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Background Vaginoplasty is the most frequent genital gender-affirming surgery. Although both functional and aesthetic outcomes after transfeminine vaginoplasty have improved over the years, cosmetic revision surgeries demand after transfeminine vaginoplasty appears to be increasing and requires updated knowledge. Methods All patients who underwent vulvar cosmetic revision surgeries at our institution following transfeminine vaginoplasty from January 2014 to April 2022 were studied. The prevalence, topography and surgical techniques of cosmetic revision surgeries after transfeminine genital gender-affirming surgery were examined using clinical charts review and statistical analysis. Results During the study period, 354 patients underwent gender-affirming vaginoplasty at our single institution (212 penile inversion vaginoplasty, 122 colovaginoplasty and 20 penile inversion vaginoplasty with scrotal skin graft patients). Forty out of these 354 patients (11.29%) required cosmetic revision surgery after transfeminine vaginoplasty; additionally, 44 patients with vaginoplasty performed at other centres also underwent vulvar cosmetic revision surgery at our clinic during the study period. From all performed cosmetic revision surgeries, most of them (31.42%) were labia corrections, followed by clitoris (23.26%) repair surgeries. Mons Venus (10.20%), urethral meatus (9.38%), spongiosus tissue remnants (8.57%) and introitus (6.53%) revisions followed in frequency. Corrections of peri-inguinal scars (5.30%), anterior commissure (2.84%) and inferior fourchette (2.42%) were less prevalent. No differences were found among the different studied vaginoplasty techniques regarding cosmetic revision surgery prevalence or topography following transfeminine vaginoplasty (p Conclusions Cosmetic revision surgeries after transfeminine vaginoplasty are frequent. In our large and long-term cohort study, labiaplasty followed by clitoroplasty were found as the most required cosmetic revision surgical procedures. Further multicentre, prospective and controlled studies are necessary to improve cosmetic outcomes and scientific evidence after transfeminine vaginoplasty. Level of evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is safe under adequate molecular monitoring, but questions remain regarding which factors may be considered predictive for TFR. Argentina Stop Trial (AST) is a multicenter TFR trial showing that 65% of patients sustain molecular remission, and the prior time in deep molecular response (DMR) was associated with successful TFR. Luminex technology was used to characterize cytokines in plasma samples. Using machine learning algorithms, MCP-1 and IL-6 were identified as novel biomarkers and MCP-1low/IL-6low patients showed eightfold higher risk of relapse. These findings support the feasibility of TFR for patients in DMR and MCP-1/IL-6 plasma levels are strong predictive biomarkers.

Background: The HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is the most common neurological manifestation associated with Human T-cell Lymphotropic Virus type-1 (HTLV-1) infection. Although cognitive impairment has been highlighted in the spectrum of HTLV-1 neurological manifestations, it may go unnoticed in those who do not spontaneously report it. We aimed at evaluating the applicability of a self-perceived memory score (SMS) and the cognitive event-related potential (P300) for the early detection of cognitive impairment in HTLV-1-infected people. Methods: The SMS was measured by a 0-10 visual analog scale combined with a sad-happy faces rating scale. The higher the number, the better was the SMS. The P300 was obtained through an oddball paradigm with a mental counting task. The participants were 15(21,4%) individuals with HAM/TSP, 20(28,6%) HTLV-1-asymptomatic carriers, and 35(50%) seronegative controls. Results: SMS (p369.0 milliseconds were considered as altered result and indicated cognitive impairment. The HAM/TSP group showed the highest prevalence of altered P300 (80%) and SMS (87%). Interestingly, the asymptomatic group also presented significant higher prevalence of altered SMS (60%) and P300 (35%) when compared to controls (Conclusion: The use of SMS in the medical consultation was a useful and easy-to-apply method to screen HTLV-1 infected subjects for everyday memory complaints.

Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The underlying mechanisms that account for the ultimate emergence of resistance to ADT, progressing to castrate-resistant prostate cancer (CRPC), include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis to assess the metabolic shift occurring in PCa that progresses with low AR expression. We used PCa patient-derived xenografts (PDXs) to assess the metabolic changes after castration of tumor-bearing mice and subsequently confirmed main findings in human donor tumor that progressed after ADT. We found that relapsed tumors had a significant increase in fatty acids and ketone body (KB) content compared with baseline. We confirmed that critical ketolytic enzymes (ACAT1, OXCT1, BDH1) were dysregulated after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT. In an in silico approach, increased ACAT1, OXCT1, BDH1 expression was also observed for a subset of PCa patients that relapsed with low AR and ERG (ETS-related gene) expression. Further, expression of these factors was also associated with decreased time to biochemical relapse and decreased progression-free survival. Our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.

Over the years, the attention towards the role of phytochemicals in dietary natural products in reducing the risk of developing cancer is rising. Cancer is the second primary cause of mortality worldwide. The current therapeutic options for cancer treatment are surgical excision, immunotherapy, chemotherapy, and radiotherapy. Unfortunately, in case of metastases or chemoresistance, the treatment options become very limited. Despite the advances in medical and pharmaceutical sciences, the impact of available treatments on survival is not satisfactory. Recently, natural products are a great deal of interest as potential anti-cancer agents. Among them, phenolic compounds have gained a great deal of interest, thanks to their anti-cancer activity. The present review focuses on the suppression of cancer by targeting BRCA gene expression using dietary polyphenols, as well as the clinical aspects of polyphenolic agents in cancer therapy. They regulate specific key processes involved in cancer progression and modulate the expression of oncogenic proteins, like p27, p21, and p53, which may lead to apoptosis, cell cycle arrest, inhibition of cell proliferation, and, consequently, cancer suppression. Thus, one of the mechanisms underlying the anti-cancer activity of phenolics involves the regulation of tumor suppressor genes. Among them, the BRCA genes, with the two forms (BRCA-1 and BRCA-2), play a pivotal role in cancer protection and prevention. BRCA germline mutations are associated with an increased risk of developing several types of cancers, including ovarian, breast, and prostate cancers. BRCA genes also play a key role in the sensitivity and response of cancer cells to specific pharmacological treatments. As the importance of BRCA-1 and BRCA-2 in reducing cancer invasiveness, repairing DNA damages, oncosoppression, and cell cycle checkpoint, their regulation by natural molecules has been examined.

Purpose Single-limb stance is a demanding postural task featuring a high number of daily living and sporting activities. Thus, it is widely used for training and rehabilitation, as well as for balance assessment. Muscle activations around single joints have been previously described, however, it is not known which are the muscle synergies used to control posture and how they change between conditions of normal and lack of visual information. Methods Twenty-two healthy young participants were asked to perform a 30 s single-limb stance task in open-eyes and closed-eyes condition while standing on a force platform with the dominant limb. Muscle synergies were extracted from the electromyographical recordings of 13 muscles of the lower limb, hip, and back. The optimal number of synergies, together with the average recruitment level and balance control strategies were analyzed and compared between the open- and the closed-eyes condition. Results Four major muscle synergies, two ankle-dominant synergies, one knee-dominant synergy, and one hip/back-dominant synergy were found. No differences between open- and closed-eyes conditions were found for the recruitment level, except for the hip/back synergy, which significantly decreased (p = 0.02) in the closed-eyes compared to the open-eyes condition. A significant increase (p = 0.03) of the ankle balance strategy was found in the closed-eyes compared to the open-eyes condition. Conclusion In healthy young individuals, single-limb stance is featured by four major synergies, both in open- and closed-eyes condition. Future studies should investigate muscle synergies in participants with other age groups, as well as pathological conditions.

Purpose Neuromuscular electrical stimulation (NMES) superimposed on voluntary muscle contraction has been recently shown as an innovative training modality within sport and rehabilitation, but its effects on the neuromuscular system are still unclear. The aim of this study was to investigate acute responses in spinal excitability, as measured by the Hoffmann (H) reflex, and in maximal voluntary contraction (MVIC) following NMES superimposed to voluntary isometric contractions (NMES + ISO) compared to passive NMES only and to voluntary isometric contractions only (ISO). Method Fifteen young adults were required to maintain an ankle plantar-flexor torque of 20% MVC for 20 repetitions during each experimental condition (NMES + ISO, NMES and ISO). Surface electromyography was used to record peak-to-peak H-reflex and motor waves following percutaneous stimulation of the posterior tibial nerve in the dominant limb. An isokinetic dynamometer was used to assess maximal voluntary contraction output of the ankle plantar flexor muscles. Results H-reflex amplitude was increased by 4.5% after the NMES + ISO condition (p p Conclusion The reported facilitation of spinal excitability following NMES + ISO could be due to a combination of greater motor neuronal and corticospinal excitability, thus suggesting that NMES superimposed onto isometric voluntary contractions may provide a more effective neuromuscular stimulus and, hence, training modality compared to NMES alone.

Numerous methods have been designed to reduce breasts size and weight. The goal today is to not only to reduce size but also to create a pleasing shape. Breast reduction techniques do not obtain the desired upper pole fullness, and commonly recurrent ptosis develops. To improve and maintain breast shape in the late postoperative period, we combine breast reduction with implants. Three hundred and sixty-six patients who underwent combined breast reduction or mastopexy with implants from January 2014 to November 2017 at IM Clinic were retrospectively reviewed. We present the indications, surgical technique, and outcomes of these patients to determine the safety and efficacy of our technique. No major complications were noted in an average of 2 years of follow-up (range 2 months to 4 years). Minor complications occurred in 61 patients, of whom 46 required revision surgery (12.6%). The most common tissue-related complications were dog ears (7.6%) and poor scarring (4.9%). The most common implant-related complication was capsular contracture (0.8%). Breast reduction with implants is a reliable option to provide additional volume to the upper pole of the breast to improve long-term breast shape and avoid ptosis recurrence. Our study indicates that the procedure is safe and has complication and revision rates comparable to traditional breast reduction or augmentation mastopexy techniques. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Background Anti-PD-1 and anti-PD-L1 checkpoint inhibitors (CIs) are clinically active in many types of cancer. However, only a minority of patients achieve a complete and/or long-lasting clinical response. We studied the effects of different doses of three widely used, orally active chemotherapeutics (vinorelbine, cyclophosphamide and 5-FU) over local and metastatic tumour growth, and the landscape of circulating and tumour-infiltrating immune cells involved in CI activity. Methods Immunocompetent Balb/c mice were used to generate models of breast cancer (BC) and B-cell lymphoma. Vinorelbine, cyclophosphamide and 5-FU (alone or in combination with CIs), were given at low-dose metronomic, medium, or maximum tolerable dosages. Results Cyclophosphamide increased circulating myeloid derived suppressor cells (MDSC). Vinorelbine, cyclophosphamide and 5-FU reduced circulating APCs. Vinorelbine and cyclophosphamide (at medium/high doses) reduced circulating Tregs. Cyclophosphamide (at low doses) and 5-FU (at medium doses) slightly increased circulating Tregs. Cyclophosphamide was the most potent drug in reducing circulating CD3+CD8+ and CD3+CD4+ T cells. Vinorelbine, cyclophosphamide and 5-FU reduced the number of circulating B cells, with cyclophosphamide showing the most potent effect. Vinorelbine reduced circulating NKs, whereas cyclophosphamide and 5-FU, at low doses, increased circulating NKs. In spite of reduced circulating T, B and NK effector cells, preclinical synergy was observed between chemotherapeutics and anti-PD-L1. Most-effective combinatorial regimens where associated with neoplastic lesions enriched in B cells, and, in BC-bearing mice (but not in mice with lymphoma) also in NK cells. Conclusions Vinorelbine, cyclophosphamide and 5-FU have significant preclinical effects on circulating and tumour-infiltrating immune cells and can be used to obtain synergy with anti-PD-L1.

A 58-year-old male patient was admitted with suspected tuberculous empyema. Due to an unfavorable clinical evolution, a thoracoscopic pleural biopsy was performed to achieve an etiological diagnosis after 6 days of hospitalization. VATS findings showing the bride’s veil or Mya’s sign helped to confirm the diagnosis, ruling out other causes. Although all the cultures were negative, the pathological study of the pleural biopsy confirmed the presence of a tuberculoid granulomatous inflammatory process. Hospital discharge occurred 4 days later. Thoracoscopic pleural biopsy is useful in the diagnosis of tuberculosis, especially when the clinical manifestations are uncertain. VATS improves drainage of the pleural space when tuberculous empyema is suspected.

Given the importance of reference materials (RM) in the structuring and maintenance of quality management systems for food analysis laboratories, RM were produced for the measurement of moisture, ash, total fat, and titratable acidity in whole milk powder. Two types of packaging and three storage temperatures were evaluated. The RM were considered homogeneous. The materials that were packaged in the pouches and those packaged in the amber glass bottles with screw caps (stored at room temperature) were not stable for moisture. Nevertheless, considering the four measurands, the amber glass bottles under refrigeration and freezing temperatures were the best packaging and storage conditions, respectively. Homogeneity and stability studies were carried out according to the ISO Guide 35, IUPAC harmonized protocol, and ISO 13528, considering the potential applicability of the produced materials as certified reference materials or even as RM for use in proficiency testing schemes. For homogeneity, despite the different criteria, there was agreement between the results. Considering the stability, the agreement depended on the evaluation of the regression assumptions, which is not required by the ISO Guide 35. The contribution of uncertainty associated with homogeneity was greater than that related to stability. The results indicated that the produced materials, i.e., the candidate certified RMs, were suitable for assessing trueness and could be submitted to further inter-laboratory characterization.

Acknowledgements section was missing.

The Educational and Career Interest scale, a self-report instrument measuring high school students’ educational and career interest in STEM, was developed and validated in two studies conducted during 2010 and 2011. Study 1 included data from 92 high school students, in which exploratory factor analysis (EFA) was conducted with an initial item pool of 20 items. EFA identified three factors: educational and career interest in science, educational and career interest in technology, and educational and career interest in mathematics. Study 2 utilized data from 658 students to revisit the three-factor model using confirmative factor analysis. The two studies provide strong evidence that the scale is both valid and reliable.

The Energy End-use Efficiency and Energy Services Directive (ESD) of the European Union requires the member states to define and attain an overall target of at least 9% annual energy savings between 2008 and 2016. Even if this target is indicative, this is the first international framework mandating countries to report on their energy savings results and prove achievement of their targets. The directive thus also required the development of harmonised calculation methods that can be used by member states for this proof and reporting. Existing literature covers most of the usual issues related to energy savings evaluation, but mostly looking at single, given energy efficiency programmes or policies. The evaluation objective for the ESD implementation is different, as it aims at accounting for the whole energy savings achieved in a country. Moreover, one of the main difficulties is the diversity in history and experience on this topic among the member states. In this context, the European project EMEEES has worked out an integrated system of bottom-up and top-down methods for the measurement of energy savings. The paper presents the overview of its final results. The proposals, inter alia, include 20 bottom-up and 14 top-down case applications of general evaluation methods. They enable more than 90% of the potential energy savings to be measured and reported. They were used as a starting point by the European Commission to develop the methods recently recommended to the member states. Furthermore, the paper briefly discusses the importance of the quantity to be measured—all or additional energy savings—and the effect of measures implemented before the entering into force of the ESD (‘early action’), and what this meant for the methods to be developed. It compares the main elements of calculation needed to ensure consistent results between bottom-up and top-down methods at the overall national level. Finally, general conclusions are drawn about what could be the next steps in developing an evaluation system that enables a high degree of comparability of results between different countries.

In the wake of a steadily expanding climate policy portfolio tradable white certificates (TWCs) are an energy-efficiency policy instrument, which is receiving increasing attention from policy makers worldwide. Many policy makers regard them as an effective instrument to improve security of supply, to minimize negative environmental impacts of energy conversion and to maximize economic efficiency of climate policies. Tradable white certificates have their roots in several preceding instrumental designs. Firstly, there is a heritage of integrated resource planning (IRP), demand side management (DSM), energy-saving obligation schemes for energy utilities. IRP started already in the 1970s and was enlarged to DSM and utility obligation programs in the 1980s (e.g. Hirst 1992; Schweitzer et al. 1991; Waide and Buchner, in this volume). The second line of heritage for TWCs comes from the development of the tradable property rights. Even though the idea has been around already for more than 40 years (Coase 1960), the implementation started only to pick up in the late seventies (‘bubble-concept’, Atkinson and Tietenberg 1991) and, more seriously, with the introduction of a capand-trade system for SO2 in the USA in the eighties. Since then, a strong trend favouring market-based instruments was prominent in many OECD countries. More specifically, the existing TWC systems have many features in common with greenhouse gas emission trade systems (notably EU ETS) and with green certificate systems, such as RECs (Gillenwater 2008a, b).

Dizziness is a common complaint in HAM/TSP and can occur due to vestibulospinal tract dysfunction. This tract can be assessed through Vestibular Evoked Myogenic Potential (VEMP). The aim was to correlate the result of VEMP generated by acoustic stimuli and dizziness in individuals with HTLV-1-asymptomatic infection and HAM/TSP. VEMP was recorded from sternocleidomastoid muscle of 60 HTLV-1-negative adults (56 ± 5 years) and 60 individuals infected with HTLV-1, being 30 asymptomatic (56 ± 8 years) and 30 with HAM/TSP (59 ± 8 years). In all groups, 90% of the participants were women. The acoustic stimuli were short tone bursts (1 kHz, 118 dBHL, rise-fall 1 ms, plateau 2 ms), stimulation rate of 5 Hz and the analysis time for each response was 60 ms; 200 responses were averaged for each run. The electromyographic signals were amplified and band-pass filtered between 10 and 1.5 KHz. Of 60 HTLV-1-negative individuals, 14(23%) reported dizziness; VEMP was normal in all. In the HTLV-1-asymptomatic group, 11(37%) complained of dizziness (P=0.22); VEMP was altered in 4(40%) subjects with dizziness and in 1(5%) without dizziness (P=0.05). In the group with HAM/TSP, dizziness was reported by 17(57%) subjects (P=0.002); VEMP was altered in 11(64%) with dizziness and in 5(38%) without dizziness (P=0.15). Damage of vestibulospinal tract seems to occur in the early stages of HAM/TSP. VEMP was previously shown to be a useful test for the follow-up of asymptomatic carriers. Dizziness without an apparent cause in HTLV-1-asymptomatic carriers deserve investigation about a possible spinal cord involvement.

The diagnosis of celiac disease patients may be delayed by misdiagnosis. Our aim was to evaluate in celiac patients the prevalence of surgery before diagnosis. Two hundred forty-four adult celiac patients and 232 controls were retrospectively investigated for surgery before diagnosis of celiac disease. The prevalence of surgery was increased in celiac patients versus controls (P = 0.001). Frequency of appendectomy (P = 0.0001), tonsillectomy (P = 0.009), and hernia repair (P = 0.05) were increased in celiac patients versus controls. Appendectomy was related to anemia (P = 0.006) and abdominal pain (P = 0.005); tonsillectomy was related to diarrhea (P = 0.02) and weight loss (P = 0,04). Appendectomy was elective in 73% of celiac patients and in 46% of controls. Cosmetic surgery was increased in celiac patients versus controls (P = 0.058). In conclusions, surgery before celiac disease diagnosis is increased in celiac patients compared to controls, as a result of doctors' misdiagnosis and/or poor health status, which increases the demand for medical intervention. The frequency of cosmetic surgery in celiac patients may be related to impaired psychological profile of patients.