Unraveling the joints: a narrative review of osteoarthritis.

Osteoarthritis (OA) is a chronic and progressive degenerative disease that affects joint structures, such as the hips, knees, and hands, involving the articular cartilage, subchondral bone, ligaments, capsule, and synovium. OA is characterized by a progressive degeneration of the joint structures, resulting in pain and decreased quality of life. Local and systemic risk factors pave the way for OA development. Different phenotypes may be identified, but three main molecular mechanisms define the endotypes: the bone-driven endotype, the synovitis-driven endotype, and the cartilage-driven endotype. The hallmark of OA pathophysiology involves more than just mechanical degradation; it includes the release of pro-inflammatory mediators, such as interleukins and TNF-α, which elucidates the significant roles of metabolic syndrome, diabetes, and cellular senescence in its development. OA is distinguished by a clinical presentation that varies significantly between people and is marked by pain, stiffness, and functional impairments. The clinical course can be split into Pre-OA, Early OA, Evident OA, and End-Stage. Depending on the stage of the disease, OA diagnosis frequently necessitates a complex strategy that combines clinical evaluation to detect joint tenderness, range of motion, and joint swelling or abnormalities, medical history assessment, imaging modalities, and laboratory investigations. There is no known treatment for OA, and different therapies are usually evaluated based on the stage of the disease to minimize pain and stiffness while maintaining joint function. Treatments are divided into the reduction of modifiable risk factors, pharmacologic therapies, rehabilitation, complementary therapies, interventional pain procedures, and surgery. OA clinical heterogeneity underlines the importance of prevention, early diagnosis, and identifying the phenotype and endotype to tailor the treatment.

Robust Institutional Support and Collaboration Between Summer Training Programs in Cancer and Biomedicine Drive the Pivot to a Virtual Format in Response to the COVID Pandemic.

Summer internships serve important roles in training the next generation of biomedical researchers and healthcare providers through laboratory and clinical experiences that excite trainees about these fields and help them make informed decisions about career paths. The SARS-CoV-2 (COVID) pandemic and associated physical distancing restrictions precluded implementation of traditional in-person summer curricula and led to the cancellation of many internships across the USA. COVID-related disruptions also created opportunities for trainees to engage in remote research, become proficient in online learning platforms, and explore multidisciplinary topics. These skills are highly relevant to trainees as virtual interfaces occupy an increasingly mainstream role in their professional paths. The response to the COVID pandemic required real-time adaptations at all levels for major biomedical institutions including the University of Maryland Baltimore (UMB). Pivoting summer programs to a virtual format as part of this response provided a "teachable moment" to expose trainees to the innovation and resilience that are essential components of the biomedical profession. UMB summer programs, which span diverse biomedical disciplines from cancer research to diabetes, consolidated resources and identified mentors with online research projects to develop a robust virtual curriculum. Herein, data from a cancer-focused internship illustrate the collaborative adaptations to established components and creation of new learning modules in the transition to, and implementation of, online training. Outcomes are presented in the context of the COVID pandemic and significant societal issues that arose in the summer of 2020. The utility of virtual components and their impact on future programs is discussed.

Laparoscopic and open liver resection for hepatocellular carcinoma with Child-Pugh B cirrhosis: multicentre propensity score-matched study.

BACKGROUND: Laparoscopic liver resection for hepatocellular carcinoma (HCC) in Child-Pugh A cirrhosis has been demonstrated as beneficial. However, the role of laparoscopy in Child-Pugh B cirrhosis is undetermined. The aim of this retrospective cohort study was to compare open and laparoscopic resection for HCC with Child-Pugh B cirrhosis. METHODS: Data on liver resections were gathered from 17 centres. A 1 : 1 propensity score matching was performed according to 17 predefined variables. RESULTS: Of 382 available liver resections, 100 laparoscopic and 100 open resections were matched and analysed. The 90-day postoperative mortality rate was similar in open and laparoscopic groups (4.0 versus 2.0 per cent respectively; P = 0.687). Laparoscopy was associated with lower blood loss (median 110 ml versus 400 ml in the open group; P = 0.004), less morbidity (38.0 versus 51.0 per cent respectively; P = 0.041) and fewer major complications (7.0 versus 21.0 per cent; P = 0.010), and ascites was lower on postoperative days 1, 3 and 5. For laparoscopic resections, patients with portal hypertension developed more complications than those without (26 versus 12 per cent respectively; P = 0.002), and patients with a Child-Pugh B9 score had higher morbidity rates than those with B8 and B7 (7 of 8, 10 of 16 and 21 of 76 respectively; P < 0.001). Median hospital stay was 7.5 (range 2-243) days for laparoscopic liver resection and 18 (3-104) days for the open approach (P = 0.058). The 5-year overall survival rate was 47 per cent for open and 65 per cent for laparoscopic resection (P = 0.142). The 5-year disease-free survival rate was 32 and 37 per cent respectively (P = 0.742). CONCLUSION: Patients without preoperative portal hypertension and Child-Pugh B7 cirrhosis may benefit most from laparoscopic liver surgery.

Exaptation of two ancient immune proteins into a new dimeric pore-forming toxin in snails.

The Membrane Attack Complex-Perforin (MACPF) family is ubiquitously found in all kingdoms. They have diverse cellular roles, however MACPFs with pore-forming toxic function in venoms and poisons are very rare in animals. Here we present the structure of PmPV2, a MACPF toxin from the poisonous apple snail eggs, that can affect the digestive and nervous systems of potential predators. We report the three-dimensional structure of PmPV2, at 17.2 Å resolution determined by negative-stain electron microscopy and its solution structure by small angle X-ray scattering (SAXS). We found that PV2s differ from nearly all MACPFs in two respects: it is a dimer in solution and protomers combine two immune proteins into an AB toxin. The MACPF chain is linked by a single disulfide bond to a tachylectin chain, and two heterodimers are arranged head-to-tail by non-covalent forces in the native protein. MACPF domain is fused with a putative new Ct-accessory domain exclusive to invertebrates. The tachylectin is a six-bladed ß-propeller, similar to animal tectonins. We experimentally validated the predicted functions of both subunits and demonstrated for the first time that PV2s are true pore-forming toxins. The tachylectin "B" delivery subunit would bind to target membranes, and then the MACPF "A" toxic subunit would disrupt lipid bilayers forming large pores altering the plasma membrane conductance. These results indicate that PV2s toxicity evolved by linking two immune proteins where their combined preexisting functions gave rise to a new toxic entity with a novel role in defense against predation. This structure is an unparalleled example of protein exaptation.

Designing a mHealth clinical decision support system for Parkinson's disease: a theoretically grounded user needs approach.

BACKGROUND: Despite the established evidence and theoretical advances explaining human judgments under uncertainty, developments of mobile health (mHealth) Clinical Decision Support Systems (CDSS) have not explicitly applied the psychology of decision making to the study of user needs. We report on a user needs approach to develop a prototype of a mHealth CDSS for Parkinson's disease (PD), which is theoretically grounded in the psychological literature about expert decision making and judgement under uncertainty. METHODS: A suite of user needs studies was conducted in 4 European countries (Greece, Italy, Slovenia, the UK) prior to the development of PD_Manager, a mHealth-based CDSS designed for Parkinson's disease, using wireless technology. Study 1 undertook Hierarchical Task Analysis (HTA) including elicitation of user needs, cognitive demands and perceived risks/benefits (ethical considerations) associated with the proposed CDSS, through structured interviews of prescribing clinicians (N = 47). Study 2 carried out computational modelling of prescribing clinicians' (N = 12) decision strategies based on social judgment theory. Study 3 was a vignette study of prescribing clinicians' (N = 18) willingness to change treatment based on either self-reported symptoms data, devices-generated symptoms data or combinations of both. RESULTS: Study 1 indicated that system development should move away from the traditional silos of 'motor' and 'non-motor' symptom evaluations and suggest that presenting data on symptoms according to goal-based domains would be the most beneficial approach, the most important being patients' overall Quality of Life (QoL). The computational modelling in Study 2 extrapolated different factor combinations when making judgements about different questions. Study 3 indicated that the clinicians were equally likely to change the care plan based on information about the change in the patient's condition from the patient's self-report and the wearable devices. CONCLUSIONS: Based on our approach, we could formulate the following principles of mHealth design: 1) enabling shared decision making between the clinician, patient and the carer; 2) flexibility that accounts for diagnostic and treatment variation among clinicians; 3) monitoring of information integration from multiple sources. Our approach highlighted the central importance of the patient-clinician relationship in clinical decision making and the relevance of theoretical as opposed to algorithm (technology)-based modelling of human judgment.

European Space Agency experiments on thermodiffusion of fluid mixtures in space.

This paper describes the European Space Agency (ESA) experiments devoted to study thermodiffusion of fluid mixtures in microgravity environment, where sedimentation and convection do not affect the mass flow induced by the Soret effect. First, the experiments performed on binary mixtures in the IVIDIL and GRADFLEX experiments are described. Then, further experiments on ternary mixtures and complex fluids performed in DCMIX and planned to be performed in the context of the NEUF-DIX project are presented. Finally, multi-component mixtures studied in the SCCO project are detailed.

Intracorporeal versus extracorporeal anastomosis after laparoscopic gastrectomy for gastric cancer. A systematic review with meta-analysis.

AIM: To perform a systematic review and meta-analyses of studies comparing the totally laparoscopic procedures with intracorporeal anastomosis (IA) to laparoscopic-assisted surgery with extracorporeal anastomosis (EA) in gastric resections. METHODS: We performed a systematic search in the electronic databases. Outcomes analysed were: intraoperative (operative time and intraoperative blood loss), oncologic (harvested nodes, distance of the tumour from proximal and distal margin), postoperative complications (gastric stasis, intraluminal and extraluminal bleeding, leakage and wound infection) recovery (time to first flatus, time to first oral intake and hospital stay). We performed meta-regression analyses after implementing a regression model with the analysed outcomes as dependent variables (y) and the demographic and pathologic covariates as independent variables (x). RESULTS: A total of 26 studies (20 on distal gastrectomy and 6 on total gastrectomy) were included in the final analysis. Regarding distal gastrectomy, there was no statistical difference between the two groups in the above-mentioned outcomes, except for intraoperative blood loss (less in IA group, P=0.003), number of harvested nodes (better in the IA group, P=0.022) and length of hospital stay (shorter in the IA group, P=0.037). Regarding total gastrectomy, there was no statistical difference for all outcomes, except for the distal margin (further in the EA group, P=0.040). Meta-regression analysis showed that a lot of variables influenced results in distal gastric resections, but not in total gastric resections. CONCLUSION: We can state laparoscopic gastric resections with IA are safe and feasible when performed by expert surgeons. However, new well-designed studies comparing the two techniques are needed to confirm the benefits of laparoscopic IA.

Confocal laser endomicroscopy in ulcerative colitis: beyond endoscopic assessment of disease activity.

BACKGROUND: The aim of this study was to investigate the role of confocal laser endomicroscopy (CLE) in the assessment of disease activity in ulcerative colitis (UC). METHODS: Consecutive patients with UC referred to our inflammatory bowel disease unit for colonoscopy were enrolled. Patients without UC were used as controls. UC activity was evaluated by white light endoscopy and classified according to the Mayo Ulcerative Colitis Endoscopic Score of Severity. Endoscopic biopsies were also taken for histological assessment of disease activity and then assessed with CLE. Three parameters were evaluated; crypt architecture (crypt diameter, inter-crypt distance, presence of fused crypts, crypts regularity), microvascular pattern (regular, dilated, irregular and deformed), fluorescein leakage. RESULTS: Fifty patients with UC and 10 controls were enrolled. At colonoscopy, 11 patients (22%), 19 patients (38%), 12 patients (24%) and 8 patients (16%) presented a Mayo score of 0, 1, 2 and 3, respectively. At CLE, fused crypts were present in all the patients with UC and absent in controls. Crypt diameter and inter-crypt distance showed a parallel increase with the Mayo score. Fluorescein leakage and irregular vessels were more frequently found in case of a high level of endoscopic severity, but were also identified in about 20% of UC patients with normal mucosa. Biopsies also demonstrated the presence of histological activity in 4 patients with endoscopically inactive colitis. CONCLUSIONS: CLE might be a useful tool to determine inflammatory activity in UC. Fused crypts appeared to be a CLE marker of UC, while other abnormalities, like microvascular alteration and fluorescein leakage, have also been identified in patients with mucosal healing at endoscopy. Larger series are required to validate these results and the advantages of a CLE-based assessment of UC activity.

Perioperative goal-directed therapy with uncalibrated pulse contour methods: impact on fluid management and postoperative outcome.

Previous meta-analyses suggest that perioperative goal-directed therapy (GDT) is useful to decrease postoperative morbidity. Most GDT studies analysed were done with pulmonary artery catheters, oesophageal Doppler and calibrated pulse contour methods. Uncalibrated pulse contour (uPC) techniques are an appealing alternative but their accuracy has been questioned. The effects of GDT on fluid management (volumes and volume variability) remain unclear. We performed a meta-analysis of randomized controlled trials investigating the effects of GDT with uPC methods on postoperative outcome. The primary endpoint was postoperative morbidity. Fluid volumes and fluid volume variability (standard deviation/mean) over the GDT period were also studied. Nineteen studies met the inclusion criteria (2159 patients). Postoperative morbidity was reduced with GDT (OR 0.46, 95% CI 0.30-0.70, P<0.001). The volume of colloids was higher [weighted mean difference (WMD) +345 ml, 95% CI 148-541 ml, P<0.001] and the volume of crystalloids was lower (WMD -429 ml, 95% CI -634 to -224 ml, P<0.01) in the GDT group than in the control group. However, the total volume of fluid (WMD -220 ml, 95% CI -590 to 150 ml, P=0.25) and the variability of fluid volume (34% vs 33%, P=0.98) were not affected by GDT. The use of GDT with uPC techniques was associated with a decrease in postoperative morbidity. It was not associated with an increase in total fluid volume nor with a decrease in fluid volume variability.

Training value of laparoscopic colorectal videos on the World Wide Web: a pilot study on the educational quality of laparoscopic right hemicolectomy videos.

INTRODUCTION: Instructive laparoscopy videos with appropriate exposition could be ideal for initial training in laparoscopic surgery, but unfortunately there are no guidelines for annotating these videos or agreed methods to measure the educational content and the safety of the procedure presented. Aim of this study is to systematically search the World Wide Web to determine the availability of laparoscopic colorectal surgery videos and to objectively establish their potential training value. METHODS: A search for laparoscopic right hemicolectomy videos was performed on the three most used English language web search engines Google.com, Bing.com, and Yahoo.com; moreover, a survey among 25 local trainees was performed to identify additional websites for inclusion. All laparoscopic right hemicolectomy videos with an English language title were included. Videos of open surgery, single incision laparoscopic surgery, robotic, and hand-assisted surgery were excluded. The safety of the demonstrated procedure was assessed with a validated competency assessment tool specifically designed for laparoscopic colorectal surgery and data on the educational content of the video were extracted. RESULTS: Thirty-one websites were identified and 182 surgical videos were included. One hundred and seventy-three videos (95%) detailed the year of publication; this demonstrated a significant increase in the number of videos published per year from 2009. Characteristics of the patient were rarely presented, only 10 videos (5.4%) reported operating time and only 6 videos (3.2%) reported 30-day morbidity; 34 videos (18.6%) underwent a peer-review process prior to publication. Formal case presentation, the presence of audio narration, the use of diagrams, and snapshots and a step-by-step approach are all characteristics of peer-reviewed videos but no significant difference was found in the safety of the procedure. CONCLUSIONS: Laparoscopic videos can be a useful adjunct to operative training. There is a large and increasing amount of material available for free on the internet, but this is currently unregulated.

Dose adjustment of biologic therapies for psoriasis in dermatological practice: a retrospective study.

INTRODUCTION: Despite the large routine use of biologic drugs in psoriasis treatment, the majority of studies do not take into consideration dose-adjustment practice in 'real-life' dermatological setting. In routine clinical practice, the disease management may include a large number of conditions requiring non-standard dosage regimens, including dose escalation, dose reduction and/or off-label treatment interruption. OBJECTIVE: The ONDA (Outcome of non-standard dosing regimen in Psoriasis and Psoriatic Arthritis) study aim was to retrospectively analyse dose-adjustment strategies among biologic therapies for psoriasis in dermatological practice during a 3-year period. RESULTS: This retrospective, observational, multicentre study was carried out in 350 patients (68% male, 32% female) affected by plaque-type psoriasis (Pso) with a coexistence of psoriatic arthritis in 164 patients (46.9%). At baseline mean PASI score was 14.9 (SD 7.2). Dose adjustment was demonstrated to be a common practice with 70/350 patients (20%) who needed a dose variation during the treatment time, in particular a dose increase in 20/70 patients (28.6%) and a dose reduction in 50/70 patients (71.4%). Dose increase was due to inefficacy on Pso parameters in 60% of cases and to inefficacy of PsA parameters in 40% of cases, while dose reduction (or temporary off-label treatment interruption) was due to prolonged remission in 54% of cases, other reason in 18% of cases, patient choice or request in 14% of cases, occurrence of concomitant event in 12% of cases. CONCLUSION: Dose adjustment is a common clinical practice, consisting of frequent dose reduction when a disease prolonged remission is obtained or dose increase to improve efficacy on Pso and PsA disease parameters.

Meta-analysis of drain amylase content on postoperative day 1 as a predictor of pancreatic fistula following pancreatic resection.

BACKGROUND: Drain amylase content in the days immediately after major pancreatic resection has been investigated previously as a predictor of postoperative pancreatic fistula (POPF). Its accuracy, however, has not been determined conclusively. The purpose of this study was to evaluate the accuracy of drain amylase content on the first day after major pancreatic resection in predicting the occurrence of POPF. METHODS: A literature search of the MEDLINE, Embase and Scopus(®) databases to 13 May 2015 was performed to identify studies evaluating the accuracy of drain amylase values on day 1 after surgery in predicting the occurrence of POPF. The area under the hierarchical summary receiver operating characteristic (ROC) curve (AUChSROC ) was calculated as an index of accuracy, and pooled estimates of accuracy indices (sensitivity and specificity) were calculated at different cut-off levels. Subgroup and meta-regression analyses were performed to test the robustness of the results. RESULTS: Thirteen studies involving 4416 patients were included. The AUChSROC was 0·89 (95 per cent c.i. 0·86 to 0·92) for clinically significant POPF and 0·88 (0·85 to 0·90) for POPF of any grade. Pooled estimates of sensitivity and specificity were calculated for the different cut-offs: 90-100 units/l (0·96 and 0·54 respectively), 350 units/l (0·91 and 0·84) and 5000 units/l (0·59 and 0·91). Accuracy was independent of the type of operation, type of anastomosis performed and octreotide administration. CONCLUSION: Evaluation of drain amylase content on the first day after surgery is highly accurate in predicting POPF following major pancreatic resection. It may allow early drain removal and institution of an enhanced recovery pathway.

In vivo assessment of tumour angiogenesis in colorectal cancer: the role of confocal laser endomicroscopy.

AIM: Tumour neoangiogenesis is a key factor in tumour progression and metastatic spread and the possibility to assess tumour angiogenesis might provide prognostic information. The aim of this study was to establish the role of probe-based confocal laser endomicroscopy (p-CLE) in the identification of vascular architecture and specific morphological patterns in normal colorectal mucosa and malignant lesions during routine endoscopy. METHOD: Fourteen consecutive patients with colorectal cancer were included. The following features were identified and then compared between normal and neoplastic mucosa on p-CLE images: vessel shape (straight vs irregular) vessel diameter the 'branching patterns' vessel permeability (fluorescein leakage) and blood flow (normal vs defective flux). Immunohistochemistry was used to confirm the presence and to study the morphology of vascular structures (CD-34 staining) and 'neo-vessels' (WT-1 staining) on tumour and normal mucosal sections. RESULTS: Tumour vessels appeared as irregular, ectatic and with a highly variable calibre and branching patterns on p-CLE images. The mean diameter of tumour vessels was significantly larger than those in normal mucosa (weighted mean difference 3.38, 95% CI 2.65-4.11, P = 0.01). Similarly, 'vessel branching' (OR 2.74, 95% CI 1.23-6.14, P = 0.01), fluorescent dye 'extravasation' (OR 3.46, 95% CI 1.39-8.57, P = 0.01) were significantly more frequent in colorectal cancer than in normal colorectal mucosa. Immunohistochemistry corroborated the p-CLE findings, showing higher vascularity in tumour sections due to neoformed vessels, presenting irregular patterns. CONCLUSION: Probe-based confocal laser endomicroscopy provides a noninvasive characterization of the microvascular architecture of colonic mucosa. Different morphological patterns have been described, discriminating normal and malignant microvascular networks in colorectal mucosa.

Effects of saltwater intrusion on pinewood vegetation using satellite ASTER data: the case study of Ravenna (Italy).

The San Vitale pinewood (Ravenna, Italy) is part of the remaining wooded areas within the southeastern Po Valley. Several studies demonstrated a widespread saltwater intrusion in the phreatic aquifer caused by natural and human factors in this area as the whole complex coastal system. Groundwater salinization affects soils and vegetation, which takes up water from the shallow aquifer. Changes in groundwater salinity induce variations of the leaf properties and vegetation cover, recognizable by satellite sensors as a response to different spectral bands. A procedure to identify stressed areas from satellite remote sensing data, reducing the expensive and time-consuming ground monitoring campaign, was developed. Multispectral Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) data, acquired between May 2005 and August 2005, were used to calculate Normalized Difference Vegetation Index (NDVI). Within the same vegetation type (thermophilic deciduous forest), the areas with the higher vegetation index were taken as reference to identify the most stressed areas using a statistical approach. To confirm the findings, a comparison was conducted using contemporary groundwater salinity data. The results were coherent in the areas with highest and lowest average NDVI values. Instead, to better understand the behavior of the intermediate areas, other parameters influencing vegetation (meteorological data, water table depth, and tree density) were added for the interpretation of the results.

An unusual case of occupational asthma in a part time magician. He has got an allergy surprise from his top hat!

In this report we describe a case of respiratory allergy induced by an unusual occupational exposure to rabbit. The patient worked as a part-time magician in theatres and private parties and the most popular performance of his show was to pull out a white rabbit from a top hat. Unfortunately, a few minutes after the extraction of rabbit from top hat, the patient experienced the onset of upper and lower airway symptoms, and in some occasions he was forced to stop the show and to use short acting ß2agonists and intramuscular steroids. The results of SPT and evaluation of serological specific IgE (ImmunoCAP and ImmunoCAP ISAC IgE) revealed allergic sensitization to rabbit (Oryctolagus cuniculus) dander as well as to Parietaria and dust mites. ImmunoCAP ISAC IgE excluded allergic sensitization to other cross-reacting animal allergens. Rabbit constitutes a reliable risk factor for allergic sensitization in individuals working as professional / part-time magicians or as animators in some recreational settings (resorts, parties, charity shows, etc).