Immune cell activity during anti-TNF treatment in patients with psoriasis and psoriatic arthritis.

Psoriasis is a chronic, inflammatory skin disease characterized by a dysregulated immune response and systemic inflammation. Up to one-third of patients with psoriasis have psoriatic arthritis (PsA). Targeted treatment with antibodies neutralizing tumor necrosis factor (TNF) can ameliorate both diseases. We here explored the impact of long-term infliximab treatment on the composition and activity status of circulating immune cells involved in chronic skin and joint inflammation. Immune cells were analyzed by multicolor flow cytometry. We measured markers of immune activation in peripheral blood mononuclear cell (PBMC) populations in 24 infliximab-treated patients with psoriasis/psoriatic arthritis compared to 32 healthy controls. We observed a significant decrease in the frequency of both peripheral natural killer (NK) cells and their subset CD56dimCD16+ NK cells in PsA compared to healthy controls and patients with psoriasis. The latter had a strong positive correlation with PASI in these patients, while CD56brightCD16- NK cells were negatively correlated with PASI. In addition, we observed an upregulation of CD69+ intermediate CD14+CD16+ and CD69+ classical CD14+CD16- monocytes in PsA and increased activity of CD38+ intermediate CD14+CD16+ monocytes in patients with psoriasis. Compared to healthy controls, psoriasis patients demonstrated shifts of the three B cell subsets with a decrease in transitional CD27-CD38high B cells. Our exploratory study indicates a preserved pathophysiological process including continuous systemic inflammation despite clinical stability of the patients treated with infliximab.

Many unreported crop pests and pathogens are probably already present.

Invasive species threaten global biodiversity, food security and ecosystem function. Such incursions present challenges to agriculture where invasive species cause significant crop damage and require major economic investment to control production losses. Pest risk analysis (PRA) is key to prioritize agricultural biosecurity efforts, but is hampered by incomplete knowledge of current crop pest and pathogen distributions. Here, we develop predictive models of current pest distributions and test these models using new observations at subnational resolution. We apply generalized linear models (GLM) to estimate presence probabilities for 1,739 crop pests in the CABI pest distribution database. We test model predictions for 100 unobserved pest occurrences in the People's Republic of China (PRC), against observations of these pests abstracted from the Chinese literature. This resource has hitherto been omitted from databases on global pest distributions. Finally, we predict occurrences of all unobserved pests globally. Presence probability increases with host presence, presence in neighbouring regions, per capita GDP and global prevalence. Presence probability decreases with mean distance from coast and known host number per pest. The models are good predictors of pest presence in provinces of the PRC, with area under the ROC curve (AUC) values of 0.75-0.76. Large numbers of currently unobserved, but probably present pests (defined here as unreported pests with a predicted presence probability >0.75), are predicted in China, India, southern Brazil and some countries of the former USSR. We show that GLMs can predict presences of pseudoabsent pests at subnational resolution. The Chinese literature has been largely inaccessible to Western academia but contains important information that can support PRA. Prior studies have often assumed that unreported pests in a global distribution database represent a true absence. Our analysis provides a method for quantifying pseudoabsences to enable improved PRA and species distribution modelling.

Achilles Tendon Reconstruction With Bone Block Allograft:Long-Term Follow-Up of Two Cases.

The treatment of neglected or chronically ruptured Achilles tendon is challenging. Various treatments for large defects associated with chronic Achilles ruptures have been described. Many surgeons recommend the use of a tendon transfer, turndown rotational flap, advancement flap, or reconstruction with Achilles tendon allograft with calcaneal bone block. Long-term outcomes of these procedures are unknown. We present 2 cases with the use of an Achilles tendon with calcaneus bone block allograft. At >8-year follow-up duration, both patients are afforded satisfactory levels of activity and are without pain or gait disturbance. This procedure is a viable option for Achilles ruptures with large defects, ruptures with small intact distal tendon portions, or re-ruptures of previously repaired Achilles tendons. The long-term outcomes of these case reports suggest that Achilles tendon reconstruction with bone block allograft is a viable option.

Isolated sphenoid sinus opacification: A systematic review.

OBJECTIVE: Unilateral sphenoid sinus opacification (SSO) on imaging is a common incidental radiologic finding. Inflammatory sinus disease is rarely isolated to one sinus cavity therefore SSO raises the potential for neoplastic etiology. The clinical significance of SSO was evaluated and compared to maxillary sinus opacification (MSO). METHODS: A systematic review of unilateral sinus opacification was performed via Medline (1966-January 12th, 2015) and Embase (1980-January 12th, 2015), limited to English literature and human subjects. Case series of patients treated with radiologic evidence of unilateral sinus opacification either from maxillary or sphenoid sinuses and with pathology results were included. Individual cases were classified as neoplastic, malignant, or a condition requiring surgical intervention (i.e. fungal ball). Exclusion criteria were single case reports, lack of primary data, series of complications, or single pathology series. Case-by-case analysis was performed for both SSO and MSO. RESULTS: Search strategy revealed 3264 studies. A total of 31 studies including 1581 patients met the inclusion criteria. In these studies, SSO was described in n=1215 (76.9%) and MSO in n=366 (23.1%). For SSO, the final diagnosis was neoplasia 18%, (malignancy in 10.9%). 58.3% of cases required surgical intervention and 13% were inflammatory. For MSO, neoplasia represented 18.3% (malignancy 7.1%), surgical intervention required in 47% of cases and 27.6%. were inflammatory. CONCLUSION: Isolated MSO and SSO is a marker of neoplasia in 18% and malignancy in 7-10% of patients presenting with these radiologic findings. Clinicians should be wary of conservative management given the high incidence of neoplasia and consider a lower threshold for early surgical intervention.

Intermediate- to Long-Term Longevity and Incidence of Revision of the Modified Broström-Gould Procedure for Lateral Ankle Ligament Repair: A Systematic Review.

The Broström-Gould procedure is an effective procedure for chronic lateral ankle instability. However, long-term studies are limited, and the durability of this procedure remains unclear. A systematic review of the published data was undertaken to determine the outcomes and incidence of revision after long-term follow-up. Eleven studies involving 669 Broström-Gould procedures met the inclusion criteria. The revision rate was 1.2% at a weighted mean follow-up period of 8.4 years. Our systematic review of the available data revealed that the Broström-Gould procedure results in low revision rates for chronic lateral ankle instability. However, additional prospective comparative analyses are needed regarding this topic.

Economic and physical determinants of the global distributions of crop pests and pathogens.

Crop pests and pathogens pose a significant and growing threat to food security, but their geographical distributions are poorly understood. We present a global analysis of pest and pathogen distributions, to determine the roles of socioeconomic and biophysical factors in determining pest diversity, controlling for variation in observational capacity among countries. Known distributions of 1901 pests and pathogens were obtained from CABI. Linear models were used to partition the variation in pest species per country amongst predictors. Reported pest numbers increased with per capita gross domestic product (GDP), research expenditure and research capacity, and the influence of economics was greater in micro-organisms than in arthropods. Total crop production and crop diversity were the strongest physical predictors of pest numbers per country, but trade and tourism were insignificant once other factors were controlled. Islands reported more pests than mainland countries, but no latitudinal gradient in species richness was evident. Country wealth is likely to be a strong indicator of observational capacity, not just trade flow, as has been interpreted in invasive species studies. If every country had US levels of per capita GDP, then 205 ± 9 additional pests per country would be reported, suggesting that enhanced investment in pest observations will reveal the hidden threat of crop pests and pathogens.

Label-free nondestructive imaging of vascular network structure in 3D culture.

Three-dimensional (3D) cell culture assays are important tools in the study of vessel assembly. Current techniques for quantitative analysis of vascular network structure have provided important insight into 3D vessel assembly. However, these methods typically require immunohistochemical staining, which requires sample destruction, or fluorescent cell labeling, which may alter cell behavior. The methods also may require sophisticated and expensive microscopy. More robust, easily quantifiable techniques are needed for imaging vascular networks non-invasively. We present an imaging method based on widefield optical sectioning and digital deconvolution (WOSD) that enables imaging of vascular networks in 3D culture without the use of cell labeling, staining, or sample destruction. WOSD can be performed using a standard optical microscope and allows non-invasive 3D monitoring of vascular network formation. This method is illustrated by imaging vascular networks in a 3D hydrogel system. WOSD enabled production of quantifiable 3D images of the network structure. Accuracy of the technique was evaluated by comparing data from WOSD with confocal images of fixed and fluorescently stained samples. Data for vessel length, diameter, and density are consistent between the two methods. The WOSD approach can be applied using standard laboratory equipment and shows great promise for use in analysis of 3D vascular network formation.

Cardiac surgery is successful in heart transplant recipients.

BACKGROUND: Improved survival of heart transplant (HTx) recipients and increased acceptance of higher risk donors allows development of late pathology. However, there are few data to guide surgical options. We evaluated short-term outcomes and mortality to guide pre-operative assessment, planning, and post-operative care. METHODS: Single centre, retrospective review of 912 patients who underwent HTx from February 1984 - June 2012, identified 22 patients who underwent subsequent cardiac surgery. Data are presented as median (IQR). RESULTS: Indications for surgery were coronary allograft vasculopathy (CAV) (n=10), valvular disease (n=6), infection (n=3), ascending aortic aneurysm (n=1), and constrictive pericarditis (n=2). There was one intraoperative death (myocardial infarction). Hospital stay was 10 (8-21) days. Four patients (18%) returned to theatre for complications. After cardiac surgery, survival at one, five and 10 years was 91±6%, 79±10% and 59±15% with a follow-up of 4.6 (1.7-10.2) years. High pre-operative creatinine was a univariate risk factor for mortality, HR=1.028, (95%CI 1.00-1.056; p=0.05). A time dependent Cox proportional hazards model of the risk of cardiac surgery post-HTx showed no significant hazard; HR=0.87 (95%CI 0.37-2.00; p=0.74). CONCLUSIONS: Our experience shows cardiac surgery post-HTx is associated with low mortality, and confirms that cardiac surgery is appropriate for selected HTx recipients.

Tibialis Anterior Tendon Reconstruction Utilizing Split Tendon Turn-down: A Case Report and Technique Guide.

Tibialis anterior tendon (TAT) ruptures are rare, equating to less than 1% of all musculotendinous injuries. These injuries can be acute or atraumatic, with the latter often associated with chronic degenerative tendinopathy. Surgical repair is indicated when conservative measures fail in meeting functional demands. Direct end-to-end repair is the preferred method for TAT ruptures but may not be feasible with a large tendon defect. Various surgical techniques have been described to address this pathology, including allograft tendon interposition or extensor hallucis longus (EHL) transfer. The authors present a unique technique utilizing a minimal incision TAT turn-down with dermal matrix allograft augmentation, and, in addition, a case implementing this technique in a patient with a large insertional defect. The patient's postoperative course and outcomes were favorable, with improvements in pain, satisfaction, functional scores, and strength. The surgical technique offers versatility and can be adapted to different tendon defect sizes. It also allows for minimal-incision exposure, beneficial for patients with comorbidities or compromised skin integrity. In conclusion, the authors present a case report and surgical technique for the management of large-deficit, chronic TAT ruptures using split TAT turn-down. This technique provides a potential solution for cases where direct end-to-end repair is not feasible.Level of Evidence: Level V.

A systematic review and meta-analysis of predictors of airway intervention in adult epiglottitis.

OBJECTIVE: Epiglottitis is typically considered a pediatric disease; however, there is growing evidence that the incidence of adult epiglottitis has changed since the introduction of the Haemophilus influenzae vaccine. The literature is composed of multiple small series with differing findings. To date, there has been no attempt to collaborate evidence on predictors of airway intervention in this disease. METHODS: The population of interest was adults with a diagnosis of epiglottitis. The primary outcome in this review was incidence of airway intervention. A comprehensive literature search was conducted of the MEDLINE and Embase databases, and a separate random-effects model meta-analysis was undertaken for all outcome data. Moderator tests for comparison between prevaccine and postvaccine estimates were made, and absolute risk difference (RD) and relative risk (RR) calculations were made for all predictors of airway intervention. RESULTS: Thirty studies and a total of 10,148 patients were finally included for meta-analysis. A significant decrease in airway intervention was seen post vaccine introduction introduction from 18.8% to 10.9% (P = 0.01). The presence of an abscess (RD 0.27, P = 0.04; RR 2.45, P < 0.001), stridor (RD 0.64, P < 0.001; RR 7.15, P < 0.001), or a history of diabetes mellitus (RD 0.11, P = 0.02; RR 2.15, P = 0.01) were associated with need for airway intervention. CONCLUSION: In the postvaccine era, clinicians should expect to have to secure airways in 10.9% of cases. The presence of an epiglottic abscess, stridor, or a history of diabetes mellitus are the most reliable clinical features associated with need for airway intervention. LEVEL OF EVIDENCE: NA Laryngoscope, 130:465-473, 2020.

Technical Report: Diagnostic Scan-Based Planning (DSBP), A Method to Improve the Speed and Safety of Radiation Therapy for the Treatment of Critically Ill Patients.

PURPOSE: Treating critically ill patients in radiation oncology departments poses multiple safety risks. This study describes a method to improve the speed of radiation treatment for patients in the intensive care unit by eliminating the need for computed tomography (CT) simulation or on-table treatment planning using patients' previously acquired diagnostic CT scans. METHODS AND MATERIALS: Initially, a retrospective planning study was performed to assess the applicability and safety of diagnostic scan-based planning (DSBP) for 3 typical indications for radiation therapy in patients in the intensive care unit: heterotopic ossification (10), spine metastases (cord compression; 10), and obstructive lung lesions (5). After identification of an appropriate diagnostic CT scan, treatment planning was performed using the diagnostic scan data set. These treatment plans were then transferred to the patients' simulation scans, and a dosimetric comparison was performed between the 2 sets of plans. Additionally, a time study of the first 10 patients treated with DSBP in our department was performed. RESULTS: The retrospective analysis demonstrated that DSBP resulted in treatment plans that, when transferred to the CT simulation data sets, provided excellent target coverage, a median D95% of 96% (range, 86%-100%) of the prescription dose with acceptable hot spots, and a median Dmax108% (range, 102%-113%). Subsequently, DSBP has been used for 10 critically ill patients. The patients were treated without CT simulation, and the median time between patient check-in to the department and completion of radiation therapy was 28 minutes (range, 18-47 minutes.) CONCLUSIONS: This study demonstrates that it is possible to safely use DSBP for the treatment of critically ill patients. This method has the potential to simplify the treatment process and improve the speed and safety of treatment.

Multidisciplinary Tracheotomy Teams: An Analysis of Patient Outcomes and Resource Allocation.

We sought to establish the effect of introducing a multidisciplinary tracheotomy management team (MDT). Tracheotomies are high-cost interventions with potentially devastating complications. Multidisciplinary teams have been introduced in many hospitals with the aim of reducing complications, however, data supporting them are lacking. There is currently insufficient evidence to conclude MDTs reduce length of hospital or intensive care unit (ICU) stay, and there is little information on cost analysis. A chart review identified patients who had a tracheotomy inserted at a major metropolitan teaching hospital with an acute spinal medicine service 2 years before and after the MDT was implemented. The primary outcome was time to decannulation. Other outcomes included tracheotomy complications, the proportion of patients decannulated, length of ICU and hospital stay, and admission cost. Our search identified 174 (78 prior and 96 post-MDT) patients. Baseline demographics were similar between groups. There was no difference in time to decannulation, the decannulation rate, or the length of hospital or ICU stay. Complication rates were low in both groups. There was an increase in the proportion of patients who received speaking valves and a reduction in cost of admission in a subgroup of patients who did not undergo head and neck surgery. There is insufficient evidence to support the widespread introduction of tracheotomy MDTs. Institutions considering introducing a tracheotomy team should carefully consider their case-mix, volume, and available resources as well as the structure and responsibilities of the team, and the timing of its activities within the working week. The potential benefits of MDTs including teaching of staff, and collaboration of teams should be acknowledged. Given the potentially significant implications for cost to the health system, a randomized trial is needed to guide policy in this area.

Stereotactic image-guided intensity modulated radiotherapy using the HI-ART II helical tomotherapy system.

The highly integrated adaptive radiation therapy (HI-ART II) helical tomotherapy unit is a new radiotherapy machine designed to achieve highly precise and accurate treatments at all body sites. The precision and accuracy of the HI-ART II is similar to that provided by stereotactic radiosurgery systems, hence the historical distinction between external beam radiotherapy and stereotactic procedures based on differing precision requirements is removed for this device. The objectives of this work are: (1) to describe stereotactic helical tomotherapy processes (SRS, SBRT); (2) to show that the precision and accuracy of the HI-ART meet the requirements defined for SRS and SBRT; and (3) to describe the clinical implementation of a stereotactic image-guided intensity modulated radiation therapy (IG-IMRT) system that incorporates optical motion management.

Comparison of plan quality provided by intensity-modulated arc therapy and helical tomotherapy.

PURPOSE: Intensity-modulated arc therapy (IMAT) is an arc-based approach to intensity-modulated radiotherapy (IMRT) that can be delivered on a conventional linear accelerator using a conventional multileaf collimator. In a previous work, we demonstrated that our arc-sequencing algorithm can produce highly conformal IMAT plans. Through plan comparisons, we explored the ability of IMAT to serve as an alternative to helical tomotherapy. METHODS AND MATERIALS: The IMAT plans were created for 10 patients previously treated with helical tomotherapy. Treatment plan comparisons, according to the target dose coverage and critical structure sparing, were performed to determine whether similar plan quality could be achieved using IMAT. RESULTS: In 8 of 10 patient cases, IMAT was able to provide plan quality comparable to that of helical tomotherapy. In 2 of these 8 cases, the use of non-axial coplanar or non-coplanar arcs in IMAT planning led to significant improvements in normal tissue sparing. The remaining 2 cases posed particular dosimetric challenges. In 1 case, the target was immediately adjacent to a spinal cord that had received previous irradiation. The second case involved multiple target volumes and multiple prescription levels. Both IMAT and tomotherapy were able to produce clinically acceptable plans. Tomotherapy, however, provided a more uniform target dose and improved critical structure sparing. CONCLUSIONS: For most cases, IMAT can provide plan qualities comparable to that of helical tomotherapy. For some intracranial tumors, IMAT's ability to deliver non-coplanar arcs led to significant dosimetric improvements. Helical tomotherapy, however, can provide improved dosimetric results in the most complex cases.

A method for deconvolution of integrated electronic portal images to obtain incident fluence for dose reconstruction.

A method to convert integrated electronic portal imaging device (EPID) images to fluence for the purpose of reconstructing the dose to a phantom is investigated here for simple open fields. Ultimately, the goal is to develop a method to reconstruct the dose to patients. The EPID images are transformed into incident intensity fluence by spatial filtering with a deconvolution kernel. The kernel uses a general mathematical form derived from a Monte Carlo calculation of the point spread function of an EPID. The deconvolution kernel is fitted using a downhill search algorithm that minimizes the difference between the reconstructed dose and the dose measured in water. The beam profile "horns" that are removed by the EPID calibration procedure are restored to the resulting images by direct multiplication using the measured in-air off-axis ratio. Applying the fitted kernel to an EPID image provides the incident fluence for that beam. This beam fluence is then entered into an independent dose calculation algorithm for phantom or patient dose reconstruction. The phantom dose was computed to an accuracy of 2.0% of the dmax dose at one standard deviation. The method is general and can possibly be applied to any EPID equipped with an integration mode. We demonstrate the application of the fitted kernel in two clinical IMRT cases.

Clinical implementation of intensity-modulated arc therapy.

PURPOSE: Intensity-modulated arc therapy (IMAT) is a method for delivering intensity-modulated radiation therapy (IMRT) using rotational beams. During delivery, the field shape, formed by a multileaf collimator (MLC), changes constantly. The objectives of this study were to (1) clinically implement the IMAT technique, and (2) evaluate the dosimetry in comparison with conventional three-dimensional (3D) conformal techniques. METHODS AND MATERIALS: Forward planning with a commercial system (RenderPlan 3D, Precision Therapy International, Inc., Norcross, GA) was used for IMAT planning. Arcs were approximated as multiple shaped fields spaced every 5-10 degrees around the patient. The number and ranges of the arcs were chosen manually. Multiple coplanar, superimposing arcs or noncoplanar arcs with or without a wedge were allowed. For comparison, conventional 3D conformal treatment plans were generated with the same commercial forward planning system as for IMAT. Intensity-modulated treatment plans were also created with a commercial inverse planning system (CORVUS, Nomos Corporation). A leaf-sequencing program was developed to generate the dynamic MLC prescriptions. IMAT treatment delivery was accomplished by programming the linear accelerator (linac) to deliver an arc and the MLC to step through a sequence of fields. Both gantry rotation and leaf motion were enslaved to the delivered MUs. Dosimetric accuracy of the entire process was verified with phantoms before IMAT was used clinically. For each IMAT treatment, a dry run was performed to assess the geometric and dosimetric accuracy. Both the central axis dose and dose distributions were measured and compared with predictions by the planning system. RESULTS: By the end of May 2001, 50 patients had completed their treatments with the IMAT technique. Two to five arcs were needed to achieve highly conformal dose distributions. The IMAT plans provided better dose uniformity in the target and lower doses to normal structures than 3D conformal plans. The results varied when the comparison was made with fixed gantry IMRT. In general, IMAT plans provided more uniform dose distributions in the target, whereas the inverse-planned fixed gantry treatments had greater flexibility in controlling dose to the critical structures. Because the field sizes and shapes used in the IMAT were similar to those used in conventional treatments, the dosimetric uncertainty was very small. Of the first 32 patients treated, the average difference between the measured and predicted doses was -0.54 +/- 1.72% at isocenter. The 80%-95% isodose contours measured with film dosimetry matched those predicted by the planning system to within 2 mm. The planning time for IMAT was slightly longer than for generating conventional 3D conformal plans. However, because of the need to create phantom plans for the dry run, the overall planning time was doubled. The average time a patient spent on the table for IMAT treatment was similar to conventional treatments. CONCLUSION: Initial results demonstrated the feasibility and accuracy of IMAT for achieving highly conformal dose distributions for different sites. If treatment plans can be optimized for IMAT cone beam delivery, we expect IMAT to achieve dose distributions that rival both slice-based and fixed-field IMRT techniques. The efficient delivery with existing linac and MLC makes IMAT a practical choice.

Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency.

Autosomal recessive mutations in UNC13D, the gene that encodes Munc13-4, are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Munc13-4 expression is obligatory for exocytosis of lytic granules, facilitating cytotoxicity by T cells and natural killer (NK) cells. The mechanisms regulating Munc13-4 expression are unknown. Here, we report that Munc13-4 is highly expressed in differentiated human NK cells and effector CD8(+) T lymphocytes. A UNC13D c.118-308C>T mutation, causative of FHL3, disrupted binding of the ETS family member ELF1 to a conserved intronic sequence. This mutation impairs UNC13D intron 1 recruitment of STAT4 and the chromatin remodeling complex component BRG1, diminishing active histone modifications at the locus. The intronic sequence acted as an overall enhancer of Munc13-4 expression in cytotoxic lymphocytes in addition to representing an alternative promoter encoding a novel Munc13-4 isoform. Mechanistically, T cell receptor engagement facilitated STAT4-dependent Munc13-4 expression in naive CD8(+) T lymphocytes. Collectively, our data demonstrates how chromatin remodeling within an evolutionarily conserved regulatory element in intron 1 of UNC13D regulates the induction of Munc13-4 expression in cytotoxic lymphocytes and suggests that an alternative Munc13-4 isoform is required for lymphocyte cytotoxicity. Thus, mutations associated with primary immunodeficiencies may cause disease by disrupting transcription factor binding.