Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022.

BACKGROUND: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. CONCLUSIONS: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030.

BACKGROUND: We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy. PATIENTS AND METHODS: We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence. RESULTS: Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10-4 (range 7.9 × 10-7-4.9 × 10-1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12. CONCLUSIONS: Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.

ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer has recently emerged as a targetable subset of breast tumors, based on the evidence from clinical trials of novel anti-HER2 antibody-drug conjugates. This evolution has raised several biological and clinical questions, warranting the establishment of consensus to optimally treat patients with HER2-low breast tumors. Between 2022 and 2023, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process focused on HER2-low breast cancer. The consensus included a multidisciplinary panel of 32 leading experts in the management of breast cancer from nine different countries. The aim of the consensus was to develop statements on topics that are not covered in detail in the current ESMO Clinical Practice Guideline. The main topics identified for discussion were (i) biology of HER2-low breast cancer; (ii) pathologic diagnosis of HER2-low breast cancer; (iii) clinical management of HER2-low metastatic breast cancer; and (iv) clinical trial design for HER2-low breast cancer. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. A review of the relevant scientific literature was conducted in advance. Consensus statements were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This article presents the developed statements, including findings from the expert panel discussions, expert opinion, and a summary of evidence supporting each statement.

Association of HER2DX with pathological complete response and survival outcomes in HER2-positive breast cancer.

BACKGROUND: The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the association of HER2DX scores with (i) pCR according to hormone receptor status and various treatment regimens, and (ii) survival outcome according to pCR status. MATERIALS AND METHODS: Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n = 765) in combination with pertuzumab (n = 328), lapatinib (n = 187) or without a second anti-HER2 drug (n = 250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e. NEOHER and PAMELA) with a pCR (n = 118) and without a pCR (n = 150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low or high risk beyond pCR status. RESULTS: HER2DX pCR score was significantly associated with pCR in all patients [odds ratio (OR) per 10-unit increase = 1.59, 95% confidence interval 1.43-1.77; area under the ROC curve = 0.75], with or without dual HER2 blockade. A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR = 2.36 (1.09-5.42). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR = 3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (P < 0.001) and OS (P = 0.006) compared with patients with HER2DX high-risk. CONCLUSIONS: HER2DX pCR score and risk score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer.

Olanzapine as an add-on, pre-operative anti-emetic drug for postoperative nausea or vomiting: a randomised controlled trial.

Postoperative nausea or vomiting occurs in up to 40% in patients with multiple risk factors, despite prophylaxis. Olanzapine is an antipsychotic drug that is used to prevent nausea and vomiting in palliative care and to treat chemotherapy-induced nausea and vomiting. This study aimed to examine whether pre-operative olanzapine, as a prophylactic anti-emetic added to intra-operative dexamethasone, ondansetron and total intravenous anaesthesia, reduced the incidence of postoperative nausea or vomiting. We performed a multiply-blinded randomised controlled trial in patients aged 18-60 years with cancer at high risk of postoperative nausea or vomiting (three or four risk factors according to the Apfel criteria) plus a previous history of chemotherapy-induced nausea and vomiting. Patients were allocated at random to receive 10 mg olanzapine or placebo orally 1 h before surgery in addition to a two-drug regimen (dexamethasone and ondansetron) and propofol anaesthesia to prevent postoperative nausea or vomiting. The primary outcome was the incidence of postoperative nausea or vomiting in the first 24 h after surgery. In total, 100 patients were enrolled; 47 in the olanzapine group and 49 in the control group completed the study. The baseline characteristics of the groups were similar. The incidence of postoperative nausea or vomiting in the first 24 h after surgery was lower in the olanzapine group (12/47, 26%) than in the control group (31/49, 63%) (p = 0.008, RR 0.40 (95%CI 0.21-0.79)). Adding pre-operative oral olanzapine to intra-operative dexamethasone and ondansetron was highly effective in reducing the risk of postoperative nausea or vomiting in the first 24 hours after surgery in patients with a previous history of chemotherapy-induced nausea and vomiting and at least three Apfel risk factors for postoperative nausea or vomiting.

Prediction of successful hearing aid treatment in first-time and experienced hearing aid users: Using the International Outcome Inventory for Hearing Aids.

OBJECTIVE: Primarily to understand whether clinically relevant factors affect the International Outcome Inventory (IOI-HA) scores and to examine if IOI-HA scores improve when renewing the hearing aids (HA) for experienced users. Secondly, to estimate the overall HA effectiveness using the IOI-HA. DESIGN: A prospective observational study. STUDY SAMPLE: In total, 1961 patients with hearing loss were included. All patients underwent a hearing examination, were fitted with HAs, and answered the IOI-HA. Factor analysis of IOI-HA separated the items into a Factor 1 (use of HA, perceived benefits, satisfaction, and quality of life) and Factor 2 (residual activity limitation, residual participation restriction and impact on others) score. RESULTS: Degree of hearing loss, word recognition score, motivation, HA usage time, tinnitus, asymmetry, and sex were significantly associated with total IOI-HA, Factor 1, or Factor 2 scores. The seven IOI-HA items increased on average by 0.4 (p < 0.001) when renewing HAs. The total median IOI-HA score at follow-up was 29 (7) for experienced (n = 460) and first-time users (n = 1189), respectively. CONCLUSIONS: Degree of hearing loss, word recognition score, motivation, tinnitus, asymmetry, and sex may be used to identify patients who require special attention to become successful HA users.

A musician-centered approach to management of performance-related upper musculoskeletal injuries.

STUDY DESIGN: Invited Clinical Commentary BACKGROUND: Performance related musculoskeletal disorders (PRMD) are common in instrumental musicians and often affect the upper extremities. These overuse injuries typically result from inadequate attention to the musculoskeletal demands required for the high-level performance of musician-students and experienced instrumentalists.1 PRMDs often interfere with career trajectory, and in extreme cases, can be career ending. Many clinicians and healthcare practitioners treating upper extremity injuries are not familiar with the specific demands faced by instrumental musicians and how to tailor treatment and prevention strategies to the specific risks and occupational needs of each instrumental group. PURPOSE OF THE STUDY: This paper describes an evidenced-based framework for the assessment, prevention, and treatment of musculoskeletal musician injuries to provide clinicians with an instrument-specific, and musician-centered guide for practice. We synthesized available literature on instrumental ergonomics, biomechanical demands, and upper extremity injuries to highlight the risks and common upper-extremity pathologies, focusing on the specific demands of instrumental groups: piano, high strings (violin and viola), low strings (cello and bass), percussion, woodwinds, and brass. Targeted assessment, prevention, and treatment strategies are reviewed in this context to provide healthcare providers with an evidence-based framework to approach the treatment of PRMD to mitigate incidence of injury during practice and performance. METHODS: A comprehensive search of electronic databases was conducted including all study designs. RESULTS: This review describes risk factors for PRMD in instrumental musicians, strategies to prevent misuse and performance injury, and musician-centered interventions to allow playing while reducing risk of misuse. CONCLUSION: The suggested assessment and treatment framework can assist clinicians with a customized patient-centered approach to prevention and treatment by addressing the gap in clinical knowledge with the goal of ultimately reducing the incidence and severity of PRMD in musicians.

TBCRC 030: a phase II study of preoperative cisplatin versus paclitaxel in triple-negative breast cancer: evaluating the homologous recombination deficiency (HRD) biomarker.

BACKGROUND: Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite different mechanisms of action, effective predictive biomarkers to preferentially inform drug selection have not been identified. The homologous recombination deficiency (HRD) assay (Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The primary objective of TBCRC 030 was to detect an association of HRD with pathologic response [residual cancer burden (RCB)-0/1] to single-agent cisplatin or paclitaxel. PATIENTS AND METHODS: This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown stage I-III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The HRD assay was carried out on baseline tissue; positive HRD was defined as a score ≥33. Crossover to an alternative chemotherapy was offered if there was inadequate response. RESULTS: One hundred and thirty-nine patients were evaluable for response, including 88 (63.3%) who had surgery at 12 weeks and 51 (36.7%) who crossed over to an alternative provider-selected preoperative chemotherapy regimen due to inadequate clinical response. HRD results were available for 104 tumors (74.8%) and 74 (71.1%) were HRD positive. The RCB-0/1 rate was 26.4% with cisplatin and 22.3% with paclitaxel. No significant association was observed between HRD score and RCB response to either cisplatin [odds ratio (OR) for RCB-0/1 if HRD positive 2.22 (95% CI: 0.39-23.68)] or paclitaxel [OR for RCB-0/1 if HRD positive 0.90 (95% CI: 0.19-4.95)]. There was no evidence of an interaction between HRD and pathologic response to chemotherapy. CONCLUSIONS: In this prospective preoperative trial in TNBC, HRD was not predictive of pathologic response. Tumors were similarly responsive to preoperative paclitaxel or cisplatin chemotherapy.

A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer.

BACKGROUND: HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy. PATIENTS AND METHODS: Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast). RESULTS: Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P = 0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P = 0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P = 0.0031). CONCLUSIONS: Our findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.

Combined tetrahydrocannabinol and cannabidiol to treat pain in epidermolysis bullosa: a report of three cases.

Epidermolysis bullosa (EB) is a genetic blistering disorder characterized by intense pain related to disease pathology and care-based interventions. Opioid-based therapies underpin pain care in EB; however, they are unable to provide adequate analgesia in a significant proportion of patients. Cannabinoid-based medicines (CBMs) have been studied increasingly for pain conditions of various aetiologies and pose as a novel dimension for pain care in EB. We present three patients with EB who were prescribed pharmaceutical-grade sublingually administered CBMs comprising tetrahydrocannabinol and cannabidiol. All three patients reported improved pain scores, reduced pruritus and reduction in overall analgesic drug intake.

Modelling of focused ion beam induced increases in sample temperature: a case study of heat damage in biological samples.

Ion beam induced heat damage in soft materials and biological samples is not yet well understood in Focused Ion Beam systems (FIBs). The work presented here discusses the physics behind the ion beam - sample interactions and the effects which lead to increases in sample temperature and potential heat damage. A model by which heat damage can be estimated and which allows parameters to be determined that reduce/prevent heat damage was derived from Fourier's law of heat transfer and compared to finite element simulations, numerical modelling results and experiments. The results suggests that ion beam induced heat damage can be prevented/minimised by reducing the ion beam current (local dose rate), decreasing the beam overlap (reduced local ion dose) and by introducing a blur (increased surface cross-section area, reduced local dose) while sputtering, patterning or imaging soft material and nonresin-embedded biological samples using FIBs. LAY DESCRIPTION: FIB/SEMs, which combine a scanning electron microscope with a focused ion beam in a single device, have found increasing interest biological research. The device allows to cut samples at precisely selected areas and reveal sub surface information as well as preparing transmission electron microscope samples from bulk materials. Preparing biological samples has proven to be challenging due to the induced heat damage. This work explores the physics behind the sample cutting and proposes a model and a method, based on physical principles which allows the user to estimate the induced heat during the cutting process and to select cutting parameters which avoid heat damage in the sample.

Electrostimulation of the lingual nerve by an intraoral device may lead to salivary gland regeneration: A case series study.

BACKGROUND: Salivary gland function is controlled by the salivary reflex, whose efferent arm is composed by the parasympathetic and the sympathetic divisions of the autonomic nervous system. Parenchymal injury is the main salivary gland involvement of Sjögren's syndrome and head and neck radiotherapy, but neural damage has been reported as well. Recently an intraoral device for electrostimulation of the lingual nerve in vicinity to the lower third molar has been introduced. At this point this nerve carries efferent fibers for the innervation of the submandibular, sublingual and several minor salivary glands and afferent fibers of the salivary reflex. Therefore, excitation of these fibers potentially leads to increased secretion of all salivary glands. Thus, the study objective was to assess whether comprehensive neural activation by electrostimulation of the lingual nerve carries the potential to induce the regeneration of damaged salivary glands. MATERIAL AND METHODS: The device was tested on three patients with no collectable resting and stimulated secretion of saliva during a double blind, sham controlled period of two months and nine open-label months. RESULTS: All three subjects developed the capacity to spit saliva, not only in direct response to the electrostimulation but also after free intervals without electrostimulation. In addition, their symptoms of dry mouth severity and frequency improved. CONCLUSIONS: This recovery is probably due to the combined effect of increase in secretory functional gland mass and regain of nervous control of the secretory elements and blood vessels. Both are phenomena that would contribute to gland regeneration.

[Medicaments and oral healthcare. Systematic review of the -literature assessing the effect of drugs on the salivary glands]. / Serie: Medicamenten en mondzorg.Systematisch literatuuronderzoek naar effect van medicatie op de speekselklieren.

Evidence-based reviews of drugs causing medication-induced salivary gland dysfunction, such as xerostomia (sensation of oral dryness) and subjective sialorrhea are lacking. To compile a list of medicaments that influence salivary gland function, electronic databases were searched for relevant articles published up to June 2013. A total of 269 papers out of 3,867 records located satisfied the inclusion criteria (relevance, quality of methodology, strength of evidence). A total of 56 active substances with a higher level of evidence and 50 active substances with a moderate level of evidence of causing salivary gland dysfunction are described in this article. While xerostomia was a commonly reported outcome, the objective effect on salivary secretion was rarely measured. Xerostomia was, moreover, mostly reported as a negative side effect instead of the intended effect of that drug. A comprehensive list of medications having documented effects on salivary gland function or symptoms was compiled, which may assist practitioners in assessing patients who complain of dry mouth while taking medications.

Heparin modification of a biomimetic bone matrix modulates osteogenic and angiogenic cell response in vitro.

In this study, the effect of heparin-modified collagen type I/hydroxyapatite (HA) nanocomposites on key processes of bone regeneration - osteogenesis and angiogenesis - was characterised in vitro. Two approaches were applied for heparin modification: it was either integrated during material synthesis (in situ) or added to the porous scaffolds after their fabrication (post). Cultivation of human bone marrow-derived stromal cells (hBMSC), in heparin-modified versus heparin-free scaffolds, revealed a positive effect of the heparin modification on their proliferation and osteogenic differentiation. The amount of heparin rather than the method used for modification influenced the cell response favouring proliferation at smaller amount (30 mg/g collagen) and differentiation at larger amount (150 mg/g collagen). A co-culture of human umbilical vein endothelial cells (HUVEC) and osteogenically induced hBMSC was applied for in vitro angiogenesis studies. Pre-vascular networks have formed in the porous structure of scaffolds which were not modified with heparin or modified with a low amount of heparin (30 mg/g collagen). The modification with higher heparin quantities seemed to inhibit tubule formation. Pre-loading of the scaffolds with VEGF influenced formation and stability of the pre-vascular structures depending on the presence of heparin: In heparin-free scaffolds, induction of tubule formation and sprouting was more pronounced whereas heparin-modified scaffolds seemed to promote stabilisation of the pre-vascular structures. In conclusion, the modification of mineralised collagen with heparin by using both approaches was found to modulate cellular processes essential for bone regeneration; the amount of heparin has been identified to be crucial to direct cell responses.

Effects of pericardiectomy on training- and myocardial infarction-induced left ventricular hypertrophy, chamber dimensions and gene expression.

The primary purpose of the study was to evaluate whether a pericardiectomy (PERI) alters training- or myocardial infarction (MI)-induced left ventricular hypertrophy (LVH), chamber geometry, gene expression and/or running performance. Mice were randomized into 6 groups: naïve control (CONT)-sedentary (Sed), CONT-trained (Tr), PERI-Sed, PERI-Tr, MI-Sed and MI-Tr. MI mice also received a pericardiectomy as part of the MI surgical procedure. 10 weeks of treadmill running resulted in enhanced running performance-to-exhaustion in all 3 trained groups (CONT-Tr, PERI-Tr, MI-Tr) compared to sedentary cohorts (P<0.001). Training also resulted in similar increases in normalized LVH (LV/BW) in CONT-Tr and PERI-Tr mice. 2D-echocardiographic evaluation of LV internal chamber dimensions revealed that stroke diameter (SD) was larger in PERI compared to MI (P<0.01) but not CONT mice. Ventricular B-type natriuretic peptide mRNA (BNP) was elevated only in the 2 MI groups. Left ventricle ß1-adrenergic receptor (ß1-AR) and melusin transcripts both demonstrated an overall increase in trained compared to sedentary mice (both P<0.05). Additionally long-term pericardiectomy did not further enhance running performance or increase LV/BW in either sedentary or trained mice.

[Genetic methods for analysis of autoinflammatory diseases]. / Genetische Methoden für die Analyse autoinflammatorischer Erkrankungen.

Over the past years the phenotypic and genetic spectrum of autoinflammatory diseases has continuously increased. Moreover, several monogenic autoinflammatory disorders have now been identified where febrile episodes are not among the leading symptoms and which can be accompanied by autoimmune phenomena and susceptibility to infections. Autoinflammatory conditions that are characterized by uncontrolled activity of cytokines, such as interleukin-1 beta (IL1ß), tumor necrosis factor alpha (TNF-α) and type 1 interferons (1-IFN), are amenable to specific therapeutic interventions. Thus, identification of the underlying genetic cause is important. During diagnostic work-up, genetic testing of a patient with autoinflammation should be carried out depending on the clinical presentation. If a distinct disorder is suspected, sequencing of the causative gene should be performed. Genetic tests using next generation sequencing (NGS), such as panel sequencing, exome sequencing and array comparative genomic hybridization (CGH) can be carried out if symptoms cannot be assigned to a specific disease entity.

Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia.

The postsynaptic density (PSD) contains a complex set of proteins of known relevance to neuropsychiatric disorders, and schizophrenia specifically. We enriched for this anatomical structure, in the anterior cingulate cortex, of 20 schizophrenia samples and 20 controls from the Stanley Medical Research Institute, and used unbiased shotgun proteomics incorporating label-free quantitation to identify differentially expressed proteins. Quantitative investigation of the PSD revealed more than 700 protein identifications and 143 differentially expressed proteins. Prominent among these were altered expression of proteins involved in clathrin-mediated endocytosis (CME) (Dynamin-1, adaptor protein 2) and N-methyl-D-aspartate (NMDA)-interacting proteins such as CYFIP2, SYNPO, SHANK3, ESYT and MAPK3 (all P<0.0015). Pathway analysis of the differentially expressed proteins implicated the cellular processes of endocytosis, long-term potentiation and calcium signaling. Both single-gene and gene-set enrichment analyses in genome-wide association data from the largest schizophrenia sample to date of 13,689 cases and 18,226 controls show significant association of HIST1H1E and MAPK3, and enrichment of our PSD proteome. Taken together, our data provide robust evidence implicating PSD-associated proteins and genes in schizophrenia, and suggest that within the PSD, NMDA-interacting and endocytosis-related proteins contribute to disease pathophysiology.

Physical exercise, pain and musculoskeletal function in patients with haemophilia: a systematic review.

INTRODUCTION: Exercise can provide numerous benefits to haemophilia patients, including bleeding reduction in muscles and joints. AIM: This systematic review (SR) aims to evaluate the effects of physical exercise on pain and the musculoskeletal function of patients with hemophilia. METHODS: Literature searches of Pubmed, Web of Science, PEDro, Cochrane, Clinical Trials SciELO and Lilacs were performed. The risks of bias were measured using the JADAD scale. RESULTS: Nine controlled clinical trials were included in the SR. CONCLUSION: Physical exercise can promote a reduction in the perception of pain and can increase ROM and muscle strength in haemophilia patients. Future RCTs with greater methodological rigor that focus on the parameters used to prescribe exercises are necessary.

World Workshop on Oral Medicine VI: a systematic review of medication-induced salivary gland dysfunction.

The aim of this paper was to perform a systematic review of the pathogenesis of medication-induced salivary gland dysfunction (MISGD). Review of the identified papers was based on the standards regarding the methodology for systematic reviews set forth by the World Workshop on Oral Medicine IV and the PRISMA statement. Eligible papers were assessed for both the degree and strength of relevance to the pathogenesis of MISGD as well as on the appropriateness of the study design and sample size. A total of 99 papers were retained for the final analysis. MISGD in human studies was generally reported as xerostomia (the sensation of oral dryness) without measurements of salivary secretion rate. Medications may act on the central nervous system (CNS) and/or at the neuroglandular junction on muscarinic, α-and ß-adrenergic receptors and certain peptidergic receptors. The types of medications that were most commonly implicated for inducing salivary gland dysfunction were those acting on the nervous, cardiovascular, genitourinary, musculoskeletal, respiratory, and alimentary systems. Although many medications may affect the salivary flow rate and composition, most of the studies considered only xerostomia. Thus, further human studies are necessary to improve our understanding of the association between MISGD and the underlying pathophysiology.

[Sustainable Implementation of Evidence-Based Programmes in Health Promotion: A Theoretical Framework and Concept of Interactive Knowledge to Action]. / Nachhaltige Implementierung evidenzbasierter Programme in der Gesundheitsförderung: Theoretischer Bezugsrahmen und ein Konzept zum interaktiven Wissenstransfer.

OBJECTIVES: This article discusses 2 current issues in the field of public health research: (i) transfer of scientific knowledge into practice and (ii) sustainable implementation of good practice projects. It also supports integration of scientific and practice-based evidence production. Furthermore, it supports utilisation of interactive models that transcend deductive approaches to the process of knowledge transfer. METHODS: Existing theoretical approaches, pilot studies and thoughtful conceptual considerations are incorporated into a framework showing the interplay of science, politics and prevention practice, which fosters a more sustainable implementation of health promotion programmes. The framework depicts 4 key processes of interaction between science and prevention practice: interactive knowledge to action, capacity building, programme adaptation and adaptation of the implementation context. RESULTS: Ensuring sustainability of health promotion programmes requires a concentrated process of integrating scientific and practice-based evidence production in the context of implementation. Central to the integration process is the approach of interactive knowledge to action, which especially benefits from capacity building processes that facilitate participation and systematic interaction between relevant stakeholders. Intense cooperation also induces a dynamic interaction between multiple actors and components such as health promotion programmes, target groups, relevant organisations and social, cultural and political contexts. The reciprocal adaptation of programmes and key components of the implementation context can foster effectiveness and sustainability of programmes. CONCLUSION: Sustainable implementation of evidence-based health promotion programmes requires alternatives to recent deductive models of knowledge transfer. Interactive approaches prove to be promising alternatives. Simultaneously, they change the responsibilities of science, policy and public health practice. Existing boundaries within disciplines and sectors are overcome by arranging transdisciplinary teams as well as by developing common agendas and procedures. Such approaches also require adaptations of the structure of research projects such as extending the length of funding.