3D Printing Adjustable Stiffness External Fixator for Mechanically Stimulated Healing of Tibial Fractures

External fixation is a long-standing but well-established method, which has been widely used for the treatment of fractures. To obtain the maximum benefit from the mechanical stimulus, the stiffness of the external fixator should be adjusted properly throughout the treatment phase. Nevertheless, the lack of a valid dynamic adjustable fixation device impedes this possibility. Based on the stiffness adjustment tolerance of the healing callus, this paper proposes an active-dynamic stiffness adjustable external fixator design method to meet stiffness requirements at different stages of the tibial fracture healing process. A novel external fixator with an adjustable stiffness configuration was designed, and the finite element method was used to simulate the stress distribution between fixator and fracture gap. The stiffness adjustment tolerance was determined based on previous studies. According to this tolerance, the optimal block structure dismantling sequence was sought and the corresponding stiffness was calculated through topology optimization for the entire external fixator model. The appropriate amount of variable stiffness at the fracture gap was applied by dismantling the configuration of the block structure external fixator during the healing process. A novel patient-specific adjustable stiffness external fixator for mechanically stimulated tibial fracture reduction and therapy was proposed. This enables surgeons to tailor the construction of the external fixator frame to the clinical needs of each patient. The presented dismantling approach of the block structure to produce conformable stiffness provides a new clinical treatment strategy for tibial fractures.

Efficient Fuzzy Image Stretching for Automatic Ganglion Cyst Extraction Using Fuzzy C-Means Quantization

Ganglion cysts are commonly observed in association with the joints and tendons of the appendicular skeleton. Ultrasonography is the favored modality used to manage such benign tumors, but it may suffer from operator subjectivity. In the treatment phase, ultrasonography also provides guidance for aspiration and injection, and the information regarding the accurate location of the pedicle of the ganglion. Thus, in this paper, we propose an automatic ganglion cyst extracting method based on fuzzy stretching and fuzzy C-means quantization. The proposed method, with its carefully designed image-enhancement policy, successfully detects ganglion cysts in 86 out of 90 cases (95.6%) without requiring human intervention.

Long term exposure of human gut microbiota with high and low emulsifier sensitivity to soy lecithin in M-SHIME model.

In the context of the potential health hazards related to food processing, dietary emulsifiers have been shown to alter the structure and function of the gut microbial community, both in vivo and in vitro. In mouse models, these emulsifier exposed gut microbiota were shown to contribute to gut inflammation. Several knowledge gaps remain to be addressed though. As such, the impact from a longer timeframe of exposure on the gut microbiota is not known and interindividual variability in microbiome response needs to be measured. To answer these research questions, in this study the faecal microbiota from two individuals, previously selected for high and low emulsifier sensitivity, were exposed to two concentrations of soy lecithin during a 7 day treatment phase in the dynamic mucosal simulator of the human intestinal microbial ecosystem (M-SHIME). The results showed mild effects from soy lecithin on the composition and functionality of these microbial communities, which depended on the original microbial composition. The effects also mostly levelled off after 3 days of exposure. The emulsifier sensitivity for which the microbiota were selected, was preserved. Some potentially concerning effects were also registered: butyrate levels, positively correlating with Faecalibacterium abundance, were lowered by soy lecithin. Also the abundance of the beneficial Bifidobacterium genus was lowered, while the abundance of the notorious unclassified Enterobacteriaceae was increased. Within the family of the unclassified Lachnospiraceae, several genera were either suppressed or stimulated. The effects that these microbial alterations would have on a living host is not yet certain, especially given the fact that large fractions of soy lecithins constituents can be absorbed. Nevertheless, choline and phosphatidylcholine, both primary and absorbable constituents of soy lecithin, have recently been linked to cardiovascular disease via the generation of TMA by the gut microbiota. Further studies that validate our findings and link them to potential health outcomes are thus justified.

ADULT SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS – A CASE SERIES

Hemophagocytic lymphohistiocytosis is a hyper-inammatory condition that is either Familial (Primary) or Secondary to autoimmune diseases , infection, malignancy or other triggers.It is a cytokine storm syndrome where there inefcient antigen removal that leads to sustained cytokine release.It is a rare phenomenon occuring in adults that has got a specic trigger which is less documented and have a good response to steroids where as Familial form is a childhood disease due to genetic defects, both of which are life threatening and may need Allogenic bone marrow transplant. Macrophage activation syndrome is also a subtype of this entity that occurs in the treatment phase of SLE and Still's disease.We describe here 8 cases of secondary HLH, their primary triggers and treatment response.

Evaluation of NLRP3 and IL-18 Levels after Periodontal Therapy

The progression of periodontitis depends on interactions between the periodontal pathogens and the host immune cytokines, including interleukin (IL)-1β and IL-18. Production of IL-1β is regulated by NOD-like receptors family pyrin domain containing 3 (NLRP3). This study aimed to evaluate the effect of periodontal treatment on the concentrations of IL-18 and NLRP3 in patients with chronic periodontitis. In this experimental study, 18 patients with chronic periodontitis and a mean age of 46.2±8.95 years, were included. The gingival crevicular fluid (GCF) was collected at the beginning of the study, 4 weeks after non-surgical (phase I), and 4 weeks after surgical periodontal treatment. The levels of NLRP3 and IL-18 were measured; using an enzyme-linked immunosorbent assay. Pearson correlation test was used to analyze the concentration of NLRP3 and IL-18 before and after the treatments with CAL and PD. There was a significant association between the level of NLRP3 and the mean values of PD and CAL before treatment. After each treatment phase, a significant decrease was observed in the NLRP3 level. There was no significant relationship between IL-18 and clinical parameters before and after periodontal treatments. Given the possible association between the level of NLRP3 and clinical parameters, we suggest it as a possible indicator of inflammation in chronic periodontitis and an index for evaluating the treatment outcome.

Strategies to Mitigate the Challenges of Short Circuiting in Waterflood Reservoirs with Tracers: A Case Study

Water short circuiting leading to early, sudden and massive water breakthroughs in producer wells has been a lingering concern to oil operators for many years. Unfavorable mobility ratio leading to viscous fingering, horizontal wells exhibiting ‘the heel-toe effect’ and fields with fracture-fault activities are more prone to these kinds of unwanted water breakthroughs, suffering from oil production losses and higher operational cost for management of the excessive produced water. A brown field in the south of the Sultanate of Oman was experiencing massive water short circuiting within two of its patterns. [MJO1]While conformance was well established and dynamically confirmed through production performance and artificial lift parameters in most patterns within the field, the complicated inverted nine spot injector-producer pattern scenario[MJO2] was making it difficult to ascertain the offending injectors or unexpected flow paths leading to the condition within the study area. The lower API oil and slightly fractured and faulted geology was exhibiting conditions for injection imbalance and the challenge was to bring the high water-cut wells back to full potential and increase oil output whilst reducing water flow. To investigate the breakthrough occurrences and mitigate the challenge, chemical water tracers were introduced in the reservoir as a part of Integrated Reservoir Management framework to identify flow directions and offending injectors. The Phase-1 of the two-phase study, discussed in this paper, was carried out to determine reservoir conformance that was contributing to short circuiting and once the cause was identified and treated, Phase-2 was carried out post well intervention to validate the success of the treatment. Phase-1 of the tracer study was initiated in October 2019 where two injectors and nineteen producers across two adjacent patterns were traced with two unique chemical water tracers. Massive tracer responses were obtained within the first few days in few wells, directly pointing out towards the offending injector(s). Sampling and analysis for Phase-1 was continued for about six months, after which, a zonal isolation was carried out in one the identified injectors in August 2020. Cement was pumped across all the perforation intervals and a new perforation was performed across the top and bottom of the reservoir avoiding the middle intervals that were taking about 70% of injection as per production logging. Phase-2 of the study was initiated in March 2021 and continued sampling and analyses are still being carried out. With about 15% reduction in water cut and a three-fold increase in oil rate at the target producer, the study validated that an integrated knowledge of reservoir geology and production behavior coupled with tracer studies was a very successful strategy for managing short circuiting in waterflood reservoirs. The study showed that this sequence and combination of methods can be useful in effective treatment for wells experiencing high water cut across the world.

SGLT2 Inhibition Increases Fasting Glucagon but Does Not Restore the Counterregulatory Hormone Response to Hypoglycemia in Participants with Type 1 Diabetes

Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (<i>n</i> = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin versus placebo, with a median within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did not correlate with decreased rates of hypoglycemia, and thus do not appear to be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2 inhibition did not change counterregulatory hormone concentrations, time to recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus, despite raising basal glucagon concentrations, SGLT inhibitor treatment did not restore the impaired glucagon response to hypoglycemia. We propose that clinical reduction in hypoglycemia associated with these agents is a result of changes in diabetes care (e.g., lower insulin doses or improved glycemic variability) as opposed to a direct, physiologic effect of these medications on alpha cell function.

SGLT2 Inhibition Increases Fasting Glucagon but Does Not Restore the Counterregulatory Hormone Response to Hypoglycemia in Participants with Type 1 Diabetes

Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (<i>n</i> = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin versus placebo, with a median within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did not correlate with decreased rates of hypoglycemia, and thus do not appear to be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2 inhibition did not change counterregulatory hormone concentrations, time to recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus, despite raising basal glucagon concentrations, SGLT inhibitor treatment did not restore the impaired glucagon response to hypoglycemia. We propose that clinical reduction in hypoglycemia associated with these agents is a result of changes in diabetes care (e.g., lower insulin doses or improved glycemic variability) as opposed to a direct, physiologic effect of these medications on alpha cell function.

Evaluation of a Clinical Pathway for Thyroid Nodular Disease: Timings and Delays in the Diagnosis and Treatment of Thyroid Cancer

Background: Due to the high prevalence of nodular thyroid disease in the general population and the need to rule out malignant tumours, a clinical pathway for nodular thyroid disease was created at our tertiary-level hospital. Our study aimed to quantify timings and delays in diagnosis and treatment in this clinical pathway, specifically for patients who were diagnosed with thyroid cancer. Methods: A retrospective review was conducted of patients who were newly diagnosed with thyroid cancer and who had been previously evaluated in the clinical pathway for nodular thyroid disease at our institution during 2015–2017. Patient demographics, previous diagnostic studies, cytological results, tumour details and key dates were analysed to identify wait times in diagnosis and treatment. Results: Forty patients with thyroid cancer were included. The diagnostic delay had a median time of 60 days, and the treatment delay was dependent on cytopathological results. The main cause for delay in the diagnostic phase was the timing of the thyroid ultrasound performed by the radiology department. In the treatment phase, patients with a cytological result of Bethesda III, V or VI underwent surgery at the suggested time, while those in the Bethesda II or IV category did not. Conclusions: The major delay found in the diagnostic phase was the timing of the thyroid ultrasound performed by the radiology department. We are not suggesting that this step must be eliminated, though the implementation of routine ultrasonography in a thyroid clinic can help identify patients who need more urgent evaluation for fine needle aspiration cytology. In our hospital, decision for surgery is based mainly on the cytopathological report. Imaging studies and/or molecular testing could be considered to reduce treatment delays.

New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia

IntroductionChagas disease (CD) affects ~7 million people worldwide. Benznidazole (BZN) and nifurtimox (NFX) are the only approved drugs for CD chemotherapy. Although both drugs are highly effective in acute and paediatric infections, their efficacy in adults with chronic CD (CCD) is lower and variable. Moreover, the high incidence of adverse events (AEs) with both drugs has hampered their widespread use. Trials in CCD adults showed that quantitative PCR (qPCR) assays remain negative for 12 months after standard-of-care (SoC) BZN treatment in ~80% patients. BZN pharmacokinetic data and the nonsynchronous nature of the proliferative mammal-dwelling parasite stage suggested that a lower BZN/NFX dosing frequency, combined with standard or extended treatment duration, might have the same or better efficacy than either drug SoC, with fewer AEs.Methods and analysisNew ThErapies and Biomarkers for ChagaS infEctiOn (TESEO) is an open-label, randomised, prospective, phase-2 clinical trial, with six treatment arms (75 patients/arm, 450 patients). Primary objectives are to compare the safety and efficacy of two new proposed chemotherapy regimens of BZN and NFX in adults with CCD with the current SoC for BZN and NFX, evaluated by qPCR and biomarkers for 36 months posttreatment and correlated with CD conventional serology. Recruitment of patients was initiated on 18 December 2019 and on 20 May 2021, 450 patients (study goal) were randomised among the six treatment arms. The treatment phase was finalised on 18 August 2021. Secondary objectives include evaluation of population pharmacokinetics of both drugs in all treatment arms, the incidence of AEs, and parasite genotyping.Ethics and disseminationThe TESEO study was approved by the National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), federal regulatory agency of the Plurinational State of Bolivia and the Ethics Committees of the participating institutions. The results will be disseminated via publications in peer-reviewed journals, conferences and reports to the NIH, FDA and participating institutions.Trial registration numberNCT03981523.