Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study.

BACKGROUND: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. METHODS: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05. RESULTS: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS. CONCLUSIONS: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.

Access to oncology care in Mali: a qualitative study on breast cancer.

BACKGROUND: Breast cancer is the most common cancer in terms of incidence and mortality among women worldwide, including in Africa, and a rapid increase in the number of new cases of breast cancer has recently been observed in sub-Saharan Africa. Oncology is a relatively new discipline in many West African countries, particularly Mali; thus, little is known about the current state of cancer care infrastructure and oncology practices in these countries. METHODS: To describe the challenges related to access to oncology care in Mali, we used a qualitative approach, following the Consolidated Criteria for Reporting Qualitative Research (COREQ). Thirty-eight semistructured interviews were conducted with health professionals treating cancer in Mali (n = 10), women with breast cancer (n = 25), and representatives of associations (n = 3), and 40 participant observations were conducted in an oncology unit in Bamako. We used the theoretical framework on access to health care developed by Levesque et al. a posteriori to organise and analyse the data collected. RESULTS: Access to oncology care is partly limited by the current state of Mali's health infrastructure (technical platform failures, repeated strikes in university hospitals, incomplete free health care and the unavailability of medicines) and exacerbated by the security crisis that has been occurring the country since 2012. The lack of specialist doctors, combined with limited screening campaigns and a centralised and fragmented technical platform in Bamako, is particularly detrimental to breast cancer treatment. Women's lack of awareness, lack of information throughout the treatment process, stereotypes and opposition to amputations all play a significant role in their ability to seek and access quality care, leading some women to therapeutically wander and others to want to leave Mali. It also leaves them in debt and jeopardises the future of their children. However, the high level of trust in doctors, the involvement of international actors, the level of social support and the growing influence of civil society on the issue of cancer also represent great current opportunities to fight cancer in Mali. CONCLUSION: Despite the efforts of successive Malian governments and the commitment of international actors, the provision of health care is still limited in the country, entrenching global inequalities in women's bodies.

Forward genetics in Wolbachia: Regulation of Wolbachia proliferation by the amplification and deletion of an addictive genomic island.

Wolbachia is one of the most prevalent bacterial endosymbionts, infecting approximately 40% of terrestrial arthropod species. Wolbachia is often a reproductive parasite but can also provide fitness benefits to its host, as, for example, protection against viral pathogens. This protective effect is currently being applied to fight arboviruses transmission by releasing Wolbachia-transinfected mosquitoes. Titre regulation is a crucial aspect of Wolbachia biology. Higher titres can lead to stronger phenotypes and fidelity of transmission but can have a higher cost to the host. Since Wolbachia is maternally transmitted, its fitness depends on host fitness, and, therefore, its cost to the host may be under selection. Understanding how Wolbachia titres are regulated and other aspects of Wolbachia biology has been hampered by the lack of genetic tools. Here we developed a forward genetic screen to identify new Wolbachia over-proliferative mutant variants. We characterized in detail two new mutants, wMelPop2 and wMelOctoless, and show that the amplification or loss of the Octomom genomic region lead to over-proliferation. These results confirm previous data and expand on the complex role of this genomic region in the control of Wolbachia proliferation. Both new mutants shorten the host lifespan and increase antiviral protection. Moreover, we show that Wolbachia proliferation rate in Drosophila melanogaster depends on the interaction between Octomom copy number, the host developmental stage, and temperature. Our analysis also suggests that the life shortening and antiviral protection phenotypes of Wolbachia are dependent on different, but related, properties of the endosymbiont; the rate of proliferation and the titres near the time of infection, respectively. We also demonstrate the feasibility of a novel and unbiased experimental approach to study Wolbachia biology, which could be further adapted to characterize other genetically intractable bacterial endosymbionts.

The nervous system and associated disorders.

Disorders of the nervous system, encompassing the brain, spinal cord and peripheral nerves, have emerged as a significant public health issue, with profound implications for individuals worldwide. These conditions result in significant morbidity and mortality. Many patients with neurological disorders often have comorbidities, further complicating their clinical presentation. Therefore, nurses must possess a comprehensive understanding of the nervous system and its associated disorders to formulate detailed care plans that address the unique needs of each patient. This article aims to explore the underlying pathophysiology of some of the most prevalent neurological disorders and how this informs effective patient assessment and diagnostic strategies. A further article will build on this to consider patient assessment and formulating a care plan in more detail.

Nursing assessment and care for a patient with a neurological disorder.

The previous article discussed the pathophysiology involved in disorders of the nervous system. Having considered some of the most prevalent disorders, this second part uses a case study to explore effective patient assessment and emphasise the importance of facilitating patient self-management for improved outcomes. By addressing these key aspects, nursing professionals can enhance the quality of care and the support provided to individuals experiencing neurological disorders.

Perturbation-based balance training leads to improved reactive postural responses in individuals with Parkinson's disease and freezing of gait.

Perturbation-based balance training (PBT) exposes individuals to a series of sudden upright balance perturbations to improve their reactive postural responses. In this study, we aimed to evaluate the effect of a short PBT program on body balance recovery following a perturbation in individuals with freezing of gait due to Parkinson's disease. Volunteers (mean age = 64 years, SD = 10.6) were pseudorandomly assigned either to a PBT (n = 9) or to a resistance training (RT, n = 10) group. PBT was implemented through balance perturbations varying in the kind, direction, side and magnitude of support base displacements. Both groups exercised with progressive difficulty/load activities twice a week for 4 weeks. Specific gains and generalization to dual-tasking and faster-than-trained support base displacements were evaluated 24 h after the end of the training, and retention was evaluated after 30 days of no training. Results showed that, compared with RT, PBT led to more stable postural responses in the 30-day retention evaluation, as indicated by decreased CoP displacement, velocity and time to direction reversal and reduced numbers of near-falls. We found no transfer either to a dual task or to a higher perturbation velocity. In conclusion, a training program based on diverse unpredictable balance perturbations improved the stability of reactive postural responses to those perturbations suffered during the training, without generalization to more challenging tasks.

Prediction of ball direction in soccer penalty through kinematic analysis of the kicker.

The penalty kick is a crucial opportunity to score and determine the outcome of a soccer match or championship. Anticipating the direction of the ball is key for goalkeepers to enhance their defensive capabilities, considering the ball's swift travel time. However, it remains unclear which kinematic cues from the kicker can predict the ball's direction. This study aimed to identify the variables that predict the ball's direction during a soccer penalty kick. Twenty U19 soccer players executed penalty kicks towards four targets positioned in the goal, while kinematic analysis was conducted using a 3D motion analysis system. Logistic regression analysis revealed that trunk rotation in the transverse plane (towards the goal - left; or slightly to the right - right) served as the primary predictor of the ball's horizontal direction at 250 and 150 ms before the kicking foot made contact. Additionally, the height of the kicking foot in the sagittal plane solely predicted the vertical direction at the moment of contact. This information, encompassing trunk rotation and kicking foot height, can be employed in perceptual training to enhance decision-making and the implementation of feints during penalty kicks.

Backseat Inclination Affects the Myoelectric Activation During the Inclined Leg Press Exercise in Recreationally Trained Men.

ABSTRACT: Marchetti, PH, Gomes, WA, Da Silva, JJ, Magalhaes, RA, Teixeira, LFM, and Whiting, WC. Backseat inclination affects the myoelectric activation during the inclined leg press exercise in recreationally trained men. J Strength Cond Res 37(10): e541-e545, 2023-Changes in the angle between the seat and backrest during the inclined leg press (ILP) exercise may influence myoelectric activity. The purpose of this study was to evaluate the myoelectric activity between 2 different angles between the seat and backrest (90° and 125°) during the ILP exercise in recreationally trained men. Fifteen young, resistance-trained men (age: 26.8 ± 5.3 years, height: 173.8 ± 6.6 cm, total body mass: 81.6 ± 7.6 kg) performed 1 set of 10 repetitions at 70% of their body mass during the ILP exercise using 2 different angles between the seat and backrest (ILP90° and ILP125°). Surface electromyography (peak RMS 90 and iEMG) was used to measure the myoelectric activity of the vastus lateralis (VL), biceps femoris (BF), and gluteus maximus (GM). A paired t test was used to measure differences in knee and hip joint displacement, peak RMS 90 , and iEMG between ILP90 and ILP125. The hip angle presented a greater displacement during the ILP125 when compared with ILP90 ( p < 0.001), considering a similar knee joint displacement. For the VL, there was observed greater myoelectric activation (peak RMS 90 and iEMG) during ILP125 when compared with ILP90 ( p < 0.05). For the BF, there was observed greater myoelectric activation (peak RMS 90 and iEMG) during ILP90 when compared with ILP125 ( p < 0.05). However, GM did not present differences between ILP90 and ILP125. In conclusion, the angle between the seat and backrest (ILP90 or ILP125) altered the myoelectric activation of the VL and BF with no difference for the GM.

"A vaccine that nonetheless remains apart": Papillomavirus and vaccination in France / « Un vaccin qui reste quand même à part ¼ : Papillomavirus et vaccination en France

Introduction: Vaccination against the human papillomavirus (HPV) is currently not widespread in France, where the vaccination rate is one of the lowest in Europe. However, this virus is encountered by 80% of the population and causes 3000 new cases of cancer per year. This vaccination constitutes a real lever for action. Purpose of research: Using a qualitative approach (semi-directive interviews), we documented the perceptions, reluctance, and obstacles of sixteen general practitioners in Ile de France. The objective was to understand the low vaccination rate and to propose sustainable solutions to increase adherence to this vaccine. Results: The HPV vaccine is different from other vaccines, which makes it more difficult for the public to understand. Firstly, because it affects the privacy of patients from a very young age. Secondly, because it has long been dedicated to a female public and the opening of vaccination to boys of the same age leads to a change in discourse and a break with its gendered image. Finally, this vaccination is taking place in a context where there is a marked reluctance to vaccinate in France, with a rapid circulation of more or less reliable information that often places the medical profession in difficulty. Conclusions: Health professionals play a key role in convincing and encouraging patients to adhere to the vaccine, and a majority of doctors are still in favor of vaccination. Relying on a wider group of health professionals could help to increase adherence to the vaccine in France.

Introduction: La vaccination contre le papillomavirus humain (HPV) est aujourd'hui peu répandue en France où le taux vaccinal est l'un des plus faibles d'Europe. Pourtant, ce virus est rencontré par 80 % de la population et entraine 3 000 nouveaux cas de cancers du col de l'utérus par an. Cette vaccination constitue un réel levier d'action, notamment par le biais des médecins généralistes. But de l'étude: L'objectif était de comprendre le faible taux vaccinal en France et de proposer des solutions durables pour augmenter l'adhésion à ce vaccin. Avec une approche qualitative, nous avons documenté les perceptions, réticences et obstacles de seize médecins généralistes en Île de France. Résultats: Le vaccin anti-HPV présente des particularités qui rendent son abord plus délicat auprès de la population. D'abord, parce qu'il touche à l'intimité des patients et ce, dès un très jeune âge. Ensuite, parce qu'il a longtemps été dédié à un public féminin ; l'ouverture de la vaccination aux garçons du même âge entraine donc une modification des discours et une rupture avec son image genrée. Enfin, cette vaccination s'inscrit dans un contexte où l'hésitation vaccinale est marquée en France, avec une circulation rapide d'informations plus ou moins fiables venant souvent mettre en difficulté le corps médical. Conclusions: Les professionnels de santé détiennent un rôle clé pour convaincre et entrainer l'adhésion des patients, et une majorité des médecins reste favorable à cette vaccination. S'appuyer sur un ensemble de professionnels de santé plus large pourrait permettre d'augmenter l'adhésion vaccinale en France.

Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1mut), while assessing the global safety of combination fulvestrant and palbociclib. METHODS: We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited and monitored for rising bESR1mut during first-line aromatase inhibitor (2·5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1-21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1mut in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1mut detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete. FINDINGS: From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1mut and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35·3 months (IQR 29·2-41·4) from inclusion and 26·0 months (13·8-34·3) from random assignment. Median progression-free survival from random assignment was 11·9 months (95% CI 9·1-13·6) in the fulvestrant and palbociclib group versus 5·7 months (3·9-7·5) in the aromatase inhibitor and palbociclib group (stratified HR 0·61, 0·43-0·86; p=0·0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 [70·3%] of 1017 patients), lymphopenia (66 [6·5%]), and thrombocytopenia (20 [2·0%]). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 [41·7%] of 84 patients in the aromatase inhibitor and palbociclib group vs 39 [44·3%] of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three [3·6%] vs four [4·5%]). 31 (3·1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1·7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1·2%) grade 4 neutropenia and one (1·2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1·1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related. INTERPRETATION: PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1mut results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials. FUNDING: Pfizer.

Transmembrane Protease Serine 2 Proteolytic Cleavage of the SARS-CoV-2 Spike Protein: A Mechanistic Quantum Mechanics/Molecular Mechanics Study to Inspire the Design of New Drugs To Fight the COVID-19 Pandemic.

Despite the development of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, there is an urgent need for efficient drugs to treat infected patients. An attractive drug target is the human transmembrane protease serine 2 (TMPRSS2) because of its vital role in the viral infection mechanism of SARS-CoV-2 by activation of the virus spike protein (S protein). Having in mind that the information derived from quantum mechanics/molecular mechanics (QM/MM) studies could be an important tool in the design of transition-state (TS) analogue inhibitors, we resorted to adiabatic QM/MM calculations to determine the mechanism of the first step (acylation) of proteolytic cleavage of the S protein with atomistic details. Acylation occurred in two stages: (i) proton transfer from Ser441 to His296 concerted with the nucleophilic attack of Ser441 to the substrate's P1-Arg and (ii) proton transfer from His296 to the P1'-Ser residue concerted with the cleavage of the ArgP1-SerP1' peptide bond, with a Gibbs activation energy of 17.1 and 15.8 kcal mol-1, relative to the reactant. An oxyanion hole composed of two hydrogen bonds stabilized the rate-limiting TS by 8 kcal mol-1. An analysis of the TMPRSS2 interactions with the high-energy, short-lived tetrahedral intermediate highlighted the limitations of current clinical inhibitors and pointed out specific ways to develop higher-affinity TS analogue inhibitors. The results support the development of more efficient drugs against SARS-CoV-2 using a human target, free from resistance development.

Is freezing of gait correlated with postural control in patients with moderate-to-severe Parkinson's disease?

Freezing of gait (FoG) is one of the main reasons for movement initiation disorders and abnormal coupling of posture and gait in Parkinson's disease (PD). Patients with FoG have poor postural control when compared to patients without FoG. However, the nature of the interrelationship between FoG and domains of postural control remains unknown. The aim of this study was to estimate the association between different domains of postural control and severity of FoG in patients with moderate-to-severe PD. Thirty patients with idiopathic PD with FoG (age range 45-80 years, Hoehn & Yahr stages 3 and 4) participated in the study. We evaluated objective (FoG-ratio during turning task) and subjective (New Freezing of Gait Questionnaire, NFoG-Q) measures of FoG severity, reactive postural adjustments in response to an external perturbation, first step anticipatory adjustment for step initiation and quiet standing stability. In the multiple regression analysis, step initiation was the strongest significant correlation of the NFoG-Q score explaining 23% of the variance of the assessment. For the objective FoG measure, mediolateral CoP amplitude in quiet standing and mediolateral CoP amplitude in step initiation explained 39% of the variance of the FoG-ratio. As main conclusions, this study identified the association between objective and subjective measure for FoG severity and postural control domains. The results support conducting step initiation training during rehabilitation of individuals with FoG.

Drosophila melanogaster establishes a species-specific mutualistic interaction with stable gut-colonizing bacteria.

Animals live together with diverse bacteria that can impact their biology. In Drosophila melanogaster, gut-associated bacterial communities are relatively simple in composition but also have a strong impact on host development and physiology. It is generally assumed that gut bacteria in D. melanogaster are transient and their constant ingestion with food is required to maintain their presence in the gut. Here, we identify bacterial species from wild-caught D. melanogaster that stably associate with the host independently of continuous inoculation. Moreover, we show that specific Acetobacter wild isolates can proliferate in the gut. We further demonstrate that the interaction between D. melanogaster and the wild isolated Acetobacter thailandicus is mutually beneficial and that the stability of the gut association is key to this mutualism. The stable population in the gut of D. melanogaster allows continuous bacterial spreading into the environment, which is advantageous to the bacterium itself. The bacterial dissemination is in turn advantageous to the host because the next generation of flies develops in the presence of this particularly beneficial bacterium. A. thailandicus leads to a faster host development and higher fertility of emerging adults when compared to other bacteria isolated from wild-caught flies. Furthermore, A. thailandicus is sufficient and advantageous when D. melanogaster develops in axenic or freshly collected figs, respectively. This isolate of A. thailandicus colonizes several genotypes of D. melanogaster but not the closely related D. simulans, indicating that the stable association is host specific. This work establishes a new conceptual model to understand D. melanogaster-gut microbiota interactions in an ecological context; stable interactions can be mutualistic through microbial farming, a common strategy in insects. Moreover, these results develop the use of D. melanogaster as a model to study gut microbiota proliferation and colonization.

Nonpalpable breast lesions: impact of a second-opinion review at a breast unit on BI-RADS classification.

OBJECTIVE: To compare BI-RADS classification, management, and outcome of nonpalpable breast lesions assessed both by community practices and by a multidisciplinary tumor board (MTB) at a breast unit. METHODS: All nonpalpable lesions that were first assigned a BI-RADS score by community practices and then reassessed by an MTB at a single breast unit from 2009 to 2017 were retrospectively reviewed. Inter-review agreement was assessed with Cohen's kappa statistic. Changes in biopsy recommendation were calculated. The percentage of additional tumor lesions detected by the MTB was obtained. The sensitivity, AUC, and cancer rates for BI-RADS category 3, 4, and 5 lesions were computed for both reviews. RESULTS: A total of 1909 nonpalpable lesions in 1732 patients were included. For BI-RADS scores in the whole cohort, a fair agreement was found (κ = 0.40 [0.36-0.45]) between the two reviews. Agreement was higher when considering only mammography combined with ultrasound (κ = 0.53 [0.44-0.62]), masses (κ = 0.50 [0.44-0.56]), and architectural distortion (κ = 0.44 [0.11-0.78]). Changes in biopsy recommendation occurred in 589 cases (31%). Ninety of 345 additional biopsies revealed high-risk or malignant lesions. Overall, the MTB identified 27% additional high-risk and malignant lesions compared to community practices. The BI-RADS classification AUCs for detecting malignant lesions were 0.66 (0.63-0.69) for community practices and 0.76 (0.75-0.78) for the MTB (p < 0.001). CONCLUSION: Agreement between community practices and MTB reviews for BI-RADS classification in nonpalpable lesions is only fair. MTB review improves diagnostic performances of breast imaging and patient management. KEY POINTS: • The inter-review agreement for BI-RADS classification between community practices and the multidisciplinary board was only fair (κ = 0.40). • Disagreements resulted in changes of biopsy recommendation in 31% of the lesions. • The multidisciplinary board identified 27% additional high-risk and malignant lesions compared to community practices.

Compensatory control between the legs in automatic postural responses to stance perturbations under single-leg fatigue.

In response to sudden perturbations of stance stability, muscles of both legs are activated for balance recovery. In conditions that one of the legs has a reduced capacity to respond, the opposite leg is predicted to compensate by responding more powerfully to restore stable upright stance. In this investigation, we aimed to evaluate between-leg compensatory control in automatic postural responses to sudden perturbations in a situation in which plantar flexor muscles of a single leg were fatigued. Young participants were evaluated in response to a series of perturbations inducing forward body sway, with a focus on activation of plantar flexor muscles: lateral and medial gastrocnemii and soleus. Muscular responses were analyzed through activation magnitude and latency of muscular activation onset. For evaluation of balance and postural stability, we also analyzed the center of pressure and upper trunk displacement and weight-bearing asymmetry between the legs. Responses were assessed in three conditions: pre-fatigue, under single-leg fatigue, and following the recovery of muscular function. Results showed (a) compensation of the non-fatigued leg through the increased magnitude of muscular activation in the first perturbation under fatigue; (b) adaptation in the non-fatigued leg over repetitive perturbations, with a progressive decrement of muscular activation over trials; and (c) maintenance of increased muscular activation of the non-fatigued leg following fatigue dissipation. These findings suggest that the central nervous system is able to modulate the descending motor drive individually for each leg's muscles apparently based on their potential contribution for the achievement of the behavioral aim of recovering stable body balance following stance perturbations.

Vigor of reactive postural responses is set from feedback and feedforward processes.

I explore a distinct perspective from that brought in the book by arguing that in postural control our organism selects the vigor of reactive responses guided by an optimization rule considering first the required postural response for balance recovery as indicated by afferent information from a myriad of sensory receptors, and second the history of previous responses to similar perturbations.

Loss of presynaptic inhibition for step initiation in parkinsonian individuals with freezing of gait.

KEY POINTS: Individuals with freezing of gait (FoG) due to Parkinson's disease (PD) have small and long anticipatory postural adjustments (APAs) associated with delayed step initiation. Individuals with FoG ('freezers') may require functional reorganization of spinal mechanisms to perform APAs due to supraspinal dysfunction. As presynaptic inhibition (PSI) is centrally modulated to allow execution of supraspinal motor commands, it may be deficient in freezers during APAs. We show that freezers presented PSI in quiet stance (control task), but they presented loss of PSI (i.e. higher ratio of the conditioned H-reflex relative to the test H-reflex) during APAs before step initiation (functional task), whereas non-freezers and healthy control individuals presented PSI in both the tasks. The loss of PSI in freezers was associated with both small APA amplitudes and FoG severity. We hypothesize that loss of PSI during APAs for step initiation in freezers may be due to FoG. ABSTRACT: Freezing of gait (FoG) in Parkinson's disease involves deficient anticipatory postural adjustments (APAs), resulting in a cessation of step initiation due to supraspinal dysfunction. Individuals with FoG ('freezers') may require functional reorganization of spinal mechanisms to perform APAs. As presynaptic inhibition (PSI) is centrally modulated to allow execution of supraspinal motor commands, here we hypothesized a loss of PSI in freezers during APA for step initiation, which would be associated with FoG severity. Seventy individuals [27 freezers, 22 non-freezers, and 21 age-matched healthy controls (HC)] performed a 'GO'-commanded step initiation task on a force platform under three conditions: (1) without electrical stimulation, (2) test Hoffman reflex (H-reflex) and (3) conditioned H-reflex. They also performed a control task (quiet stance). In the step initiation task, the H-reflexes were evoked on the soleus muscle when the amplitude of the APA exceeded 10-20% of the mean baseline mediolateral force. PSI was quantified by the ratio of the conditioned H-reflex relative to the test H-reflex in both the tasks. Objective assessment of FoG severity (FoG-ratio) was performed. Freezers presented lower PSI levels during quiet stance than non-freezers and HC (P < 0.05). During step initiation, freezers presented loss of PSI and lower APA amplitudes than non-freezers and HC (P < 0.05). Significant correlations were only found for freezers between loss of PSI and FoG-ratio (r = 0.59, P = 0.0005) and loss of PSI and APA amplitude (r = -0.35, P < 0.036). Our findings suggest that loss of PSI for step initiation in freezers may be due to FoG.

Instantaneous interjoint rescaling and adaptation to balance perturbation under muscular fatigue.

Adaptation of automatic postural responses (APR) to balance perturbations might be thought to be impaired by muscle fatigue, given the associated proprioceptive and effector deficits. In this investigation, we aimed to evaluate the effect of muscular fatigue on APR adaptation over repetitive balance perturbations through support base backward translations. APR adaptation was evaluated in three epochs: (a) pre-fatigue; (b) post-fatigue, immediately following fatigue of the plantiflexor muscles through isometric contractions and (c) post-recovery, 30 min after the end of fatiguing activity. Results showed the following: (a) Decreasing amplitudes of joints' maximum excursion over repetitive perturbations in the three fatigue-related epochs. (b) Modulation of joints' excursion was observed in the first trial in the post-fatigue epoch. (c) In the post-fatigue epoch, we found interjoint rescaling, with greater amplitude of hip rotation associated with reduced amplitude of ankles' rotation. (d) Amplitudes of ankles' rotation were similar between the post-fatigue and post-recovery epochs. These findings lead to the conclusions that adaptation of automatic postural responses over repetitive trials was effective under focal muscular fatigue; modulation of the postural response took place in the first perturbation under fatigue, and generalization of response characteristics from post-fatigue to post-recovery suggests that feedforward processes in APRs generation are affected by the recent history of postural responses to stance perturbations.

Automatic postural responses are scaled from the association between online feedback and feedforward control.

Generation of automatic postural responses (APRs) scaled to magnitude of unanticipated postural perturbations is required to recover upright body stability. In the current experiment, we aimed to evaluate the effect of previous postural perturbations on APR scaling under conditions in which the current perturbation is equal to or different from the previous perturbation load inducing unanticipated forward body sway. We hypothesized that the APR is scaled from the association of the current perturbation magnitude and postural responses to preceding perturbations. Evaluation was made by comparing postural responses in the contexts of progressive increasing versus decreasing magnitudes of perturbation loads. Perturbation was applied by unanticipatedly releasing a cable pulling the body backwards, with loads corresponding to 6%, 8% and 10% of body mass. We found that the increasing as compared to the decreasing load sequence led to lower values of (a) displacement and (b) velocity of center of pressure, and of activation rate of the muscle gastrocnemius medialis across loads. Muscular activation onset latency decreased as a function increasing loads, but no significant effects of load sequence were found. These results lead to the conclusion that APRs to unanticipated perturbations are scaled from the association of somatosensory feedback signaling balance instability with feedforward control from postural responses to previous perturbations.

A Randomized, Controlled Trial of Exercise for Parkinsonian Individuals With Freezing of Gait.

BACKGROUND: Exercises with motor complexity induce neuroplasticity in individuals with Parkinson's disease (PD), but its effects on freezing of gait are unknown. The objective of this study was to verify if adapted resistance training with instability - exercises with motor complexity will be more effective than traditional motor rehabilitation - exercises without motor complexity in improving freezing-of-gait severity, outcomes linked to freezing of gait, and brain function. METHODS: Freezers were randomized either to the adapted resistance training with instability group (n = 17) or to the active control group (traditional motor rehabilitation, n = 15). Both training groups performed exercises 3 times a week for 12 weeks. The primary outcome was the New Freezing of Gait Questionnaire. Secondary outcomes were freezing of gait ratio (turning task), cognitive inhibition (Stroop-III test), motor signs (Unified Parkinson's Disease Rating Scale part-III [UPDRS-III]), quality of life (PD Questionnaire 39), anticipatory postural adjustment (leg-lifting task) and brain activation during a functional magnetic resonance imaging protocol of simulated anticipatory postural adjustment task. Outcomes were evaluated before and after interventions. RESULTS: Only adapted resistance training with instability improved all the outcomes (P < 0.05). Adapted resistance training with instability was more effective than traditional motor rehabilitation (in improving freezing-of-gait ratio, motor signs, quality of life, anticipatory postural adjustment amplitude, and brain activation; P < 0.05). Our results are clinically relevant because improvement in the New Freezing of Gait Questionnaire (-4.4 points) and UPDRS-III (-7.4 points) scores exceeded the minimally detectable change (traditional motor rehabilitation group data) and the moderate clinically important difference suggested for PD, respectively. The changes in mesencephalic locomotor region activation and in anticipatory postural adjustment amplitude explained the changes in New Freezing of Gait Questionnaire scores and in freezing-of-gait ratio following adapted resistance training with instability, respectively. CONCLUSIONS: Adapted resistance training with instability is able to cause significant clinical improvement and brain plasticity in freezers. © 2020 International Parkinson and Movement Disorder Society.