Methods: The SAGhE (Safety and Appropriateness of Growth Hormone Treatments in Europe) study assembled cohorts of patients treated in childhood with recombinant human growth hormone (r-hGH) in 8 European countries since the first use of this treatment in 1984 and followed them for cause-specific mortality and cancer incidence. Expected rates were obtained from national and local general population data. The cohort consisted of 24,232 patients, most commonly treated for isolated growth failure (53%), Turner syndrome (13%) and growth hormone deficiency linked to neoplasia (12%). This paper describes in detail the study design, methods and data collection and discusses the strengths, biases and weaknesses consequent on this., Conclusion: The SAGhE cohort is the largest and longest follow-up cohort study of growth hormone-treated patients with follow-up and analysis independent of industry. It forms a major resource for investigating cancer and mortality risks in r-hGH patients. The interpretation of SAGhE results, however, will need to take account of the methods of cohort assembly and follow-up in each country., (© 2015 The Author(s) Published by S. Karger AG, Basel.)

Baropodometry and multi-segmental foot kinematics are frequently employed to obtain insight into the mechanics of the foot-ground interaction in both basic research and clinical settings. However, nothing hitherto has been reported on the full integration of kinematics with baropodometric parameters, and only a few studies have addressed the association between intersegmental kinematics and plantar loading within specific foot regions. The aim of this study was to understanding the relationships between foot joint mobility and plantar loading by focusing on the correlation between these two measures. An integrated pressure-force-kinematics system was used to measure plantar pressure and rotations between foot segments during the stance phase of walking in 10 healthy subjects. An anatomically-based mask was applied to each footprint to obtain six regions according to the position of the markers; hence each kinematic segment was paired with a corresponding area of the plantar surface. Relationships between segmental motion and relevant baropodometric data were explored by means of correlation analysis. Negative, weak-to-moderate correlations (R(2)<0.5) were found between pressure (mean and peak) and inter-segmental range of motion across all foot joints except the Calcaneus-Midfoot. Temporal profiles of sagittal-plane kinematics and baropodometric parameters were well correlated, particularly at the ankle joint. Larger motion in the foot joints during walking was associated with lower plantar pressure in almost all regions. The study helps improve our understanding of the relationship between joint mobility and plantar loading in the healthy foot and represents a critical preliminary analysis before addressing possible clinical applications., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Central precocious puberty (CPP) and phenylketonuria (PKU) are two rare conditions, the latter being the rarer. To date, only one case featuring both these conditions has been reported, and hyperphenylalaninemia was assumed triggering CPP., Case Presentation: We present a 3.2 years old girl referred with a 12 months history of breast and pubic hair development, and vaginal discharge. Hyperphenylalaninemia had been identified by newborn screening and PKU subsequently confirmed by plasma amino acid and genetic analysis. Early dietary control of plasma phenylalanine had been excellent afterwards, resulting in phenylalanine concentrations consistently within the recommended range. Clinical scenario, hormonal assessment and imaging were in keeping with true idiopathic central precocious puberty. Treatment with long lasting gonadotropin-releasing hormone analogue led to regression of secondary sexual characteristics., Conclusion: We describe for the first time CPP in a girl affected with PKU but with persistently well controlled blood phenylalanine concentrations. This finding is in contrast to a previous report which suggested persistently high phenylalaninemia levels as potential trigger for CPP in PKU patients. Our report, together with the lack of evidence in published cohort studies of children with PKU, strongly suggests this rare association is coincidental and independent of the presence of severe hyperphenylalaninemia.

Background: Foot musculoskeletal deficits are seldom addressed by preventive medicine despite their high prevalence in patients with diabetic polyneuropathy., Aim: To investigate the effects of strengthening, stretching, and functional training on foot rollover process during gait., Methods: A two-arm parallel-group randomized controlled trial with a blinded assessor was designed. Fifty-five patients diagnosed with diabetic polyneuropathy, 45 to 65 years-old were recruited. Exercises for foot-ankle and gait training were administered twice a week, for 12 weeks, to 26 patients assigned to the intervention group, while 29 patients assigned to control group received recommended standard medical care: pharmacological treatment for diabetes and foot care instructions. Both groups were assessed after 12 weeks, and the intervention group at follow-up (24 weeks). Primary outcomes involved foot rollover changes during gait, including peak pressure (PP). Secondary outcomes involved time-to-peak pressure (TPP) and pressure-time integral (PTI) in six foot-areas, mean center of pressure (COP) velocity, ankle kinematics and kinetics in the sagittal plane, intrinsic and extrinsic muscle function, and functional tests of foot and ankle., Results: Even though the intervention group primary outcome (PP) showed a not statistically significant change under the six foot areas, intention-to-treat comparisons yielded softening of heel strike (delayed heel TPP, p=.03), better eccentric control of forefoot contact (decrease in ankle extensor moment, p<.01; increase in function of ankle dorsiflexion, p<.05), earlier lateral forefoot contact with respect to medial forefoot (TPP anticipation, p<.01), and increased participation of hallux (increased PP and PTI, p=.03) and toes (increase in PTI, medium effect size). A slower COP mean velocity (p=.05), and an increase in overall foot and ankle function (p<.05) were also observed. In most cases, the values returned to baseline after the follow-up (p<.05)., Conclusions: Intervention discreetly changed foot rollover towards a more physiological process, supported by improved plantar pressure distribution and better functional condition of the foot ankle complex. Continuous monitoring of the foot status and patient education are necessary, and can contribute to preserving the integrity of foot muscles and joints impaired by polyneuropathy., Trial Registration: ClinicalTrials.gov Identifier: NCT01207284, registered in 20th September 2010.