The Year 2022 in biomaterials research: A perspective from the editors of six leading journals.

The field of biomaterials science is highly active, with a steadily increasing number of publications and new journals being founded. This article brings together contributions from the editors of six leading journals in the area of biomaterials science and engineering. Each contributor highlights specific advances, topics, and trends that have emerged through the publications in their respective journal in the calendar year 2022. It presents a global perspective on a wide range of material types, functionalities, and applications. The highlighted topics include a diversity of biomaterials; from proteins, polysaccharides, and lipids to ceramics, metals, advanced composites, and a variety of new forms of these materials. Important advances in dynamically functional materials are presented, including a range of fabrication techniques such as bioassembly, 3D bioprinting and microgel formation. Similarly, several applications are highlighted in drug and gene delivery, biological sensing, cell guidance, immunoengineering, electroconductivity, wound healing, infection resistance, tissue engineering, and treatment of cancer. The goal of this paper is to provide the reader with both a broad view of recent biomaterials research, as well as expert commentary on some of the key advances that will shape the future of biomaterials science and engineering.

Retrieval analysis of the Essure® micro insert female sterilization implant: Methods for metal ion and microscopic analysis.

The Essure® Device is a female sterilization implant comprised of four alloys (Ni-Ti, 316L SS, Pt-Ir and Sn-Ag) and Dacron fibers. As part of the mandated 522 post-market surveillance study, implant retrieval and metal-ion analysis methods were developed separate from patient clinical data, to quantify trace metal ions found in tissue and to assess implant degradation present. Three segments of tissue (proximal implant, distal implant, and tissue distal from the implant) stored in neutral buffered formalin, were retrieved. Tissue was prepared for metal ion analysis using inductively coupled mass spectrometry (ICP-MS). Implant sections from four patients, were analyzed using digital optical microscopy (DOM), scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). Image analysis showed Sn-Ag solder corroded and elevated Sn ion levels in tissue proximal to the solder compared to tissues more remote in all cases observed. The 316L SS exhibited signs of degradation with high surface concentrations of molybdenum and chromium and low iron compared to the parent alloy. Evidence of elevated iron, chromium and nickel within the tissues and storage solutions combined with precipitation of an iron-calcium-phosphorous material on some implants indicate evidence of SS corrosion. Ni-Ti, Pt-Ir and Dacron appear to have no major damage. This study includes preliminary results as part of the ongoing 522 study and therefore no final conclusions regarding the device or patient data can be drawn from this present study until the entire 522 study is complete. STATEMENT OF SIGNIFICANCE: The Essure Device is a female sterilization implant that was implanted into approximately 750,000 women. The device is composed of polyethylene terephthalate fibers and 4 metal alloys, 316L stainless steel, Nickel-Titanium, Tin-Silver and Platinum-Iridium. Following an increase in patient reported adverse events, the FDA required a 522-post market surveillance study. As part of this study, implants are retrieved from patients via salpingectomy or hysterectomy. This study focuses on the development of the implant retrieval methods following surgery, with focus on measuring local tissue metal ions, their distribution and assessing the degradation of the implant without correlation to patient clinical condition.

Electrocautery-induced molten metal particle generation from total joint replacements: Morphology and chemistry.

Electrosurgical techniques are used during surgery to cauterize, and their damaging effects have primarily been documented in terms of tissue necrosis, charring, and localized heat accumulation. Metallic implants as well as the surgical blade can experience incidental electrosurgical current arcing that results in the generation and transfer of melted metallic particles. This work examines the composition, particle size distribution, and chemical state of the melted alloy surfaces and particles produced in vitro. Using scanning electron microscopy and energy dispersive spectroscopy, a flash-melting particle generation phenomenon between source 304 SSL blades and polished cobalt-chromium-molybdenum (CoCrMo) and titanium-6-aluminum-4-vandaium (Ti6Al4V) surfaces was documented where 304 SSL mixed heterogeneously with the CoCrMo and Ti6Al4V ejecting "splatter" particles from the cautery site. The spherical micron-sized particles were embedded with sub-micron-sized particles with 42% of the total sample population measuring between 0.25 and 0.35 µm in diameter. CoCrMo-304 SSL particles were principally made of high concentrations of iron, oxygen, and nickel with embedded sub-micron-sized particles containing oxygen, chromium, and cobalt with lower concentrations of iron and molybdenum. Ti6Al4V-304 SSL interactions resulted in similar micron-sized particles made up of high concentrations of iron, nickel, and chromium with embedded sub-micron-sized particles containing titanium, oxygen, and small amounts of aluminum. X-ray photoelectron spectroscopy of damaged CoCrMo surfaces confirmed the presence of chromium (VI) following dry electrocautery contact in coagulation mode. The structural effects of electrocautery-induced damage are becoming visible in retrieval analysis, but the long-term physiological implications during the lifetime of the implant from this damage mode have yet to be defined.

Self-reinforced poly(ether ether ketone) and polyethylene composite gaskets for prevention of mechanically-assisted corrosion in modular taper junctions: Seating, micromotion and short-term fretting corrosion.

Mechanically-assisted crevice corrosion (MACC) is a phenomenon known to cause complications in modular orthopedic implants, particularly at metal-metal taper junctions. Previous studies of the properties and corrosion performance of an interfacial polymeric self-reinforced composite (SRC) gaskets have shown its capability as a high-strength, insulating barrier against oxide abrasion and metal degradation of metal-metal (or metal-hard) contacts in MACC conditions. This study characterizes the short-term tribocorrosion performance of poly (ether ether ketone) SRCs (SRC-PEEK) and polyethylene SRC (SRC-PE) films under in vitro test conditions for head-neck modular junction designs in hip replacement devices. SRC films composed of SRC-PEEK and SRC-PE were seated between 9/10 femoral head bores and stem tapers as thin interfacial gaskets and tested against metal-metal controls under short-term cyclic loading conditions in a custom in vitro test setup. Head-neck seating mechanics were measured, followed by incremental cyclic fretting corrosion testing with monitoring of fretting current, force, and relative micromotion between head and neck components during cyclic loading. SRC-PEEK tapers had a seating subsidence that was approximately three times that of the SRC-PE tapers and nine times that of controls. SRC-PE tapers, likely due to low friction, partially failed to lock during seating resulting in a pushing up of the head on the taper. Average fretting currents were significantly lower for both SRC groups (less than 0.3 µA at 4000 N) compared to control tapers experiencing fretting corrosion currents between 1.7 µA and 32 µA, (p < 0.05). SRC-PEEK gaskets exhibited similar subsidence and micromotion performance as controls while SRC-PE tapers experienced over 240 µm of subsidence during seating and loading conditions. The SRC-PE low-friction properties likely caused insufficient taper locking, which may increase the risk of improper head seating or head disassociation. These results show that SRC-PEEK gaskets, unlike SRC-PE gaskets, can maintain adequate frictional locking at the taper junction and prevent the onset of MACC. SRC-PEEK gaskets improve the performance of modular taper junctions and could be considered as a potential solution to mitigate fretting corrosion.

Synthetic periprosthetic synovial fluid development for in vitro cell-tribocorrosion testing using the Taguchi array approach.

Synovial fluid is dynamic in vivo with biological components changing in ratio and size depending on the health of the joint space, making it difficult to model in vitro. Previous efforts to develop synthetic synovial fluid have typically focused on single organic-tribological interactions with implant surfaces, thus ignoring interplay between multiple solution components. Using a Taguchi orthogonal array, we were able to isolate the individual effects of five independent synovial fluid composition variables: ratios of (1) hyaluronic acid to phospholipids (HA:PL) and (2) albumin to globulin (A:G), and concentrations of (3) hydrogen peroxide (H2 O2 ), (4) cobalt (Co2+ ) and (5) chromium (Cr3+ ) ions on macrophage viability and reduced glutathione production, local solution pH and the comprehensive CoCrMo alloy electrochemical response. While no single synovial fluid variable significantly affected the collective response, HA:PL ratio resulted in the largest impact factor (Δ) on 12 of the 13 measured responses with significant effects (p < .05) on the average macrophage survival rate and electrochemical capacitive state of the CoCrMo surface. Cluster analysis separated significant responses from all trials into three groups, corresponding to healthy, mild, or severely inflamed fluids, respectively; with the healthy synovial fluid composition having mid-range HA:PL ratios with no Co2+ ions, and the severely inflamed fluids consisting of low and high HA:PL ratios with H2 O2 and Co2+ ions. By utilizing the Taguchi approach in combination with cluster analysis, we were able to advance our knowledge of complex multivariate synthetic synovial fluids influence on macrophage and electrochemical behavior at the cell-solution-metal interface.

In vitro fretting crevice corrosion damage of CoCrMo alloys in phosphate buffered saline: Debris generation, chemistry and distribution.

Fretting crevice corrosion in modular tapers of total hip replacements has become a major concern in orthopedic medical devices. Solid and ionic debris arising from fretting crevice corrosion have been implicated in device failure and revision surgery. This study aims to use a 2D pin-on-disk fretting corrosion test system to visualize damage progression and debris generation during fretting corrosion of CoCrMo alloys in phosphate buffered saline (PBS). The results provide direct evidence of rapid debris generation during fretting corrosion (after only 12 min of testing). Debris was generated and either extruded from the contact region or impacted into adjacent crevice sites as long as fretting continued. After testing, the fretting region consisted of a damaged and plastically deformed contact region surrounded by a halo of fretting debris consisting entirely of oxides and phosphates within the crevice region. Evidence of pitting corrosion and grain boundary corrosion was observed. Solid debris consisted of chromium (Cr), phosphate (P) and oxygen (O). X-ray photoelectron spectroscopy analysis of the near-fretted metal surface area showed a thicker oxygen (O1s) containing film with the depth profile of O1s above 10% penetrating up to 5.75 nm while the O1s concentration on the unfretted area fell to below 10% after 1 nm depth. Ion concentration in the PBS, measured using inductively coupled mass spectrometry, showed cobalt (Co) ions were most prevalent (1.46 ppm) compared to chromium (Cr) (0.07 ppm) and molybdenum (Mo) (0.05 ppm) (p <0.05). All of these results are consistent with the analysis of in vivo modular taper corrosion processes. STATEMENT OF SIGNIFICANCE: CoCrMo alloys has been widely used as a metallic biomaterial for implant devices and can lose their durability and reliability due to wear, corrosion and tribocorrosion. Debris, as one of the major products of these reactions, is associated with implant device failure. In the first time, we developed a fretting corrosion testing system to visualize the debris generation process in real-time between CoCrMo alloy pin and disk samples. Debris was generated rapidly during fretting corrosion and some of the debris egressed from the crevice site while also accumulating within the crevice area as fretting continued. Our study opens a new method for future studies to advance understanding of debris generation processes during wear and tribocorrosion phenomenon.

Screening and Treatment Outcomes in Adults and Children With Type 1 Diabetes and Asymptomatic Celiac Disease: The CD-DIET Study.

OBJECTIVE: To describe celiac disease (CD) screening rates and glycemic outcomes of a gluten-free diet (GFD) in patients with type 1 diabetes who are asymptomatic for CD. RESEARCH DESIGN AND METHODS: Asymptomatic patients (8-45 years) were screened for CD. Biopsy-confirmed CD participants were randomized to GFD or gluten-containing diet (GCD) to assess changes in HbA1c and continuous glucose monitoring over 12 months. RESULTS: Adults had higher CD-seropositivity rates than children (6.8% [95% CI 4.9-8.2%, N = 1,298] vs. 4.7% [95% CI 3.4-5.9%, N = 1,089], P = 0.035) with lower rates of prior CD screening (6.9% vs. 44.2%, P < 0.0001). Fifty-one participants were randomized to a GFD (N = 27) or GCD (N = 24). No HbA1c differences were seen between the groups (+0.14%, 1.5 mmol/mol; 95% CI -0.79 to 1.08; P = 0.76), although greater postprandial glucose increases (4-h +1.5 mmol/L; 95% CI 0.4-2.7; P = 0.014) emerged with a GFD. CONCLUSIONS: CD is frequently observed in asymptomatic patients with type 1 diabetes, and clinical vigilance is warranted with initiation of a GFD.

Sensing Localized Surface Corrosion Damage of CoCrMo Alloys and Modular Tapers of Total Hip Retrievals Using Nearfield Electrochemical Impedance Spectroscopy.

Wear and corrosion damage of biomedical alloys alters the structure and electrochemical properties of the surface heterogeneously. It was hypothesized that local regions on the same surface systematically differ from one another in terms of their impedance characteristics. To test this hypothesis, CoCrMo disks exposed to electrosurgical and inflammatory-species-driven damage were characterized using a localized impedance technique, nearfield electrochemical impedance spectroscopy (NEIS), to assess point-specific surface integrity in response to applied damage. It was found that electrosurgical damage, as may arise during primary arthroplasty and revision surgeries, and hydrogen peroxide concentrations of 5-10 mM significantly alter the corrosion susceptibility of the local surface compared to the as-polished CoCrMo surface. A CoCrMo retrieved neck taper (Goldberg score of 4) was scored in different local regions on the basis of visual appearance, and it was found that there is a direct relationship between increasing debris coverage and decreasing impedance, with the global surface impedance closest to the most severely scored local region. This noninvasive method, which uses a millielectrode configuration to test localized regions, can measure the heterogeneous electrochemical impedance of an implant surface and be tailored to assess specific damage and corrosion mechanisms revealed on retrieval surfaces.

Body mass in adolescents with chronic pain: observational study.

OBJECTIVE: In a paediatric chronic pain population, to determine whether higher body mass was associated with poorer functioning, mood or treatment outcome. DESIGN: Cross-sectional study with examination of treatment outcomes. SETTING: Tertiary specialist adolescent pain rehabilitation unit. PATIENTS: 355 adolescents with relatively severe non-malignant chronic pain. INTERVENTIONS: Intensive 3-week pain rehabilitation programme. MAIN OUTCOME MEASURES: Objective physical measures (walk, sit-to-stand); self-reported functioning and mood RESULTS: Average body mass index (BMI) in the sample was relatively high (24.2 (SD 5.6)) with 20.5% being classified as obese. However, there were no relationships between body mass and objective physical measures, physical or social functioning, depression or anxiety (all p>0.05). There was a small relationship between higher body mass and greater pain-related fear (r=0.17, p<0.01). Treatment improved all variables (p<0.001) apart from pain intensity. There were no relationships between higher body mass and poorer treatment outcome; in fact, patients with higher BMI showed slightly greater decreases in depression (r=0.12, p<0.05) and pain-specific anxiety (r=0.18, p<0.01) during treatment. CONCLUSIONS: Higher body mass does not worsen functioning, mood or treatment response in adolescents with disabling chronic pain. Childhood obesity and chronic pain are both stigmatised conditions; clinicians should avoid implying that high body mass alone is a causal factor in the struggles of a young person with chronic pain.

Fretting initiated crevice corrosion of 316LVM stainless steel in physiological phosphate buffered saline: Potential and cycles to initiation.

Mechanically assisted crevice corrosion (MACC) has been associated with implant failure in vivo and is a serious concern in numerous metallic implant systems. Stainless steel medical devices may be subjected to fretting and crevice corrosion in the human body as are titanium and CoCrMo alloys due to the presence of a passive oxide film on their surface. One mechanism of MACC that has not been clearly identified and studied is fretting-initiated crevice corrosion (FICC) of stainless steel where an initial fretting event can initiate a rapid propagating crevice corrosion process even when fretting has ceased. FICC pin-on-disk experiments were performed at varying potential conditions and duration of fretting to explore the role of potential and fretting duration on the initiation of crevice corrosion. Triggering of a propagating crevice corrosion reaction on stainless steel at 250 mV vs Ag/AgCl/KCl (saturated) in PBS solution required only 2 s (2 cycles at 1 Hz) of fretting. Crevice corrosion continued to propagate under a 1.8 mm diameter pin with only 100 µm of direct contact, dissolving in both the depth and width dimension away from the fretting contact while the currents rose from 0.2 µA to 15 µA within 5 min. Three different potential-dependent FICC regions were identified that included unstable crevice corrosion (50 mV and above), metastable crevice corrosion (-100 mV to 0 mV) and stable fretting corrosion (between -500 mV and -150 mV). Crevice corrosion can be induced by fretting at potentials as low as -100 mV. Below -100 mV, there was no FICC, but rather fretting corrosion stopped immediately after fretting ceased and returned to a stable baseline current. Metastable FICC was shown at potentials between -100 mV and 0 mV, when the crevice corrosion current gradually decreased over several seconds or longer after fretting ceased. Self-sustained, unstable crevice corrosion started at 50 mV, where prior to fretting the currents were low, and after just a few cycles of fretting the crevice current rose rapidly and continued to increase after fretting stopped. Increase of potential increased the susceptibility of stainless steel to FICC. Scanning electron microscopy and digital optical microscopy revealed pitting and crevice corrosion on samples at -100 mV and higher potentials, where FICC was developing. By removing the oxide film, fretting motion significantly facilitates the critical crevice solution development, lowering the critical crevice potential and decreasing the initiation time for crevice corrosion. These results indicate that fretting initiated crevice corrosion may affect the performance of stainless steel in vivo. STATEMENT OF SIGNIFICANCE: AISI 316L stainless steel has been widely used as a metallic biomaterial for orthopaedic, spinal, dental and cardiovascular implants. Crevice corrosion has been a serious concern for stainless steel implants. For the first time we demonstrated and systematically studied the process of fretting-initiated crevice corrosion (FICC) in 316L stainless steel in simulated physiological solution of phosphate buffered saline. By removing the oxide film, fretting motion significantly facilitates the critical crevice solution development, lowering the critical crevice potential and decreasing the initiation time for crevice corrosion. Our findings indicate fundamental differences between the FICC mechanism and conventional crevice corrosion theory, showing that fretting can play a significant role in the initiation of crevice corrosion of stainless steel.

How Effective Is the Multidisciplinary Team Approach in Bariatric Surgery?

BACKGROUND: Multidisciplinary team (MDT) meetings are widely recommended in the management of bariatric surgery patients; however, there is limited evidence for their effectiveness. The aims of this study were to evaluate the decision-making process of a single-day bariatric MDT clinic and secondly to evaluate whether these MDT decisions were implemented. METHODS: This was a retrospective observational study analysing MDT treatment decisions from February 2012 to June 2013 using an MDT proforma. The decision-making process of the MDT meeting was investigated by assessing the alterations in management plan between the surgeon and the rest of the MDT. Adherence to MDT decisions was also assessed. RESULTS: Decisions regarding 200 consecutive patients were analyzed. There was MDT agreement for 55%, and patients were listed for surgery on the day of the MDT. There was MDT disagreement regarding 45%, with conflicting opinions expressed by surgeons in 33/200 (17%), anaesthetists in 60/200 (30%) and dieticians in 65/200 (33%). The MDT plan was instigated in 78% and the most common reason for failure was patients failing to attend for further assessment. By the end of the study, 85% of patients underwent bariatric surgery, 11.5% declined further input, 2.5% chose further weight loss and 1% were removed from waiting list. CONCLUSION: Use of a single-day MDT clinic format resulted in a change in plan for a significant number of patients. This can be interpreted as improved quality of care for these patients, and we conclude the MDT approach is valuable.

Electrochemical potential zone of viability on CoCrMo surfaces is affected by cell type: Macrophages under cathodic bias are more resistant to killing.

Electrochemical interactions at the cell-metal interface determine cell viability and influence behavior in response to different electrode potential conditions, specifically cathodic biases. Mechanically assisted crevice corrosion, for example, induces cathodic potentials and the associated electrochemical consequences of increased reduction reactions at the implant surface may affect cell viability in a manner that is different for various cell phenotypes. Monocyte macrophage-like U937 cells were cultured on cobalt-chromium-molybdenum (CoCrMo) metal surfaces in vitro for 24 h to assess cell behavior in response to sustained applied voltages. The electrochemical zone of viability for U937 cells polarized for 24 h in vitro was -1000 ≤ mV < +500, compared to -400 < mV < +500 for MC3T3-E1 preosteoblast-like cells cultured under the same conditions, likely as a result of intrinsic apoptosis. Voltages above +250 mV had a lethal effect on U937 cells that was similar to that seen previously for MC3T3-E1 cells on biased CoCrMo surfaces. It appears that cell phenotype directly influences behavior in response to cathodic electrochemical stimuli and that the monocyte macrophage-like cells are more resistant to cathodic potential stimuli than preosteoblasts. This may be due to a glutathione-based increased ability to quench reactive oxygen species and inflammatory-associated radicals hypothesized to be generated during reduction of oxygen. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 526-534, 2019.

In vitro cytotoxicity of galvanically coupled magnesium-titanium particles on human osteosarcoma SAOS2 cells: A potential cancer therapy.

Osteosarcoma is a malignant bone cancer that occurs mostly in children and young adults. This study investigated the cytotoxicity of Mg and Mg-Ti microparticles to human osteosarcoma cells. Osteosarcoma cells were killed in a dosage-dependent manner when cells, with a cell seeding density of 30,000 cells/cm2 , were cultured with 0 to 2500 µg/mL of Mg or Mg-Ti in cell culture media for 24-72 h. Mg-Ti killed cells more effectively, where 1250 µg/mL of Mg-Ti killed cells completely by 24 h, while 2500 µg/mL of Mg killed nearly all cells, but not all. Killing due to particle corrosion occurred mostly during the first 24 h, and so the percent cell viability between 24 and 72 h showed not much variability. However, the measurement of live and dead cell numbers, over the timeframe of 24-72 h, showed more insight, such as cell recovery. If particle concentrations were low, the number of live cells increased after 24 h, indicating cell proliferation. If particle concentrations were high, the number of live cells either remained steady or decreased, indicating cell quiescence or continued killing, respectively. Increase in the number of dead cells also indicated killing, while plateau meant discontinued killing. In addition, repeated killing of recovered cells exhibited the same dose-dependent killing profile as the initial experiment, implying little development of cell resistance to treatment. These results, together, show that osteosarcoma cells are susceptible to killing by way of exposure to corroding particles, showing highly effective killing using the galvanic couple of Mg-Ti. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 178-189, 2019.

Clinical trials from the patient perspective: survey in an online patient community.

BACKGROUND: Developing new medicines relies on the successful conduct of clinical trials. As trial protocols become more arduous, it becomes harder to recruit and retain patient volunteers, although recent efforts such as OMERACT and I-SPY2 show that partnering with patients can be beneficial. We sought to describe drivers and barriers to trial participation, as well as condition-specific trial preferences. METHODS: An online survey was fielded via the patient-powered research network PatientsLikeMe to 1,621 members living with nine selected chronic health conditions. Questions included demographics, trial experience, reasons for non-participation, questions relating to aspects of trial design, and an adaptation of the Net Promoter Score (NPS) for trial satisfaction. RESULTS: Mean age of respondents was 55 years; most patients were white (93%), female (67%), and living in the United States (72%). Primary conditions were MS (21%), Parkinson's (20%), fibromyalgia (15%), ALS (10%), type 2 diabetes (10%), rheumatoid arthritis (RA, 8%), epilepsy (8%), major depressive disorder (MDD, 5%) and systemic lupus erythematosus (SLE, 3%). Most patients had not discussed a trial with their physician and only 21% had ever enrolled, with rates highest in ALS (36%), Parkinson's disease (36%) and MS (20%) and lowest among SLE (9%), MDD (11%) and Fibromyalgia (11%). Common reasons for non-participation were eligibility criteria, inconvenience of travel and concerns about side effects. NPS suggested that many patients were unsatisfied; patients with lupus, epilepsy, RA, and fibromyalgia reported negative scores, i.e. they would dissuade other patients like them from taking part in trials. The most important considerations in trial participation were the opportunity to improve one's own health and that of others, the reputation of the institution, and having medical bills covered in case of injury. Least important were remuneration and possibility of receiving a placebo. ALS patients were more willing to tolerate undesirable aspects of trials. CONCLUSIONS: Most patients are willing to enroll yet very few are invited. When they do, trial participation is often burdensome, but patients are willing to help improve their design. Researchers should let patients help design better trials to overcome recruitment and retention issues and hasten the development of new medicines.

SGLT2 Inhibitor-associated Diabetic Ketoacidosis: Clinical Review and Recommendations for Prevention and Diagnosis.

PURPOSE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of antihyperglycemic agents available on the market. Regulator warnings and concerns regarding the risk of developing diabetic ketoacidosis (DKA), however, have dampened enthusiasm for the class despite the combined glycemic, blood pressure, and occasional weight benefits of SGLT2 inhibitors. With the goal of improving patient safety, a cross-Canada expert panel and writing group were convened to review the evidence to-date on reported SGLT2 inhibitor-related DKA incidents and to offer recommendations for preventing and recognizing patients with SGLT2 inhibitor-associated DKA. METHODS: Reports covering DKA events in subjects taking SGLT2 inhibitors that were published in PubMed, presented at professional conferences, or in the public domain from January 2013 to mid-August 2016 were reviewed by the group independently and collectively. Practical recommendations for diagnosis and prevention were established by the panel. FINDINGS: DKA is rarely associated with SGLT2 inhibitor therapy. Patients with SGLT2 inhibitor-associated DKA may be euglycemic (plasma glucose level <14 mmol/L). DKA is more likely in patients with insulin-deficient diabetes, including those with type 2 diabetes, and is typically precipitated by insulin omission or dose reduction, severe acute illness, dehydration, extensive exercise, surgery, low-carbohydrate diets, or excessive alcohol intake. SGLT2 inhibitor-associated DKA may be prevented by withholding SGLT2 inhibitors when precipitants develop, avoiding insulin omission or inappropriate insulin dose reduction, and by following sick day protocols as recommended. IMPLICATIONS: Preventive strategies should help avoid SGLT2 inhibitor-associated DKA. All SGLT2 inhibitor-treated patients presenting with signs or symptoms of DKA should be suspected to have DKA and be investigated for DKA, especially euglycemic patients. If DKA is diagnosed, SGLT2 inhibitor treatment should be stopped, and the DKA should be treated with a traditional treatment protocol.

Ceramic Heads Decrease Metal Release Caused by Head-taper Fretting and Corrosion.

BACKGROUND: Metal release resulting from taper fretting and corrosion is a clinical concern, because wear and corrosion products may stimulate adverse local tissue reactions. Unimodular hip arthroplasties have a conical taper between the femoral head (head bore taper) and the femoral stem (stem cone taper). The use of ceramic heads has been suggested as a way of reducing the generation of wear and corrosion products from the head bore/stem cone taper junction. A previous semiquantitative study found that ceramic heads had less visual evidence of fretting-corrosion damage compared with CoCr heads; but, to our knowledge, no studies have quantified the volumetric material loss from the head bore and stem cone tapers of a matched cohort of ceramic and metal heads. QUESTIONS/PURPOSES: We asked: (1) Do ceramic heads result in less volume of material loss at the head-stem junction compared with CoCr heads; (2) do stem cone tapers have less volumetric material loss compared with CoCr head bore tapers; (3) do visual fretting-corrosion scores correlate with volumetric material loss; and (4) are device, patient, or intraoperative factors associated with volumetric material loss? METHODS: A quantitative method was developed to estimate volumetric material loss from the head and stem taper in previously matched cohorts of 50 ceramic and 50 CoCr head-stem pairs retrieved during revision surgery for causes not related to adverse reactions to metal particles. The cohorts were matched according to (1) implantation time, (2) stem flexural rigidity, and (3) lateral offset. Fretting corrosion was assessed visually using a previously published four-point, semiquantitative scoring system. The volumetric loss was measured using a precision roundness machine. Using 24 equally spaced axial traces, the volumetric loss was estimated using a linear least squares fit to interpolate the as-manufactured surfaces. The results of this analysis were considered in the context of device (taper angle clearance, head size, head offset, lateral offset, stem material, and stem surface finish) and patient factors that were obtained from the patients' operative records (implantation time, age at insertion, activity level, and BMI). RESULTS: The cumulative volumetric material losses estimated for the ceramic cohort had a median of 0.0 mm(3) per year (range, 0.0-0.4 mm(3)). The cumulative volumetric material losses estimated for the CoCr cohort had a median of 0.1 mm(3) per year (range, 0.0-8.8 mm(3)). An order of magnitude reduction in volumetric material loss was found when a ceramic head was used instead of a CoCr head (p < 0.0001). In the CoCr cohort, the femoral head bore tapers had a median material loss of 0.02 mm(3) (range, 0.0-8.7 mm(3)) and the stem cone tapers had a median material loss of 0.0 mm(3) (range, 0.0-0.32 mm(3)/year). There was greater material loss from femoral head bore tapers compared with stem cone tapers in the CoCr cohort (p < 0.001). There was a positive correlation between visual scoring and volumetric material loss (Spearman's ρ = 0.67, p < 0.01). Although visual scoring was effective for preliminary screening to separate tapers with no or mild damage from tapers with moderate to severe damage, it was not capable of discriminating in the large range of material loss observed at the taper surfaces with moderate to severe fretting-corrosion damage, indicated with a score of 3 or 4. We observed no correlations between volumetric material loss and device and patient factors. CONCLUSIONS: The majority of estimated material loss from the head bore-stem cone junctions resulting from taper fretting and corrosion was from the CoCr head bore tapers as opposed to the stem cone tapers. Additionally, the total material loss from the ceramic cohort showed a reduction in the amount of metal released by an order of magnitude compared with the CoCr cohort. CLINICAL RELEVANCE: We found that ceramic femoral heads may be an effective means by which to reduce metal release caused by taper fretting and corrosion at the head bore-stem cone modular interface in THAs.

Cytotoxic effect of galvanically coupled magnesium-titanium particles.

Recent work has shown that reduction reactions at metallic biomaterial surfaces can induce significant killing of cells in proximity to the surface. To exploit this phenomenon for therapeutic purposes, for example, for cancer tumor killing or antibacterial effects (amongst other applications), magnesium metal particles, galvanically coupled to titanium by sputtering, have been evaluated for their cell-killing capability (i.e. cytotoxicity). Magnesium (Mg) particles large enough to prevent particle phagocytosis were investigated, so that only electrochemical reactions, and not particle toxicity per se, caused cytotoxic effects. Titanium (Ti) coated magnesium particles, as well as magnesium-only particles were introduced into MC3T3-E1 mouse pre-osteoblast cell cultures over a range of particle concentrations, and cells were observed to die in a dosage-dependent manner. Ti-coated magnesium particles killed more cells at lower particle concentration than magnesium alone (P<0.05), although the pH measured for magnesium and magnesium-titanium had no significant difference at similar particle concentrations. Complete cell killing occurred at 750µg/ml and 1500µg/ml for Mg-Ti and Mg, respectively. Thus, this work demonstrates that galvanically coupled Mg-Ti particles have a significant cell killing capability greater than Mg alone. In addition, when the pH associated with complete killing with particles was created using NaOH only (no particles), then the percentage of cells killed was significantly less (P<0.05). Together, these findings show that pH is not the sole factor associated with cell killing and that the electrochemical reactions, including the reduction reactions, play an important role. Reduction reactions on galvanically coupled Mg-Ti and Mg particles may generate reactive oxygen intermediates that are able to kill cells in close proximity to the particles and this approach may lead to potential therapies for infection and cancer. STATEMENT OF SIGNIFICANCE: This paper demonstrates that during active corrosion of both Mg and Mg-Ti particles cells cultured with the particles are killed in a dose-dependent particle concentration fashion. Additionally, galvanically-coupled magnesium-titanium microparticles kill cells more effectively than magnesium particles alone. The killing effect was shown to not be due to pH shifts since no differences were seen for different particle types and pH adjusted medium without particles did not exhibit the same level of killing. The significance of this work is the recognition of this killing effect with Mg particles and the potential therapeutic applications in infection control and cancer treatment that this process may provide.

The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) protocol: a randomised controlled study to evaluate treatment of asymptomatic coeliac disease in type 1 diabetes.

INTRODUCTION: Coeliac disease (CD) is an autoimmune condition characterised by gluten-induced intestinal inflammation, and observed at a 5-10 fold greater prevalence in type 1 diabetes. While universal screening for CD in patients with diabetes is frequently advocated, objective data is limited as to benefits on diabetes control, bone health or quality of life related to the adoption of a gluten-free diet (GFD) in the large proportion of patients with diabetes with asymptomatic CD. The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) study is a multicenter, randomised controlled trial to evaluate the efficacy and safety of a GFD in patients with type 1 diabetes with asymptomatic CD. METHODS AND ANALYSIS: Children and adults (8-45 years) with type 1 diabetes will be screened for asymptomatic CD. Eligible patients with biopsy-proven CD will be randomly assigned in a 1:1 ratio to treatment with a GFD for 1 year, or continue with a gluten-containing diet. The primary outcome will evaluate the impact of the GFD on change in glycated haemoglobin. Secondary outcomes will evaluate changes in bone mineral density, blood glucose variability and health-related quality of life between GFD-treated and the regular diet group over a 1-year period. The study was initiated in 2012 and has subsequently expanded to multiple paediatric and adult centres in Ontario, Canada. ETHICS AND DISSEMINATION: The findings from this study will provide high-quality evidence as to the impact of GFD treatment on glycaemic control and complications in asymptomatic children and adults with CD and type 1 diabetes. TRIAL REGISTRATION NUMBER: NCT01566110.

A systematic review of randomized controlled trials for management of persistent post-treatment fatigue in thyroid cancer survivors.

BACKGROUND: Fatigue that persists post-treatment is commonly reported by thyroid cancer (TC) survivors. METHODS: A systematic review of published English language randomized controlled trials (RCTs) on interventions for management of persistent post-treatment fatigue in TC was conducted. This review excluded studies on short-term interventions used in preparation for radioactive iodine diagnostic scans or treatment. An electronic search was executed in six databases and supplemented by a hand search. Two reviewers independently reviewed all citations from the electronic search and relevant full-text studies. Two abstractors independently critically appraised included studies and abstracted the data. The data were qualitatively summarized. RESULTS: A total of 1086 unique citations and 25 full-text studies were reviewed. Four studies summarizing the results of three RCTs were included. The interventions included: combination triiodothyronine with levothyroxine (L-T4) therapy compared to L-T4 alone (one RCT), reduction in degree of thyrotropin (TSH) suppression using L-T4 compared to maintenance of TSH suppression (one RCT), and supervised exercise compared to inactivity (two RCTs examining different fatigue outcomes in same population). Trial duration ranged from 10 weeks to six months. All trials had limitations, and the number of TC survivors included in respective RCTs ranged from 15 to 36. Hormonal treatment RCTs had mixed fatigue outcome results within respective trials. However, multiple measures suggesting improvement in fatigue were reported following the exercise intervention. CONCLUSIONS: There is paucity of RCTs to guide evidence-based management of persistent post-treatment fatigue in TC survivors. RCTs of interventions for prevention or treatment of fatigue in TC survivors are needed.

Modern trunnions are more flexible: a mechanical analysis of THA taper designs.

BACKGROUND: There is renewed concern surrounding the potential for corrosion at the modular head-neck junction to cause early failure in contemporary THAs. Although taper corrosion involves a complex interplay of many factors, a previous study suggested that a decrease in flexural rigidity of the femoral trunnion may be associated with an increased likelihood of corrosion at retrieval. QUESTIONS/PURPOSES: By analyzing a large revision retrieval database of femoral stems released during a span of three decades, we asked: (1) how much does flexural rigidity vary among different taper designs; (2) what is the contribution of taper geometry alone to flexural rigidity of the femoral trunnion; and (3) how have flexural rigidity and taper length changed with time in this group of revised retrievals? METHODS: A dual-center retrieval analysis of 85 modular femoral stems released between 1983 and 2012 was performed, and the flexural rigidity and length of the femoral trunnions were determined. These stems were implanted between 1991 and 2012 and retrieved at revision or removal surgery between 2004 and 2012. There were 10 different taper designs made from five different metal alloys from 16 manufacturers. Digital calipers were used to measure taper geometries by two independent observers. RESULTS: Median flexural rigidity was 228 N-m(2); however, there was a wide range of values among the various stems spanning nearly an order of magnitude between the most flexible (80 N-m(2)) and most rigid (623 N-m(2)) trunnions, which was partly attributable to the taper geometry and to the material properties of the base alloy. There was a negative correlation between flexural rigidity and length of the trunnion and release date of the stem. CONCLUSIONS: There is wide variability in flexural rigidity of various taper designs, with a trend toward trunnions becoming shorter and less rigid with time. CLINICAL RELEVANCE: This temporal trend may partly explain why taper corrosion is being seen with increasing frequency in modern THAs.