Study of pH and Thermodynamic Parameters via Circular Dichroism Spectroscopy of a Recombinant Human Lactoferrin.

The production of human recombinant proteins to be used for therapeutic or nutritional purposes must focus on obtaining a molecule that is as close as possible to the native human protein. This biotechnological tool has been documented in various studies published in recent decades, with lactoferrin being one of those that has generated the most interest, being a promising option for recombinant technology. However, stability studies including thermodynamic parameters have not been reported for recombinant lactoferrin (Lf). The objective of this work was to obtain the human recombinant protein using the yeast Komagataella phaffii to study structural changes modifying pH and temperature using circular dichroism spectroscopy (CD). Thermodynamic parameters such as ΔH, ΔS and Tm were calculated and compared with commercial human lactoferrin. We propose the potential use of CD and thermodynamic parameters as a criterion in the production of recombinant proteins to be used in the production of specialized recombinant proteins.

The International Consortium on Primary Graft Dysfunction: Redefining Clinical Risk Factors in the Contemporary Era of Heart Transplantation.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of morbidity and mortality early after heart transplantation (HT). The International Consortium on PGD is a multicenter collaboration dedicated to identifying the clinical risk factors for PGD in the contemporary era of HT. The objectives of the current report were (1) to assess the incidence of severe PGD in an international cohort; (2) to evaluate the performance of the most strongly validated PGD risk tool, the RADIAL score, in a contemporary cohort; and (3) to redefine clinical risk factors for severe PGD in the current era of HT. METHODS: This is a retrospective, observational study of consecutive adult HT recipients between 2010 and 2020 in 10 centers in the United States, Canada and Europe. Patients with severe PGD were compared to those without severe PGD (comprising those with no, mild and moderate PGD). The RADIAL score was calculated for each transplant recipient. The discriminatory power of the RADIAL score was evaluated using receiver operating characteristic (ROC) analysis, and its calibration was assessed by plotting the percentage of PGD predicted vs that which was observed. To identify clinical risk factors associated with severe PGD, we performed multivariable mixed-effects logistic regression modeling to account for among-center variability. RESULTS: A total of 2746 patients have been enrolled in the registry to date, including 2015 (73.4%) from North America, and 731 (26.6%) from Europe; 215 participants (7.8%) met the criteria for severe PGD. There was an increase in the incidence of severe PGD over the study period (P value for trend by difference sign test = 0.004). The Kaplan-Meier estimate for 1-year survival was 75.7% (95% CI 69.4-80.9%) in patients with severe PGD as compared to 94.4% (95% CI 93.5-95.2%) in those without severe PGD (log-rank P value < 0.001). The RADIAL score performed poorly in our contemporary cohort and was not associated with severe PGD; it had an AUC of 0.53 (95% CI 0.48-0.58). In the multivariable regression model, acute preoperative dialysis (OR 2.41, 95% CI 1.31-4.43), durable left ventricular assist device support (OR 1.77, 95% CI 1.13-2.77), and total ischemic time (OR 1.20 for each additional hour, 95% CI 1.02-1.41) were associated with an increased risk of severe PGD. CONCLUSIONS: Our consortium has identified an increasing incidence of PGD in the modern transplant era. We identified contemporary risk factors for this early post-transplant complication, which confers a high mortality risk. These results may enable the identification of patients at high risk for developing severe PGD in order to inform peri-transplant donor and recipient management practices.

Leaf endophytic microbiomes of different almond cultivars grafted to the same rootstock.

AIMS: We compared the bacterial endophytic communities of three genetically different almond cultivars that were all grafted on the same type of rootstock, growing side by side within a commercial orchard. METHODS AND RESULTS: We examined the diversity of leaf bacterial endophytes using cultivation-independent techniques and assessed the relative abundance of bacterial families. Two of these three cultivars were dominated by Pseudomonadaceae, while the bacterial composition of the third cultivar consisted mainly of Streptococcaceae. CONCLUSIONS: The experimental set up allowed us to analyse the impact of the shoot cultivar on endophytes, minimizing the influence of rootstock, biogeography, and cultivation status. Our data suggest that the shoot cultivar can shape the leaf endophytic community composition of almond trees. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results suggest that the shoot cultivar controls the composition of the foliar bacterial endophytic community of almonds. Overall, our results could provide a first step to develop strategies for a more sustainable almond agriculture.

Do Unhelpful Thoughts or Confidence in Problem Solving Have Stronger Associations with Musculoskeletal Illness?

BACKGROUND: Measures of unhelpful thoughts and distress correlate with the intensity of pain and the magnitude of incapability among people seeking musculoskeletal specialty care. In this evolving knowledge area, we want to be sure we have not neglected other important mental health factors. This study addressed how measures of confidence in problem solving as well as past and current ability to achieve goals account for variation in symptoms and capability independent of unhelpful thoughts and distress. QUESTIONS/PURPOSES: (1) Are measures of confidence in problem solving ability and past and current ability to achieve goals regarding future outcomes associated with variation in capability, independent of measures of symptoms of depression and anxiety (distress) and measures of unhelpful thoughts (worst-case thinking, negative pain thoughts)? (2) Are these measures independently associated with variation in pain intensity? (3) Are these measures associated with measures of symptoms of depression, symptoms of anxiety, and unhelpful thoughts? METHODS: Over a 7-month period during the pandemic, we enrolled sporadically from the offices of four surgeons treating patients who sought care for various upper and lower extremity conditions. We invited approximately 200 adult new and returning patients to participate (the number of invitations was not formally tracked) and 187 accepted. Thirty-one were excluded due to markedly incomplete entries (related to a problematic attempt to use the patient's cell phone to complete questionnaires as a pandemic work around), leaving 156 for analysis. Patients completed an 11-point ordinal rating of pain intensity, two measures of unhelpful thoughts (the Pain Catastrophizing Scale and the Negative Pain Thoughts Questionnaire), the Adult Hope Scale to measure past and current ability to achieve goals, the Personal Optimism and Self-Efficacy Optimism Scale to measure confidence in problem solving ability, the Patient-reported Outcomes Measurement Information System (PROMIS) computer adaptive test to measure symptoms of anxiety, the PROMIS computer adaptive test to measure symptoms of depression, and the PROMIS physical function computer adaptive test to assess the magnitude of capability. All questionnaires were validated in previous studies. We used bivariate analyses to identify factors associated with magnitude of capability, pain intensity, confidence in problem solving ability, and past and current ability to achieve goals. All factors with a p value of less than 0.1 were included in multivariable analyses to seek associations between these measures accounting for confounders. We reported partial η2 as a measure of effect size for all multivariable regression models. The following rules of thumb are used to interpret values for partial η2: a value of 0.01 = small, 0.06 = medium, and values of 0.14 and higher show large effect size. RESULTS: Greater capability was modestly associated with fewer negative pain thoughts (ß = -0.63 [95% CI -1.0 to -0.22]; standard error = 0.20; partial η2 = 0.06; p = 0.003) and no self-reported comorbidities (ß = 2.6 [95% CI 0.02 to 5.3]; standard error = 1.3; partial η2 = 0.03; p = 0.048) after controlling for education, symptoms of depression and anxiety, worst-case thinking, as well as past and current ability to achieve goals. In a similar multivariable model, greater pain intensity was modestly associated with greater worst-case thinking (ß = 0.33 [95% CI 0.20 to 0.45]; standard error = 0.06; partial η2 = 0.16; p < 0.001) and established patients (ß = -1.1 [95% CI -1.8 to -0.31]; standard error = 0.38; partial η2 = 0.05; p = 0.006). In another similar multivariable model, having more confidence in problem solving ability had a limited association with higher ratings of past and current ability to achieve goals (ß = 0.15 [95% CI 0.09 to 0.21]; standard error = 0.03; partial η2 = 0.13; p < 0.001). In a final multivariable model, lower past and current ability to achieve goals was independently associated with having greater symptoms of depression (ß = -0.45 [95% CI -0.67 to -0.23]; standard error = 0.11; partial η2 = 0.1; p < 0.001) and more negative pain thoughts (ß = -0.49 [95% CI -0.89 to -0.09]; standard error = 0.20; partial η2 = 0.04; p = 0.02). CONCLUSION: The observation that unhelpful thoughts about symptoms are more strongly associated with symptom intensity than past and current ability to achieve goals and confidence in problem solving ability add to the evidence that attentiveness to unhelpful thinking is an important aspect of musculoskeletal health. Musculoskeletal specialists can prioritize communication strategies such as relationship building and motivational interviewing that develop trust and facilitate reorientation of common unhelpful thoughts. LEVEL OF EVIDENCE: Level II, prognostic study.

Indirect regulation of temperature in raceway reactors by optimal management of culture depth.

Temperature and irradiance are the two most relevant factors determining the performance of microalgae cultures in open raceway reactors. Moreover, inadequate temperature strongly reduces the biomass productivity in these systems even if enough sunlight is available. Controlling the temperature in large open raceway reactors is considered unaffordable because of the large amount of energy required. This study presents an indirect method for temperature regulation in microalgae raceway reactors by optimizing the culture depth. First, the effect of the culture depth on the raceway temperature is analyzed for different seasons of the year. Afterward, a simulation study is presented where the proposed control approach is compared to the normal operation mode with constant volume in the reactor. This study is also extended to industrial scale. Relevant improvements on the temperature factor and biomass production are presented. The developed knowledge allows the improvement of the performance in open raceway reactors up to 12% without involving additional energy and costs, being a suitable solution for large industrial reactors that until now have no options for controlling the temperature.

Contraindications to intravenous thrombolysis in prehospital triage of thrombectomy candidates.

BACKGROUND AND PURPOSE: The existence of contraindications to intravenous thrombolysis (IVT) is considered a criterion for direct transfer of patients with suspected acute stroke to thrombectomy-capable centers in the prehospital setting. Our aim was to assess the utility of this criterion in a setting where routing protocols are defined by the Madrid - Direct Referral to Endovascular Center (M-DIRECT) prehospital scale. METHODS: This was a post hoc analysis of the M-DIRECT study. Reported contraindications to IVT were retrospectively collected from emergency medical services reports and categorized into late window, anticoagulant treatment and other contraindications. Final diagnosis and treatment rates were compared between patients with and without reported IVT contraindications and according to anticoagulant treatment or late window categories. RESULTS: The M-DIRECT study included 541 patients. Reported IVT contraindications were present in 227 (42.0%) patients. Regarding final diagnosis no significant differences were found between patients with or without reported IVT contraindications: ischaemic stroke (any) 65.6% vs. 62.1%, ischaemic stroke with large vessel occlusion (LVO) 32.2% vs. 28.3%, hemorrhagic stroke 15.4% vs. 15.6%, stroke mimic 18.9% vs. 22.3% respectively. Amongst patients with LVO, endovascular thrombectomy (EVT) was performed less often in the presence of IVT contraindications (56.2% vs. 74.2%). M-DIRECT-positive patients had higher rates of LVO and EVT compared with M-DIRECT-negative patients independent of reported IVT contraindications. CONCLUSIONS: Reported IVT contraindications alone do not increase EVT likelihood and should not be considered to determine routing in urban stroke networks.

Simple methods to remove microbes from leaf surfaces.

Endophytes have been defined as microorganisms living inside plant tissues without causing negative effects on their hosts. Endophytic microbes have been extensively studied for their plant growth-promoting traits. However, analyses of endophytes require complete removal of epiphytic microorganisms. We found that the established tests to evaluate surface sterility, polymerase chain reaction, and leaf imprints, are unreliable. Therefore, we used scanning electron microscopy (SEM) as an additional assessment of epiphyte removal. We used a diverse suite of sterilization protocols to remove epiphytic microorganisms from the leaves of a gymnosperm and an angiosperm tree to test the influence of leaf morphology on the efficacy of these methods. Additionally, leaf tissue damage was also evaluated by SEM, as damaging the leaves might have an impact on endophytes and could lead to inaccurate assessment of endophytic communities. Our study indicates, that complete removal of the leaf cuticle by the sterilization technique assures loss of epiphytic microbes, and that leaves of different tree species may require different sterilization protocols. Furthermore, our study demonstrates the importance of choosing the appropriate sterilization protocol to prevent erroneous interpretation of host-endophyte interactions. Moreover, it shows the utility of SEM for evaluating the effectiveness of surface sterilization methods and their impact on leaf tissue integrity.

Enhancing Capacity of Community-Academic Partnerships to Achieve Health Equity: Results From the CBPR Partnership Academy.

Community-based participatory research (CBPR) is an equitable partnership approach that links academic researchers, community organizations, and public health practitioners to work together to understand and address health inequities. Although numerous educational materials on CBPR exist, few training programs develop the skills and knowledge needed to establish effective, equitable partnerships. Furthermore, there are few professional development opportunities for academic researchers, practitioners, and community members to obtain these competencies in an experiential co-learning process. In response, the Detroit Community-Academic Urban Research Center developed the CBPR Partnership Academy, an innovative, yearlong capacity-building program facilitated by experienced community and academic partners, involving an intensive short course, partnership development, grant proposal preparation and funding, mentoring, online learning forums, and networking. Three diverse cohorts (36 teams) from 18 states and 2 tribal nations have participated. We describe the rationale and components of the training program and present results from the first two cohorts. Evaluation results suggest enhanced competence and efficacy in conducting CBPR. Outcomes include partnerships established, grant proposals submitted and funded, workshops and research conducted, and findings disseminated. A community-academic partner-based, integrated, applied program can be effective for professional development and establishing innovative linkages between academics and practitioners aimed at achieving health equity.

Diurnal and nocturnal pH control in microalgae raceway reactors by combining classical and event-based control approaches.

The pH control in raceway reactors is crucial for an optimal performance of the system. Classical pH control is exclusively performed during the daytime period for cost saving reasons. This paper demonstrates that pH can be controlled 24 hours a day by using both a continuous-based and an event-based control approach, being able to improve the system's performance and reducing costs at the same time. Thus, experimental tests on a raceway reactor for several days are presented to show a comparison between traditional control algorithms during the daytime period versus an event-based control approach operating during both daytime and night-time periods. As a result, the combination of classical PI control for the daytime period and the event-based control for the night-time period is presented as a promising pH control architecture in raceway reactors.

Interstellar

Earth is constantly bombarded with extraterrestrial dust containing invaluable information about extraterrestrial processes, such as structure formation by stellar explosions or nucleosynthesis, which could be traced back by long-lived radionuclides. Here, we report the very first detection of a recent ^{60}Fe influx onto Earth by analyzing 500 kg of snow from Antarctica by accelerator mass spectrometry. By the measurement of the cosmogenically produced radionuclide ^{53}Mn, an atomic ratio of ^{60}Fe/^{53}Mn=0.017 was found, significantly above cosmogenic production. After elimination of possible terrestrial sources, such as global fallout, the excess of ^{60}Fe could only be attributed to interstellar ^{60}Fe which might originate from the solar neighborhood.

Retention of cricothyrotomy skills by paramedics using a wire guided technique.

INTRODUCTION: Cricothyrotomy may be necessary for airway management when a patient's airway cannot be maintained through standard techniques such as oral airway placement, blind insertion airway device, or endotracheal intubation. Wire-guided cricothyrotomy is one of many techniques used to perform a cricothyrotomy. Although there is some controversy over which cricothyrotomy technique is superior, there is no published data regarding long term retention rates. The purpose of this study is to determine whether ground based paramedics can be taught and are able to retain the skills necessary to successfully perform a wire-guided cricothyrotomy. METHODS: This retrospective study was performed in a suburban county with a population of 160,000 with 23,000 EMS calls per year. Participants were ground-based paramedics who were taught wire-guided cricothyrotomy as part of a standardized paramedic educational update program. After viewing an instructional video, the paramedics were shown each the steps of the procedure on a simulation model, using a low fidelity task trainer previously developed to train emergency medicine residents. Using a 16 step procedural checklist, participants were allowed open-ended practice using the task trainer. Critical steps in the checklist were marked in bold lettering indicating automatic failure. Each paramedic was then individually supervised performing a minimum of 5 successful simulations. Retention was assessed using the same 16 step checklist 6 to 12 weeks following the initial training. RESULTS: A total of 55 paramedics completed both the initial training and reassessment during the time period studied. During the initial training phase 100% (55 of 55) of the paramedics were successful in performing all 16 steps of the wire-guided cricothyrotomy. During the retention phase, 87.3% (48 of 55) of paramedics retained the skills necessary to successfully perform the wire-guided cricothyrotomy. On the 16 step checklist, most steps were performed successfully by all the paramedics or missed by only 1 of the 55 paramedics. The step involving removal of the needle prior to advancing the airway device over the guide wire was missed by 34.5% (19 of 55) of the participants. This was not an automatic failure since most participants immediately self-corrected and completed the procedure successfully. CONCLUSION: Paramedics can be taught and can retain the skills necessary to successfully perform a wire-guided cricothyrotomy on a simulator. Future research is necessary to determine if paramedics can successfully transfer these skills to real patients.

The Direct Referral to Endovascular Center criteria: a proposal for pre-hospital evaluation of acute stroke in the Madrid Stroke Network.

BACKGROUND AND PURPOSE: For patients with acute ischaemic stroke due to large-vessel occlusion, it has recently been shown that mechanical thrombectomy (MT) with stent retrievers is better than medical treatment alone. However, few hospitals can provide MT 24 h/day 365 days/year, and it remains unclear whether selected patients with acute stroke should be directly transferred to the nearest MT-providing hospital to prevent treatment delays. Clinical scales such as Rapid Arterial Occlusion Evaluation (RACE) have been developed to predict large-vessel occlusion at a pre-hospital level, but their predictive value for MT is low. We propose new criteria to identify patients eligible for MT, with higher accuracy. METHODS: The Direct Referral to Endovascular Center criteria were defined based on a retrospective cohort of 317 patients admitted to a stroke center. The association of age, sex, RACE scale score and blood pressure with the likelihood of receiving MT were analyzed. Cut-off points with the highest association were thereafter evaluated in a prospective cohort of 153 patients from nine stroke units comprising the Madrid Stroke Network. RESULTS: Patients with a RACE scale score ≥ 5, systolic blood pressure <190 mmHg and age <81 years showed a significantly higher probability of undergoing MT (odds ratio, 33.38; 95% confidence interval, 12-92.9). This outcome was confirmed in the prospective cohort, with 68% sensitivity, 84% specificity, 42% positive and 94% negative predictive values for MT, ruling out 83% of hemorrhagic strokes. CONCLUSIONS: The Direct Referral to Endovascular Center criteria could be useful for identifying patients suitable for MT.

ELECTRONIC DEVICES FOR COGNITIVE IMPAIRMENT SCREENING: A SYSTEMATIC LITERATURE REVIEW.

OBJECTIVES: The reduction in cognitive decline depends on timely diagnosis. The aim of this systematic review was to analyze the current available information and communication technologies-based instruments for cognitive decline early screening and detection in terms of usability, validity, and reliability. METHODS: Electronic searches identified 1,785 articles of which thirty-four met the inclusion criteria and were grouped according to their main purpose into test batteries, measures of isolated tasks, behavioral measures, and diagnostic tools. RESULTS: Thirty one instruments were analyzed. Fifty-two percent were personal computer based, 26 percent tablet, 13 percent laptop, and 1 was mobile phone based. The most common input method was touchscreen (48 percent). The instruments were validated with a total of 4,307 participants: 2,146 were healthy older adults (M = 73.59; SD = 5.12), 1,104 had dementia (M = 74.65; SD = 3.98) and 1,057 mild cognitive impairment (M = 74.84; SD = 4.46). Only 6 percent were administered at home, 19 percent reported outcomes about usability, and 22 percent about understandability. The methodological quality of the studies was good, the weakest methodological area being usability. Most of the instruments obtained acceptable values of specificity and sensitivity. CONCLUSIONS: It is necessary to create home delivered instruments and to include usability studies in their design. Involvement of people with cognitive decline in all phases of the development process is of great importance to obtain valuable and user-friendly products. It would be advisable for researchers to make an effort to provide cutoff points for their instruments.

Evaluating the impacts of agricultural land management practices on water resources: A probabilistic hydrologic modeling approach.

Evaluating the effectiveness of agricultural land management practices in minimizing environmental impacts using models is challenged by the presence of inherent uncertainties during the model development stage. One issue faced during the model development stage is the uncertainty involved in model parameterization. Using a single optimized set of parameters (one snapshot) to represent baseline conditions of the system limits the applicability and robustness of the model to properly represent future or alternative scenarios. The objective of this study was to develop a framework that facilitates model parameter selection while evaluating uncertainty to assess the impacts of land management practices at the watershed scale. The model framework was applied to the Lake Creek watershed located in southwestern Oklahoma, USA. A two-step probabilistic approach was implemented to parameterize the Agricultural Policy/Environmental eXtender (APEX) model using global uncertainty and sensitivity analysis to estimate the full spectrum of total monthly water yield (WYLD) and total monthly Nitrogen loads (N) in the watershed under different land management practices. Twenty-seven models were found to represent the baseline scenario in which uncertainty of up to 29% and 400% in WYLD and N, respectively, is plausible. Changing the land cover to pasture manifested the highest decrease in N to up to 30% for a full pasture coverage while changing to full winter wheat cover can increase the N up to 11%. The methodology developed in this study was able to quantify the full spectrum of system responses, the uncertainty associated with them, and the most important parameters that drive their variability. Results from this study can be used to develop strategic decisions on the risks and tradeoffs associated with different management alternatives that aim to increase productivity while also minimizing their environmental impacts.

Validation of the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic model for first-line pazopanib in metastatic renal carcinoma: the Spanish Oncologic Genitourinary Group (SOGUG) SPAZO study.

BACKGROUND: Patients with metastatic renal carcinoma (mRCC) treated with first-line pazopanib were not included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. SPAZO (NCT02282579) was a nation-wide retrospective observational study designed to assess the effectiveness and validate the IMDC prognostic model in patients treated with first-line pazopanib in clinical practice. PATIENTS AND METHODS: Data of 278 patients, treated with first-line pazopanib for mRCC in 34 centres in Spain, were locally recorded and externally validated. Mean age was 66 years, there were 68.3% male, 93.5% clear-cell type, 74.8% nephrectomized, and 81.3% had ECOG 0-1. Metastatic sites were: lung 70.9%, lymph node 43.9%, bone 26.3%, soft tissue/skin 20.1%, liver 15.1%, CNS 7.2%, adrenal gland 6.5%, pleura/peritoneum 5.8%, pancreas 5%, and kidney 2.2%. After median follow-up of 23 months, 76.4% had discontinued pazopanib (57.2% due to progression), 47.9% had received second-line targeted therapy, and 48.9% had died. RESULTS: According to IMDC prognostic model, 19.4% had favourable risk (FR), 57.2% intermediate risk (IR), and 23.4% poor risk (PR). No unexpected toxicities were recorded. Response rate was 30.3% (FR: 44%, IR: 30% PR: 17.3%). Median progression-free survival (whole population) was 11 months (32 in FR, 11 in IR, 4 in PR). Median and 2-year overall survival (whole population) were 22 months and 48.1%, respectively (FR: not reached and 81.6%, IR: 22 and 48.7%, PR: 7 and 18.8%). These estimations and their 95% confidence intervals are fully consistent with the outcomes predicted by the IMDC prognostic model. CONCLUSION: Our results validate the IMDC model for first-line pazopanib in mRCC and confirm the effectiveness and safety of this treatment.

Interstellar

A dying massive star ends in a supernova explosion ejecting a large fraction of its mass into the interstellar medium. If this happens nearby, part of the ejecta might end on Solar System bodies and, in fact, radioactive ^{60}Fe has been detected on the Pacific ocean floor in about 2 Ma old layers. Here, we report on the detection of this isotope also in lunar samples, originating presumably from the same event. The concentration of the cosmic ray produced isotope ^{53}Mn, measured in the same samples, proves the supernova origin of the ^{60}Fe. From the ^{60}Fe concentrations found we deduce a reliable value for the local interstellar fluence in the range of 1×10^{8} at/cm^{2}. Thus, we obtain constraints on the recent and nearby supernova(e).

Trans-scleral diode laser cyclophotocoagulation for refractory glaucoma after high-risk penetrating keratoplasty.

To analyze the intraocular pressure reduction, number of anti-glaucoma medications needed, and post-operative complications of trans-scleral diode laser cyclophotocoagulation (DCPC) in patients with high-risk penetrating keratoplasty (PKP) and secondary refractory glaucoma. Prospective interventional, longitudinal, non-comparative series of cases, including 16 eyes of 15 patient's post-PKP on maximal anti-glaucoma medical therapy with intraocular pressures above 22 mmHg. All patients received 18 shots, 360° peri-limbal (avoiding the long posterior ciliary nerves and arteries at 3 and 9 o'clock positions) of trans-scleral DCPC (2000 mW, time: 2.0 s/shot). There was a 55.5 % reduction (total of 14.0 mmHg) of the mean pre-operative IOP (31.5 mmHg) after the first diode laser application (p = 0.0020). Re-treatment was required in 31.2 % of eyes over a mean period of 10.7 months. In these five eyes, the mean pre-operative IOP was 40.4 mmHg, which decreased to 15.0 mmHg post-therapy, and a mean IOP reduction of 25.4 mmHg (p = 0.0218). There was a 51.0 % reduction in the mean number of medications used after the first, and a 57.1 % reduction after a second laser application. The incidence of failure (IOP ≥ 22 mmHg or need of additional medical therapy) from initial intervention to loss of follow-up was 1.3 % per person-month. DCPC effectively reduces the intraocular pressure and the number of anti-glaucoma medications with few complications in patients after high-risk PKP and secondary glaucoma. Only, one-third of the eyes needed a second intervention to control the intraocular pressure. Post-DCPC complications were limited to phthisis bulbi and endothelial dysfunction, one eye each. Please check and confirm the author names and initials are correct. Also, kindly confirm the details in the metadata are correct.

Treatment escalation options for patients with type 2 diabetes after failure of exenatide twice daily or glimepiride added to metformin: results from the prospective European Exenatide (EUREXA) study.

AIMS: To evaluate third-line thiazolidinedione (TZD) or glimepiride therapy in patients inadequately controlled on metformin + exenatide twice daily, and third-line exenatide twice daily in patients inadequately controlled on metformin + glimepiride. METHODS: In this randomized, open-label, multicentre trial, 144 patients with type 2 diabetes inadequately controlled [glycated haemoglobin (HbA1c) >9% (75 mmol/mol) after 3 months' treatment or >7% (53 mmol/mol) at two consecutive visits 3 months apart, after 6 months' treatment] on metformin + exenatide twice daily were re-randomized to add-on TZD or glimepiride, and 166 patients inadequately controlled on metformin + glimepiride received add-on exenatide twice daily. Changes in HbA1c, body mass index (BMI), lipids, hypoglycaemia and vital signs were evaluated. RESULTS: The median duration of triple therapy was ∼2 years. In patients inadequately controlled on metformin + exenatide twice daily, add-on TZD decreased HbA1c levels significantly better than add-on glimepiride: 130-week difference 0.48% [95% confidence interval (CI) 0.19-0.77] or 5.2 mmol/mol (95% CI 2.1-8.4; p = 0.001), but with significantly increased BMI and systolic blood pressure. The ratio of documented symptomatic (blood glucose ≤70 mg/dl [3.9 mmol/l]) hypoglycaemia rates for add-on glimepiride to add-on TZD was 8.48 (p < 0.0001). Add-on exenatide twice daily after metformin + glimepiride significantly reduced HbA1c levels: mean [standard deviation (s.d.)] change from baseline -0.35 (0.89)% [-3.8 (9.7) mmol/mol] and BMI: mean (s.d.) change from baseline -0.82 (1.9) kg/m(2) at 130 weeks, with a slightly increased rate of documented symptomatic hypoglycaemia from metformin + glimepiride (ratio 1.49). CONCLUSIONS: TZD, but not glimepiride, was an effective and well tolerated third-line therapy in patients without glycaemic control after long-term therapy with metformin + exenatide twice daily. Exenatide twice daily was an effective and well tolerated third-line therapy in patients inadequately controlled on metformin + glimepiride.

Antagonistic effects of indoloquinazoline alkaloids on antimycobacterial activity of evocarpine.

AIMS: The interaction of quinolone and indoloquinazoline alkaloids concerning their antimycobacterial activity was studied. METHODS AND RESULTS: The antimycobacterial and modulating activity of evodiamine (1), rutaecarpine (2) and evocarpine (3) was tested on mycobacteria including three multidrug-resistant (MDR) clinical isolates of Mycobacterium tuberculosis. Antagonistic effects were concluded from fractional inhibitory concentration (FICI) values. Interaction energies of the compounds were calculated using GLUE docking module implemented in GRID. 1 and 2 exhibited weak inhibition of rapidly growing mycobacteria, however, 1 was active against Myco. tuberculosis H37Rv (MIC = 10 mg l(-1) ) while 2 was inactive. Both 1 and 2 showed a marked antagonistic effect on the susceptibility of different mycobacterial strains to 3 giving FICI values between 5 and 9. The interaction energies between compounds 1 and 2 with compound 3 suggested the possibility of complex formation in solution. CONCLUSIONS: Indoloquinazoline alkaloids markedly reduce the antimycobacterial effect of the quinolone alkaloid evocarpine. Complex formation may play a role in the attenuation of its antimycobacterial activity. SIGNIFICANCE AND IMPACT OF THE STUDY: This study gives a striking example of antagonism between compounds present in the same plant extract which should be considered in natural product based screening projects.

Economic evaluation of occupational health and safety programmes in health care.

BACKGROUND: Evidence-based resource allocation in the public health care sector requires reliable economic evaluations that are different from those needed in the commercial sector. AIMS: To describe a framework for conducting economic evaluations of occupational health and safety (OHS) programmes in health care developed with sector stakeholders. To define key resources and outcomes to be considered in economic evaluations of OHS programmes and to integrate these into a comprehensive framework. METHODS: Participatory action research supported by mixed qualitative and quantitative methods, including a multi-stakeholder working group, 25 key informant interviews, a 41-member Delphi panel and structured nominal group discussions. RESULTS: We found three resources had top priority: OHS staff time, training the workers and programme planning, promotion and evaluation. Similarly, five outcomes had top priority: number of injuries, safety climate, job satisfaction, quality of care and work days lost. The resulting framework was built around seven principles of good practice that stakeholders can use to assist them in conducting economic evaluations of OHS programmes. CONCLUSIONS: Use of a framework resulting from this participatory action research approach may increase the quality of economic evaluations of OHS programmes and facilitate programme comparisons for evidence-based resource allocation decisions. The principles may be applicable to other service sectors funded from general taxes and more broadly to economic evaluations of OHS programmes in general.