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Abstract | migraine | MIGRAINE, DILATION, INTRACRANIAL VASCULAR | There are several endogenous molecules that can trigger migraine attacks when administered to humans. Notably, calcitonin gene-related peptide (CGRP) has been identified as a key player in a signalling cascade involved in migraine attacks, acting through the second messenger cyclic adenosine monophosphate (cAMP) in various cells, including intracranial vascular smooth muscle cells. However, it remains unclear whether intracellular cAMP signalling requires CGRP receptor activation during a migraine attack in humans. To address this question, we conducted a randomized, double-blind, placebo-controlled, parallel trial using a human provocation model involving the administration of CGRP and cilostazol in individuals with migraine pretreated with erenumab or placebo. Our study revealed that migraine attacks can be provoked in patients by cAMP-mediated mechanisms using cilostazol, even when the CGRP receptor is blocked by erenumab. Furthermore, the dilation of cranial arteries induced by cilostazol was not influenced by the CGRP receptor blockade. These findings provide clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. This discovery opens up new possibilities for the development of mechanism-based drugs for the treatment of migraine.Using a human migraine provocation model, Do See Levy ( | PMC10690017 |
Introduction | migraine, Migraine | MIGRAINE, DISEASE, MIGRAINE | Migraine is a highly prevalent disease affecting more than 1 billion people worldwide.A key feature of migraine is that various environmental and endogenous trigger factors can initiate an attack.Thus, it is timely to ascertain whether migraine attack generation requires CGRP receptor activation. This can be established through the use of human provocation models. We hypothesized that treatment with erenumab would mitigate the physiological effects of administration of CGRP, but not those of cilostazol. To test this hypothesis, we conducted a randomized, double-blind, placebo-controlled, parallel trial. | PMC10690017 |
Materials and methods | The protocol was approved by the Regional Health Research Ethics Committee of the Capital Region of Denmark (identifier: H-19073983), the Danish Data Protection Agency (P-2020-652) and the Danish Medicines Agency (identifier: 2020033418). We obtained a signed consent form at the time of screening before any protocol-related procedures or assessments. All study-related procedures complied with the Declaration of Helsinki, with later revisions. The study is registered in ClinicalTrials.gov (identifier: NCT04452929). | PMC10690017 |
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Participants | migraine, ICHD-3 | MIGRAINE, HEADACHE DISORDERS | Adults aged 18–65 years old with a diagnosis of migraine according to the International Classification of Headache Disorders, Third Edition (ICHD-3), | PMC10690017 |
Study design and procedures | migraine, headache | MIGRAINE | We enrolled participants in a randomized, double-blind, placebo-controlled, parallel trial at a single centre in Denmark (
Patients arrived between 08:00 a.m. and 12:00 p.m. on the experimental study days. Patients were in a supine-position during study-related procedures and assessments. Patients were not allowed to consume any medication within 24 h or four times the plasma half-life of the drug (whichever longest) on the experimental study days except for oral contraception. Furthermore, to remain eligible, participants could not have had a migraine attack during the preceding 48 h nor a headache during the preceding 24 h prior to administration of the experimental trigger. | PMC10690017 |
Headache characteristics and diary | migraine, headache | MIGRAINE, ADVERSE EVENTS | A headache specialist conducted a semi-structured interview at the screening visit. The interview included information on medical history, headache characteristics and frequency, family history of migraine and prior pharmacological treatment; these data were confirmed by review of medical records.On the experimental study days, investigators recorded data on headache characteristics, vital signs and adverse events every 10 min for 90 min after administration of the experimental trigger. After the in-hospital phase, patients were discharged with a 12-h headache diary for hourly recordings of headache features, accompanying symptoms, intake of any rescue medication and adverse events. | PMC10690017 |
Haemodynamic variables | CORTEX | Patients rested in a quiet room for at least 30 min in a supine position before any measurements. During the in-hospital phase, we conducted electrocardiography and measured the blood pressure and heart rate. Furthermore, we used a high-resolution ultrasonography unit (Dermascan C; Cortex Technology: 20 MHz, bandwidth 5 MHz) as previously described to measure the diameter of the frontal branch of the superficial temporal artery and the radial artery. | PMC10690017 |
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Statistical considerations and analysis | migraine | MIGRAINE | Sample size calculations were based on the difference between two unpaired groups reporting migraine attacks. After administration of CGRP, we assumed that 51% of participants would report migraine attack in the placebo-treatment arm and 20% in the active-treatment arm. After administration of cilostazol, we assumed that 66% of participants would report migraine attack in the placebo-treatment arm and 20% in the active-treatment arm. These assumptions were based on previous migraine provocation studies, in which ∼66% of participants with migraine developed attacks after administration of CGRP and ∼86% after cilostazol,The primary end point was the incidence of migraine attacks in a 12-h observational period after administration of experimental triggers. | PMC10690017 |
Results | PMC10690017 |
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Study population characteristics | A total of 80 patients provided informed consent from July 2020 to July 2021; 75 patients completed both experimental study days and were included in the final analysis (
Clinical characteristics of the study populationBMI = body mass index; SD = standard deviation.
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Intracellular mechanisms can induce migraine attacks independent of CGRP receptor activation | nausea, migraine-associated, phonophobia, migraine, Migraine, photophobia | MIGRAINE, MIGRAINE | We demonstrated that erenumab can alleviate migraine attack induction with CGRP with 10 of 37 [27% (95% CI, 13–41)] participants developing migraine attacks compared to 20 out of 38 [53% (95% CI, 37–69)] participants who received placebo (
Migraine attack induction rateCalcitonin gene-related peptide (CGRP): There was a significant difference in the incidence of migraine attacks following administration of CGRP in individuals with migraine randomized to erenumab compared to placebo (We found no difference in cilostazol-induced migraine attacks between participants who received erenumab versus placebo. Cilostazol-induced migraine attacks in 28 of 37 [76% (95% CI, 62–90)] participants in the erenumab group compared to 31 out of 38 [82% (95% CI, 69–94)] participants in the placebo group (
The incidence of migraine-associated symptoms in the active-treatment group compared to the placebo-treatment group was, for nausea, 17 (46%) and 22 (58%), photophobia, 24 (65%) and 23 (61%), and phonophobia, 17 (46%) and 19 (50%), respectively. The median time to onset in the active-treatment group compared to the placebo-treatment group was, for nausea, 240 min (range, 10–660 min) and 300 min (range, 10–660 min), photophobia, 310 min (range, 10–420 min) and 240 min (range, 10–540 min), and phonophobia, 180 min (range, 10–420 min) and 240 min (range, 20–540 min), respectively; the median time of duration in the active-treatment group compared to the placebo-treatment group was, for nausea, 210 min (range, 60–540 min) and 150 min (range, 30–340 min), photophobia, 300 min (range, 50–710 min) and 420 min (range, 30–710 min), and phonophobia, 315 min (range, 30–640 min) and 240 min (range, 50–600 min), respectively. | PMC10690017 |
CGRP-mediated vasodilation is mitigated by a blockade of the CGRP receptor | DILATION | We found that erenumab significantly attenuated CGRP-induced dilation of the superficial temporal artery (AUC
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Adverse events | palpitations, migraine, flushing | ADVERSE EVENTS, MIGRAINE | The proportion of patients reporting warm sensations, palpitations and flushing in the erenumab group was lower than in the placebo group (Adverse eventsReports of adverse events following administration of calcitonin gene-related peptide (CGRP) and cilostazol in individuals with migraine randomized to erenumab or placebo.Warm sensations and palpitations are common adverse events after intake of cilostazol in individuals with migraine. | PMC10690017 |
Discussion | migraine | MIGRAINE, RECRUITMENT | A novel finding of our study is that migraine attacks induced by upregulation of intracellular cAMP levels are not affected by blocking the CGRP receptor. Our work provides clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. We want to highlight three important observations in this context: (i) patients who were pretreated with erenumab still experienced migraine attacks when cilostazol was administered; (ii) patients who were susceptible to migraine attacks following CGRP administration also had migraine attacks induced by cilostazol; and (iii) most participants who did not experience migraine attacks after receiving CGRP did have migraine attacks when cilostazol was administered.Cilostazol, a PDE-3-inhibitor, blocks both isoforms of PDE3, which is responsible for metabolizing cAMP.Cilostazol primarily inhibits the isoform PDE3A, which is predominantly found in vascular smooth muscle cells.We found that CGRP receptor blockade did not completely prevent CGRP-induced migraine attacks. One-quarter of patients in the erenumab group still experienced a migraine attack following administration of CGRP, which exceeds the expected rate of a nocebo response [8.1% (95% CI, 2.5–15.5%)].Although we applied rigorous criteria during recruitment and standardized experimental procedures, we could not rule out various environmental factors (e.g. stress, food intake) after discharge from the laboratory and the subsequent outpatient 12-h observation phase. However, alternative 12-h inpatient monitoring would have limited the feasibility of the study. In addition, the migraine attack induction rates for CGRP and cilostazol in the placebo arm were comparable to previously reported studies with these substances. | PMC10690017 |
Conclusions | migraine | MIGRAINE | The present data provide further evidence for the crucial role of second messenger signalling in a migraine attack. We demonstrate that migraine attack generation does not require CGRP receptor activation. These findings highlight the relevance of targeting downstream signalling pathways or other molecules involved in cAMP signalling, such as PACAP, as potential therapeutic targets for the treatment of migraine. | PMC10690017 |
Acknowledgements | Håkan | RITTER | M.A. was supported by the Lundbeck Foundation Professor Grant (R310-2018-3711). The authors thank Dr Haidar Al-Khazali, Dr Faisal Mohammad Amin, Dr Håkan Ashina, Dr Hande Coskun, Dr Afrim Iljazi, Dr Lanfranco Pellesi, Dr Henrik Winther Schytz, Dr Nita Katarina Frifelt Wienholtz, pharmacologist Fatima Azzahra Elbahi and lab technicians Lene Elkjær and Winnie Grønning for their assistance during the conduct of this study. Statistical support was provided by Shannon Ritter, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. | PMC10690017 |
Data availability | Anonymized datasets generated and/or analysed during the current study are available upon reasonable request and following the acquisition of necessary permissions. | PMC10690017 |
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Funding | This research was funded by and conducted in collaboration with Novartis Pharma AG, Basel, Switzerland. | PMC10690017 |
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Competing interests | M.A. is a consultant, speaker or scientific advisor for AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis and Teva, and a primary investigator for ongoing AbbVie/Allergan, Amgen, Eli Lilly, Lundbeck, Novartis and Teva trials. M.A. has no ownership interest and does not own stocks of any pharmaceutical company. M.A. serves as associate editor of | PMC10690017 |
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References | PMC10690017 |
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Background | diabetic, Diabetic Retinopathy | EYE, DIABETIC RETINOPATHY, RETINA | Diabetic Retinopathy (DR) is an important public health issue in Nepal. Despite the availability of retinal services, people may not access them because of the lack of knowledge about DR and poor referral systems. DR screening uptake was low at Reiyukai Eiko Masunaga Eye Hospital(REMEH) since retina services were started. Scheer Memorial Hospital is a multispeciality hospital near to REMEH. It has no eye department but has been running a regular diabetic clinic. This was a site for referring diabetic patients for DR screening. Improving DR awareness among general physicians has the potential to address these challenges. | PMC9905012 |
Methods | diabetic retinopathy, diabetic, diabetes | DIABETIC RETINOPATHY, DIABETES | The aim of our study was to investigate the effectiveness of providing health education to selected health personnel and establish a referral pathway on the attendance of diabetic patients for retinal screening at REMEH. This was a non-randomized, pre-post intervention study design. Total of three health education sessions were provided to the health care professionals of Scheer on diabetic retinopathy using Power Point presentations, posters, pamphlets and videos. The study period was 16 months (2020 June –2021 September) and divided into 8 months pre-intervention(baseline data collection) and 8 months post intervention period. The proportional increase in number of diabetes attendance pre and post intervention was calculated by Z test. The change in knowledge of health care personnels pre and post intervention was scored and evaluated through a questionnaire and calculated by paired- t test. Data was analyzed using Excel and Epi Info 7.The Protocol was published on August 21, 2021, in JMIR Publications. | PMC9905012 |
Results | diabetes | DIABETES | The proportional increase in number of referrals of diabetes attendance post intervention increased from 50 to 95% and was statistically significant ( | PMC9905012 |
Conclusion | This study shows that a well-planned health education intervention changes the knowledge in physicians about DR. There is an increase in the number of referrals and attendance of patients for DR screening with the change in knowledge and referral mechanism. | PMC9905012 |
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Trial Registration | Clinical Trials.gov NCT04829084; | PMC9905012 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12913-023-09105-3. | PMC9905012 |
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Keywords | PMC9905012 |
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Background | Diabetic retinopathy, blindness, Diabetic Retinopathy, diabetic, vision loss, Non-proliferative Diabetic Retinopathy, diabetes | DIABETIC RETINOPATHY, DIABETIC RETINOPATHY, BLINDNESS, DIABETIC RETINOPATHY, COMPLICATION, RETINA, PROLIFERATIVE DIABETIC RETINOPATHY, MACULAR EDEMA, EYE, DIABETES | Diabetic retinopathy (DR) is a complication of diabetes damaging the retinal vessels that can lead to blindness if left untreated [The worldwide prevalence of Diabetic Retinopathy (DR) was found to be 34.6% [DR is an emerging cause of blindness in developing countries like Nepal. SK Mishra et al. showed that 10% of the people with diabetes had some form of DR in Nepal. The prevalence of Non-proliferative Diabetic Retinopathy, Proliferative Diabetic Retinopathy, and complete vision loss due to macular edema was found to be 9.1%, 0.5%, and 0.3% respectively in Nepal [Our organization, Reiyukai Eiko Masunaga Eye Hospital (REMEH) is a non-profitable community-based hospital in Banepa, Nepal providing eye care services to a population of 411,057 in the Kavrepalanchowk district. In 2019, the hospital launched the retina clinic and started retinal services. Since the uptake of DR screening did not increase as expected, we conducted a problem tree analysis and identified that lack of referral system is one of the major reasons for the low uptake of DR screening at our hospital. Scheer Memorial Hospital is a multispeciality hospital about 2 km distance to Reiyukai Eiko Masunaga Eye Hospital. It has no eye department but has been running a regular diabetic clinic. This is a site for referring diabetic patients for DR screening. We identified that creating referral pathway between Scheer and REMEH would increase the uptake of diabetic retinopathy. Similarly, Piyasena et al. identified that the lack of knowledge and awareness on DR, and zero awareness of the importance of regular DR screening and follow-up, combined with poor information on referral pathways were key elements to be improved for better uptake of DR in the context of Sri Lanka [Published studies on referral pathways in Nepal are scarce. The aim was to investigate the effectiveness/ impact of providing health education intervention to selected health personnel and establishing a referral pathway on the attendance of patients with DM for retinal screening at REMEH. This was a pilot study as no such study was previously conducted in Nepal. | PMC9905012 |
Method | PMC9905012 |
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Research Objective | blindness | BLINDNESS | The aim of this study was to increase retinal screening uptake among patients with DM and to decrease DR-associated blindness by augmenting the referral pathway in a selected hospital in Nepal. | PMC9905012 |
Hypothesis | diabetes | DIABETES | Providing DR health education to selected health personnel and creating a referral pathway would increase the uptake of retinal services (screening and treatment) by diabetes patients referred to REMEH. | PMC9905012 |
Study design | This was a non-randomized pre- and post-intervention study without a control group. | PMC9905012 |
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Study setting | diabetic | EYE | Reiyukai Eiko Masunaga Eye Hospital (REMEH) is an eye hospital. Scheer Memorial Hospital is the intervention hospital. It is a multispeciality hospital with no eye department and has been conducting regular diabetic clinics.There was no baseline data on referral of patients from Scheer to REMEH before the study. | PMC9905012 |
Study period | The total duration was 16 months from June 2020 to September 2021. The initial 8 months from June 2020 to January 2021 was for base line data collection (pre-intervention period). The remaining 8 months from February 2021 to September 2021 was the post intervention period. | PMC9905012 |
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Study participants | diabetes mellitus, diabetic | DIABETES MELLITUS | Selected Health personnel of Scheer Memorial Hospital (The intervention hospital) who are directly involved in providing health services to diabetes mellitus patients in the diabetic clinic at Scheer. Physicians, paediatricians, medical officers and their assistants were included. Those health personnel who didn't attend at least 2 sessions of intervention were excluded.List of health personnel | PMC9905012 |
Sampling techniques | diabetes | DIABETES | Complete enumerations of all health personnel managing patients with diabetes in the intervention hospital. | PMC9905012 |
Inclusion criteria | diabetes | DIABETES | All health personnel involved in the management of patients with diabetes at the intervention hospital. | PMC9905012 |
Materials | The Information Education and Communication (IEC)material developed by the Indian Institute of Public Health-Hyderabad; India (IPHH) was used for intervention after converting into Nepalese language. The IEC materials were PPT, poster (Annex | PMC9905012 |
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Implementation of intervention | DM | RETINA | The retina specialist and the optometrist/outreach coordinator of REMEH conducted the intervention. The assistant manager of the hospital was responsible for the logistics. There was no control group in this study. A pilot was done before the main intervention started.A pilot was conducted In Feb 19,2021 to the health professionals of Krishna Prasad Hospital on Feb1The intervention for selected health personnel of Scheer was conducted after 8 months of baseline data collection as a once-a-month health education session for three months. (February 2021-April 2021) in REMEH. The post intervention data collection started from February 2021 as soon as the first intervention started.First intervention was conducted on health personnel of Scheer memorial Hospital on February 6, 2021. Proper COVID-19 guidelines were followed with social distancing and masks. The participants were provided with transportation and refreshments.Before we began our intervention, all the participants signed the consent form that included details of age, gender, qualification, and years of experience. In the first session, we conducted a pre- intervention assessment by providing a baseline questionnaire to the participants. Questionnaire was translated into native language. At the end we judged their knowledge with pre intervention questionnaire. We made sure all questions were attempted. The principal investigator, retina specialist made power point presentation.We conducted the second round of intervention on March 16, 2021.Fourteen participants attended the session. Two medical officers from the previous session did not participate and two new medical officers participated in the second session. Our optometrist distributed the pamphlets and explained the contents. Participants were reminded to counsel DM patients to visit REMEH, use referral slip while referring patients to REMEH, handover DR-related pamphlets to DM patients and finally record total cases referred to REMEH in a month.The third and final intervention was held on April 23, 2021. Total of 14 participants participated in this session. The session started with post intervention questionnaire. We collected answer sheets and gave answers to all questions in an interactive session. At the end we distributed additional referral slips and pamphlets.The same questionnaire was shared with all the participants via goggle form after 2 months on July1, 2021. All the 14 participants filled the answers. | PMC9905012 |
Data collection | Data collection included the pre-post intervention after health education at Scheer Memorial, as well as patient referral data at REMEH. Data was entered into the EXCEL sheet every week. The data tools are mentioned in the Annex ( | PMC9905012 |
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Data analysis | The baseline and post intervention patient referral data was compared and the proportional increase due to intervention was calculated. The change in knowledge of health personnel was assessed by pre and post assessment questionnaire. In patients’ data, Information on DR and duration of DM was collected, visual acuity and stage of DR was noted. Descriptive analysis for the same was done. Information on the referred data was collected from the intervention hospital. Mean median and Standard deviation were calculated for the demographic variables. Z test was applied to determine the number of referrals to justify the research hypothesis that the proportion of referral cases after the intervention is improved. The change in mean knowledge after the intervention, i.e. the mean knowledge score pre and post-intervention are tested using the paired t-test.Data was analyzed using excel and Epi info 7. The ethical approval for this study was obtained from the Ethical Review Board of Nepal Health Research Council on 22/12/2020(ERB Protocol Registration Number#582/2020P).Protocol of the study was published on August 21, 2021, in JMIR Publications. Clinical trials registration: NCT04829084 [ | PMC9905012 |
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Outcome | Primary outcome:1. Change in the proportion of referred patients from Scheer Memorial to REMEH when compared to baseline referrals before the intervention.Secondary outcome:2.Change in knowledge on DR in the Health Care Personnel (HCP) who participated in health education sessions in Scheer Memorial. | PMC9905012 |
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Results | diabetes, Diabetes Mellitus, SD, ’ | DIABETES MELLITUS, DIABETES | Of the 14 health care personnel enrolled in health education intervention 10(71.43%) were physicians with median experience of 4.5 years (IQR 3–6.75) and 4 (28.57%) were non physicians with median experience of 27.5 years. The male and female ratio in health care personnel was equal with an mean age of 35.8 years (SD ± 9.4) years (Table Socio demographic profile of the Health care providersThe mean score of the physicians DR knowledge and awareness increased at post intervention (8.8 ± 1.32) as compared to pre intervention (6.4 ± 1.51) (Change in knowledge level of health care personnel at pre and post interventionProportion of referral to REMEH from Scheer in per and post intervention periodTotal of 71 patients with Diabetes Mellitus attended from intervention hospital (Scheer) during the study period from 1Referral cases from Scheer were further divided based on the experience and position of health care physicians. Total of 8 (80%) health care personnel had experience of less than or equal to 5 years and they referred a total of 8 (88.89%) and 44 (70.97%) patients from pre and post intervention period and rest of the patients were referred by physicians with > 5 years’ experience. Internal medicine doctors referred more, followed by medical officer and pediatricians but it was not statistically significant (Table Health care personnel experience and post associated with Referral From ScheerPosition/PostIn Pre-intervention period, 6 (66.67%) males and 3 (33.33%) females attended REMEH, whereas 24(38.71%) males and 38(61.29%) females attended REMEH at post intervention. The average age of pre intervention patients was 56.67 years (SD ± 17.30) while that of post intervention patients was 55.39 years (SD ± 12.51). Mean duration of diabetes in the pre intervention was 7.05 (SD ± 6.37) and post intervention was 5.12 (SD ± 5.80). Almost 66.67% patients had smoking habit in per intervention whereas post intervention was 48.39% patients. A total of 7 (77.78%) and 45 (72.78%) patients were a normal lipid profile. It was observed that basic and clinical characteristics were not significantly different in pre and post intervention group (Table Socio demographic and clinical profile of the patients attended at REMEHTable | PMC9905012 |
Discussion | diabetic retinopathy, DM, Diabetic retinopathy, ±, diabetes mellitus, SD, diabetic, diabetes | DIABETIC RETINOPATHY, DIABETIC RETINOPATHY, DIABETES MELLITUS, PCP, DIABETES | We conducted a non-randomized pre-post health education intervention study on health personnel with an objective to increase the referral of DM patients for DR screening. The health professionals were provided health education to create awareness and knowledge of DR using PPTs, posters, pamphlets, and referral slips. There was a significant increase in referral and attendance of DM patients in REMEH for DR screening after the intervention. There was also a significant increase in knowledge among the physicians after the intervention.Few studies in Nepal have mentioned the need of stakeholders to enhance and provide quality eye care services to diabetic people. The need to establish coordination between general medical service providers and the eye care service providers to develop a coordinated service system for diabetes and diabetic retinopathy care has also been discussed [Our study should be the first study involving stakeholders in health education session on DR aiming to increase the DR referral in Nepal. Piyasena et al. in their study involved patients with diabetes mellitus and stakeholders in health education intervention sessions to improve the uptake of screening for DR. They also developed strategies to improve knowledge on diabetic retinopathy in Sri Lanka, like our study [The male and female ratio in health care personnel was equal with overall average age of 35.8 years Ten (71.43%) were physicians with median experience of4.5 years and 4 (28.57%) were non physicians with median experience of 27.5 years. Anwar et al. in their study in Pakistan enrolled 36 physicians for DR related health education intervention. The mean age was33.10 ± 11.2 years and 64% were female and 36% were male. Most of the participating physicians, 61% (In our study, the mean score of the physicians DR knowledge and awareness increased at post intervention as compared to pre intervention. We did a follow up after 2 months by sending questionnaire via goggle forms. All the participants except the helpers responded and the overall mean score was 7.71 ± 2.30 not decreased for the physicians. Similarly other studies have also assessed the DR awareness of physicians by calculating Diabetic retinopathy awareness index (DRAI) and found the need of referral communication with the physicians and ophthalmologists/retina specialist [Similarly, we used a referral slip as a mode of communication between an ophthalmologist and health care personnel providing medical care to the patients with diabetes at Scheer Memorial hospital. Storey et al. also found that written communication between an ophthalmologist and a primary care physician (PCP) and referral vice versa was effective to change the behavior of the referring physicians [We also conducted a pilot before the health education intervention and there were only two physicians. Therefore, it was easy to compare the before and after score of the physicians. Pilot made us realize that pre post questionnaire needed to be written in Nepali language as well, to eliminate language barrier. We missed to distribute information sheet and consent form which we corrected during the final sessions. We used posters, pamphlets, videos and PPTs with diabetic retinopathy awareness message in our educational sessions which helped change the behavior of the physicians. Similarly, printed educational messages and posters increased behavior and change in attitude of primary care physicians and assistants of a multi-specialty hospital in Ireland and increased diabetic retinopathy screening like our study [There was a significant increase in the number of diabetic retinopathy patients attendance post intervention in our study. The use of printed educational messages like the use of pamphlets and referral slips also increased the number of referrals by primary health care professionals to ophthalmologist [Few studies have shown that lesser experienced primary health care professionals and internists could miss the diagnosis and refer a smaller number of diabetic retinopathy than the experienced health care professionals [In our study female patients attended for diabetic retinopathy screening more than males in both the pre and post intervention period. Similarly in other study females were found to be more than males for diabetic retinopathy screening [The mean age of pre intervention patients was 56.67 years (SD ± 17.30) while that of post intervention patients was 55.39 years (SD ± 12.51). Similarly in few other studies the mean age 55.43 ± 11.86 years [ | PMC9905012 |
Conclusion | EYE | A well-planned health education intervention changes the knowledge in physicians about DR. With the change in knowledge and structured referral system, there is significant increase in the number of referrals and attendance of patients for DR screening. This study clearly shows the need to mobilize and link physicians in general hospital with Eye Hospital. | PMC9905012 |
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Strength and limitations | DIABETIC RETINOPATHY | The strength of our study is that it is one of the first studies in Nepal that includes health care professionals involved in DM management and strengthens the referral for the screening of diabetic retinopathy. The pilot gave us information on re-comprehension of the content of the materials to be used for the main study.Due to COVID-19, the number of selected health personnel participating in health education was less than expected. We did not have a control hospital to compare our intervention and the effect of the referral pathway in 2 hospitals, which could limit our study’s generalizability. Due to COVID-19 the number of patients attending Scheer and REMEH might have been affected. It will be useful to have further studies with a qualitative component to understand the barriers faced by health personnel on the referral process and reasons for delays, if any. | PMC9905012 |
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Acknowledgements | GILBERT | We gratefully acknowledge the SEVA Foundation and Indian Institute of Public Health – Hyderabad for their valuable guidance and support of this work and the staff at REMEH for their contribution to various aspects of the work of this initiative. The Study Group is funded by SEVA Foundation. We are also grateful to all the health care personals of Scheer Memorial Hospital for participating in the study.The Operational Research Capacity Building Study Group helped in providing training for research methodology. Indian Institute of Public Health, Hyderabad (Public Health Foundation of India): Professor Gudlavalleti Venkata Satyanarayana Murthy, Dr Suresh Kumar Rathi, Dr Rajan Shukla, Dr Samiksha Singh, Dr Shailaja Tetali, Dr Hemant Mahajan, Dr Tripura Batchu, Dr Anirudh G Gudlavalleti, Dr Melissa G Lewis, Dr Varun Agiwal, Mr Hira Pant. SEVA: Dr Suzanne Gilbert, Dr Ken Bassett, Ms Priya Adhisesha Reddy, Ms Parami Dhakhwa, Mr Ram Prasad Kandel, Mr Kuldeep Singh, Mr Prasanna Sharma. | PMC9905012 |
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Author’s contributions | TB, RS, PD | HBP | RS, PS, PD, ST, and TB conceptualized and designed the study. RS, PS, PD, PST, VA and HBP were responsible for the data handling. RS, ST, and TB drafted the manuscript. “All authors have read and approved the manuscript”. | PMC9905012 |
Funding | SEVA Foundation, Kathmandu, Nepal. | PMC9905012 |
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Availability of data and materials | Datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC9905012 |
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Declarations | PMC9905012 |
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Ethics approval and consent to participate | The research has been performed in accordance with the Declaration of Helsinki. The ethical approval for this study has been obtained from the Ethical Review Board of the Nepal Health Research Council (ERB Protocol Registration Number # 582/2020P). Written informed consent was taken from the participants. | PMC9905012 |
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Consent for publication | Written informed consent has been taken from all subjects and/or their legal guardian(s) for publication of identifying information/images in an online open-access publication. | PMC9905012 |
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Competing interests | The authors declare no competing interests. | PMC9905012 |
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References | PMC9905012 |
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Dr. Yan-xin Chen | liver and pancreatic cancer | was born and raised in the coastal city of Guangdong Province, China. He majored in anesthesiology and obtained a medical master’s degree from Southern Medical University. He completed his anesthesiology residency training at Southern Medical University, where he started his basic-medical research. His clinical interest is in general surgery, especially liver and pancreatic cancer anesthesia. His research has focused on perioperatively cerebral functional protection.
Bicycle riding is his favorite sport which he takes on daily.
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Background | POSTOPERATIVE COMPLICATIONS, INFLAMMATORY RESPONSE | Laparoscopic pancreaticoduodenectomy (LPD) may induce intense inflammatory response which might be related to the patient’s outcomes. Clinical dexmedetomidine (DEX) has been widely used for opioid-sparing anesthesia and satisfactory sedation. The objective of this study was to investigate the influence of DEX on inflammatory response and postoperative complications in LPD. | PMC9803753 |
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Methods | POSTOPERATIVE COMPLICATIONS | Ninety-nine patients undergoing LPD were randomly assigned to two groups: normal saline (NS) and DEX. The primary outcome was the neutrophil-to-lymphocyte ratio (NLR) differences postoperatively within 48 h. Secondary outcomes were postoperative complications, the length of postoperative hospital stay and the incidence of ICU admission. Other outcomes included anesthetics consumption and intraoperative vital signs. | PMC9803753 |
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Results | NLR at postoperative day 2 to baseline ratio decreased significantly in the DEX group ( | PMC9803753 |
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Conclusions | LPD | COMPLICATIONS, INFLAMMATORY RESPONSE | Intraoperative DEX reduced the early postoperative inflammatory response in LPD. It also reduced the use of narcotics that may related to reduced major complications, which need additional research further. | PMC9803753 |
Introduction | cancer death, Pancreatic cancer, death | PANCREATIC CANCER, POSTOPERATIVE COMPLICATIONS, INFLAMMATORY RESPONSE | Pancreatic cancer is currently the seventh leading cause of cancer death worldwide and the third leading cause of cancer-related death in the USA [Dexmedetomidine (DEX) is a highly selective As a result of the potential immunomodulation of DEX, we hypothesized that the use of DEX could attenuate the inflammatory response induced by LPD. In parallel, we also investigated the incidence of postoperative complications related. | PMC9803753 |
Methods | PMC9803753 |
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Ethics | Ethical approval for this study (Z2017-129–01) was provided by the Ethics Committee of Guangdong Provincal Hospital of Chinese Medicine (Chairperson Professor Jun Liu), Guangzhou, China, on 8 September 2017. This randomized, double-blinded, controlled trial was registered on Chinese Clinical Trial Registry (ChiCTR 1,800,017,065, July 10, 2018) and conducted between 10 July 2018 and 10 January 2022 at the Department of Anaesthesiology of The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China. Written informed consent was obtained from each eligible patient on the day before surgery. | PMC9803753 |
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Study design | LPD | The inclusion criteria for patients were that they planned to receive LPD, aged 18 to 65 years, body mass index (BMI) <28.0 kg m | PMC9803753 |
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Anesthesia management and groups | To ensure the randomization of groups, random number was generated by computer and stored in sequentially numbered envelopes. A nurse who did not participate in the trial prepared drug X [DEX or normal saline (NS)] according to the number in the envelope. Only this nurse was aware of patient allocation. General anaesthesia was induced with propofol (TCI 3ug ml | PMC9803753 |
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Outcome measures | pancreatic fistula | INTRA-ABDOMINAL INFECTION, BILE LEAKAGE, POSTOPERATIVE COMPLICATIONS, POSTOPERATIVE COMPLICATION, POSTOPERATIVE HEMORRHAGE, COMPLICATIONS, SECONDARY, PANCREATIC FISTULA, LEAKAGE, DELAYED GASTRIC EMPTYING | The primary outcome was NLR differences perioperatively. The secondary outcomes were the postoperative complications, the incidence of postoperative ICU admission, and the length of postoperatively hospital stay. Postoperative complications include pancreatic fistula, bile leakage, chylous leakage, postoperative hemorrhage, delayed gastric emptying, and intra-abdominal infection. Major complications include pancreatic fistula Grade B / C [ | PMC9803753 |
Sample size and statistical analysis | According to previous studies [ | PMC9803753 |
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Discussion | inflammation, cancer | POSTOPERATIVE COMPLICATIONS, INFLAMMATION, CANCER, PANCREATIC CANCER, TUMOR ANGIOGENESIS | Surgical resection is the mainly possible cure for pancreatic cancer; however, surgery itself induces intense stress response to cause immunosuppression and excessive pro-inflammatory responses, which could promote tumor angiogenesis and increase postoperative complications [As an inflammatory indicator, NLR indicates the balance between innate and adaptive immune responses and it is an excellent indicator of inflammation and stress together. Neutrophils are a part of the innate immune response, which can exert several pro-tumor activities in cancer and promote progression through different mechanisms [ | PMC9803753 |
Limitations | cancer type, cancer, tumor | CANCER, TUMOR, PERIAMPULLARY CARCINOMA | There are several limitations in this study. Firstly, the inflammatory indicators we examined were relatively single, and there may be differences in other immune cells and cytokines. Furthermore, long-term indicators are important for cancer prognosis, and we only collect short-term outcome indicators and pay more attention to the immune-related situation, did not follow up after discharge from the hospital. Secondly, patients undergoing LPD include different types of periampullary carcinomas, and the bias caused by cancer type cannot be completely ruled out, although the distribution of tumor types in two groups was similar. Thirdly, we only collected and measured samples every 24 h after surgery. For the lack of detection within 24 h after surgery, the dynamic changes of inflammatory factors and immune cells may not be observed in time. | PMC9803753 |
Funding | The Guangzhou Municipal Science and Technology Project, China (Grant No.202102010243). | PMC9803753 |
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Declarations | PMC9803753 |
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Conflict on interest | The authors declare that they have no conflicts of interest. | PMC9803753 |
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Ethical approval | Ethical approval for this study (Z2017-129–01) was provided by the Ethics Committee of Guangdong Provincal Hospital of Chinese Medicine (Chairperson Professor Jun Liu), Guangzhou, China, on 8 September 2017. | PMC9803753 |
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Informed consent | Informed consent was obtained from all individual participants included in the study. | PMC9803753 |
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References | PMC9803753 |
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Background | Chagas disease, EH | DISEASE, CHAGAS DISEASE | I have read the journal’s policy and the authors of this manuscript have the following competing interests: AMR and JA are members of the Research Career of CONICET, Argentina. JA has acted as a consultant to Bayer for the design, conduct and review of the CHICO and CHICO SECURE studies. UG is an employee of Bayer AG. EH is an employee of Bayer US LLC.¶ Membership of the CHICO and CHICO SECURE study groups is provided in Measurement of the success of antitrypanosomal treatment for Chagas disease is difficult, particularly in the chronic phase of the disease, because anti- | PMC10325040 |
Methods and principal findings | Chagas disease | CHAGAS DISEASE | In a phase 3, randomized, double-blind, parallel-group, historically controlled study (ClinicalTrials.gov NCT02625974), blood samples obtained from children diagnosed with Chagas disease and treated with nifurtimox for either 60 days or 30 days were analyzed using an ELISA with an F29 recombinant protein as the antigen, as well as conventional serological tests (recombinant ELISA and indirect hemagglutination assay). In an exploratory approach, serological response to nifurtimox treatment was evaluated for 4 years post-treatment. In both treatment groups, the number of patients with negative ELISA F29 values increased over the period of observation. The incidence rate of negative seroconversion using ELISA F29 was 22.94% (95% CI: 19.65%, 26.63%) in the 60-day treatment group and 21.64% (95% CI: 17.21%, 26.86%) in the 30-day treatment group. In the subpopulation of patients who tested seropositive for F29 before nifurtimox treatment, 88 patients (67.7%) in the 60-day regimen and 39 patients (59.1%) in the 30-day regimen were F29 seronegative at 4 years post-treatment. All patients who had a positive ELISA F29 test at baseline and seroconverted to negative measured by conventional serology reached seronegativity in ELISA F29 earlier than in conventional serology. | PMC10325040 |
Conclusions | CHAGAS DISEASE | The results demonstrate a serological response to treatment with nifurtimox measured by the ELISA F29 test in children diagnosed with Chagas disease. The F29-based ELISA can be considered a potential early marker of response to antitrypanosomal therapy for Chagas disease. | PMC10325040 |
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Trial registration | ClinicalTrials.gov | PMC10325040 |
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Author summary | Chagas disease | AMERICAN TRYPANOSOMIASIS, PARASITIC DISEASE, CHAGAS DISEASE | Chagas disease (American trypanosomiasis) is a potentially life-threatening parasitic disease caused by | PMC10325040 |
Data Availability | The study protocol, statistical analysis plan and the results of the study are available at | PMC10325040 |
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Introduction | Chagas disease | AMERICAN TRYPANOSOMIASIS, DISEASE, PARASITIC DISEASE, CHAGAS DISEASE | Chagas disease (American trypanosomiasis) is a potentially life-threatening parasitic disease that for many years has been endemic in 21 Latin American countries and areas of southern USA [The protozoan The diagnostics recommended by national organizations and the Pan American Health Organization (PAHO) includes the combining of two positive serological tests: enzyme-linked immunosorbent assay (ELISA) and indirect hemagglutination assay (IHA) or indirect immunofluorescent assay (IFA), with potentially a third test if the results are conflicting [Potential biomarkers of early therapeutic responses have been tested in different clinical contexts. An ELISA using a 29 kDa flagellar recombinant F29 antigen of the parasite (ELISA F29) was developed [In a prospective, historically controlled, phase 3 clinical trial, the CHagas disease In Children treated with nifurtimOx follow-up for SEroconversion and CURE (CHICO and CHICO SECURE) trial, we followed pediatric patients with Chagas disease over a period of 4 years after treatment with a new formulation of nifurtimox and evaluated the incidence rate of seronegative conversion and their serological response to nifurtimox treatment using conventional serological methods (recombinant ELISA, total purified antigen ELISA, and IHA) and ELISA F29 at annual follow-ups. The progress of seronegative conversion detected by ELISA F29 and conventional serological methods during follow-up was compared. The results obtained for conventional serology, parasitological tests, and safety, as well as for ELISA F29 at first year of follow-up, are reported elsewhere [ | PMC10325040 |
Methods | PMC10325040 |
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Ethics statement | DEL | The study was approved by the respective independent ethics committees of participating investigational sites (Argentina: Comité de Ética, Hospital General de Agudos J. A. Fernández, Buenos Aires; Comité de Ética Independiente en Investigación Clínica "Dr. Carlos A. Barclay", Buenos Aires; Comité Institucional de Revisión de Protocolos de Investigación, Hospital de Niños Sor María Ludovica, La Plata; Comité de Ética en Investigación del Hospital de Niños Ricardo Gutiérrez, Buenos Aires; Comité de Ética en Investigación, San Miguel de Tucumán; Comité de Ética en Investigación del Hospital General de Niños, Buenos Aires; Comité de Ética en Investigación Hospital FJ Muñiz, Buenos Aires; Comité Independiente de Ética Médica del Noroeste Argentino, San Miguel de Tucumán; Comité de Ética del Hospital Pediátrico Dr Humberto Notti, Mendoza; Comité de Bioética, Hospital Dr Fernando Barreyro, Posadas. Colombia: Comité de Ética en Investigaciones de la Fundación Cardiovascular de Colombia, Floridablanca; Centro de Atención e Investigación Médica CAIMED S.A., Bogota; Comité de Ética en Investigación Hospital Mental Antioquia, Bello; Universidad del Norte, Barranquilla; Bolivia: Comité de Ética de CEADES, Cochabamba; Comité de Ética Hospital Manuel Ascencio Villarroel, Punata). Written informed consent of the patient and/or their parent(s) or legally authorised representative(s) was obtained prior to screening according to age and local regulations. In addition, depending on their age, patient assent was obtained if required by locally applicable laws and regulations in each country. | PMC10325040 |
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Study design and procedures | Chagas disease | BLOOD, CHAGAS DISEASE | In a phase 3, randomized, double-blind, parallel-group, historically controlled study (ClinicalTrials.gov NCT02625974), blood samples obtained from children diagnosed with Chagas disease were analyzed using ELISA F29. Blood samples were obtained for ELISA F29 immediately before nifurtimox treatment (baseline), on Days 7 (±1), 30 (±3), and 60 (±3) after the start of treatment and on Months 6 (±7 days), 12 (±7 days), 24 (±6 weeks), 36 (±6 weeks), and 48 (±6 weeks) after end of treatment.Details of the study design and outcomes have been published elsewhere [The design and all aspects of the conduct, evaluation, and documentation of the study conformed with good clinical practice guidelines and the guiding principles of the current version of the Declaration of Helsinki. The study also complied with applicable local law(s) and regulation(s), and all information identifying patients was collected, stored and analyzed in strict confidence and in accordance with local data protection laws. | PMC10325040 |
ELISA F29 laboratory test | An ELISA containing a recombinant 29 kDa | PMC10325040 |
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Outcomes | The serological response using ELISA F29 over time and the incidence rate of seronegative conversion measured by ELISA F29 were evaluated after treatment with nifurtimox. Furthermore, the time at which seronegative conversion was detected was compared for ELISA F29 and conventional serological methods: recombinant ELISA, total purified antigen ELISA, and IHA. | PMC10325040 |
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Statistical analyses | Analysis of patient characteristics used the full analysis set (FAS), which included all patients who received at least one dose of study drug. For analysis of ELISA F29, a subpopulation was defined that included all patients in the FAS who had positive ELISA F29 results at baseline.The incidence rate of seronegative conversion measured and confirmed by ELISA F29 in patients from the FAS was calculated. Incidence rate is the number of new cases of seronegative conversion over the study period, i.e. 4 years after end of nifurtimox treatment, divided by the total number of person-years, which was the estimate of the actual number of at-risk years for all patients who contributed to the study. Patients who used antitrypanosomal drugs other than the study drug before they were seroconverted to negative were not considered as seroconverted, but their time of observation until the first use of antitrypanosomal drugs was factored into the person-time calculation.All analyses were descriptive, and no formal testing was performed. All statistical analyses were performed using Statistical Analysis System version 9.2 or higher (SAS Institute, Cary, NC, USA). | PMC10325040 |
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Results | PMC10325040 |
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Patient characteristics | Among the 330 patients randomly assigned to nifurtimox treatment for 60 days or 30 days, 318 completed part 1 of the study (CHICO) [Among the 295 patients who were followed for 4 years post-treatment, 53.2% were females and 46.8% were males. The median age was 8.5 years (interquartile range: 2–13 years). About two-thirds of the patients were aged between either >6 and ≤12 years (37.3%) or >12 and <18 years (33.6%) at randomization ( | PMC10325040 |
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Patient characteristics at randomization (FAS). | PMC10325040 |
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ELISA F29 | In both treatment groups, the number of patients with negative ELISA F29 results increased over the period of observation after the end of nifurtimox treatment. At the 4-year follow-up the proportion of patients with seronegative ELISA F29 values was 77.2% in the 60-day regimen and 66.3% in the 30-day regimen ( | PMC10325040 |
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Serological responses to 60-day and 30-day nifurtimox treatment using ELISA F29 over the study period (FAS). | A total of 99 of the 295 patients (33.6%) showed negative ELISA F29 values at baseline, and the proportion of such patients was similar in the two nifurtimox treatment groups (60-day regimen: 67 patients [34.0%]; 30-day regimen: 32 patients [32.7%]) ( | PMC10325040 |
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Serological responses to 60-day and 30-day nifurtimox treatment using ELISA F29 over the study period (subpopulation of FAS | *The subpopulation of FAS consists of all patients with positive ELISA F29 results at baseline. | PMC10325040 |
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Kaplan-Meier survival curve of seronegative conversion in patients with positive ELISA F29 results at baseline. | PMC10325040 |
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Comparison of serological response to nifurtimox treatment measured by ELISA F29 and by conventional serology | At the 4-year follow-up, the number of patients with seronegative ELISA F29 values was higher in both treatment groups compared with the number of patients with seronegative values measured by either recombinant ELISA, total purified antigen ELISA, or IHA (Number of patients with nonreactive values measured by ELISA F29, recombinant ELISA, total purified antigen ELISA, and IHA in the 60-day (A) and 30-day (B) nifurtimox treatment groups over the study period (FAS). | PMC10325040 |
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Discussion | Chagas disease | CHAGAS DISEASE, CHRONIC CHAGAS DISEASE | Until now, there has not been an adequate parameter that reflects the early response or failure of etiological treatment for Chagas disease. Currently, the evaluation of the negativization of serology demonstrated by more than one type of conventional assay is the accepted criterion to establish successful treatment for Chagas disease [In this study, an ELISA containing a recombinant protein of the parasite (F29) was used to evaluate the serological profile in pediatric patients treated with nifurtimox and followed for 4 years post-treatment. The results clearly demonstrate conversion of ELISA F29 values to negative after antitrypanosomal therapy with nifurtimox in pediatric patients with acute and chronic Chagas disease. Similar results were observed in several previous clinical studies. In a retrospective cross-sectional study, for example, serum samples from patients with chronic Chagas disease (n = 118) followed for up to 23 years and either treated with trypanocidal therapy (nifurtimox or benznidazole) or left untreated were evaluated by ELISA F29, and its relation to conventional serology, blood parasite levels evaluated by xenodiagnosis, and clinical aspects were analyzed [It is known that different serological tests used to identify anti-In contrast to tests using a single antigen, such as the ELISA F29, the sensitivity of assays that include multiple antigens is higher, as recently shown in a multiplex serological approach [In conclusion, our results demonstrate a serological response to treatment with nifurtimox, an established antitrypanosomal drug, evidenced by a decrease in anti-F29 antibodies in children diagnosed with Chagas disease. Our results are consistent with previous studies showing that ELISA F29 is a reliable and appropriate biomarker to assess response to antitrypanosomal therapy in Chagas disease. The earlier disappearance of antibodies against F29 relative to those detected in conventional ELISAs indicates variation within the overall serological response to antitrypanosomal treatment, and may be indicative of the subsequent elimination of the parasite. | PMC10325040 |
Supporting information | PMC10325040 |
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Study site principal investigators of the CHICO and CHICO SECURE Study Groups. Investigators participated in both studies unless indicated otherwise. | (DOCX)Click here for additional data file.We thank the study participants and their families. The CHICO and CHICO SECURE Study Group members are listed in | PMC10325040 |
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