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Autologous cranioplasty (CP) following decompressive craniectomy (DC) carries a risk of bone flap resorption (BFR). The current literature offers limited information regarding the natural progression of BFR and the rate at which it occurs. We aim to characterize the progression of BFR over time and elucidate risk factors for accelerated BFR.A retrospective analysis was conducted on patients who underwent DC and autologous CP. Serial computed tomography (CT) images were used to quantify the degree of BFR over time. Risk factors included age, diabetes, smoking status, flap fragmentation, defect size, and DC-CP time interval. χOverall, 82% of patients demonstrated evidence of clinically relevant resorption on CT. On average, the bone flap decreased in volume by 36.7% within the first year, with a linear loss in volume after multiple years of follow-up. Individuals who developed greater BFR were significantly younger (43 ± 17 vs. 56 ± 12, P = 0.022), had a lower incidence of diabetes (5.9% vs. 43%, P = 0.037), and had more bone flap fragments (1.4 ± 0.67 vs. 1.00 ± 0, P 0.001) than those who did not.Resorption following CP with cryopreserved bone appears to progress in a fairly linear and continuous fashion over time. Using serial CT images, we found a resorption rate of 82% at our institution. We identified several possible risk factors for resorption, including flap fragmentation, younger age, and absence of diabetes.

Background: Children with the most severe parental mental health conditions have an elevated risk of numerous adversities including somatic morbidity. However, there is no knowledge concerning physical health in most children affected by parental mental health conditions. Therefore, the aim was to examine the association between different severities of parental mental health conditions and somatic morbidity in children of different age-groups and further explore the combinations of maternal and paternal mental health conditions on child somatic morbidity.Methods: In this register-based cohort study, we included all children born in Denmark between 2000-2016 and linked parents. Parental mental health conditions were categorised into four severity groups (no, minor, moderate, and severe). Somatic morbidity in offspring was categorised into broad disease categories corresponding to the International Classification of Diseases. We estimated the risk ratio (RR) using Poisson regression, of the first registered diagnosis in different age-groups.Results: Of the around 1 million children in the study > 14.5% were exposed to minor parental mental health conditions and < 2.3% were exposed to severe parental mental health conditions. Overall, the analyses revealed a higher risk of morbidity in exposed children across all disease categories. The strongest association was observed for digestive diseases in children aged < 1 year exposed to severe parental mental health conditions (RR: 1.87 (95% CI: 1.74-2.00). Generally, the risk of somatic morbidity increased the more severe the parental mental health conditions. Both paternal and especially maternal mental health conditions were associated with a higher risk of somatic morbidity. The associations were strongest if both parents had a mental health condition.Conclusion: Children with different severities of parental mental health conditions experience a higher risk of somatic morbidity. Although children with severe parental mental health conditions had the highest risk, children with minor parental mental health conditions should not be neglected as more children are exposed. Children with both parents having a mental health condition were the most vulnerable to somatic morbidity and maternal mental health conditions were more strongly associated with somatic morbidity than paternal. More support and awareness of families with parental mental health conditions is highly needed. Background: Children with the most severe parental mental health conditions have an elevated risk of numerous adversities including somatic morbidity. However, there is no knowledge concerning physical health in most children affected by parental mental health conditions. Therefore, the aim was to examine the association between different severities of parental mental health conditions and somatic morbidity in children of different age-groups and further explore the combinations of maternal and paternal mental health conditions on child somatic morbidity. Methods: In this register-based cohort study, we included all children born in Denmark between 2000–2016 and linked parents. Parental mental health conditions were categorised into four severity groups (no, minor, moderate, and severe). Somatic morbidity in offspring was categorised into broad disease categories corresponding to the International Classification of Diseases. We estimated the risk ratio (RR) using Poisson regression, of the first registered diagnosis in different age-groups. Results: Of the around 1 million children in the study > 14.5% were exposed to minor parental mental health conditions and < 2.3% were exposed to severe parental mental health conditions. Overall, the analyses revealed a higher risk of morbidity in exposed children across all disease categories. The strongest association was observed for digestive diseases in children aged < 1 year exposed to severe parental mental health conditions (RR: 1.87 (95% CI: 1.74–2.00). Generally, the risk of somatic morbidity increased the more severe the parental mental health conditions. Both paternal and especially maternal mental health conditions were associated with a higher risk of somatic morbidity. The associations were strongest if both parents had a mental health condition. Conclusion: Children with different severities of parental mental health conditions experience a higher risk of somatic morbidity. Although children with severe parental mental health conditions had the highest risk, children with minor parental mental health conditions should not be neglected as more children are exposed. Children with both parents having a mental health condition were the most vulnerable to somatic morbidity and maternal mental health conditions were more strongly associated with somatic morbidity than paternal. More support and awareness of families with parental mental health conditions is highly needed.

Since the introduction of transcutaneous-transcricoidal needle approaches, electromyography (EMG) of the posterior cricoarytenoid muscle (PCA) became easier to perform and teach. Among the Neurolaryngology working group of the European Laryngological Society, several centers have adopted PCA EMG as part of their routine EMG workup in vocal fold immobility collectively gathering long-term experience. The purpose is to give an update and an extension to already existing guidelines on laryngeal EMG with specific regard to PCA EMG.Consensus of all co-authors is based on continuous exchange of ideas and on joint laryngeal EMG workshop experiences over at least 7 years. A Delphi method of consensus development was used, i.e., the manuscript was circulated among the co-authors until full agreement was achieved.Step-by-step instructions on how to perform and interpret PCA EMG are provided.Further research should include the establishment of normal values for PCA and thyroarytenoid muscle (TA) EMG as well as studies on the nature of some unusual activation pattern commonly seen in chronically lesioned PCA.

Aim: Parental mental health conditions adversely affect the children. Information on the prevalence of parental mental health conditions is needed to help policymakers allocate resources appropriately. Therefore, the aim of this study was to estimate the prevalence of children with parental mental health conditions in Denmark and further estimate the age-specific prevalence and geographical variation. Methods: In this nationwide register-based cross-sectional study, we included all children born between 2000 and 2016 if they resided in Denmark on 31 December 2016. Information on both maternal and paternal mental health conditions was retrieved from primary and secondary healthcare registers. Parental mental health conditions were categorised in three severity groups: minor, moderate, and severe. We estimated the proportion of children with parental mental health conditions on 31 December 2016. Results: Of the 1,106,459 children aged 0–16 years, 39.1% had at least one parent with a mental health condition. The prevalence increased with age of the children until the age of six years. Geographical variation in the prevalence ranged from 29.0% to 48.3% in the 98 municipalities. Minor parental mental health conditions (23.5%) were more common than moderate (13.5%) and severe parental mental health conditions (2.2%). Hospital-diagnosed parental mental health conditions were prevalent in 12.8% of the children. Conclusions: Two in five children aged 0–16 years in Denmark have parents with a mental health condition and geographical variation exists. The high prevalence of children with parental mental health conditions is an important public health challenge, which calls for attention.

OBJECTIVES: The purpose of the present survey is to give an update of European experts' opinion on infection control and prevention in dentistry during second wave of pandemic. The secondary aim was to analyse how experts' opinion changed in the light of the new scientific evidence since the first wave. MATERIAL & METHODS: An anonymous online 14-item questionnaire was sent to a total of 27 leading academic experts in Oral (and Maxillofacial) Surgery from different European countries, who had completed a previous survey in April-May 2020. The questionnaire covered the topics of dental setting safety, personal protective equipment (PPE), and patient-related measures to minimise transmission risk. Data collection took place in November-February 2020/21. RESULTS: 26 experts participated in the follow-up survey. The overall transmission risk in dental settings was scored significantly lower compared to the initial survey (P

Despite new combination therapies improving survival of breast cancer patients with estrogen receptor α (ER+) tumors, the molecular mechanisms for endocrine-resistant disease remain unresolved. Previously we demonstrated that expression of the RNA binding protein and N6-methyladenosine (m6A) reader HNRNPA2B1 (A2B1) is higher in LCC9 and LY2 tamoxifen (TAM)-resistant ERα breast cancer cells relative to parental TAM-sensitive MCF-7 cells. Here we report that A2B1 protein expression is higher in breast tumors than paired normal breast tissue. Modest stable overexpression of A2B1 in MCF-7 cells (MCF-7-A2B1 cells) resulted in TAM- and fulvestrant- resistance whereas knockdown of A2B1 in LCC9 and LY2 cells restored TAM and fulvestrant, endocrine-sensitivity. MCF-7-A2B1 cells gained hallmarks of TAM-resistant metastatic behavior: increased migration and invasion, clonogenicity, and soft agar colony size, which were attenuated by A2B1 knockdown in MCF-7-A2B1 and the TAM-resistant LCC9 and LY2 cells. MCF-7-A2B1, LCC9, and LY2 cells have a higher proportion of CD44+/CD24-/low cancer stem cells (CSC) compared to MCF-7 cells. MCF-7-A2B1 cells have increased ERα and reduced miR-222-3p that targets ERα. Like LCC9 cells, MCF-7-A2B1 have activated AKT and MAPK that depend on A2B1 expression and are growth inhibited by inhibitors of these pathways. These data support that targeting A2B1 could provide a complimentary therapeutic approach to reduce acquired endocrine resistance.

While Trauma-informed care (TIC) has the potential to improve the quality of aged and dementia care, the challenge remains in translating the principles of TIC into practice. This study aimed to characterise what trauma-informed aged care looks like in practice, by learning from an aged care service acknowledged as delivering trauma-informed aged care effectively.We conducted an appreciative inquiry study within a residential aged care service catering for veterans and others with trauma histories. Observation of care behaviours, interviews with staff and residents, and organisational policy mapping were used to identify elements that maximised care safety and accessibility for trauma survivors. Data were analysed and triangulated using a framework analysis approach.The aged care provider embedded the principles of TIC into its staff training (i) to promote understanding of how trauma may affect experiences in care, and (ii) to adapt care when appropriate to promote safety. The service promoted a calm atmosphere where residents could make choices and felt safe. Uniforms and signage provided consistency, clarity, and transparency for residents. Staff behaviours demonstrated respect, fostered trust, and anticipated needs without unnecessarily imposing care. Staff consistently offered choices, used residents' names, sought permission before providing care, and offered reassurance. Staff reported high morale with a commitment to delivering high quality care, and feedback to management. Effective communication promoted information sharing and trust among staff.Trauma-informed practice was facilitated through organisational policy, a dignified environment, and thoughtful staff behaviour creating safety, choice, and control for residents.

The objectives of this study were to describe the anatomy, histology, and ultrastructure of the equine filum terminale (FT) and to describe the FT in hereditary equine regional dermal asthenia (HERDA), a model of human Ehlers-Danlos syndromes (EDS). Those humans suffer from tethered cord syndrome (TCS) caused by an abnormally structured FT wherein its attachment at the base of the vertebral column leads to long-term stretch-induced injury to the spinal cord. The pathophysiology of TCS in EDS is poorly understood, and there is a need for an animal model of the condition. Histopathologic and ultrastructural examinations were performed on FT from HERDA ( n = 4) and control horses ( n = 5) and were compared to FT from human TCS patients with and without EDS. Adipose, fibrous tissue, and neuronal elements were assessed. CD3 and CD20 immunohistochemistry was performed to clarify cell types (HERDA n = 2; control n = 5). Collagen fibrils were assessed in cross-section for fibril diameter and shape, and in longitudinal section for fibril disorganization, swelling, and fragmentation. The equine and human FT were similar, with both containing fibrous tissue, ependyma, neuropil, and nerve twigs. Hypervascularity was observed in both HERDA horses and human EDS-TCS patients and was not observed in equine or human controls. Moderate to severe abnormalities in collagen fibril orientation and architecture were observed in all HERDA horses and were similar to those observed in human EDS-TCS patients.

It has been well demonstrated that the cerebellum is associated with cognitive and affective processing as well as the traditionally conceptualized motor function. In the present chapter, we explore the behavioral and neurobiological implications of a common congenital cerebellar condition, Chiari malformation Type I, on cognitive and affective processing. We also emphasize the associations between Chiari-related chronic pain, cognitive dysfunction, and emotion dysregulation. Based on our review of the literature, we argue that chronic pain can account for a substantial amount of the cognitive dysfunction and emotion dysregulation in Chiari malformation Type I. Yet, there also exists aspects of Chiari-related cognitive dysfunction and emotion dysregulation that appear to be at least partially independent of chronic pain and more directly associated with abnormalities in cerebrospinal fluid flow dynamics and cerebro-cerebellar communication pathways.

BACKGROUND: Patients with hypermobile Ehlers-Danlos syndrome (hEDS), a heritable connective tissue disorder, present frequently with symptoms of tethered cord syndrome (TCS) but without a low-lying conus. Currently, surgical treatment of such cases is controversial. Because connective tissue disorder affects fibrous structures, we hypothesized that a diseased filum terminale (FT) might cause TCS in hEDS, justifying surgical transection for treatment. METHODS: We investigated FT pathology, FT biomechanics, clinical presentation, and outcome following FT excision in 78 radiologically occult hEDS-TCS cases and for comparison in 38 typical TCS cases with low-lying conus and/or fatty FT infiltration but without hEDS. RESULTS: In hEDS-TCS, electron microscopy revealed inherited collagen fibril abnormalities and acquired fibril damage. Biomechanical tension tests revealed elastic properties of the FT in both study groups, but they were impaired in the hEDS TCS. Follow-up examinations at 3 and 12 months after FT excision showed statistically significant improvement of urinary, bowel, and neurologic symptoms in both study groups; intergroup comparison revealed no differences in outcome except more pronounced neurologic improvement in the hEDS-TCS group. CONCLUSIONS: Both morphologic findings and biomechanical tests indicate limited elastic properties of the FT in hEDS, which is no more able to dampen but still transmitting spine movement-related stretch forces. That mechanism exposes the conus medullaris to unphysiologic stretch forces, causing TCS, especially when considering the hypermobile spine in hEDS. This notion is supported by the observed clinical improvement following FT resection in hEDS-TCS cases without a low-lying conus. ispartof: WORLD NEUROSURGERY vol:162 pages:E492-E502 ispartof: location:United States status: published

Estrogen receptor-positive breast cancer (ER+ BC) is the most common form of breast carcinoma accounting for approximately 70% of all diagnoses. Although ER-targeted therapies have improved survival outcomes for this BC subtype, a significant proportion of patients will ultimately develop resistance to these clinical interventions, resulting in disease recurrence. Phosphoserine aminotransferase 1 (PSAT1), an enzyme within the serine synthetic pathway (SSP), has been previously implicated in endocrine resistance. Therefore, we determined whether expression of SSP enzymes, PSAT1 or phosphoglycerate dehydrogenase (PHGDH), affects the response of ER+ BC to 4-hydroxytamoxifen (4-OHT) treatment. To investigate a clinical correlation between PSAT1, PHGDH, and endocrine resistance, we examined microarray data from ER+ patients who received tamoxifen as the sole endocrine therapy. We confirmed that higher PSAT1 and PHGDH expression correlates negatively with poorer outcomes in tamoxifen-treated ER+ BC patients. Next, we found that SSP enzyme expression and serine synthesis were elevated in tamoxifen-resistant compared to tamoxifen-sensitive ER+ BC cells in vitro. To determine relevance to endocrine sensitivity, we modified the expression of either PSAT1 or PHGDH in each cell type. Overexpression of PSAT1 in tamoxifen-sensitive MCF-7 cells diminished 4-OHT inhibition on cell proliferation. Conversely, silencing of either PSAT1 or PHGDH resulted in greater sensitivity to 4-OHT treatment in LCC9 tamoxifen-resistant cells. Likewise, the combination of a PHGDH inhibitor with 4-OHT decreased LCC9 cell proliferation. Collectively, these results suggest that overexpression of serine synthetic pathway enzymes contribute to tamoxifen resistance in ER+ BC, which can be targeted as a novel combinatorial treatment option.

As cardio metabolic disease manifestations tend to cluster in families there is a need to better understand the underlying mechanisms in order to further develop preventive strategies. In fact, genetic markers used in genetic risk scores, important as they are, will not be able alone to explain these family clusters. Therefore, the search goes on for the so called missing heritability to better explain these associations. Shared lifestyle and social conditions in families, but also early life influences may be of importance. Gene-environmental interactions should be explored. In recent years interest has grown for the role of diet-microbiota associations, as microbiota patterns may be shared by family members. In the Malmö Offspring Study that started in 2013, we have so far been able to examine about 4700 subjects (18–71 years) representing children and grandchildren of index subjects from the first generation, examined in the Malmö Diet Cancer Study during 1991 to 1996. This will provide rich data and opportunities to analyse family traits of chronic disease across three generations. We will provide extensive genotyping and phenotyping including cardiovascular and respiratory function, as well as markers of glucose metabolism. In addition, also cognitive function will be assessed. A 4-day online dietary recall will be conducted and gut as well as oral microbiota analysed. The ambition is to provide one of the first large-scale European family studies with individual data across three generations, which could deepen our knowledge about the role of family traits for chronic disease and its underlying mechanisms. Electronic supplementary material The online version of this article (10.1007/s10654-020-00695-4) contains supplementary material, which is available to authorized users.

Neural components of the fibrous filum terminale (FT) are well known but are considered as embryonic remnants without functionality.To investigate the ultrastructure of human FT specimens for sensory nerve endings and record paraspinal muscle activity on electrostimulation of the FT.We prospectively investigated a cohort of 53 patients who underwent excision of the FT for the treatment of tethered cord syndrome. Surgical FT specimens were investigated by light and transmission electron microscopy. Intraoperative electrophysiological routine monitoring was extended by recording paraspinal muscles above and below the laminotomy level.Light microscopy revealed tiny peripheral nerves piercing the pia mater of the FT and entering its fibrous core. Transmission electron microscopy unveiled within the fibrous core of the FT myelinated nerve structures in 8 of the 53 patients and unmyelinated ones in 10 of the 53 patients. Both nerve endings encapsulated in fibrous tissue or unencapsulated nonmyelinated Schwann cell nerve bundles, that is, Remak cells, were found. Those nerve endings resembled mechanoreceptor and nociceptive receptor structures found in human skin, muscle tendons, and skeletal ligaments. Specifically, we found Ruffini mechanoreceptors and in addition nerve endings which resembled nociceptive glioneural structures of the skin. Bipolar electrostimulation of the FT was associated with paraspinal muscle activity above and below the spinal segment at which the FT was stimulated.Morphological and electrophysiological results indicate the presence of functional sensory nerve endings in the FT. Like other spine ligaments, the FT may serve as a proprioceptive element but may also contribute to back pain in spine disorders.

BACKGROUND: Functional constipation (FC) and irritable bowel syndrome constipation type (IBS-C) share many similarities, and it remains unknown whether they are distinct entities or part of the same spectrum of disease. Magnetic resonance imaging (MRI) allows quantification of intraluminal fecal volume. We hypothesized that colonic volumes of patients with FC would be larger than those of patients with IBS-C, and that both patient groups would have larger colonic volumes than healthy controls (HC).METHODS: Based on validated questionnaires, three groups of participants were classified into FC (n = 13), IBS-C (n = 10), and HC (n = 19). The colonic volume of each subject was determined by MRI. Stool consistency was described by the Bristol stool scale and colonic transit times were assessed with radiopaque makers.KEY RESULTS: Overall, total colonic volumes were different in the three groups, HC (median 629 ml, interquartile range (IQR)(562-868)), FC (864 ml, IQR(742-940)), and IBS-C (520 ml IQR(489-593)) (p = 0.001). Patients with IBS-C had lower colonic volumes than patients with FC (p = 0.001) and HC (p = 0.019), but there was no difference between FC and HC (p = 0.10). Stool consistency was similar in the two patient groups, but patients with FC had longer colonic transit time than those with IBS-C (117.6 h versus 43.2 h, p = 0.019).CONCLUSION: Patients with IBS-C have lower total colonic volumes and shorter colonic transit times than patients with FC. Future studies are needed to confirm that colonic volume allows objective distinction between the two conditions.

Background During the COVID-19 pandemic, the University of Leipzig completely switched to online teaching. Thus, we developed a practice-oriented digital substitute for a two-week mandatory general practice (GP) clerkship. Main components were processing of clinical cases and additional GP topics, visual diagnoses, information and examination videos, and regular remote exchanges with associated GP teachers. We took the chance to comprehensively evaluate the new teaching formats (acceptance, use, working enjoyment, learning gain, practical relevance, insights into general practice) and to compare evaluations with two previous semesters to gain insights for future blended learning concepts. Methods Cross-sectional post-hoc online evaluation among fourth year (of six) medical students participating in the digital mandatory 2-week GP clerkship during summer semester 2020; additional cohort comparison with two previous semesters (face-to-face clerkship). Results Out of 192 participants in the digital clerkship, 99 completed our questionnaire (response rate = 51.6%). Results were compared with 277 previous evaluations (face-to-face semesters). Most participants reported having enjoyed the online-based clerkship (87.9%), having learned a lot (89.9%), having gained insights into general practice (76.8%), and perceived high practical relevance (90.9%). Implementing the new teaching formats into future face-to-face clerkships was welcomed by 65.6%. Clinical cases, visual diagnoses, examination videos and communication with GP teachers were rated best regarding working enjoyment, learning gain, practical relevance and insights into a GP’s work. Cohort comparison revealed somewhat better evaluations regarding knowledge transfer for the digital clerkship while imparting of skills and attitudes was reportedly worse. Conclusions Students welcomed the digital content and perceived relevant learning gain. Our results may help to develop future blended learning concepts. Clinical cases, examination videos and visual diagnoses appear to be particularly suitable as useful online complements which could enrich face-to-face teaching. As students especially valued the exclusive time for exchanges with their preceptor, this should be facilitated in face-to-face clerkships.

BACKGROUND Thermal flow evaluation (TFE) is a non-invasive method to assess ventriculoperitoneal shunt function. Flow detected by TFE is a negative predictor of the need for revision surgery. Further optimization of testing protocols, evaluation in multiple centers, and integration with clinical and imaging impressions prompted the current study. OBJECTIVE To compare the diagnostic accuracy of 2 TFE protocols, with micropumper (TFE+MP) or without (TFE-only), to neuro-imaging in patients emergently presenting with symptoms concerning for shunt malfunction. METHODS We performed a prospective multicenter operator-blinded trial of a consecutive series of patients who underwent evaluation for shunt malfunction. TFE was performed, and preimaging clinician impressions and imaging results were recorded. The primary outcome was shunt obstruction requiring neurosurgical revision within 7 d. Non-inferiority of the sensitivity of TFE vs neuro-imaging for detecting shunt obstruction was tested using a prospectively determined a priori margin of −2.5%. RESULTS We enrolled 406 patients at 10 centers. Of these, 68/348 (20%) evaluated with TFE+MP and 30/215 (14%) with TFE-only had shunt obstruction. The sensitivity for detecting obstruction was 100% (95% CI: 88%-100%) for TFE-only, 90% (95% CI: 80%-96%) for TFE+MP, 76% (95% CI: 65%-86%) for imaging in TFE+MP cohort, and 77% (95% CI: 58%-90%) for imaging in the TFE-only cohort. Difference in sensitivities between TFE methods and imaging did not exceed the non-inferiority margin. CONCLUSION TFE is non-inferior to imaging in ruling out shunt malfunction and may help avoid imaging and other steps. For this purpose, TFE only is favored over TFE+MP.

Cardiovascular diseases still account for the majority of deaths worldwide, although significant improvements in survival, after being affected by cardiovascular disease, have been achieved in the last decades. Periodontal diseases are also a common global burden. Several studies have shown a link between cardiovascular disease and periodontitis, although evidence is still lacking regarding the direct cause-effect relation. During the 2012 "Periodontitis and systemic diseases" workshop, the available evidence on the association between cardiovascular and periodontal diseases was discussed, covering biologic plausibility and clinical studies. The objective of the present narrative review was to update the previous reviews presented at the 2012 workshop, following similar methodological approaches, aiming to critically assess the available evidence. With regard to biologic plausibility, two aspects were reviewed: (a) for microbiologic mechanisms, assessing periodontal bacteria as a contributing factor to atherosclerosis based on seven "proofs," substantial evidence was found for Proofs 1 through 6, but not for Proof 7 (periodontal bacteria obtained from human atheromas can cause atherosclerosis in animal models), concluding that periodontal pathogens can contribute to atherosclerosis; (b) mechanistic studies, addressing five different inflammatory pathways that could explain the links between periodontitis and cardiovascular disease with the addition of some extra pathways , suggest an association between both entities, based on the presence of higher levels of these inflammatory markers in patients with periodontitis and cardiovascular disease, vs healthy controls, as well as on the evidence that periodontal treatment reduces serum levels of these mediators. When evidence from clinical studies was analyzed, two aspects were covered: (a) epidemiologic studies support the estimation that the incidence of atherosclerotic disease is higher in individuals with periodontitis than in individuals with no reported periodontitis, irrespective of many common risk factors, but with a substantial variability in the definitions used in reporting of exposure to periodontal diseases in different studies; (b) intervention trials have shown that periodontal therapy can reduce serum inflammatory mediators, improve the lipids profile, and induce positive changes in other cardiovascular disease surrogate measures, but no evidence is available to support that adequate periodontal therapy is able to reduce the risk for cardiovascular diseases, or the incidence of cardiovascular disease events in periodontitis patients.

Minocycline has shown therapeutic promise in pre-clinical animal models and early phase clinical trials for a variety of psychiatric disorders. Previous studies on minocycline have shown its ability to suppress microglia activity and reduce inflammatory cytokine levels, and its amelioration of depressive-like behaviour in animals and humans. However, the underlying mechanisms that lead to minocycline’s psychotropic effects are not clear. In this study, we investigated the psychological and biochemical effects of an acute dose of minocycline or placebo in 40 healthy adult volunteers. Psychological changes in emotional processing, implicit learning, and working memory were assessed. Plasma inflammatory markers, measured with enzyme-linked immunosorbent assays, and serum metabolites, measured with proton nuclear magnetic resonance combined with multi-variate analysis techniques, were also studied. Results showed that minocycline administration decreased fear misclassification and increased contextual learning, which suggested that reducing negative biases and improving cognition, respectively, may underlie the antidepressant actions of this agent. An examination of serum metabolites revealed higher levels of lipoproteins, particularly cholesterol, in the minocycline group. Minocycline also decreased circulating concentrations of the inflammatory marker C-Reactive Peptide, which is consistent with previous research. These effects highlight two important psychological mechanisms that may be relevant to the efficacy of minocycline reported in clinical trials, and also suggest a possible largely unexplored lipid-related biochemical pathway for the action of this drug.

Background: Groin hernia management has a significant worldwide diversity with multiple surgical techniques and variable outcomes. The International guidelines for groin hernia management serve to help in groin hernia management, but the acceptance among general surgeons remains unknown. The aim of our study was to gauge the degree of agreement with the guidelines among health care professionals worldwide. Methods: Forty-six key statements and recommendations of the International guidelines for groin hernia management were selected and presented at plenary consensus conferences at four international congresses in Europe, the America’s and Asia. Participants could cast their votes through live voting. Additionally, a web survey was sent out to all society members allowing online voting after each congress. Consensus was defined as > 70% agreement among all participants. Results: In total 822 surgeons cast their vote on the key statements and recommendations during the four plenary consensus meetings or via the web survey. Consensus was reached on 34 out of 39 (87%) recommendations, and on six out of seven (86%) statements. No consensus was reached on the use of light versus heavy-weight meshes (69%), superior cost-effectiveness of day-case laparo-endoscopic repair (69%), omitting prophylactic antibiotics in hernia repair, general or local versus regional anesthesia in elderly patients (55%) and re-operation in case of immediate postoperative pain (59%). Conclusion: Globally, there is 87% consensus regarding the diagnosis and management of groin hernias. This provides a solid basis for standardizing the care path of patients with groin hernias.

Guidelines recommend colonoscopy after an episode of diverticulitis to exclude neoplasia but the effectiveness of testing is uncertain. Patients with complicated diverticulitis may be at higher risk for neoplasia, but most patients have uncomplicated disease. We examined the incidence of colorectal cancer (CRC) and advanced adenoma (AA) in patients with diverticulitis compared with patients undergoing screening colonoscopy.CT scans from January 1, 2008, to May 1, 2013, at the University of Pittsburgh Medical Center (UPMC) were reviewed to identify those with confirmed acute diverticulitis. Subsequent surgical, colonoscopy, and pathology reports were abstracted to identify those with a diagnosis of AA and CRC. The incidence of neoplasia was compared with that reported for screening colonoscopy from a meta-analysis (n = 68,324), and from colonoscopy examinations at UPMC between 2013 and 2015 (n = 28,573).A total of 5167 abdominal/pelvic CT scan reports identified 978 patients with acute diverticulitis, among which 474 (48.5%) patients had undergone at least 1 colonoscopy or gastrointestinal surgery to April 2015. The CRC rate in patients with diverticulitis (13/474, 2.7%) was significantly higher (P .0001) compared with both the meta-analysis (0.8%) and UPMC (0.3%). The AA rate (19/474, 4.0%) was similar to the rate in the meta-analysis (5.0%, P = .39) but significantly lower than at UPMC (7.7%, P = .003). The incidence of AA or CRC in complicated diverticulitis (10/141, 7.1%) did not differ significantly (P = .85) from the incidence of AA or CRC in uncomplicated diverticulitis (22/332, 6.6%).CRC after diverticulitis was significantly higher than that observed at screening colonoscopy and was not limited to complicated disease. Colonoscopy is advisable after the diagnosis of diverticulitis.

AIM: The metabolite 3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) is a fatty fish-intake biomarker. We investigated the association between plasma levels of CMPF in relation to gingival inflammation and periodontitis case definition, as well as extent and severity variables. METHODS: The Malmö Offspring Study (MOS) is a population-based study, and the Malmö Offspring Dental Study (MODS) is its dental arm, including periodontal charting. Plasma CMPF was measured using liquid chromatography-mass spectrometry and studied in relation to periodontal diagnosis and parameters using multivariable linear or logistic regression modelling adjusting for age, sex, education, BMI, fasting glucose and smoking. RESULTS: Metabolite data were available for 922 MODS participants. Higher CMPF levels were associated with less gingival inflammation (beta -2.12, p=0.002), and lower odds of severe periodontitis (OR 0.74, 95% CI=0.56-0.98). Higher CMPF levels were also associated with more teeth (beta 0.19, p=0.001), lower number of periodontal pockets (>4 mm) (beta -1.07, p=0.007) and lower odds of having two or more >6 mm periodontal pockets (OR 0.80, 95% CI=0.65-0.98) in fully adjusted models. CONCLUSION: CMPF, a validated biomarker of fatty fish consumption, is associated with less periodontal inflammation and periodontitis. Residual confounding cannot be ruled out and future studies are warranted. This article is protected by copyright. All rights reserved.

Chiari malformation Type I (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum. The pathophysiology of CMI is not well elucidated; however, the prevailing theory focuses on the underdevelopment of the posterior cranial fossa which results in tonsillar herniation. Symptoms are believed to be due to the herniation causing resistance to the natural flow of cerebrospinal fluid (CSF) and exerting a mass effect on nearby neural tissue. However, asymptomatic cases vastly outnumber symptomatic ones and it is not known why some people become symptomatic. Recently, it has been proposed that CMI symptoms are primarily due to instability of either the atlanto-axial (AA) or the atlanto-occipital (AO) joint and the cerebellar tonsils herniate to prevent mechanical pinching. However, only a small percentage of patients exhibit clinical instability and these theories do not account for asymptomatic herniations. We propose that the pathophysiology of adult CMI involves a combination of craniocervical abnormalities which leads to tonsillar herniation and reduced compliance of the cervical spinal canal. Specifically, abnormal AO and/or AA joint morphology leads to chronic cervical instability, often subclinical, in a large portion of CMI patients. This in turn causes overwork of the suboccipital muscles as they try to compensate for the instability. Over time, the repeated, involuntary activation of these muscles leads to mechanical overload of the myodural bridge complex, altering the mechanical properties of the dura it merges with. As a result, the dura becomes stiffer, reducing the overall compliance of the cervical region. This lower compliance, combined with CSF resistance at the same level, leads to intracranial pressure peaks during the cardiac cycle (pulse pressure) that are amplified during activities such as coughing, sneezing, and physical exertion. This increase in pulse pressure reduces the compliance of the cervical subarachnoid space which increases the CSF wave speed in the spinal canal, and further increases pulse pressure in a feedback loop. Finally, the abnormal pressure environment induces greater neural tissue motion and strain, causing microstructural damage to the cerebellum, brainstem, and cervical spinal cord, and leading to symptoms. This hypothesis explains how the combination of craniocervical bony abnormalities, anatomic CSF restriction, and reduced compliance leads to symptoms in adult CMI.

Purpose The treatment of cancer has transformed over the past forty years, with medical oncologists, radiation oncologists and surgeons working together to prolong survival times and minimize treatment related morbidity. With each advancement, the risk-benefit scale has been calibrated to provide an accurate assessment of surgical hazard. The goal of this review is to look back at how the role of surgery has evolved with each new medical advance, and to explore the role of surgeons in the future of cancer care. Methods A literature review was conducted, highlighting the key papers guiding surgical management of spinal metastatic lesions. Conclusion The roles of surgery, medical therapy and radiation have evolved over the past forty years, with new advances requiring complex multidisciplinary care.

Background: Polychlorinated biphenyl (PCB) exposures have been associated with liver injury in human cohorts, and steatohepatitis with liver necrosis in model systems. MicroRNAs (miRs) maintain cellular homeostasis and may regulate the response to environmental stress. Objectives: We tested the hypothesis that specific miRs are associated with liver disease and PCB exposures in a residential cohort. Methods: Sixty-eight targeted hepatotoxicity miRs were measured in archived serum from 734 PCB-exposed participants in the cross-sectional Anniston Community Health Survey. Necrotic and other liver disease categories were defined by serum keratin 18 (K18) biomarkers. Associations were determined between exposure biomarkers (35 ortho-substituted PCB congeners) and disease biomarkers (highly expressed miRs or previously measured cytokines), and Ingenuity Pathway Analysis was performed. Results: The necrotic liver disease category was associated with four up-regulated miRs (miR-99a-5p, miR-122-5p, miR-192-5p, and miR-320a) and five down-regulated miRs (let-7d-5p, miR-17-5p, miR-24-3p, miR-197-3p, and miR-221-3p). Twenty-two miRs were associated with the other liver disease category or with K18 measurements. Eleven miRs were associated with 24 PCBs, most commonly congeners with anti-estrogenic activities. Most of the exposure-associated miRs were associated with at least one serum hepatocyte death, pro-inflammatory cytokine or insulin resistance bioarker, or with both. Within each biomarker category, associations were strongest for the liver-specific miR-122-5p. Pathways of liver toxicity that were identified included inflammation/hepatitis, hyperplasia/hyperproliferation, cirrhosis, and hepatocellular carcinoma. Tumor protein p53 and tumor necrosis factor α were well integrated within the top identified networks. Discussion: These results support the human hepatotoxicity of environmental PCB exposures while elucidating potential modes of PCB action. The MiR-derived liquid liver biopsy represents a promising new technique for environmental hepatology cohort studies. https://doi.org/10.1289/EHP9467

Exposure to polychlorinated biphenyls (PCBs) has been associated with liver injury in human cohorts and with nonalcoholic steatohepatitis (NASH) in mice fed a high fat diet (HFD). N (6)-methyladenosine (m6A) modification of mRNA regulates transcript fate, but the contribution of m6A modification on the regulation of transcripts in PCB-induced steatosis and fibrosis is unknown. This study tested the hypothesis that PCB and HFD exposure alters the levels of m6A modification in transcripts that play a role in NASH in vivo. Male C57Bl6/J mice were fed a HFD (12 wks) and administered a single oral dose of Aroclor1260, PCB126, or Aroclor1260 + PCB126. Genome-wide identification of m6A peaks was accomplished by m6A mRNA immunoprecipitation sequencing (m6A-RIP) and the mRNA transcriptome identified by RNA-seq. Exposure of HFD-fed mice to Aroclor1260 decreased the number of m6A peaks and m6A-containing genes relative to PCB vehicle control whereas PCB126 or the combination of Aroclor1260 + PCB126 increased m6A modification frequency. ~41% of genes had one m6A peak and ~49% had 2–4 m6A peaks. 117 m6A peaks were common in the four experimental groups. The Aroclor1260 + PCB126 exposure group showed the highest number (52) of m6A-peaks. qRT-PCR confirmed enrichment of m6A-containing fragments of the Apob transcript with PCB exposure. A1cf transcript abundance, m6A peak count, and protein abundance was increased with Aroclor1260 + PCB126 co-exposure. Irrespective of the PCB type, all PCB groups exhibited enriched pathways related to lipid/lipoprotein metabolism and inflammation through the m6A modification. Integrated analysis of m6A-RIP-seq and mRNA-seq identified 242 differentially expressed genes (DEGs) with increased or reduced number of m6A peaks. These data show that PCB exposure in HFD-fed mice alters the m6A landscape offering an additional layer of regulation of gene expression affecting a subset of gene responses in NASH.

Background Meningocele manque (MM) is characterized by tethering of the spinal cord, nerve roots, or filum terminale by fibrous attachments formed by atrophic or incomplete meningoceles. Patients with MM can present with symptoms of tethered cord syndrome (TCS). Case Description We present the case of an MM discovered incidentally during microsurgical resection of filum terminale for occult TCS. The MM was not visible on the preoperative magnetic resonance imaging (MRI) studies. After L2-L3 laminotomy, an extradural mass was appreciated adherent to the spinal dura, which was found to be an MM. The nerve roots of the cauda equina were found to protrude through the dura, consistent with tethered cauda equina. After microsurgical resection of the filum terminale, the tethered cauda nerve roots were stimulated, and redundant electromyographic signals were detected at both the left- and the right-sided muscles of the lower extremities. Microsurgical repair of the MM was performed, assuming that the patient's symptoms of TCS would also be explained by the MM and that her symptoms would likely have been incompletely addressed by filum terminale release alone. A review of the preoperative 3-dimensional constructive interference in steady state MRI sequence revealed pathological features at the L2-L3 level suspicious for our intraoperative findings of an MM. Conclusions Surgeons planning filum terminale release for occult TCS should always be aware of the possibility of associated pathological features of tethering that might be overlooked. In retrospect, the detection of MM was enabled by the high-resolution 3-dimensional constructive interference in steady state MRI sequence. This finding advocates for the use of high-resolution MRI for patients undergoing evaluation for occult TCS to detect pathological features that might otherwise be undetected.

Background: Periodontal disease is associated with cardiovascular disease (CVD) but it is unknown if periodontal disease severity is associated with asymptomatic carotid plaque. The aim of the current population-based, observational study was to investigate if signs of periodontal disease are associated with the occurrence of carotid plaque and total plaque area (TPA). Methods: The Malmo Offspring Study (MOS) is a population-based study. MOS participants underwent a thorough cardiovascular phenotyping, including carotid ultrasonography. The Malmo Offspring Dental Study (MODS) invited participants of MOS for dental examination, including periodontal charting. Multivariable regression models were used to analyse the presence of carotid plaque and TPA in relation to periodontal parameters. Results: In all, 831 MODS participants were recruited, out of which 495 belonged to the children generation with mean age of 53 years, 63% had carotid plaque and 38% had moderate or severe periodontal disease. In models adjusted for CVD risk factors, the OR for having carotid plaque in subjects with vs without periodontal disease was 1.75 (95% CI: 1.11–2.78). In a linear model with TPA as dependent and number of periodontal pockets ≥ 4 mm as independent variable, the adjusted beta-coefficient was 0.34 mm2 (95% CI 0.16–0.52). Conclusion: Individuals within the highest quartile of periodontal pockets are expected to have 9 mm2 larger TPA compared to those without pockets. Our results suggest that intervention studies addressing periodontal disease could be useful for prevention of CVD. (Less)

Background Inequality in preterm birth is a world-wide challenge that has proved difficult for maternity care services to meet. Reducing the inequality requires identification of pregnant women at particularly high risk of preterm birth in order to target interventions. Therefore, the aim was to estimate the risk of preterm birth in women with different combinations of socioeconomic position, mental health conditions, and age. Methods In this nationwide register-based cohort study, we included all first-time mothers that gave birth to a singleton liveborn infant in Denmark between 2000 and 2016. The absolute and relative risk of preterm birth ( Results Of the 415,523 included first-time mothers, 6.3% gave birth prematurely. The risk of preterm birth increased with decreasing educational level and increasing severity of mental health conditions in all age strata, but most in women aged ≥31 years. The highest absolute risk was 12.9% [95% CI: 11.2;14.8%] in women aged ≥31 years with low education and moderate/severe mental health conditions resulting in a relative risk of 2.23 [95% CI: 1.93–2.58] compared to the unexposed reference group in that age strata. We found positive additive interaction between low education and mental health conditions in women aged 24–30 and ≥ 31 years and between age ≥ 31 years and combinations of mental health conditions and educational levels. Conclusion The inequality in preterm birth increased with increasing age. To reduce inequality in preterm birth focused attention on women with higher age further combined with lower educational levels and mental health conditions is essential.

Background During the first peak of the COVID-19 pandemic in the Netherlands, relatives of patients with COVID-19 admitted to Intensive Care Units (ICUs) were severely restricted in visiting their relatives and in communicating with treating physicians. Family communication is a core element of critical care, however, this pandemic forced medical ICU staff to arrange alternative family support for instance by Family Support Teams (FSTs), consisting of non-ICU affiliated staff who telephonically contacted relatives. This study aims to examine relatives’ experiences with FSTs on two ICUs of a Dutch university medical centre, and to evaluate its working strategies. . Methods In a semi-structured interview study, relatives of patients with COVID-19 admitted to ICU’s, who had been supported by the FSTs, were sampled purposively. Twenty-one interviews were conducted telephonically by three researchers. All interviews were topic list guided and audio-recorded. Data was analysed thematically. Results All participants indicated they went through a rough time. Almost all evaluated the FSTs positively. Four major themes were identified. First, three important pillars of the FSTs were providing relatives with transparency about the patients’ situation, providing attention to relatives’ well-being, and providing predictability and certainty by calling on a daily basis in a period characterised by insecurity. Second, relatives appeared to fulfil their information needs by calls of the FSTs, but also by calling the attending ICU nurse. Information provided by the FSTs was associated with details and reliability, information provided by nurses was associated with the patient’s daily care. Third, being a primary family contact was generally experienced as both valuable and as an emotional burden. Last, participants missed proper aftercare. Family support often stopped directly after the patient died or had left the ICU. Relatives expressed a need for extended support after that moment since they had strong emotions after discharge or death of the patient. Conclusions Family support in times of the extreme COVID-19 situation is important, as relatives are restricted in communication and have a strong need for information and support. Relatives feel encouraged by structure, frequency, support and understanding by FSTs. However, remote family support should be tailored to the needs of relatives. A fixed contact person on de ICU and video calling might be good extra options for family support, also in future post COVID-19 care, but cannot replace physical visits.

INTRODUCTION: The ribosome catalyzes protein synthesis in all cells by coupling the decoding of messenger RNA by the small ribosomal subunit with peptide bond formation by the large ribosomal subunit. As both subunits are composed of ribosomal RNA and ribosomal proteins, the assembly of these molecular machines is tightly controlled. In human cells, more than 200 ribosome assembly factors catalyze the maturation of both ribosomal subunits. Ribosome assembly is initiated in the nucleolus, a biomolecular condensate formed through multivalent protein–nucleic acid interactions. Inside this biomolecular condensate, the first stable eukaryotic ribosome assembly intermediate of the small subunit, the small subunit (SSU) processome, is formed. Within the SSU processome, more than 70 proteins and an RNA chaperone, the small nucleolar RNA (snoRNA) U3, work in concert to bring about RNA folding, modifications, rearrangements, and cleavage as well as targeted degradation of preribosomal RNA by the RNA exosome. The essential nature of this process is highlighted by mutations in ribosomal proteins and ribosome assembly factors that have been associated with human diseases. RATIONALE: Little is known about the structure, function, and maturation of the human SSU processome in the nucleolus as it transitions through different states to assemble the small ribosomal subunit. The retention of preribosomal particles within the biomolecular condensate of the nucleolus has thus far prevented their biochemical and structural characterization. To elucidate the nucleolar maturation of the human SSU processome, the isolation of these preribosomal particles from the nucleolus was therefore a key hurdle. To this end, we have developed a human genome editing platform to biallelically affinity tag the endogenous SSU processome and have established biochemical procedures for its isolation from the nucleolus for structural studies. RESULTS: The cryo–electron microscopy (cryo-EM) structures of three distinct states of the human SSU processome (denoted pre-A1, pre-A1*, and post-A1) were obtained at resolutions of 3.6, 3.9, and 2.7 Å, respectively. Together these structures reveal the molecular mechanisms responsible for the progression during nucleolar SSU processome maturation. Intricate layers of regulation are exerted through the concerted interplay of ribosome assembly factors that control irreversible steps of ribosome assembly, such as RNA processing by the RNA exosome, RNA unwinding by the DEAH-box helicase DHX37 (Dhr1 in yeast), and RNA cleavage by the endonuclease UTP24. The earliest state, pre-A1, highlights how only a small portion of a large preribosomal RNA segment, the 5′ external transcribed spacer (5′ ETS) is recognized by the SSU processome. We have generated a synthetic human ribosomal DNA (rDNA) locus that enables the production of recombinant ribosomes in human cells. By derivatizing this rDNA locus, we have identified a minimal 5′ ETS that can function to generate mature small ribosomal subunits in human cells. As the SSU processome transitions from states pre-A1 and pre-A1* to post-A1, a specific binding site for the RNA exosome-associated exoribonuclease EXOSC10 (Rrp6 in yeast) is generated. In the context of the post-A1 state, the DEAH-box helicase DHX37 is recruited, and its helicase activity must be tightly regulated to prevent the premature unwinding of preribosomal RNA from the RNA chaperone U3. By combining x-ray crystallography with cryo-EM, we show that DHX37 is initially autoinhibited and tightly controlled on the SSU processome through a precisely choreographed interplay that dictates the availability of binding sites and the accessibility of an activating peptide of the ribosome assembly factor UTP14. Within the core of the SSU processome, we have identified a network of proteins that guide cleavage at site A1, thereby generating the mature end of the small ribosomal subunit RNA. Lastly, the structure of the human SSU processome in state post-A1 provides further insight into human diseases, showing how the mammalian-specific ribosome assembly factor AROS stabilizes ribosomal protein eS19, which is most abundantly mutated in Diamond-Blackfan anemia. CONCLUSION: The cryo-EM structures of three human SSU processome complexes presented here reveal the structural plasticity of the human SSU processome, which endows this particle with the ability to coordinate conformational changes with distinct stages of ribosome assembly. The combined cryo-EM, x-ray crystallography, and functional data serve as a framework for the mechanistic understanding of the human SSU processome.

Myocardial infarction is a frequent cause of out-of-hospital cardiac arrest. However, the benefits of early coronary angiography and revascularization in resuscitated patients without electrocardiographic evidence of ST-segment elevation are unclear.In this multicenter trial, we randomly assigned 554 patients with successfully resuscitated out-of-hospital cardiac arrest of possible coronary origin to undergo either immediate coronary angiography (immediate-angiography group) or initial intensive care assessment with delayed or selective angiography (delayed-angiography group). All the patients had no evidence of ST-segment elevation on postresuscitation electrocardiography. The primary end point was death from any cause at 30 days. Secondary end points included a composite of death from any cause or severe neurologic deficit at 30 days.A total of 530 of 554 patients (95.7%) were included in the primary analysis. At 30 days, 143 of 265 patients (54.0%) in the immediate-angiography group and 122 of 265 patients (46.0%) in the delayed-angiography group had died (hazard ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.63; P = 0.06). The composite of death or severe neurologic deficit occurred more frequently in the immediate-angiography group (in 164 of 255 patients [64.3%]) than in the delayed-angiography group (in 138 of 248 patients [55.6%]), for a relative risk of 1.16 (95% CI, 1.00 to 1.34). Values for peak troponin release and for the incidence of moderate or severe bleeding, stroke, and renal-replacement therapy were similar in the two groups.Among patients with resuscitated out-of-hospital cardiac arrest without ST-segment elevation, a strategy of performing immediate angiography provided no benefit over a delayed or selective strategy with respect to the 30-day risk of death from any cause. (Funded by the German Center for Cardiovascular Research; TOMAHAWK ClinicalTrials.gov number, NCT02750462.).

Background and Objectives: The rapid spread of the novel coronavirus disease (COVID-19) has become the most challenging global health pandemic since the 1918 flu. In Germany, more than 3.4 million cases are confirmed so far, including 83,000 deaths. Increased fatality rates among patients with pre-existing cardiovascular diseases (CVD) represent this group at particular risk. The aim of this study was to evaluate changes in health perception among patients with aortic diseases during the first (w1) and second wave (w2) of the COVID-19 pandemic in Germany. Material and Methods: Patients (n = 262) diagnosed with aortic disease participated in telephone interviews during w1 and w2. The perception of COVID-19 as a threat was examined using relevant items of the Brief Illness Perception (BIP) questionnaire. Results: The BIP score increased from 9.18 (SD = 7.132) to 14.58 (SD = 6.956) between w1 and w2 (p &lt, 0.001). Although this population is at high risk their overall perception of COVID-19 as a threat was low in the beginning, but surged during w2. Main reasons were increased effects on personal life and elevated concerns about the pandemic, but did not include the educational aspect of COVID-19. Conclusions: Tailored risk communication strengthens the mental health of people in a public health crisis and ensures the success of governmental guidelines.

Exposure to high fat diet (HFD) and persistent organic pollutants including polychlorinated biphenyls (PCBs) is associated with liver injury in human populations and non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in animal models. Previously, exposure of HFD-fed male mice to the non-dioxin-like (NDL) PCB mixture Aroclor1260, dioxin-like (DL) PCB126, or Aroclor1260 + PCB126 co-exposure caused toxicant-associated steatohepatitis (TASH) and differentially altered the liver proteome. Here unbiased mRNA and miRNA sequencing (mRNA- and miRNA- seq) was used to identify biological pathways altered in these liver samples. Fewer transcripts and miRs were up- or down- regulated by PCB126 or Aroclor1260 compared to the combination, suggesting that crosstalk between the receptors activated by these PCBs amplifies changes in the transcriptome. Pathway enrichment analysis identified "positive regulation of Wnt/β-catenin signaling" and "role of miRNAs in cell migration, survival, and angiogenesis" for differentially expressed mRNAs and miRNAs, respectively. We evaluated the five miRNAs increased in human plasma with PCB exposure and suspected TASH and found that miR-192-5p was increased with PCB exposure in mouse liver. Although we observed little overlap between differentially expressed mRNA transcripts and proteins, biological pathway-relevant PCB-induced miRNA-mRNA and miRNA-protein inverse relationships were identified that may explain protein changes. These results provide novel insights into miRNA and mRNA transcriptome changes playing direct and indirect roles in the functional protein pathways in PCB-related hepatic lipid accumulation, inflammation, and fibrosis in a mouse model of TASH and its relevance to human liver disease in exposed populations.

When celebrating 100 yr of dental research in the Nordic dental research community (i.e. Nordisk Odontologisk Förening (NOF)), it is relevant to include dental implant treatment. In essence, the successful progress of implant treatment has added both to the quality of life for patients and also to many aspects of professional development and job satisfaction for dentists. When appreciating the success story it also seems relevant to highlight some of the problems related to this treatment. Both technical and biological complications have often been ignored when reporting long-term results following implant treatment. Different opinions have been expressed in relation to the etiology of peri-implant diseases. Some even choose to ignore this condition as a clinical problem. This article presents a short overview of peri-implant diseases (i.e. peri-implant mucositis and peri-implantitis). The lack of internationally agreed disease definitions for peri-implant diseases, as with periodontitis, results in wide variation of estimates for the occurrence of peri-implant diseases when epidemiological data are reported. The profession still strives to find and define the best way to deal with peri-implant diseases once they are accurately diagnosed. Awareness of the tissue conditions in the peri-implant area, and relevant action when indicated, seems to be critical for the continued long-term successful outcome of dental implant treatment.

Objectives The current COVID‐19 pandemic highlighted the need for a review of guidelines on infection control and prevention to ensure safe delivery of dental care. However, it is not clear to what extent the rapidly published European guidelines reflect the current evidence and thus provide homogeneous recommendations. Material & Methods Guidelines from all European Union countries, Scotland, Switzerland and United Kingdom were retrieved. Information on triage, mouth rinse, personal protective equipment (PPE) for aerosol free/ generating procedures (non‐AGP/AGP) and treatment of potentially infectious patients were summarised, and compared with recommendations from international organizations (WHO, ECDC, CDC). Results All included countries (30/30) published COVID‐19 guidelines in 2020. All countries recommended triage and to postpone non‐urgent treatment of potentially infectious patients. Hydrogen peroxide (1‐1.5%) was the most frequently recommended antiseptic mouth rinse to reduce viral load (24/30). PPE for non‐AGP treatments included mainly surgical masks (21/30) or FFP2/FFP3/N95 masks (16/30), whereas FFP2/FFP3 masks (25/30) and face shields (24/30) were recommended for AGP by the vast majority of guidelines. For high‐risk/COVID positive patients, most countries recommended maximum protection, and treatment in specialised dental clinics (22/30). Conclusion There was general agreement among recommendations for triage, mouth rinse, and PPE during AGP and treatment of potentially infectious patients. In contrast, recommendations on PPE for non‐AGP treatment varied considerably among the European countries possibly due to limited scientific evidence regarding transmission risk during non‐AGP treatments.

Today, the world is experiencing the COVID-19 health contingency, which prevents people from being exposed to one another and restricts physical contact. Under this context, the use of technology has become an essential tool to face the challenges of daily life, and virtual reality can be an alternative in the development of solutions that effectively support the acquisition of learning skills and knowledge transmission through the execution of tasks designed by multi-disciplinary groups. In addition, it can encourage the user to continue with the acquisition of learning skills in a friendly and fun way in a health and education context. This work proposes the use of virtual reality environments as an alternative to support the learning process in children with special educational needs such as Attention Deficit Hyperactivity Disorder (ADHD) and other associated disorders that occur in basic education. These proposed reality environments are designed under the Lean UX process model and their contents are designed according to expert therapeutic guidelines. As a result of this proposal, a case study is presented in which the user experience is evaluated through the use of an interactive environment to support the special educational needs of elementary school children attending an educational institution in Mexico.

Chiari malformation type I (CMI) is a neural disorder with sensory, cognitive, and motor defects, as well as headaches. Radiologically, the cerebellar tonsils extend below the foramen magnum. To date, the relationships among adult age, brain morphometry, surgical status, and symptom severity in CMI are unknown. The objective of this study was to better understand the relationships among these variables using causal modeling techniques. Adult CMI patients (80% female) who either had (n = 150) or had not (n = 151) undergone posterior fossa decompression surgery were assessed using morphometric measures derived from magnetic resonance images (MRI). MRI-based morphometry showed that the area of the CSF pocket anterior to the cervico-medullary junction (anterior CSF space) correlated with age at the time of MRI (r = - .21). Also, self-reported pain increased with age (r = .11) and decreased with anterior CSF space (r = - .18). Age differences in self-reported pain were mediated by anterior CSF space in the cervical spine area-and this effect was particularly salient for non-decompressed CMI patients. As CMI patients age, the anterior CSF space decreases, and this is associated with increased pain-especially for non-decompressed CMI patients. It is recommended that further consideration of age-related decreases in anterior CSF space in CMI patients be given in future research.

Purpose. Incidental cerebellar tonsillar ectopia (ICTE) that meets the radiographic criterion for Chiari malformation type I (CMI) is an increasingly common finding in the clinical setting, but its significance is unclear. The present study examined posterior cranial fossa (PCF) morphometrics and a broad range of health instruments of pediatric ICTE cases and matched controls extracted from the Adolescent Brain Cognitive Development (ABCD) dataset. Methods. 106 subjects with ICTE and 106 matched controls without ICTE were identified from 11,411 anatomical MRI of healthy screened pediatric subjects from the ABCD project. Subjects were matched by sex, age, body mass index, race, and ethnicity. Twenty-two brain morphometrics and 22 health instruments were compared between the two groups to identify unrecognized CMI symptoms and assess the general health impact of ICTE. Results. Twelve and 15 measures were significantly different between the ICTE and control groups for females and males, respectively. Notably, for females, the anterior CSF space was significantly smaller (p = 0.00005) for the ICTE group than controls. For males, the clivus bone length was significantly shorter (p = 0.0002) for the ICTE group compared to controls. No significant differences were found among the 22 health instruments between the two groups. Conclusion. This study demonstrated that pediatric ICTE subjects have similar PCF morphometrics to adult CMI. ICTE alone did not appear to cause any unrecognized CMI symptoms and had no impact on the subjects' current mental, physical, or behavioral health. Still, given their cranial and brain morphology, these cases may be at risk for adult-onset symptomatic CMI.

Purpose Laryngeal electromyography (LEMG) has been considered as gold standard in diagnostics of vocal fold movement impairment, but is still not commonly implemented in clinical routine. Since the signal interpretation of LEMG signals (LEMGs) is often a subjective and semi-quantitative matter, the goal of this study was to evaluate the inter-rater reliability of neurolaryngologists on LEMGs of volitional muscle activity. Methods For this study, 52 representative LEMGs of 371 LEMG datasets were selected from a multicenter registry for a blinded evaluation by 7 experienced members of the neurolaryngology working group of the European Laryngological Society (ELS). For the measurement of the observer agreement between two raters, Cohen’s Kappa statistic was calculated. For the interpretation of agreements of diagnoses among the seven examiners, we used the Fleiss’ Kappa statistic. Result When focusing on the categories “no activity”, “single fiber pattern”, and “strongly decreased recruitment pattern”, the inter-rater agreement varied from Cohen’s Kappa values between 0.48 and 0.84, indicating moderate to near-perfect agreement between the rater pairs. Calculating with Fleiss’ Kappa, a value of 0.61 showed good agreement among the seven raters. For the rating categories, the Fleiss’ Kappa value ranged from 0.52 to 0.74, which also showed a good agreement. Conclusion A good inter-rater agreement between the participating neurolaryngologists was achieved in the interpretation of LEMGs. More instructional courses should be offered to broadly implement LEMG as a reliable diagnostic tool in evaluating vocal fold movement disorders in clinical routine and to develop future algorithms for therapy and computer-assisted examination.

Purpose To evaluate a minimum 15-year clinical and radiographic follow-up after anteromedial tibial tubercle transfer (anteromedialization [AMZ]) for lateral and/or distal patellar facet arthrosis. Methods Patients treated from 1996 to 2000 were contacted. The inclusion criteria were a minimum of 15 years' follow-up after AMZ for isolated persistent retropatellar pain related to lateral and/or distal patellar chondrosis. The exclusion criteria were clinical patellar instability, revision, and significant medial patellar facet or adjacent compartment chondrosis. The anatomic location(s) and severity of arthrosis, as well as the degree of lateral maltracking, were documented. Follow-up data included pain, activity level, and satisfaction. Results Of 23 patients, 15 met the inclusion criteria. All were women (17 knees) followed up for a mean of 17.1 years (range, 15.4-18.8 years). The mean age at surgery was 29.5 years. Satisfactory results were reported in 94% of knees (16 of 17), based simply on patients' subjective evaluation of the degree of success perceived. An important criterion of satisfaction was that these patients stated they would opt to undergo surgery again under the same circumstances. For 35% of knees, patients reported engaging in recreational activities, whereas for 18%, patients were minimally active. The average pain score (range, 0-10) for 75% was 2.1, and most of these patients showed grade I or II arthrosis. Post-AMZ symptomatic medial patellar subluxation was corrected successfully in 2 patients. Removal of hardware was performed in 59% of knees, and additional procedures were required in 41%. No cases of postoperative lateral patellar instability or conversion to knee arthroplasty occurred. Conclusions Anteromedial tibial tubercle transfer without articular cartilage implantation is effective in patellofemoral joint preservation, ameliorating symptoms and facilitating active lifestyles for a minimum of 15 years to nearly 20 years in patients with lateral and/or distal patellofemoral arthrosis. For 94% of knees, patients would choose to undergo the procedure again under the same circumstances. Fifty-nine percent underwent screw removal, and 41% required additional procedures, mostly arthroscopic. No patients in this therapeutic case series underwent an arthroplasty procedure. Level of Evidence Level IV, therapeutic cases series.

International audience; Background: Apathy is present in several psychiatric and neurological conditions and has been found to have a severe negative effect on disease progression. In older people, it can be a predictor of increased dementia risk. Current assessment methods lack objectivity and sensitivity, thus new diagnostic tools and broad-scale screening technologies are needed. Objective: This study is the first of its kind aiming to investigate whether automatic speech analysis could be used for characterization and detection of apathy. Methods: A group of apathetic and non-apathetic patients (n = 60) with mild to moderate neurocognitive disorder were recorded while performing two short narrative speech tasks. Paralinguistic markers relating to prosodic, formant, source, and temporal qualities of speech were automatically extracted, examined between the groups and compared to baseline assessments. Machine learning experiments were carried out to validate the diagnostic power of extracted markers.Results: Correlations between apathy sub-scales and features revealed a relation between temporal aspects of speech and the subdomains of reduction in interest and initiative, as well as between prosody features and the affective domain. Group differences were found to vary for males and females, depending on the task. Differences in temporal aspects of speech were found to be the most consistent difference between apathetic and non-apathetic patients. Machine learning models trained on speech features achieved top performances of AUC = 0.88 for males and AUC = 0.77 for females. Conclusions: These findings reinforce the usability of speech as a reliable biomarker in the detection and assessment of apathy.

Normal pressure hydrocephalus (NPH) and degenerative cervical myelopathy (DCM) can each lead to gait dysfunction and urinary incontinence and may occur concurrently in some patients. In patients presenting with NPH and DCM, there is a paucity of literature describing the medical and surgical complications of treatment and the potential consequences of the sequence of surgical procedures. The aim of this study is to evaluate patients with DCM, NPH, and dual pathology to determine epidemiology and how the order of surgical intervention for both conditions may impact complications and patient outcomes.The PearlDiver Mariner database was queried between 2010 and 2020 to identify patients by their diagnosis of NPH, DCM, or both. Additional groups were created to identify cohorts of patients who underwent ventriculoperitoneal (VP) shunting, DCM surgery, or both surgeries, as determined by the CPT, ICD9, and ICD10 codes included in the dataset. Overall demographics were reported for these cohorts of patients including age, gender, and region. Multivariable logistic regression, controlling for age, sex, and Charlson Comorbidity Index, was used to calculate odds ratios for the rates of perioperative complications within 1 year of initial ventriculoperitoneal (VP) shunt and/or DCM surgery.A total of 825,989 patients were identified with DCM and/or NPH: 725,433 (87.8%) had myelopathy alone, 96, 411 (11.7%), had NPH alone, and 4145 patients (0.5%) had both NPH and DCM. Of all patients with NPH, 4.8% underwent DCM surgery. Of all patients with DCM, 0.08% underwent VP shunting. Compared to NPH only patients who underwent VP shunting, patients with both pathologies undergoing VP shunting had higher odds of revision at 1-year (OR: 1.33, p-value: 0.04) and 5-years (OR: 1.36, p-value: 0.011), as well as spinal cord injury (OR: 7.77, p-value 0.016), dysphonia (OR: 2.88, p-value: 0.004), cervicalgia (OR: 2.95, p-value: 0.004), cervical kyphosis (OR: 17.49, p-value: 0.004), and limb paralysis (OR: 2.02, p-value: 0.002). Compared to DCM only patients who underwent DCM surgery, patients with both pathologies undergoing DCM surgery had higher odds of cardiac complications (OR: 1.12, p-value: 0.002), dural tear (OR: 1.66, p-value: 0.029), and dysphagia (OR: 1.28, p-value:0.001). Patients who underwent VP shunting prior to DCM surgery had higher odds of revision shunting surgery at 1-year (OR:1.61, p-value:0.03) and 5- years (OR:2.16, p-value:0.001).This is the largest study to date examining patients with dual cervical myelopathy and normal pressure hydrocephalus. Surgeons should carefully consider the order of VP shunting and DCM surgery, as complication rates differ depending on the order in which these surgeries are performed. Shunt revision is more common when VP shunting is performed prior to spinal decompression.

SummaryThe androgen receptor (AR) is a steroid receptor and master transcription factor that governs gene expression programs required for luminal development of prostate epithelium, formation of muscle tissue and maintenance of the male phenotype. AR misregulation is a hallmark of multiple malignancies, including prostate cancer, where AR hyperactivation and expansion of its transcriptome occur in part through AR gene amplification and interaction with oncoprotein cofactors. Despite its biological importance, how AR’s individual domains and its protein cofactors cooperate to bind DNA have remained elusive. Using a combination of reconstitution biochemistry and single particle cryo-electron microscopy (EM), we have isolated three conformational states of AR bound to DNA. We observe that AR forms a non-obligate dimer, with the buried dimer interface utilized by related ancestral nuclear receptors repurposed to facilitate cooperative DNA binding. We identify surfaces bridging AR’s domains responsible for allosteric communication, that are compromised in partial androgen insensitivity syndrome (PAIS), and are reinforced by AR’s oncoprotein cofactor, ERG, and DNA binding site motifs. Finally, we present evidence that this plastic dimer interface for transcriptional activation may have been adopted by AR at the expense of DNA binding. Our work highlights how fine-tuning of AR’s cooperative interactions translate to consequences in development and disease.

Antimicrobial peptides (AMPs) are a diverse family of peptides that defend the mucosal surfaces of the oral cavity and other locations. Many AMPs have multiple functions and properties that influence aspects of innate defense and colonization by microorganisms. The human oral cavity is home to the second-most diverse microbiome, and the health of the mouth is influenced by the presence of these bacteria as well as by extrinsic factors such as periodontitis and smoking. This study hypothesized that the AMP profile is different in the presence of extrinsic factors and that this would also be reflected in the bacteria present. The AMP profile was analyzed by quantitative selected-reaction-monitoring mass spectrometry analysis and 40 bacterial species were quantified by DNA-DNA hybridization in saliva donated by 41 individuals. Periodontal status was assessed through dental examination and smoking status through medical charting. Periodontal health (in nonsmokers) was associated with a higher abundance of ribonuclease 7, protachykinin 1, β-defensin 128, lipocalin 1, bactericidal permeability-increasing protein fold-containing family B member 3, and bone-marrow proteoglycan. Nonsmoking periodontal disease was associated with an abundance of neutrophil defensin 1 and cathelicidin. However, 7 AMPs were overabundant in periodontal disease in smokers: adrenomedullin, eosinophil peroxidase, 3 different histones, myeloperoxidase, and neutrophil defensin 1. There were no differentially abundant AMPs in smokers versus nonsmokers with periodontal health. Correlation network inference of healthy nonsmokers, healthy smokers, nonsmoking periodontitis, or smoking periodontitis donors demonstrated very different networks growing in complexity with increasing numbers of stressors. The study highlights the importance of the interaction between the oral cavity and its resident microbiota and how this may be influenced by periodontal disease and smoking.

In the past 25 years, genetic and biochemical analyses of ribosome assembly in yeast have identified most of the factors that participate in this complex pathway and have generated models for the mechanisms driving the assembly. More recently, the publication of numerous cryo-electron microscopy structures of yeast ribosome assembly intermediates has provided near-atomic resolution snapshots of ribosome precursor particles. Satisfyingly, these structural data support the genetic and biochemical models and provide additional mechanistic insight into ribosome assembly. In this Review, we discuss the mechanisms of assembly of the yeast small ribosomal subunit and large ribosomal subunit in the nucleolus, nucleus and cytoplasm. Particular emphasis is placed on concepts such as the mechanisms of RNA compaction, the functions of molecular switches and molecular mimicry, the irreversibility of assembly checkpoints and the roles of structural and functional proofreading of pre-ribosomal particles.

MicroRNAs are dysregulated in breast cancer. Heterogeneous Nuclear Ribonucleoprotein A2/B1 (HNRNPA2/B1) is a reader of the N(6)-methyladenosine (m6A) mark in primary-miRNAs (pri-miRNAs) and promotes DROSHA processing to precursor-miRNAs (pre-miRNAs). We examined the expression of writers, readers, and erasers of m6A and report that HNRNPA2/B1 expression is higher in tamoxifen-resistant LCC9 breast cancer cells as compared to parental, tamoxifen-sensitive MCF-7 cells. To examine how increased expression of HNRNPA2/B1 affects miRNA expression, HNRNPA2/B1 was transiently overexpressed (~5.4-fold) in MCF-7 cells for whole genome miRNA profiling (miRNA-seq). 148 and 88 miRNAs were up- and down-regulated, respectively, 48 h after transfection and 177 and 172 up- and down-regulated, respectively, 72 h after transfection. MetaCore Enrichment analysis identified progesterone receptor action and transforming growth factor β (TGFβ) signaling via miRNA in breast cancer as pathways downstream of the upregulated miRNAs and TGFβ signaling via SMADs and Notch signaling as pathways of the downregulated miRNAs. GO biological processes for mRNA targets of HNRNPA2/B1-regulated miRNAs included response to estradiol and cell-substrate adhesion. qPCR confirmed HNRNPA2B1 downregulation of miR-29a-3p, miR-29b-3p, and miR-222 and upregulation of miR-1266-5p, miR-1268a, miR-671-3p. Transient overexpression of HNRNPA2/B1 reduced MCF-7 sensitivity to 4-hydroxytamoxifen and fulvestrant, suggesting a role for HNRNPA2/B1 in endocrine-resistance.