The genomic trajectory of ovarian high-grade serous carcinoma can be observed in STIC lesions.

Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a TP53 mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinoma (STIC) lesions, which in turn progress into invasive HGSC, which readily spreads to the ovary and disseminates around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole-genome duplication (WGD) observed in late-stage disease were determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded (FFPE) samples from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole-genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next-generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was a strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of WGD, arises early in HGSC and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Epithelial ovarian cancer and brain metastases: might the BRCA status, PARP inhibitor administration, and surgical treatment impact the survival?

OBJECTIVE: To evaluate disease characteristics and survival according to BRCA status, administration of poly-(ADP-ribose) polymerase inhibitors (PARPi), and surgery in patients with ovarian cancer and brain metastases. METHODS: This is a monocentric retrospective cohort of patients with ovarian cancer and brain metastases treated between 2000 and 2021. Data were collected by a retrospective review of medical records and analyzed according to: (1) BRCA mutation; (2) PARPi before and after brain metastases; (3) surgery for brain metastases. RESULTS: Eighty-five patients with ovarian cancer and brain metastasis and known BRCA status (31 BRCA mutated (BRCAm), 54 BRCA wild-type (BRCAwt)) were analyzed. Twenty-two patients had received PARPi before brain metastases diagnosis (11 BRCAm, 11 BRCAwt) and 12 after (8 BRCAm, 4 BRCAwt). Brain metastases occurred >1 year later in patients who had received previous PARPi. Survival was longer in the BRCAm group (median post-brain metastasis survival: BRCAm 23 months vs BRCAwt 8 months, p=0.0015). No differences were found based on BRCA status analyzing the population who did not receive PARPi after brain metastasis (median post-brain metastasis survival: BRCAm 8 months vs BRCAwt 8 months, p=0.31). In the BRCAm group, survival was worse in patients who had received previous PARPi (median post-brain metastasis survival: PARPi before, 7 months vs no-PARPi before, 24 months, p=0.003). If PARPi was administered after brain metastases, survival of the overall population improved (median post-brain metastasis survival: PARPi after, 46 months vs no-PARPi after, 8 months, p=0.00038).In cases of surgery for brain metastases, the prognosis seemed better (median post-brain metastasis survival: surgery 13 months vs no-surgery 8 months, p=0.036). Three variables were significantly associated with prolonged survival at multivariate analysis: BRCA mutation, multimodal treatment, and ≤1 previous chemotherapy line. CONCLUSIONS: BRCA mutations might impact brain metastasis occurrence and lead to better outcomes. In a multimodal treatment, surgery seems to affect survival even in cases of extracranial disease. PARPi use should be considered as it seems to prolong survival if administered after brain metastasis.

Do Brazilian regulatory measures promote sustainable and healthy eating in the school food environment?

BACKGROUND: Regulatory measures regarding food in the school environment aim to promote a healthier food environment in public and private schools. In Brazil, implementing regulations in the school food environment does not occur the same way across states and cities, and no national regulation covers public and private schools. The present study aims to analyze regulatory measures for school food environments in Brazilian states and cities and develop a score to evaluate them. METHODS: A systematic search of the regulatory measures in force and implemented until 2021 was conducted. The score was developed based on the Model Law Project prepared by the Brazilian Institute for Consumer Protection. It considered food and nutrition education actions, restrictions on the sale and distribution of food, a ban or restriction on food advertising and marketing, and points of excellence. These points included regulations that addressed the importance of supervision and social control, laws regulated by decree, the mention of a ban on ultra-processed foods, and whether the regulatory measures covered public and private schools. RESULTS: Sixty-five cities and states regulatory measures in force were found to be evaluated jointly by a federal entity (n = 43). Among the federal entities evaluated, only 13.95% fulfilled the function of promoting sustainable and healthy eating (8-12 points). CONCLUSIONS: Brazilian children and adolescents are exposed to a school food environment with regulations that partially fulfill the function of promoting an adequate, healthy, and sustainable diet. In this sense, it is necessary to improve regulatory measures or to encourage states and cities to develop effective legal provisions that are in line with the food guide for the Brazilian population and with the perspective of a healthy school food environment for the effective promotion of adequate, healthy and sustainable and healthy food in schools.

Educar para o comer e o comer para educar: o processo de articulação e compreensão da prática da intersetorialidade entre as Políticas de Alimentação Escolar e Segurança Alimentar e Nutricional na promoção da alimentação adequada e saudável / Educating to eat and eating to educate: the process of articulating and understanding the practice of intersectoriality between School Feeding Policies and Food and Nutritional Security in promoting adequate and healthy eating

As políticas de alimentação e educação são agendas estratégicas para analisar processos de articulação democrática e intersetorialidade já que necessitam de visões integradas e regionalizadas. O Programa Nacional de Alimentação Escolar (PNAE) caracteriza-se como a política pública de maior longevidade do país na área de segurança alimentar e nutricional e a prática da intersetorialidade tornou-se um elemento essencial para concretizar suas diretrizes. A perspectiva da Sociologia da Ação Pública pode ser um importante eixo analítico para apoiar na compreensão dos elementos que promovem a intersetorialidade e participação social, já que reconhece que a ação pública é concebida como um espaço sociopolítico construído principalmente pela atuação dos agentes da política, as dinâmicas internas a esses grupos e as relações de força que exercem entre si. O objetivo deste estudo foi compreender a prática da intersetorialidade e os elementos de intersecção entre as PNAE e segurança alimentar e nutricional (SAN), por meio de uma pesquisa documental do processo de construção do Plano Estadual de Segurança Alimentar e Nutricional do estado de São Paulo (PLANSAN/SP). Foram investigados os elementos de contexto, historicidade e a cronologia das etapas de construção do plano para permitir uma análise relativista dos dados coletados nos documentos. Para coleta de dados, foram identificadas todas as ações relacionadas à educação básica que eram mencionadas nesses documentos e essas menções foram sistematizadas por temas. Os dados encontrados foram analisados e interpretados por meio de uma discussão entre os temas, objeto de pesquisa e referenciais teóricos. Ao analisar as menções por tema ao longo do processo, foi possível observar como as contribuições da sociedade se tornaram propostas finais das conferências e como essas propostas foram ou não consideradas na formulação da política. Nessa sistematização, observou-se que ações da educação básica na política de SAN do estado de São Paulo puderam ser agrupadas em três conceitos-chave: Educação Alimentar e Nutricional, Ambiente Alimentar e garantia do Direito Humano à Alimentação Adequada e Saudável. Esses conceitos-chaves tiveram subcategorias temáticas que apontaram para os pontos práticos de intersecção entre essas políticas e eles foram analisados separadamente. Nessa análise, de forma panorâmica, fica visível o movimento de retroalimentação onde o ambiente educa e a educação gera conscientização e demanda para transformar o ambiente. É possível afirmar que o processo de construção do PLANSAN/SP se mostrou um excelente campo para investigar o processo político complexo de articulação entre SAN e alimentação escolar e permitiu compreender o quanto as ações da alimentação escolar integram a política de segurança alimentar e nutricional reforçando a necessidade dessas políticas serem tratadas de maneira integrada e intersetorial. O estudo ainda indica que com uma boa estruturação do processo democrático, é possível envolver a população na construção das soluções, que tendem a ser mais eficientes e eficazes quando se une diferentes saberes com criatividade. Para consolidação desse processo, é muito importante que se criem mais mecanismos de exigibilidade no estado de São Paulo e principalmente que se implementem formas efetivas e transparentes de monitoramento da execução do PLANSAN/SP.

Food and education policies are strategic agendas to analyze democratic articulation and intersectoriality processes since they are presented from integrated and regionalized visions. The National School Feeding Program (PNAE for its initials in portuguese) is characterized as the longest public policy in the area of food and nutrition security (FNS), and the practice of intersectoriality has become an essential element to implement its guidelines. The perspective of the Sociology of Public Action is an important analytical axis to support the understanding of the elements that promote intersectoriality and social participation, since it recognizes that public action is conceived as a sociopolitical space built mainly by the actions of policy agents and the power relations they exert among themselves. The objective of this study was to understand the practice of intersectionality and the elements of intersection between school feeding policies and FNS, through a documentary research of the construction process of the State Plan for Food and Nutritional Security in the state of São Paulo (PLANSAN/SP- for its initials in portuguese). Elements of context, historicity and the chronology of the construction stages of the plan and their respective documents were investigated to allow a relativistic analysis of the data collected in the documents. All actions related to basic education that were recorded in these documents were identified by reading and these mentions were systematized by themes. The data found were analyzed and interpreted through a discussion between the themes, the research object and the theoretical references. By analyzing mentions by topic throughout the process, it was possible to observe how society's contributions have become final proposals of the conferences and, these proposals, which were considered in the formulation of the policy. In this systematization, it was observed that basic education actions in the FNS policy of the state of São Paulo were grouped into three key concepts: Food and Nutrition Education, Food Environment and guarantee of the Human Right to Adequate and Healthy Food. These key concepts had thematic subcategories that pointed to the practical points of intersection between these policies and they were analyzed separately. In this analysis, in a panoramic way, is visible the feedback movement where the environment educates and education generates awareness and demand to transform the environment. It can be affirmed that that the construction process of PLANSAN/SP proved to be an excellent field to investigate the complex political process of articulation between FNS and school feeding and allow understanding to what extent the food security policy complements the actions of school feeding, and vice versa, reinforcing the need for these policies to be addressed in an integrated and intersectoral manner. The study also indicates that it is possible to involve the population in the construction of solutions with a good structuring of the democratic process, which tend to be more efficient and effective when different types of knowledge are united with creativity. It´s very important to create more enforcement mechanisms in the state of São Paulo and implement effective and transparent ways of monitoring the execution of PLANSAN/SP to consolidate this process.

Risk reducing surgery with peritoneal staging in BRCA1-2 mutation carriers. A prospective study.

INTRODUCTION: International guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) in BRCA1-2 mutations carriers to decrease ovarian cancer occurrence. In this prospective study, we describe the incidence of occult malignancies and the surgical outcomes in asymptomatic BRCA mutation carriers submitted to RRSO. METHODS: Data on BRCA1-2 carriers undergoing RRSO with peritoneal washing and peritoneal/omental biopsies (PeS), between January 2019 until March 2021, were prospectively collected. RESULTS: A total of 132 patients were enrolled: 74 BRCA1 and 58 BRCA2 mutation carriers. 31.1% women underwent RRSO and PeS (16.2% of BRCA1 and 50% of BRCA2 carriers), while 68.9% patients were submitted also to concomitant hysterectomy. Almost all the procedures (99.2%) were performed by minimally invasive surgery. Postoperative complications occurred in twelve patients (9.1%): 10 in the concomitant hysterectomy group and two complications in the RRSO group. At the final pathological examination, 6 (4.5%) occult carcinomas were diagnosed: 3 fallopian tube carcinomas, one ovarian carcinoma and two serous tubal intraepithelial carcinomas (STICs), with negative PeS. Median age of occult carcinomas patients at RRSO was 54 (range: 48-79) years. The mean follow up was 20 (range: 7-34) months. During the follow up, no primary peritoneal cancer has been diagnosed. CONCLUSIONS: Occult pathologic findings in RRSO occurred in 4.5% (3% invasive carcinomas, STIC 1.5%) among our patients. The routine use of peritoneal biopsies does not improve the detection of occult malignancies. Our data confirm the importance of timely performing RRSO in BRCA1-2 carriers.

TRPP2 dysfunction decreases ATP-evoked calcium, induces cell aggregation and stimulates proliferation in T lymphocytes.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is mainly characterised by the development and enlargement of renal cysts that lead to end-stage renal disease (ESRD) in adult patients. Other clinical manifestations of this pathology include hypertension, haematuria, abdominal pain, cardiovascular system alterations and intracranial aneurysms. ADPKD is linked to mutations in either PKD1 or PKD2 that codifies polycystin-1 (PC1) and polycystin-2 (PC2 or TRPP2), respectively. PC1 and TRPP2 are membrane proteins that function as receptor-channel elements able to regulate calcium homeostasis. The function of polycystins has been mainly studied in kidney cells; but the role of these proteins in T lymphocytes is not well defined. METHODS: T lymphocytes were produced from ADPKD1 and ADPKD2 patients as well as from non-ADPKD subjects undergoing renal replacement therapy (RRT) and healthy controls. Protein expression and phosphorylation levels were analysed by western blotting, cell proliferation was calculated by direct counting using trypan blue assay and intracellular calcium concentration was measured by Fura-2 method. RESULTS: PKD2 mutations lead to the significant reduction of TRPP2 expression in T lymphocytes derived from ADPKD patients. Furthermore, a smaller TRPP2 truncated protein in T lymphocytes of patients carrying the mutation R872X in PKD2 was also observed, suggesting that TRPP2 mutated proteins may be stably expressed. The silencing or mutation of PKD2 causes a strong reduction of ATP-evoked calcium in Jurkat cells and ADPKD2 T lymphocytes, respectively. Moreover, T lymphocytes derived from both ADPKD1 and ADPKD2 patients show increased cell proliferation, basal chemotaxis and cell aggregation compared with T lymphocytes from non-ADPKD subjects. Similarly to observations made in kidney cells, mutations in PKD1 and PKD2 dysregulate ERK, mTOR, NFkB and MIF pathways in T lymphocytes. CONCLUSIONS: Because the alteration of ERK, mTOR, NFkB and MIF signalling found in T lymphocytes of ADPKD patients may contribute to the development of interstitial inflammation promoting cyst growth and kidney failure (ESRD), the targeting of inflammasome proteins could be an intriguing option to delay the progression of ADPKD.

Temporal validation of the CT-PIRP prognostic model for mortality and renal replacement therapy initiation in chronic kidney disease patients.

BACKGROUND: A classification tree model (CT-PIRP) was developed in 2013 to predict the annual renal function decline of patients with chronic kidney disease (CKD) participating in the PIRP (Progetto Insufficienza Renale Progressiva) project, which involves thirteen Nephrology Hospital Units in Emilia-Romagna (Italy). This model identified seven subgroups with specific combinations of baseline characteristics that were associated with a differential estimated glomerular filtration rate (eGFR) annual decline, but the model's ability to predict mortality and renal replacement therapy (RRT) has not been established yet. METHODS: Survival analysis was used to determine whether CT-PIRP subgroups identified in the derivation cohort (n = 2265) had different mortality and RRT risks. Temporal validation was performed in a matched cohort (n = 2051) of subsequently enrolled PIRP patients, in which discrimination and calibration were assessed using Kaplan-Meier survival curves, Cox regression and Fine & Gray competing risk modeling. RESULTS: In both cohorts mortality risk was higher for subgroups 3 (proteinuric, low eGFR, high serum phosphate) and lower for subgroups 1 (proteinuric, high eGFR), 4 (non-proteinuric, younger, non-diabetic) and 5 (non-proteinuric, younger, diabetic). Risk of RRT was higher for subgroups 3 and 2 (proteinuric, low eGFR, low serum phosphate), while subgroups 1, 6 (non-proteinuric, old females) and 7 (non-proteinuric, old males) showed lower risk. Calibration was excellent for mortality in all subgroups while for RRT it was overall good except in subgroups 4 and 5. CONCLUSIONS: The CT-PIRP model is a temporally validated prediction tool for mortality and RRT, based on variables routinely collected, that could assist decision-making regarding the treatment of incident CKD patients. External validation in other CKD populations is needed to determine its generalizability.

[Geriatric nephrology: an overview]. / Nefrologia geriatrica: an overview.

INTRODUCTION: Chronic kidney disease (CKD) is a highly prevalent condition and its prevalence is increasing worldwide, particularly in adults aged 70 years. Epidemiological studies showed that as many as 2054% of the older adults suffer from CKD in stages 3-5. Nevertheless the question whether this lower eGFR is a consequence of kidney disease or if it is the result of a physiological aging is still debated, even if it implies a reduced renal reserve and vulnerability to drugs overdose with increased risk of acute kidney injury (AKI). MATERIALS AND METHODS: PubMed search was conducted for available English literature, describing the actual knowledge about specific and frequent issues reported in the acute and chronic kidney disease in older adults. Prospective and retrospective studies, as well as meta-analyses and latest systematic reviews were included. RESULTS: Most of the studies examined and reviewed were discarded for wrong population or intervention or deemed unfit. Only 103 met the inclusion criteria for the review. The studies included in the review were grouped into two areas: chronic and acute kidney disease in older adults and we have analysed the peculiar and frequently found issues in this population. CONCLUSIONS: The geriatric population is increasing worldwide. We should consider peculiar aspects of this population, such as sarcopenia, malnutrition, psychological and cognitive deficits and increased risk of AKI, in order to reach a good quality of life, with improved doctor / patient relationship, a greater adherence to therapy, a reduction in health care costs, and if possible, adequate "end of life", as far as it is approved by the patient and his family. The achievement of these objectives requires an organized work in multidisciplinary teams that evaluate overall the geriatric patient.

Renal replacement therapy in elderly patients: peritoneal dialysis.

Management of chronic uremia in elderly patients presents several clinic and organizational difficulties. Hemodialysis (HD) and chronic peritoneal dialysis (CPD) are both available for the elderly, and the choice depends on the individual, clinical and familial conditions. Several reports have compared the outcomes for older patients treated by HD or peritoneal dialysis, with those for younger or older patients undergoing peritoneal dialysis. CPD is a successful dialysis option for elderly patients, in both patient and technique survival terms. All nutritional parameters are of pivotal importance. Several barriers, such as medical and social factors, physician bias, late referral and education irrespective of the needs of older patients, influence the choice of CPD. The development of assisted peritoneal dialysis, using community-based nurses or health care assistants, can overcome some of the barriers and enable frail older patients to have home-based dialysis treatment. Increasing age is associated with higher peritonitis rates among patients who started CPD in the 1990s, while age is not associated with peritonitis in more recent CPD cohorts, and no greater frequency of adverse outcomes of peritonitis has been seen among those who began CPD after the year 2000. In elderly dialysis patients, the management of quality of life (QOL) is important as well as adequacy of dialysis, nutritional status and survival rate. To obtain a good standard of QOL, it is essential to select carers who are properly educated and who can access an adequate support system, both physical and psychological, to help them cope with their burden.

Maintaining over time clinical performance targets on anaemia correction in unselected population on chronic dialysis at 20 Italian centres. Data from a retrospective study for a clinical audit.

BACKGROUND: The Italian and European Best Practice Guidelines (EBPG) recommend a target haemoglobin value greater than 11 g/dl in most patients with Chronic Kidney Diseases. However, it is still difficult to maintain these values at a steady rate. Thus, the main aim of the study was to evaluate, throughout 2005, how many patients steadily maintained the performance targets related to anaemia treatment. METHODS: The survey was conducted on 3283 patients on haemodialysis (HD) and peritoneal dialysis (PD) at 20 Italian dialysis centres. 540 patients were randomly selected; each centre provided a statistically significant sample proportional to its total number of patients. Maintenance of the following target levels was assessed over time: Haemoglobin (HB) 11-12 gr/dl; Iron: 60-160 mcg/dl; Ferritin: 30-400 mcg/l; Transferrin: 200-360 mg/dl; Transferrin saturation percentage (TSAT %):> 25 <50; Dialysis doses (KT/V): >1.2 <2.0 for non-diabetic HD patients; >1.5 <2.2 for diabetic HD patients; DP: >1.8 <2.5.Outcome included:1- Percentage of target maintenance for each parameter.2- Erythropoietin dose in relation to dialysis techniques, presence of cancer or myeloma, diabetic status, Vitamin B therapy.3- Erythropoietin dose (International Units/kg/week) (IU/kg/wk) depending on: haemoglobin values, hospitalization of more than 3 days. RESULTS: Mean age was 65.1; mean haemoglobin concentration over the whole population was 11.3 gr/dl (Standard Deviation (SD): 0.91). The clinical performance targets were maintained over time as follows: HB: 4.3% (Mean 11.43 gr/dl) (SD: 0.42); Ferritin: 71.1% (Mean: 250.23 mcg/L (SD:104.07); Iron: 95.0% (Mean 59.79 mcg/dl)(SD:16.76); Transferrin: 44.8% (Mean 216.83 mg/dl) (SD: 19,50); TSAT %: in 8.4% (Mean: 34.33% (SD: 6.56); HD KT/V: 61.0% (Mean:1.46) (SD: 0.7); PD KT/V:31.4% (Mean: 2.10) (SD: 0.02). The average weekly dose of Erythropoietin (IU/Kg/Wk) was significantly lower for the peritoneal dialysis technique; the higher haemoglobin values, the lower the Erythropoietin dose (IU/Kg/Wk). CONCLUSION: A very low percentage of patients maintained haemoglobin target values over time. We need to identify precise criteria to evaluate the stability over time of clinical performance targets proposed by the guidelines.

Acute and long-term effects of an exercise program for dialysis patients prescribed in hospital and performed at home.

BACKGROUND: Exercise has positive psychophysical effects on dialysis patients, thus effective programs should be identified. We evaluated the effects of an original 6-month walking program on physical capacity, health-related quality of life (HRQL) and postdialysis fatigue (PDF). METHODS: Thirty-one dialysis patients (19 male, mean age 65 -/+ 11 years) were divided into exercise (group E; n=17) and control (group C; n=14) groups, and evaluated upon entry, after the 6-month program and 19 -/+ 3 months later. Outcome measures were 6-minute walking distance (6MWD), SF-36 scale scores, self-reported PDF and recovery time. E group was assigned 2 daily 10-minute home walking sessions on the nondialysis day at a speed 50% below maximal treadmill speed as determined and updated monthly at the hospital. C group: no exercise. RESULTS: Twenty patients (13 from E, 7 from C) completed the study. The E group, unlike the C group, increased 6MWD (308 -/+ 105 m, to 351 -/+ 118 m, p=0.0007), and HRQL, significantly for bodily pain, physical role and mental health (p<0.05), decreased PDF and recovery time (p<0.05). At the follow-up, 15 patients were reevaluated (9 from E, 6 from C). The E group was still active and showed 6MWD similar to baseline, with a decline of 0.13 -/+ 1.72 m/mo. The C group decreased 6MWD (p=0.026) with a decline of 3.43 -/+ 3.2 m/mo. For both groups, HRQL, PDF and recovery time showed slight variations from baseline. CONCLUSIONS: In dialysis patients, a 6-month exercise program prescribed at the hospital and performed at home improved physical capacity, HRQL and PDF symptoms. Patients maintained an active lifestyle after discharge and showed a slow functional decline over a 2-year period.

Exercise training in peripheral vascular arterial disease in hemodialysis patients: a case report and a review.

BACKGROUND: Peripheral arterial disease (PAD) is frequently diagnosed in subjects with chronic kidney disease. Hemodialysis (HD) patients with PAD show increased morbidity and mortality and health care costs increase. Management of this complication requires time and skill by nephrologists, although negative results are frequent. CASE REPORT: A 59-year-old Caucasian man on HD with advanced lower extremities peripheral disease and massive calcification of a plaque in the abdominal aorta has been enrolled in a home-based exercise training program. His compliance was high and claudication improved. Pain threshold speed (PTS) and maximal walking speed rose from 2.8 and 3.3 to 3.6 and 4.6 Km/h respectively. The increasing functional capability improved his quality of life and changed positively his life-style. CONCLUSIONS: Physical exercise confirms its effectiveness in reducing symptoms due to PAD. A rehabilitation program performed at home at a specific velocity, just below the PTS, and maintained by a metronome appears to be well suited for HD patients because it induces functional improvements and vascular adaptations with low costs.