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Background There is an increase in the numbers of high energy tarsometatarsal / Lisfranc fracture dislocation. In this type of trauma, the specialist in orthopedics and traumatology cannot consider only the fracture as the challenge to be overcome, the injury to the soft tissues of the foot ends up being of equal or greater importance throughout the treatment. Our aim is to demonstrate, through a case report and literature review, that staged multidisciplinary surgical treatment is a good option for the treatment of these complex cases. Case We report a case of a 28-year-old female victim of a motorcycle collision with a car. She was diagnosed with complex lesion of the right foot (fracture the medial cuneiform, fracture of the lateral cuneiform, cuboid fracture and loss of the intermediate cuneiform, detaching wound of dorsal skin, loss of the extensor hallux longus tendon, anterior tibial artery and deep peroneal nerve). In the emergency setting the patient was submitted to an initial debridement and gross reduction fixation with Kirschner wires. The further course was complicated with local infection and need for staged debridements, modification of the fixation and negative pressure wound dressing. She was later submitted to a flap coverage at the dorsum of the foot and in a last approach, arthrodesis of the medial tarsometatarsal and navicular joints. Conclusions Lisfranc complex injuries continue to be an important source of pain and disability for patients worldwide. This case description show decision making challenges in a scenario without all resources available. The literature review demonstrates thar 2 phases of treatment principles must be respected: early damage control and definitive treatment. The key factors for improved outcomes are: early soft tissue coverage and restore axial, sagittal, and coronal alignment of the medial and lateral columns of the foot.

PURPOSE To assess the technical and clinical success rates of superior rectal artery embolization in the treatment of symptomatic Grades 2 and 3 hemorrhoidal disease. MATERIALS AND METHODS Since March 2019, 43 patients (24 men and 19 women; mean age, 52 years [18-77 years]) with symptomatic hemorrhoidal disease have been treated and completed the 6-month follow-up with anamnestic questionnaire and disease scores, including French bleeding, Goligher prolapse, visual analog scale for pain, and quality of life. Clinical success was assessed at 7 days, 1 month, and 6 months of follow-up by updating the clinical scores. Statistical analysis was performed using SPSS 25.0. RESULTS In all, 25 patients had Grade 2 prolapse and 18 patients had Grade 3 prolapse, with 96% and 77%, respectively, having bleeding as a symptom. All patients were discharged within 24 hours. The reduction in the French bleeding score (global and single entity) in Grade 3 prolapse was statistically significant (P = .001). Improvement in the quality of life was significant in both groups (P < .05). No serious complications were registered. CONCLUSIONS Hemorrhoidal embolization was a safe and effective technique in the treatment of symptomatic hemorrhoidal disease with minimal hospitalization, pain, and disruption of daily activities. It can be offered to patients unwilling to undergo a surgical procedure but can also be indicated in the emergency setting for patients on anticoagulant therapy or those unfit for surgery.

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4–14%] for women born in 1940 to 22% [CI = 19–25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

Objective: To determine the microbiological profile and antimicrobial susceptibility patterns of organisms isolated from chronic osteomyelitis secondary to neuropathic foot ulcers; secondarily, to describe the clinical outcomes of 52 patients admitted to a neuropathic foot referral center. Methods: Retrospectively chart review of 52 patients with clinically infected neuropathic foot ulcers admitted to our service for treatment between 2005 and 2013. Tissue samples were collected for culture at the operating room after extensive debridement in order to determine the infectious agents and their resistance profile using the disk-diffusion technique, following CLSI criteria. Results: A total of 52 patients were analyzed (40 males and 12 females). The mean age was 58 (37-72) years. Each patient presented with an average of 2.13 microorganisms, distributed as follows: 51% Gram-positive cocci, 43% Gram-negative bacilli. Among Staphylococcus aureus isolates, the prevalence of methicillin resistance was almost 50%, and the prevalence of coagulase-negative staphylococci (CoNS) was more than 75%. Conclusion: S. aureus, E. faecalis, and CoNS were the most frequently isolated pathogens. Methicillin resistance was highly prevalent. A combination of extensive surgical debridement and prolonged antimicrobial therapy led to remission of infection in 77% of patients. Level of Evidence IV; Therapeutic Studies; Case Series.

The objective of this study was to investigate the effects of maternal breastfeeding, artificial feeding, types of introduction of complementary food introduction and the use of bottle and pacifier on lip /tongue pressure and maximum molar bite force of school children. Thirty-five healthy children with mixed dentition (20 boys and 15 girls), aged 6-10 years, participated in this study. The children were evaluated based on anthropometry, electronic scale and portable stadiometer, feeding practices (breastfeeding, artificial feeding, introduction of complementary food), bottle and pacifier use, tongue and lips strength and molar bite force. The results were submitted to ANOVA (p

Tarsal coalition is an abnormal connection between tarsal bones, caused by an embryogenic failure. Its most common forms are calcaneonavicular and talocalcaneal coalition, which are present in 53% and 37% of the cases, respectively. The onset of symptoms is related to tarsal bone ossification, and mean age for this event is estimated at 16 years for calcaneonavicular coalition. Surgical treatment is indicated for patients who did not improve symptoms with conservative treatment. The aim of this study is to present a surgical technique as a treatment option for resection of calcaneonavicular coalition associated with abnormal cuboid-navicular joint. Level of Evidence V; Therapeutic Studies; Expert Opinion.

Resumo Objetivo Este estudo tem como objetivo descrever um novo método radiográfico com carga fisiológica para visualizar as cabeças dos cinco metatarsos no plano coronal. Métodos Os indivíduos foram radiograficamente avaliados com carga, com o tornozelo a 20° de flexão plantar e as articulações metatarsofalângicas a 10° de extensão, posicionadas em um dispositivo de madeira. As medidas foram aferidas por dois avaliadores independentes, sendo que um deles mediu em dois momentos distintos, obtendo a correlação inter e intraobservador, com o coeficiente de correlação intraclasses. Resultados Examinamos 63 pés, obtendo um coeficiente de correlação interobservador do método radiográfico para as alturas das cabeças dos metatarsos no plano coronal do 1°, 2°, 3°, 4° e 5° metatarsos de, respectivamente, 0,90, 0,85, 0,86, 0,83, 0,89. O coeficiente de correlação intraobservador foi, respectivamente, 0,95, 0,93, 0,93, 0,86, 0,92. Conclusão Essas correlações demonstram que o método é preciso e pode ser usado para investigar os desalinhamentos de cabeça dos metatarsos nesse plano.

Objective The present study aims to describe a new weightbearing radiographic method to visualize the heads of the five metatarsals on the coronal plane, evaluating their accuracy through intraclass correlation coefficients. Methods The subjects were evaluated, with weightbearing, with the ankle at 20 degrees of plantar flexion and the metatarsophalangeal joints at 10 degrees of extension, positioned on a wooden device. Two independent foot and ankle surgeons evaluated the radiography, with one of them doing it twice, at different moments, achieving an inter and intraobserver correlation, with intraclass correlation coefficients. Results We radiographed 63 feet, achieving an interobserver correlation coefficient of the radiographic method for the metatarsal heads heights in the coronal plane of the 1st, 2nd, 3rd, 4th, and 5th metatarsals of, respectively, 0.90, 0.85, 0.86, 0.83, 0.89. The intraobserver correlation coefficient were, respectively, 0.95, 0.93, 0.93, 0.86, 0.92. Conclusion Those correlations demonstrate that the method is accurate and can be used to investigate metatarsal head misalignments in this plane. Resumo Objetivo Este estudo tem como objetivo descrever um novo método radiográfico com carga fisiológica para visualizar as cabeças dos cinco metatarsos no plano coronal. Métodos Os indivíduos foram radiograficamente avaliados com carga, com o tornozelo a 20º de flexão plantar e as articulações metatarsofalângicas a 10º de extensão, posicionadas em um dispositivo de madeira. As medidas foram aferidas por dois avaliadores independentes, sendo que um deles mediu em dois momentos distintos, obtendo a correlação inter e intraobservador, com o coeficiente de correlação intraclasses. Resultados Examinamos 63 pés, obtendo um coeficiente de correlação interobservador do método radiográfico para as alturas das cabeças dos metatarsos no plano coronal do 1º, 2º, 3º, 4º e 5º metatarsos de, respectivamente, 0,90, 0,85, 0,86, 0,83, 0,89. O coeficiente de correlação intraobservador foi, respectivamente, 0,95, 0,93, 0,93, 0,86, 0,92. Conclusão Essas correlações demonstram que o método é preciso e pode ser usado para investigar os desalinhamentos de cabeça dos metatarsos nesse plano.

Objectives: To describe the surgical treatment of fractures that involves the hallux interphalangeal joint, current indications and management options. Methods: we performed a literature review of relevant clinical studies in multiple databases, including PubMed, MedLine and Scopus, from January 1989 to October 2020. Results: There is consensus for surgical treatment of intra-articular fractures with a deviation greater than 2 mm, metadiaphyseal fractures with malrotation and/or malangulation, open fractures and unstable fractures. Conclusion: The use of more rigid implants allow alignment maintenance during healing process and lower risk of reduction loss. Valgus deformity and interphalangeal joint osteoarthritis are possible complications that must be avoided. Level of Evidence III, Systematic review of Level III studies. RESUMO Objetivos: destacar o tratamento cirúrgico das fraturas que envolvem a articulação interfalangiana do hálux, suas indicações atuais e as opções de tratamento. Métodos: Realizamos uma revisão da literatura de estudos clínicos relevantes em múltiplas bases de dados, incluindo PubMed, MedLine e Scopus, de janeiro de 1989 a outubro de 2020. Resultados: Há consenso para o tratamento cirúrgico de fraturas intra-articulares com desvio superior a 2 mm, fraturas metadiafisárias com má rotação e/ou malangulação, fraturas expostas e fraturas instáveis. Conclusão: O uso de implantes mais rígidos permite a manutenção do alinhamento durante o processo de consolidação e menor risco de perda da redução. As complicações que devem ser evitadas são a deformidade em valgo e a osteoartrite da articulação interfalangeana. Nível de Evidência III, Revisão sistemática de Estudos de Nível III.

Complex trauma of the foot and ankle is characterized by fractures with severe soft tissue damage associated with neurovascular injury and joint involvement. These injuries are frequently present in the polytraumatized patient and are a predictor of unfavorable clinical outcome. In the initial approach to a patient with complex foot and ankle trauma, the decision between amputation and reconstruction is crucial. The various existing classification systems are of limited effectiveness and should serve as tools to assist and support a clinical decision rather than as determinants of conduct. In the emergency department, one of two treatment options must be adopted: early complete treatment or staged treatment. The former consists of definitive fixation and immediate skin coverage, using either primary closure (suturing) or flaps, and is usually reserved for less complex cases. Staged treatment is divided into initial and definitive. The objectives in the first phase are: prevention of the progression of ischemia, necrosis and infection. The principles of definitive treatment are: proximal-to-distal bone reconstruction, anatomic foot alignment, fusions in severe cartilage lesions or gross instabilities, stable internal fixation and adequate skin coverage. Level of evidence III, Systematic review of level III studies. RESUMO O trauma complexo do pé e tornozelo, caracterizado por fraturas com dano grave aos tecidos moles, associado a lesões vasculares e nervosas e com acometimento articular, está presente com frequência no paciente politraumatizado e é preditor de desfecho clínico desfavorável. Na abordagem inicial de um paciente com trauma complexo do pé e tornozelo, a decisão entre amputação ou preservação do membro é crucial. Os diversos sistemas de classificação existentes são de eficácia limitada e devem servir como ferramentas que auxiliam e fortalecem uma decisão clínica, e não como determinantes de uma conduta. No atendimento de emergência, uma das duas opções de tratamento deve ser adotada: tratamento total precoce ou tratamento estagiado. O primeiro consiste na fixação definitiva e na cobertura cutânea imediata, seja por sutura primária ou por meio de retalhos, sendo geralmente reservado a casos menos complexos. O tratamento estagiado é dividido em inicial e definitivo, e o objetivo, na primeira fase, é a prevenção da progressão da isquemia, da necrose e da infecção. Os princípios do tratamento definitivo são: reconstrução óssea de proximal para distal, alinhamento anatômico do pé, fusões nas lesões graves da cartilagem ou nas instabilidades grosseiras, fixação interna estável e cobertura cutânea adequada. Nível de evidência III, Revisão sistemática de estudos de nível III.

Tibial hemimelia is a rare disease characterized by the absence or hypoplasia of the tibia. Because of the difficulties of reconstruction due to joint involvement in more severe cases, knee disarticulation and above-knee amputations are a treatment option. We report the case of a patient treated with knee disarticulation amputation and pedicled foot fillet flap. Level of Evidence V; Therapeutic Studies; Expert Opinion.

The rostral prefrontal cortex (rPFC) is crucial in prospective memory (PM) behavior. Several functional magnetic resonance imaging studies showed that its medial (mrPFC) and lateral (lrPFC) portions dissociate during PM tasks. In light of the Multiprocess theory (McDaniel and Einstein 2000), here we tested whether the two portions of the rPFC are dissociable by modulating strategic vs. spontaneous processes during a PM task. We investigated these two processes by means of a 2 × 2 experimental design in which focal vs. non-focal conditions were modulated by varying the conjoint nature of the ongoing task (i.e., lexical decision vs. syllable matching) and the PM cue (words vs. syllables). Using the two portions of the rPFC as regions of interest, we found an effect of the non-focal condition in the lrPFC and, conversely, an effect of the focal condition in the mrPFC. In the whole-brain analysis we found an effect of the non-focal condition in the bilateral intraparietal sulcus, the bilateral middle frontal gyrus, the supplementary motor areas and the vermis of the cerebellum, whereas we found an effect of the focal condition in the ventromedial PFC. Overall, our results show that different brain regions are involved when multiple processes underlying PM behavior are modulated.

Objective: To describe and quantify the complications arising in consecutive neuropathic patients undergoing partial longitudinal amputations of the foot. Method: A retrospective study was conducted with data collected from the medical records of patients monitored at the Insensitive Foot Clinic of the Foot and Ankle Group of our institution who underwent partial amputation of foot rays from 2000 to 2016. Results: A total of 28 patients met the inclusion criteria, with a total of 31 amputated/partially amputated feet. Of these, 18 (58.1%) feet were amputated/partially amputated due to diabetes, seven (22.6%) due to leprosy, two (6.5%) due to alcoholic neuropathy, two (6.5%) secondary to traumatic peripheral nerve injury, and two (6.5%) due to other causes. Fifth ray amputation was the most frequent type (n=12). The cause of amputation was the presence of an infected ulcer in 93.6% of the samples. At a mean follow-up time of 60 months, 13 (41.9%) feet required new amputations—five (38.5%) transtibial, five (38.5%) transmetatarsal, two (15.4%) of the toes, and one (7.7%) at Chopart's joint. Patients with diabetes had a 50.0% reamputation rate. Patients who initially underwent amputation of the fifth ray had a 58.3% reamputation rate. Conclusion: Partial longitudinal amputation of the foot in neuropathic patients exhibited a high reoperation rate, especially in patients with diabetes or in patients with initial amputation of the peripheral rays. Declaration of interest: The authors have no conflicts of interest.

IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. DESIGN, SETTING, AND PARTICIPANTS: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18?957 SCZ cases and 22?673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12?247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. MAIN OUTCOMES AND MEASURES: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. RESULTS: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2?=?1.1E-03, P?=?4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers. This research is supported by grants 613602, 1047956, 1078901, 1080157, 1087889, and 1067795 from the Australian National Health and Medical Research Council and by grants DE130100614 and DP160102126 from the Australian Research Council. Primary analyses of the SchizophreniaWorking Group of the Psychiatric Genomics Consortium data were conducted on the Genetic Cluster Computer (http://www .geneticcluster.org) hosted by SURFsara and supported by grant NOW480-05-003 from the Netherlands Scientific Organization, along with a supplement from the Dutch Brain Foundation and the Vrije Universitiet Amsterdam. TwinsUK was funded by theWellcome Trust, by grant FP7/2007-2013 from the European Community’s Seventh Framework Programme, and by support from the National Institute for Health Research–funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy’s and St Thomas’ National Health Service Foundation Trust in partnership with King’s College London, and single-nucleotide polymorphism genotyping was performed by theWellcome Trust Sanger Institute and National Eye Institute via the National Institute for Health/Center for Inherited Disease Research. Estonian Genome Center Biobank, University of Tartu, received targeted financing by grant IUT20-60 from the Estonian Research Council, Center of Excellence in Genomics, and University of Tartu, and data analyses were carried out in part in the High Performance Computing Center of the University of Tartu. The Swedish Twin Registry is supported by Karolinska Institutet. Mr Tropf received funding from sciencestarter.de for a research visit to The University of Queensland. The research leading to these results received funding from the European Research Council via an ERC Consolidator Grant SOCIOGENOME (grant 615603 awarded to Dr Mills [http://www.sociogenome.com]).

Background: The rationale of transmission prevention is related to transmission mechanisms, and evidence from observations has shown an improper use of personal protective equipment (PPE). Objective: We aim to describe the evidence on the transmission mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) and related prevention practices. Method: Review of the published literature on coronavirus disease 2019 (COVID-19) in the Scopus, Science Direct, and PubMed databases. Results: Transmission of respiratory viruses, including SARS CoV-2, could be by aerosols, droplets and contact with contaminated surfaces. Evidence suggests that the primary route of transmission of these viruses is by droplet and short distance. Scientific evidence in relation to the transmission of COVID-19 assigns the highest risk to the aerosol-generating procedures and by droplets in closed environments with poor ventilation, and the lowest risk of transmission by direct contact with contaminated surfaces. Conclusion: Prevention practices must be in correspondence with the evidence about the transmission of COVID-19, which will facilitate the rational use of available resources.

Acquired brain injuries, such as stroke, are a major cause of long-term disability worldwide. When an injury occurs within primary motor cortex (M1) there is both a loss of descending information to the spinal cord and a disruption in the communication within and between spared regions, which can lead to hemiparesis and other motor dysfunctions. Recently, activity-dependent stimulation (ADS), a closed loop intracortical neurostimulation technique, was shown to significantly improve behavioural recovery in rodent models following a unilateral traumatic brain injury in the primary motor cortex. While behavioural benefits of this approach have been described, the neurophysiological changes have not yet been fully characterized. In this study, we investigated how neural activity in the form of local field potential (LFP) was impacted by an ischemic lesion and how it changed following prolonged ADS sessions. Intracortical microelectrodes arrays were used to record and stimulate from the rostral forelimb area (RFA) and the primary somatosensory cortex (S1) of 12 rats (Long Evans). An ischemic injury induced with Endothelin-1 microinjections in the caudal forelimb area (CFA) was used as an injury model. We found that the ET-1 caused lesion led to widespread drop of LFP power across all the frequency bands in both the monitored areas. The lesion did not change the functional connectivity within the brain areas, while it increased the synchronization between them. Following stimulation, LFP power generally increased in both areas. Stimulation also led to a decrement in connectivity between S1 and RFA, while causing the within S1 connectivity to increase.

Background Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder caused by the deficient activity of the branched‐chain α‐keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by four genes: BCKDHA, BCKDHB, DBT, and DLD. MSUD is predominantly caused by mutations in the BCKDHA, BCKDHB, and DBT genes which encode the E1α, E1β, and E2 subunits of the BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD in a cohort of Chilean MSUD patients by identifying point mutations in the BCKDHA, BCKDHB, and DBT genes and to describe their impact on the phenotypic heterogeneity of these patients. Methods This manuscript describes a cross‐sectional study of 18 MSUD patients carried out using PCR and DNA sequencing. Results Four novel pathogenic mutations were identified: one in BCKDHA (p.Thr338Ile), two in BCKDHB (p.Gly336Ser e p.Pro240Thr), and one in DBT (p.Gly406Asp). Four additional pathogenic mutations found in this study have been described previously. There were no correlations between the genotype and phenotype of the patients. Conclusion If MSUD is diagnosed earlier, with a newborn screening approach, it might be possible to establish genotype‐phenotype relationships more efficiently., This manuscript describes a cross‐sectional study of 18 MSUD patients carried out using PCR and DNA sequencing. Four novel pathogenic mutations were identified: one in BCKDHA (p.Thr338Ile), two in BCKDHB (p.Gly336Ser e p.Pro240Thr), and one in DBT (p.Gly406Asp). Four additional pathogenic mutations found in this study have been described previously. There were no correlations between the genotype and phenotype of the patients.

As our understanding of volitional motor function increases, it is clear that complex movements are the result of the interactions of multiple cortical regions rather than just the output properties of primary motor cortex. However, our understanding of the interactions among these regions is limited. In this study, we used the activity-dependent stimulation (ADS) technique to determine the short/long-term effects on network activity and neuroplasticity of intracortical connections. ADS uses the intrinsic neural activity of one region to trigger stimulations in a separate region of the brain and can manipulate neuronal connectivity in vivo. Our aim was to compare single-unit neuronal activity within premotor cortex (rostral forelimb area, [RFA] in rats) in response to ADS (triggered from RFA) and randomly-generated stimulation in the somatosensory area (S1) within single sessions and across 21 consecutive days of stimulation. We examined firing rate and correlation between spikes and stimuli in chronically-implanted healthy ambulatory rats during spontaneous and evoked activity. At the end of the treatment, we evaluated changes of synaptophysin expression. Our results demonstrated the ability of ADS to modulate RFA firing properties and to promote synaptogenesis in S1, strengthening the idea that this Hebbian-inspired protocol can be used to modulate cortical connectivity.

Cutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The TP53 gene, the guardian of the genome, which is altered in more than 50% of human cancers, is rarely mutated in melanoma. More recently, researchers started to appreciate the importance of shorter p53 isoforms as potential modifiers of the p53-dependent responses. We analyzed the expression of p53 and p73 isoforms both at the RNA and protein level in a panel of melanoma-derived cell lines with different TP53 and BRAF status, in normal conditions or upon treatment with common anti-cancer DNA damaging agents or targeted therapy. Using lentiviral vectors, we also generated stable clones of H1299 p53 null cells over-expressing the less characterized isoforms Δ160p53α, Δ160p53β, and Δ160p53γ. Further, we obtained two melanoma-derived cell lines resistant to BRAF inhibitor vemurafenib. We observed that melanoma cell lines expressed a wide array of p53 and p73 isoforms, with Δ160p53α as the most variable one. We demonstrated for the first time that Δ160p53α, and to a lesser extent Δ160p53β, can be recruited on chromatin, and that Δ160p53γ can localize in perinuclear foci, moreover, all Δ160p53 isoforms can stimulate proliferation and in vitro migration. Lastly, vemurafenib-resistant melanoma cells showed an altered expression of p53 and p73 isoforms, namely an increased expression of potentially pro-oncogenic Δ40p53β and a decrease in tumor-suppressive TAp73β. We therefore propose that p53 family isoforms can play a role in melanoma cells’ aggressiveness.

How prospective memory (PM) weakens with increasing age has been largely debated. We hypothesized that automatic and strategic PM processes, respectively mediated by focal and non-focal cues, are differently affected by aging, even starting from 50–60 years of age. We investigated this issue using a 2 × 2 design in which focal and non- focal experimental conditions were created by varying the conjoint nature of the ongoing task (lexical decision vs. syllable matching tasks) and the PM cue (words vs. syllables). In the whole-brain analysis we found that the left inferior frontal gyrus and the middle cingulate cortex were more activated when young compared to older indivi-duals performed a PM task; moreover, the anterior cingulate cortex was selectively activated during non-focal PM when the cues were words. In a region-of-interest analysis we observed that the medial and the lateral portions of the rostral prefrontal cortex were associated with the focal and non-focal conditions respectively, more in young than in older adults. Our findings provide evidence in support of early age-related differences in automatic/strategic PM functioning.

Working memory (WM) performance is very often measured using the n‐back task, in which the participant is presented with a sequence of stimuli, and required to indicate whether the current stimulus matches the one presented n steps earlier. In this study, we used high‐density electroencephalography (hdEEG) coupled to source localization to obtain information on spatial distribution and temporal dynamics of neural oscillations associated with WM update, maintenance and readout. Specifically, we a priori selected regions from a large fronto‐parietal network, including also the insula and the cerebellum, and we analyzed modulation of neural oscillations by event‐related desynchronization and synchronization (ERD/ERS). During update and readout, we found larger θ ERS and smaller β ERS respect to maintenance in all the selected areas. γLOW and γHIGH bands oscillations decreased in the frontal and insular cortices of the left hemisphere. In the maintenance phase we observed decreased θ oscillations and increased β oscillations (ERS) in most of the selected posterior areas and focally increased oscillations in γLOW and γHIGH bands in the frontal and insular cortices of the left hemisphere. Finally, during WM readout, we also found a focal modulation of the γLOW band in the left fusiform cortex and cerebellum, depending on the response trial type (true positive vs. true negative). Overall, our study demonstrated specific spectral signatures associated with updating of memory information, WM maintenance, and readout, with relatively high spatial resolution., Specific spectral signatures are associated with updating of memory information, working memory maintenance, and readout in a large fronto‐parietal network, including also the insula and the cerebellum.

Background Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disease caused by deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by BCKDHA, BCKDHB, DBT, and DLD genes. MSUD is predominantly caused by Variants in BCKDHA, BCKDHB, and DBT genes encoding the E1α, E1β, and E2 subunits of BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD by identifying the point variants in BCKDHA, BCKDHB, and DBT genes in a cohort of Brazilian MSUD patients and to describe their phenotypic heterogeneity. It is a descriptive cross-sectional study with 21 MSUD patients involving molecular genotyping by Sanger sequencing. Results Eight new variants predicted as pathogenic were found between 30 variants (damaging and non-damaging) identified in the 21 patients analyzed: one in the BCKDHA gene (p.Tyr120Ter); five in the BCKDHB gene (p.Gly131Val, p.Glu146Glnfs * 13, p.Phe149Cysfs * 9, p.Cys207Phe, and p.Lys211Asn); and two in the DBT gene (p.Glu148Ter and p.Glu417Val). Seventeen pathogenic variants were previously described and five variants showed no pathogenicity according to in silico analysis. Conclusion Given that most of the patients received late diagnoses, the study results do not allow us to state that the molecular features of MSUD variant phenotypes are predictive of clinical severity.

As our understanding of how motor output is generated increases, it is clear that there is a need to understand the interactions of multiple distinct regions rather than just the output properties of primary motor cortex. This becomes even more imperative when trying to understand how different regions may contribute to recovery following injury. In this study we used a technique that promotes functional motor recovery after injury, activity-dependent stimulation (ADS), to determine the short- and long-term effects on network activity and neuroplasticity of intracortical connections. ADS uses recorded neural activity to trigger stimulation of the brain and may be utilized to manipulate neuronal connectivity in vivo, representing a novel technique to shape intrinsic neuroplasticity. The aim of this work was to compare the effect of ADS to randomly-generated stimulation (RS) of the somatosensory area (S1) on the single units’ patterns of activity taking place in the premotor cortex (RFA) and to investigate whether synaptic plasticity changes occur in S1 as a consequence of 21 consecutive days of stimulation. In particular, we examined both firing rate changes and correlation between spiking activity and stimuli in chronically-implanted healthy ambulatory rats during both spontaneous and evoked activity, resulting from the two stimulation paradigms. Finally, we evaluated changes in expression of synaptophysin at the end of the treatment. This experimental procedure demonstrated the ability of ADS to modulate firing properties of RFA within daily recording sessions and to promote synaptogenesis in S1, further strengthening the idea that this Hebbian-inspired protocol can be used to effectively modulate cortical connectivity and thus suggesting its translational potential for promoting recovery after brain injury.

Working memory (WM) performance is very often measured using the n-back task, in which the participant is presented with a sequence of stimuli, and required to indicate whether the current stimulus matches the one presented n steps earlier. In this study, we used high-density electroencephalography (hdEEG) coupled to source localization to obtain information on spatial distribution and temporal dynamics of neural oscillations associated with WM update, maintenance and readout. Specifically, we a priori selected regions from a large fronto-parietal network, including also the insula and the cerebellum, and we analyzed modulation of neural oscillations by event-related desynchronization and synchronization (ERD/ERS).During update and readout, we found larger θ ERS and smaller β ERS respect to maintenance in all the selected areas. γLOWand γHIGHbands oscillations decreased in the frontal and insular cortices of the left hemisphere. In the maintenance phase we observed focally decreased θ oscillations and increased β oscillations (ERS) in most of the selected posterior areas and focally increased oscillations in γLOWand γHIGHbands in the frontal and insular cortices of the left hemisphere. Finally, during WM readout, we also found a focal modulation of the γLOWband in the left fusiform cortex and cerebellum, depending on the response trial type (true positive vs. true negative).Overall, our study demonstrated specific spectral signatures associated with updating of memory information, WM maintenance and readout, with relatively high spatial resolution.

Age at first sexual intercourse (AFS) and age at first birth (AFB) have implications for health and evolutionary fitness. In the largest genome-wide association study to date (AFS, N=387,338; AFB, N=542,901), we identify 370 independent signals, 11 sex-specific, with a 5-6% polygenic score (PGS) prediction. Heritability of AFB shifted from 9% [CI=4-14] for women born in 1940 to 22% [CI=19-25] in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility, and spermatid differentiation. Polycystic Ovarian Syndrome leads to later AFB, linking with infertility. Late AFB is protective against later-life disease and associated with parental longevity. Higher childhood socioeconomic circumstances and those in the highest PGS decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, for understanding longevity, and guiding experimentation into mechanisms of infertility.

Objective: Compare the real need for rest of chronic plantar fasciitis patients with the leave of absence time and criteria used by national and international technical medical expert examination manuals. Methods: We conducted a review of the medical literature from 2013 to 2018, selecting only randomized controlled clinical trials on the treatment of chronic plantar fasciitis. National and international medical expert examination manuals were also selected. The treatment time for chronic plantar fasciitis was then compared with the leave of absence time recommended by the manuals. Results: Of the six articles selected, we ascertained that three articles evaluating second-line treatment managed to reduce the VAS by 60% after 4 weeks, one after 3 months, one after 6 months, and one that showed no improvement at all. In all studies, no control group receiving first-line treatment alone achieved a 60% reduction in the VAS during the follow-up period. The evaluated manuals recommend leave from work ranging from zero to 21 days, with only two using the criterion of the type of work performed by the employee for the expert decision. Conclusion: We observed that none of the medical expert examination manuals provides support for the medical expert to grant leave to workers with chronic plantar fasciitis from their work-related activities to receive secondary treatment for at least four weeks. In addition, stratification by acute or chronic disease is not observed. Two manuals scale leave time by type of activity. Level of Evidence III; Economic and Decision Analyses; Analyses Based on Limited Costs and Alternatives.

Objective: To evaluate the functional outcome and quality of life of patients with rheumatoid arthritis (RA) who underwent resection arthroplasty of the first to fifth metatarsal heads. Methods: Prospective case series study in which 8 feet of 5 patients underwent resection arthroplasty of the five metatarsal heads via a plantarapproach to the lateral rays and via a medial approach to the first metatarsal. Dressing and orthotics were used for 3 months to correct the position of the toes. Patients were evaluated in the preoperative period and at least one year after the procedure using two functional evaluation scales (AOFAS lesser toes and AOFAS hallux) and one quality of life scale (EQ-5D). All results were subjected to statistical validation using theMann-Whitney U test. Results: The subjects had a mean age of 71 years, with a prevalence of the female gender. The mean AOFAS lesser toe and AOFAS hallux scores increased from 38.6 and 24.5 preoperatively to 85.7 and 83.1 postoperatively, respectively (p

Objective: The main objective of this study is to describe the preliminary results of modified osteotomy with elevation of the first metatarsal to repair cavovarus foot deformities. Methods: In a five-case series, radiographic findings related to the modified osteotomy with elevation of the first ray were analysed.Results: Five patients who underwent a modified osteotomy with elevation were followed up for a minimum of six months. One hundred percent consolidation rates were observed, with no complications related to the materials, such as screw breakage, screw loosening and/or pseudoarthrosis (0% of the cases), regardless of age and gender. Conclusion: The modified technique generates an osteotomy plane that is more horizontal, reducing the technical difficulty and resulting in less risk of loss of fixation during passage of the screw. Using a single screw for fixation reduces the cost of the procedure and pseudarthrosis rates. Level of Evidence IV; Therapeutic Studies; Case series.

Absence of 'live' residual poliovirus in Inactivated Poliovirus Vaccine (IPV) is routinely checked using Primary Monkey Kidney Cells (PMKC). However, the increasing demand for IPV and the ethical, technical and safety issues associated with the use of non-human primates in research and quality control, has made the replacement of primary cells with an established cell line a priority, in line with the principles of the 3Rs (Replacement, Reduction and Refinement in animal testing). As an alternative to PMKC, we evaluated the L20B cell line; a mouse cell-line genetically engineered to express human poliovirus receptor, CD155. L20B is already used for the detection and diagnosis of poliovirus in clinical samples. We demonstrate the stability of L20B cells in terms of CD155 gene and receptor expression, and permissivity to polioviruses for at least 16 sequential passages. In addition, the L20B cell line was found to be at least as sensitive as PMKC in detecting the presence of 'live' poliovirus in IPV samples. Equivalence or superiority of L20B cells versus PMKCs was demonstrated for assessing the presence of residual 'live' poliovirus in formaldehyde-inactivated preparations for the three poliovirus serotypes. These results demonstrate that the L20B cell line is a suitable alternative to PMKC in IPV inactivation testing.

Background: Talar body and neck nonunions and malunions may undergo a reconstructive surgery when joint cartilage is still viable, and no talar collapse or infection has occurred. This is a rare condition and the studies supporting the procedure have small number of cases. The objective of the present study is to report a case series of six patients who underwent talar reconstructions. Materials and Methods: Six patients with talar malunions or nonunions who underwent surgical treatment were reviewed in this retrospective study. There were three nonunions and two malunions of the talar body and one malunion of the talar neck. Clinical evaluation included all the parameters used in the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot scale. Arthritic degeneration of the ankle joint was assessed according to a modified Bargon scale. Results: The mean followup was 86 months (range 24-282 months). There were no cases of postoperative avascular necrosis of the talus. Four of the six patients in our series required a subtalar fusion as part of the reconstruction procedure. The average preoperative AOFAS hindfoot score was 34, and at the time of the last evaluation, it was 74. The mean preoperative score on the modified Bargon scale for the tibiotalar joint was 1.17. At the last followup, it rose to 1.33. Three different deformities of the talus were identified (a) flattening of the talus (b) extra-articular step and (c) intraarticular step. Conclusion: Reconstruction of talar nonunions and malunions improved function in selected patients with a low risk of complications. Three different anatomical patterns of talar nonunions and malunions were identified.

Bioelectrical impedance vectorial analysis (BIVA) can be considered a favorable method for evaluation and monitoring of nutritional and hydration status without assumptions regarding body composition or requirement of prediction formulas. The present study aimed to determine bivariate tolerance intervals of the whole-body impedance vector for healthy term infants aged 1 to 3 months.This is a descriptive cross-sectional study. Anthropometric and bioelectrical impedance data (800 mA-50 kHz) were obtained. Bivariate vector analysis was conducted with the resistance-reactance (RXc) graph method. BIVA software was used to construct the graphs.A total of 150 appropriate for gestational age infants (48.7% boys) who were exclusively breastfed and were 56.4 (SD = 23.1) days of age were studied. RXc tolerance ellipses (50, 75, and 95%) were constructed for boys and girls, but a general reference graph was defined for all infants considering the overlapping of ellipses between the genders. All graphs differed from those in national and foreign studies.New reference tolerance ellipses (95, 75, and 50%) for 1- to 3-month-old infants were constructed, pointing out the need for specific reference values of total body impedance vectors in different regions of Brazil. The RXc tolerance ellipses can be used for clinical practice and provide an easy method to evaluate and monitor body composition and hydration status.

Bacteriophages, or phages, are ubiquitous microorganisms that only infect bacteria. They were briefly used, mainly in the West, in the early 20th century to treat human bacterial infections, before being replaced by antibiotics in the 1940s. In the 1970s, the phage display technology, which consists of presenting multiple copies of small polypeptides at the surface of the phage, led to consider phages as vaccine antigen producers. However, the technology potential for this use remains limited to small or truncated antigens that required the use of an adjuvant. Nowadays, phages are gaining a growing interest as vaccine antigen delivery vehicles. Evidence of the phage intrinsic adjuvant properties, which can be enhanced by targeting the particles to various eucaryotic cells, combined with a demonstrated inocuity in human and at low production cost make it possible to envisage in a near future the use of virus-based vaccines-like phagic particles (i.e. virus-like particles). This review describes, in a non-exhaustive way, some of the most promising technological approaches. In addition, there is a growing body of evidence from the literature showing that phages play a major role in the equilibrium of the human intestinal microbiota and protection against mucosal infection, opening new opportunities for vaccine research, targeting pathogens at the first natural host barrier protection.

Background: Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder caused by the deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by four genes: BCKDHA, BCKDHB, DBT, and DLD. MSUD is predominantly caused by mutations in the BCKDHA, BCKDHB, and DBT genes which encode the E1α, E1β, and E2 subunits of the BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD in a cohort of Chilean MSUD patients by identifying point mutations in the BCKDHA, BCKDHB, and DBT genes and to describe their impact on the phenotypic heterogeneity of these patients. This manuscript describes a cross-sectional study of 18 MSUD patients carried out using PCR and DNA sequencing.Results: Four novel pathogenic mutations were identified: one in BCKDHA (p.Thr338Ile), two in BCKDHB (p.Gly336Ser e p.Pro240Thr), and one in DBT (p.Gly406Asp). Four additional pathogenic mutations found in this study have been described previously.Conclusion: There were no correlations between the genotype and phenotype of the patients. Thus, if MSUD is diagnosed earlier, with a neonatal screening approach, it might be possible to establish genotype-phenotype relationships more efficiently.

Goal: Functional connectivity (FC) is an important indicator of the brain's state in different conditions, such as rest/task or health/pathology. Here we used high-density electroencephalography coupled to source reconstruction to assess frequency-specific changes of FC during resting state. Specifically, we computed the Small-World Propensity (SWP) index to characterize network small-world architecture across frequencies. Methods: We collected resting state data from healthy participants and built connectivity matrices maintaining the heterogeneity of connection strengths. For a subsample of participants, we also investigated whether the SWP captured FC changes after the execution of a working memory (WM) task. Results: We found that SWP demonstrates a selective increase in the alpha and low beta bands. Moreover, SWP was modulated by a cognitive task and showed increased values in the bands entrained by the WM task. Conclusions: SWP is a valid metric to characterize the frequency-specific behavior of resting state networks. ispartof: IEEE Open Journal of Engineering in Medicine and Biology vol:1 pages:57-64 ispartof: location:United States status: published

The proteasome is the key player in the cellular protein degradation machinery and is pivotal for protein homeostasis and Schistosoma mansoni (S. mansoni) survival. Our group study provides insights into proteasome inhibitors and reveals that selective schistosomiasis agents represent an interesting branch of proteasome research linked to the development of new drugs for this neglected disease. Here, we explored the phenotypic response of S. mansoni to b-AP15, a bis-benzylidine piperidone that inhibits 26S proteasome deubiquitinases (DUBs), ubiquitin-specific protease 14 (USP14), and ubiquitin carboxyl-terminal hydrolase 5 (UCHL5). b-AP15 induces a modest decrease in egg production in vitro and reduces viability, leading to the death of parasite couples. This inhibitor also induces a twofold increase in the accumulation of polyubiquitinated proteins in S. mansoni adult worms and causes tegument changes such as disintegration, wrinkling, and bubble formation, both throughout the length of the parasite and in the oral sucker. b-AP15 alters the cell organelles of adult S. mansoni worms, and we specifically observed mitochondrial alterations, which are suggestive of proteotoxic stress leading to autophagy. Taken together, these results indicate that the deubiquitinase function of the proteasome is essential for the parasite and support the hypothesis that the proteasome constitutes an interesting drug target for the treatment of schistosomiasis.