Neurogenic appendicopathy: A rare differential diagnosis of acute appendicitis.

AIM OF THE STUDY: In histologically non-inflamed but clinically suspect appendices, changes described as neurogenic appendicopathy with fibrous or fibrolipomatous obliterations can be observed. The purpose of this study was to analyse the incidence of these entities of the appendix in a longitudinal patient cohort. PATIENTS AND METHODS: This is a retrospective single-centre study of 457 patients undergoing laparoscopic appendectomy from 2017 to 2020 due to suspected acute appendicitis. RESULTS: In 72 patients (15.8%) with clinically suspected acute appendicitis, the appendix showed no distinct signs of acute inflammation during the procedure. In 43 patients, histological analysis revealed neurogenic appendicopathy or fibrous and fibrolipomatous obliteration. Female gender (P=0.088), younger age (P<0.0001), longer pain duration (P<0.0001) and repetitive pain episodes were more frequent in these patients than in those with acute appendicitis. Inflammation markers were also decreased in the group of patients with neurogenic appendicopathy (leukocytes 9.8±3.5 vs. 13.0±4.5 G/L and C-reactive protein 38.7±60.7 vs. 59.4±70.5mg/L). CONCLUSION: Neurogenic appendicopathy with fibrous/fibrolipomatous obliteration is a differential diagnosis of acute appendicitis that can only be confirmed by pathology. Female gender, young age, prolonged duration with repetitive episodes of pain, and relatively low inflammatory markers are evocative of this diagnosis.

Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

The role of medications in successful aging.

Successful aging includes good health and low levels of disability. To that end, primary prevention is far better than managing subsequent organ damage. When medication is needed to prevent or manage disease, the preferred choice should be associated with the greatest benefits and fewest adverse effects. Cardiovascular diseases are the leading cause of morbidity and mortality in postmenopausal women worldwide. Considering disease-adjusted life years, other leading causes are chronic obstructive pulmonary disease, diabetes mellitus, dementias, hearing loss, cancers of the breast, lung and bowel, osteoporosis, fractures and falls, depression, osteoarthritis, refractive errors of the eye and non-diabetic chronic kidney disease. This review explores the global prevalence of these diseases in women aged 50 years and older, and medications commonly used for them, and contrasts the effects of menopausal hormone therapy (MHT) with others. When initiated early, there is good evidence for MHT benefit in all-cause mortality and primary prevention of cardiovascular disease, diabetes and osteoporosis; fair evidence for benefit in dementias, depression and osteoarthritis; limited evidence for benefit in chronic obstructive pulmonary disease, hearing loss, non-diabetic chronic kidney disease and colorectal cancer; null effects on lung cancer and refractive errors; and varied effects on breast cancer and stroke. Relative benefits and adverse effects of other medications warrant consideration.

Hormone replacement therapy - where are we now?

Hormone replacement therapy (HRT) was the standard of care for menopause management until 2002, when perceptions changed following release of the initial results from the Women's Health Initiative (WHI) trial. Fears of breast cancer and heart attacks engendered by that report were not supported by the data, especially for recently menopausal women. Clinically, HRT is usually initiated near menopause. The WHI tested something different - the effects of HRT started a decade or more after menopause. As it turned out, age at starting HRT is critical in determining benefit/risk. HRT use plummeted following the WHI in 2002 and has remained low, prompting strong interest in alternative treatments. None provide the range of benefits across multiple organ systems offered by estrogen. Most have concerning adverse effects in their own right. HRT can provide effective relief for a wide range of health conditions, potentially avoiding the need for multiple treatments for separate problems. Unfortunately, among many women and clinicians, the perception of HRT benefit/risk is distorted, and its use avoided, leading to unnecessary distress. Following the WHI, many clinicians have not received adequate training to feel comfortable prescribing HRT. When initiated within 10 years of menopause, HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementias.

Dopamine and beta-band oscillations differentially link to striatal value and motor control.

Parkinson's disease is characterized by decreased dopamine and increased beta-band oscillatory activity accompanying debilitating motor and mood impairments. Coordinate dopamine-beta opposition is considered a normative rule for basal ganglia function. We report a breakdown of this rule. We developed multimodal systems allowing the first simultaneous, chronic recordings of dopamine release and beta-band activity in the striatum of nonhuman primates during behavioral performance. Dopamine and beta signals were anticorrelated over seconds-long time frames, in agreement with the posited rule, but at finer time scales, we identified conditions in which these signals were modulated with the same polarity. These measurements demonstrated that task-elicited beta suppressions preceded dopamine peaks and that relative dopamine-beta timing and polarity depended on reward value, performance history, movement, and striatal domain. These findings establish a new view of coordinate dopamine and beta signaling operations, critical to guide novel strategies for diagnosing and treating Parkinson's disease and related neurodegenerative disorders.

Mucin expression in gastric- and gastro-oesophageal signet-ring cell cancer: results from a comprehensive literature review and a large cohort study of Caucasian and Asian gastric cancer.

BACKGROUND: The literature on the prognostic relevance of signet-ring cell (SRC) histology in gastric cancer (GC) is controversial which is most likely related to inconsistent SRC classification based on haematoxylin-eosin staining. We hypothesised that mucin stains can consistently identify SRC-GC and predict GC patient outcome. METHODS: We performed a comprehensive literature review on mucin stains in SRC-GC and characterised the mucin expression in 851 Caucasian GC and 410 Asian GC using Alcian Blue (AB)-Periodic Acid-Schiff (PAS), MUC2 (intestinal-type mucin), and MUC5AC (gastric-type mucin). The relationship between mucin expression and histological phenotype [poorly cohesive (PC) including proportion of SRCs, non-poorly cohesive (non-PC), or mucinous (MC)], clinicopathological variables, and patient outcome was analysed. RESULTS: Depending on mucin expression and cut-offs, the positivity rates of SRC-GC reported in the literature varied from 6 to 100%. Patients with MUC2 positive SRC-GC or SRC-GC with (gastro)intestinal phenotype had poorest outcome. In our cohort study, PC with ≥ 10% SRCs expressed more frequently MUC2, MUC5AC, and ABPAS (p < 0.001, p = 0.004 and p < 0.001, respectively). Caucasians with AB positive GC or combined ABPAS-MUC2 positive and MUC5AC negative had poorest outcome (all p = 0.002). This association was not seen in Asian patients. CONCLUSIONS: This is the first study to suggest that mucin stains do not help to differentiate between SRC-GC and non-SRC-GC. However, mucin stains appear to be able to identify GC patients with different outcome. To our surprise, the relationship between outcome and mucin expression seems to differ between Caucasian and Asian GC patients which warrants further investigations.

Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.

The US Preventive Services Task Force (USPSTF) Draft Recommendation statement on Menopausal Hormone Therapy: Primary Prevention for Chronic Diseases, released in May 2017, perpetuates a major disconnect between the primary population affected, women within roughly 10 years of menopause, and the data cited. Furthermore, major elements of the evidence relied upon have been misinterpreted or misstated, particularly in regard to coronary heart disease and breast cancer, for which there is no statistically significant evidence of harm. As currently drafted, the recommendations reiterate the USPSTF statements of 2012, 2005 and 2002, and will perpetuate egregious harm to the public health. In an attempt to avoid that outcome and to facilitate a return to rational discourse regarding menopausal hormone therapy, an ad hoc group of experts in menopausal health submitted this comprehensive response to the USPSTF.

The evidence base for HRT: what can we believe?

Prior to the unexpected early termination of the Women's Health Initiative (WHI) trial of continuous conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA), the prevailing view was that hormone replacement therapy (HRT) was a low-risk intervention with immediate value for symptom relief in recently menopausal women, and that it probably conferred long-term protection against the major chronic diseases that affect women after menopause. Rather than replicating prior studies, the WHI was designed to test whether the beneficial associations consistently seen in women starting HRT near menopause would be found in women well beyond menopause. Views of the benefits and risks of HRT changed dramatically in 2002 with the unexpected early termination of the CEE + MPA trial and the alarming initial WHI report. HRT use plummeted world-wide, driven by fear of breast cancer and skepticism about cardiovascular benefits. Stunningly, the contrasting findings of the WHI trial of CEE alone reported 2 years later - suggesting prevention of coronary heart disease in women who began HRT at age <60 years, and a reduction in breast cancer overall - were largely ignored. Key lessons from the WHI are that the effects of HRT on most organ systems vary by age and time since last physiologic exposure to hormones and that there are differences between regimens. In the years since the first WHI report, we have learned much about the characteristics of women who are likely to benefit from HRT. The range of HRT regimens has also increased. Not all women have indications for HRT, but for those who do and who initiate within 10 years of menopause, benefits are both short-term (vasomotor, dyspareunia), and long-term (bone health, coronary risk reduction). Critically, the 'facts' that most women and clinicians consider in making the decision to use, or not use, HRT are frequently wrong or incorrectly applied.

Investigation on contribution of neutron monitor data to estimation of aviation doses.

Recently, many efforts have appeared to routinely measure radiation exposure (RE) of aircraft crew due to cosmic rays (CR). On the other hand real-time CR data measured with the ground based neutron monitors (NMs) are collected worldwide and available online. This is an opportunity for comparison of long-term observations of RE at altitudes of about 10km, where composition and energy spectra of secondary particles differ from those on the ground, with the data from NMs. Our contribution presents examples of such type of comparison. Analysis of the silicon spectrometer Liulin measurements aboard aircraft is presented over the period May-September 2005 and compared with data from a single NM at middle latitude. While extreme solar driven events observed by NMs have clearly shown an impact on dosimetric characteristics as measured on the airplanes, the transient short time effects in CR of smaller amplitude have been not studied extensively in relation to RE. For the period May-September 2005, when aircraft data become available and several Forbush decreases (FDs) are observed on the ground, a small improvement in the correlation between the dose measured and multiple linear regression fit based on two key parameters (altitude and geomagnetic cut-off rigidity), is obtained, if the CR intensity at a single NM is added into the scheme.

Poly(glycoamidoamine) brush nanomaterials for systemic siRNA delivery in vivo.

Delivery is the key challenge for siRNA based therapeutics. Here, we report the development of new poly(glycoamidoamine) brush nanomaterials for efficient siRNA delivery. GluN4C10 polymer brush nanoparticles, a lead material, demonstrated significantly improved delivery efficiency for siRNA against factor VII (FVII) in mice compared to poly(glycoamidoamine) brush nanomaterials reported previously.

A novel approach to administration of peptides in women: Systemic absorption of a GnRH agonist via transvaginal ring delivery system.

UNLABELLED: trans-Epithelial delivery of medication across the vagina has proven successful for administration of small, lipophilic molecules such as sex steroids. However, little information is available regarding the vaginal delivery of larger and more polar molecules that currently require parenteral administration because the vaginal epithelium is perceived as a barrier to absorption of larger molecular weight (MW) molecules. Six healthy women underwent administration of 18 or 36mg of leuprolide, a GnRH agonist and a larger MW peptide, via a novel ethylene vinyl acetate (EVA) ring transvaginal drug delivery system (TVDS). Serum levels rose within 8h following insertion: low dose at 310pg/ml and high dose at 1220pg/ml, i.e. levels typically following parenteral injections of leuprolide. GnRHa biological activity was validated by secretion of gonadotropins and sex steroids. These results demonstrate that the non-keratinized vaginal epithelium permits a rapid absorption of a biologically active peptide and that there is significant potential for a novel TVDS to deliver peptides and possibly other macromolecules therapeutically. SIGNIFICANCE STATEMENT: Current routes of administration of medications can include oral, subcutaneous, intravenous, intramuscular, transcutaneous, etc. Many of these approaches have limitations, including pain, poor tolerability, lack of adherence, and inadequate delivery. Peptides, in particular, cannot typically be given orally because they are broken down in the intestinal tract before they are absorbed. While the skin is an attractive way to deliver medications, its superb intrinsic barrier function often makes this route untenable at times. The vaginal epithelium, in contrast, is not keratinized and can allow absorption of other molecules. In this study, we demonstrate that a novel transvaginal drug delivery system (TVDS) is capable of delivering peptide therapeutics to women in a non-parenteral fashion as demonstrated by both blood levels and biologic effects of its delivery.

Physiologic Status Monitoring via the Gastrointestinal Tract.

Reliable, real-time heart and respiratory rates are key vital signs used in evaluating the physiological status in many clinical and non-clinical settings. Measuring these vital signs generally requires superficial attachment of physically or logistically obtrusive sensors to subjects that may result in skin irritation or adversely influence subject performance. Given the broad acceptance of ingestible electronics, we developed an approach that enables vital sign monitoring internally from the gastrointestinal tract. Here we report initial proof-of-concept large animal (porcine) experiments and a robust processing algorithm that demonstrates the feasibility of this approach. Implementing vital sign monitoring as a stand-alone technology or in conjunction with other ingestible devices has the capacity to significantly aid telemedicine, optimize performance monitoring of athletes, military service members, and first-responders, as well as provide a facile method for rapid clinical evaluation and triage.

Probing the effect of heterocycle-bonding in PNX-type ruthenium pre-catalysts for reactions involving H2.

A series of ruthenium(ii) complexes with three novel PNX-type pincer ligands is reported, in which X denotes a heterocyclic donor group (PNX = Ph2PCH2CH2N(H)CH2-X, X = 2-pyridyl, 2-furanyl, 2-thiophenyl or 2-pyrrolyl). The reaction of [(Ph3P)3RuCl2] with one equivalent of ligand leads to the trans-dichloro complexes [(PNX)RuCl2(PPh3)] (1-4) for all ligands, whereas the complexation of [(Ph3P)3Ru(H)(Cl)(CO)] results in different types of complexes. The variation of the heterocyclic donor group is in line with different binding properties and a labilization of this group. Investigations on the catalytic activity of different types of ruthenium(ii) complexes in hydrogenation and dehydrogenation reactions reveal that more labile bound heterocycle donors result in a decrease of catalytic productivity and activity.

Reliable LC3 and p62 autophagy marker detection in formalin fixed paraffin embedded human tissue by immunohistochemistry.

Autophagy assures cellular homeostasis, and gains increasing importance in cancer, where it impacts on carcinogenesis, propagation of the malignant phenotype and development of resistance. To date, its tissue-based analysis by immunohistochemistry remains poorly standardized. Here we show the feasibility of specifically and reliably assessing the autophagy markers LC3B and p62 (SQSTM1) in formalin fixed and paraffin embedded human tissue by immunohistochemistry. Preceding functional experiments consisted of depleting LC3B and p62 in H1299 lung cancer cells with subsequent induction of autophagy. Western blot and immunofluorescence validated antibody specificity, knockdown efficiency and autophagy induction prior to fixation in formalin and embedding in paraffin. LC3B and p62 antibodies were validated on formalin fixed and paraffin embedded cell pellets of treated and control cells and finally applied on a tissue microarray with 80 human malignant and non-neoplastic lung and stomach formalin fixed and paraffin embedded tissue samples. Dot-like staining of various degrees was observed in cell pellets and 18/40 (LC3B) and 22/40 (p62) tumors, respectively. Seventeen tumors were double positive for LC3B and p62. P62 displayed additional significant cytoplasmic and nuclear staining of unknown significance. Interobserver-agreement for grading of staining intensities and patterns was substantial to excellent (kappa values 0.60 - 0.83). In summary, we present a specific and reliable IHC staining of LC3B and p62 on formalin fixed and paraffin embedded human tissue. Our presented protocol is designed to aid reliable investigation of dysregulated autophagy in solid tumors and may be used on large tissue collectives.

The cardiovascular safety aspects of calcium supplementations: where does the truth lie? A personal perspective.

Clinical guidelines may change with time, as more information from topline studies emerges. Calcium plus vitamin D supplementation became routine decades ago, especially in the older population, based on the assumption that it may promote bone health and prevent fractures, and perhaps induce additional favorable health outcomes. During the past years, an ongoing debate defies this paradigm, mainly because of a potential cardiovascular risk on the one hand, and uncertainty in regard to the extent of the beneficial bone effects on the other hand. The following article summarizes the main recent developments, trying to put some order into the controversial information and opinions which have been published in the medical literature. We conclude that the best current evidence supports a primary strategy of obtaining recommended intakes of calcium and vitamin D from dietary sources. But, since most western diets are inadequate in that regard, and since there is no clear evidence of harm from modest supplementation (up to 1000 mg of elemental calcium and 400 IU of vitamin D3), supplementation is appropriate when dietary intake is inadequate.

Chemically diverse polymer microarrays and high throughput surface characterisation: a method for discovery of materials for stem cell culture†Electronic supplementary information (ESI) available. See DOI: 10.1039/c4bm00054dClick here for additional data file.

Materials discovery provides the opportunity to identify novel materials that are tailored to complex biological environments by using combinatorial mixing of monomers to form large libraries of polymers as micro arrays. The materials discovery approach is predicated on the use of the largest chemical diversity possible, yet previous studies into human pluripotent stem cell (hPSC) response to polymer microarrays have been limited to 20 or so different monomer identities in each study. Here we show that it is possible to print and assess cell adhesion of 141 different monomers in a microarray format. This provides access to the largest chemical space to date, allowing us to meet the regenerative medicine challenge to provide scalable synthetic culture ware. This study identifies new materials suitable for hPSC expansion that could not have been predicted from previous knowledge of cell-material interactions.

The search for the primary tumor in metastasized gastroenteropancreatic neuroendocrine neoplasm.

Gastroenteropancreatic neuroendocrine tumors (NETs) often present as liver metastasis from a carcinoma of unknown primary. We recently showed that primary NETs from the pancreas, small intestine and stomach as well as their respective liver metastases differ from each other by the expression profile of the three genes CD302, PPWD1 and ABHB14B. The gene and protein expression of CD302, PPWD1, and ABHB14B was studied in abdominal NET metastases to identify the site of the respective primary tumors. Cryopreserved tissue from NET metastases collected in different institutions (group A: 29, group B: 50, group C: 132 specimens) were examined by comparative genomic hybridization (Agilent 105 K), gene expression analysis (Agilent 44 K) (groups A and B) and immunohistochemistry (group C). The data were blindly evaluated, i.e. without knowing the site of the primary. Gene expression analysis correctly revealed the primary in the ileum in 94 % of the cases of group A and in 58 % of group B. A pancreatic primary was predicted in 83 % (group A) and 20 % (group B), respectively. The combined sensitivity of group A and B was 75 % for ileal NETs and 38 % for pancreatic NETs. Immunohistochemical analysis of group C revealed an overall sensitivity of 80 %. Gene and protein expression analysis of CD302 and PPWD1 in NET metastases correctly identifies the primary in the pancreas or the ileum in 80 % of the cases, provided that the tissue is well preserved. Immunohistochemical profiling revealed CD302 as the best marker for ileal and PPWD1 for pancreatic detection.