Purpose: There are few studies on the glucose metabolic characteristics of the extra-hypothalamic cortex in the hypothalamic hamartomas (HH). A comprehensive understanding of pathogenic progression of the disease is required from the perspective of cortical metabolism; therefore, we aimed to characterize metabolic characteristics of extra-hypothalamic in HH patients.Methods: We investigated the metabolic characteristics of 16 HH patients, all of whom underwent epilepsy evaluation at Xuan Wu Hospital between 2017 and 2019. The lateralization and cortical distribution pattern of hypometabolism was assessed and related to HH mass neuroanatomy on magnetic resonance imaging (MRI) as well as scalp-electroencephalogram  abnormalities. Furthermore, asymmetry measurements of region of interest (ROI) in the temporal cortex  were quantitatively assessed based on the normalized average positron emission tomography (PET) voxel values. The surgery prognosis was assessed using the International League Against Epilepsy (ILAE) classification system.Results: The lateralization of hypometabolism in global visual ratings was consistent with the HH mass lateralization seen on MRI. Cortical hypometabolism showed three patterns depending whether the HH mass involved mammillary bodies, middle hypothalamus nucleus, or both. The three patterns were hypometabolism of the mesial temporal cortex with symptom of mesial temporal epilepsy , lateral temporal, and extratemporal  cortex with symptom of neocortex temporal or frontal epilepsy , and mesial and lateral temporal cortex and extratemporal  cortex with varied symptoms , respectively. A significant difference in PET voxel values was found between bilateral hippocampal formation (P = 0.001) and lateral temporal neocortex in the third group (P = 0.005). We suggest that the hypometabolic characteristics of the extra-hypothalamic cortex in HH patients have three patterns. The final cortical hypometabolic pattern depends on the neuroanatomic location of the HH mass and was consistent with the main involved cortex of the interictal and ictal discharges. The third hypometabolic pattern with the most extensive cortical hypometabolism has a poorer prognosis. Hypothalamic hamartomas (HH) are characterized by a variety of clinical spectrum, evolving from disease with epilepsy, central precocious puberty, or cognitive and behavioral impairment to catastrophic epileptic encephalopathy –6. The d18F]-fluorodesoxyglucose positron emission tomography [[18F] FDG-PET] provides additional, independent information for structural neuroimaging. The SPECT and PET tracers can measure regional cerebral blood flow and glucose metabolism associated with epileptic dysfunction. Therefore, they can be used as surrogate markers of the functional deficit cortex , and [t cortex .One SPECT study found two hyperperfusion patterns in the cortex of HH-related epilepsy . One patPET studies show higher sensitivity and specificity in the localization of the functional deficit cortex than SPECT studies . In a PE18F] FDG-PET scans were acquired in patients with multiple seizure types other than gelastic seizure or with severe cognitive or behavioral disorders, completely in accordance with clinical needs. In addition, EEG and MRI were acquired in the context of presurgical evaluation and were available for retrospective analysis. The clinical characteristics of the included patients are shown in The present retrospective study included 16 patients  with medically intractable epilepsy due to HH, all of whom underwent epilepsy evaluation, and thermocoagulation was performed at Xuan Wu Hospital between 2017 and 2019. We excluded cases with (a) previous history of surgical intervention and (b) any brain abnormalities other than HH in image.  and compared between the contralateral and ipsilateral temporal cortex with the Wilcoxon signed-rank test. Wilcoxon signed-rank tests were calculated with the Statistical Package for the Social Sciences for Windows .HH lateralization seen on MRI was consistent with the lateralization of reduced glucose metabolism in global visual ratings. In seven of the 16 patients, HH mass was attached or predominantly attached to the left hypothalamus, and the hypometabolism of the extra-hypothalamic cortex was on the left hemisphere. In another nine patients, HH attached or predominantly attached to the right hypothalamus, causing lateralization of the cortical hypometabolism in the right. For further details, see The extra-hypothalamic cortex in patients with HH mainly presented three hypometabolic patterns, which were related to the neuroanatomical location of HH mass and electroclinical abnormalities see . In threThe first pattern (pattern I) showed three patients  whose cortical hypometabolism was mainly in the limbic cortex of the mesial temporal lobe, including the hippocampal formation, parahippocampal gyrus, or entorhinal cortex. Three patients showed reduced glucose metabolism only in the mesial temporal cortex . The T1-The second pattern (pattern II) showed five patients  whose cortical hypometabolism was mainly in the lateral temporal cortex. It may also involve the extratemporal cortex, such as the frontal cortex and the parietal cortex, while the mesial temporal cortex is rarely affected . The latThe third pattern (pattern III) among the other eight patients showed the most extensive range of reduced glucose metabolism in the extra-hypothalamic cortex, including the mesial and lateral temporal, frontal, and parietal cortex . Two pat18F] FDG PET in ROI of the temporal cortex. In the hypometabolic pattern group I, no statistically significant asymmetry was found between the hippocampal formation , amygdala , and lateral temporal neocortex . In the hypometabolic pattern group II, no statistically significant asymmetry was found between the hippocampal formation , amygdala , and lateral temporal neocortex . In the hypometabolic pattern group III, the mean normalized PET voxel values were significantly higher in the contralateral hippocampus formations than that in the ipsilateral hippocampus formations ; and the mean normalized PET voxel values were significantly higher in the contralateral lateral temporal neocortex than that in the ipsilateral lateral temporal neocortex . No significant differences were found between bilateral amygdale  (= 0.083) .The prognosis after surgery of the hypometabolic pattern groups was defined according to the ILAE classification system. A good prognosis corresponded to ILAE classes 1, 2, and 3 . Of the To our knowledge, this is one study with a relatively large sample size focusing on metabolic distribution characteristics of extra-hypothalamic cortex in patients with HH. With respect to the cortical glucose metabolic characteristics in patients with HH, we found that HH mass lateralization seen on MRI was significantly correlated with the lateralization of cortical hypometabolism. This is consistent with previous findings. For example, Wagner et al.'s  corticalIn addition, our research found that the hypometabolism pattern of extra-hypothalamic cortex can be divided into three patterns, mainly related to the neuroanatomical location of the HH mass and was concordant with the cortical regions of the interictal and ictal discharges. In a PET study of five patients with HH, Ryvlin et al.  found thWe found that the first pattern of cortical hypometabolism was in the limbic structures of the mesial temporal lobe. In this group of cases, MRI showed that HH masses were entirely located below the third ventricle and inside the interpeduncular cistern. The T1 image showed the structure of the mammillary bodies was interrupted and unclear, suggesting that HH masses may invade the mammillary bodies. Previous literature shows that HH have a tight connection with the limbic system, such as mesial temporal cortex, through the mammillary bodies . List etCortical hypometabolism in the second group of cases was mainly in the lateral temporal cortex, and it can also involve the extratemporal cortex, such as the frontal and parietal cortex. Consistently, MRI in this group showed HH masses mainly located above the third ventricle, inside the middle hypothalamic nucleus. The HH masses in this group were mainly attached to the middle nucleus of the hypothalamus, sparing the mammillary bodies. T1 images show the intact mammillary body structure without interruption. Therefore, the hypometabolism of the cortex in this group may be due to the anatomical and functional connection of the HH masses with the cortex through the middle hypothalamic nucleus. Anterograde tracing studies showed that the middle hypothalamic neurons project through the medial forebrain bundle into the cerebral cortex. At the preoptic area, fibers run ventrally to globus pallidus, putamen, and external capsule, from which they project to much of the lateral temporal cortex outside the hippocampal formation . A DTI sThe third group of cases has the widest range of cortical hypometabolic regions, including the mesial and lateral temporal cortex, frontal cortex, and parietal cortex. T1-MPRAGE of this group showed that the HH mass located both above and below the third ventricle, with part of the HH mass inside the third ventricle and with part across the floor of the third ventricle, entering the interpeduncular cisterna. The portion of the HH mass below the third ventricle may affect the mammillary bodies, while the portion of the HH mass above the third ventricle may involve the middle nucleus of the hypothalamus. The HH mass in this group can connect to extra-hypothalamic cortex through both pathways described in the first and second groups. Therefore, the cortical hypometabolic region of this group was the most extensive, and the cortex of EEG discharge was diffused, with weak localization values. The patient's seizure patterns were the most diverse, with gelastic seizure, focal impaired awareness seizure, and focal to generalized tonic-clonic seizures. Generalized tonic-clonic seizures showed the highest frequency in this group of patients. The prognosis of patients with the third type was the worst, which is also consistent with previous literature reports indicating that the higher the extension of the hypometabolism in cortex, the worst is the prognosis after surgery. The previous study showed the prognosis of those with hypometabolism in the mesial temporal lobe is better than that of those with hypometabolism in cortex other than the mesial temporal lobe among patients with mesial temporal epilepsy . This poWe believe that our study was an initial step toward metabolic characterization of patients with HH according to the clinical question that the single epileptogenic hamartoma might lead to cortical abnormality outside HH during the disease process. In our patients, the fact that the lateralization of hypometabolism always occurred ipsilateral in MRI and EEG findings reinforced the view that the ipsilateral extra-hypothalamic cortical area is affected during the disease process. As for the hypometabolism pattern of extra-hypothalamic cortex, we combined visual analysis with quantification of the asymmetry value because of the difficulty to obtain normative FDG data from matched healthy control subjects to compare with the affected patients, especially for children. The results demonstrated that, in the third group, differences were found between the contralateral and ispilateral sides of the hippocampal formation and the lateral temporal neocortex. By contrast, no statistically significant asymmetry was found between the hippocampal formations, or in the lateral temporal neocortex, in the first and second groups, respectively. Lack of asymmetry value in these groups may be a result of an insufficient sample size because significantly hypometabolic regions were present with visual rating in these patients. In the future, we will continue to enroll more cases to better characterize glucose metabolism associated with HH neuroanatomy and therein further elucidate the complex pathophysiology of aberrant connection with remote cortex in patients with HH.Several limitations of our study must be pointed out. First, because PET is an invasive examination, PET data from a group of healthy individuals was difficult to be obtained, and there were no such data retained in the early stage. The asymmetry assessment method used in the paper ignored potential age-related changes in normal metabolic asymmetries and could not address potential bilateral hypometabolism in these regions. Second, EEG was not monitored during the tracer uptake period; thus, subclinical seizures or frequent interictal epileptiform activity might affect metabolism. Third, due to the small sample data and limited statistical analysis, the study was an initial step to suggest three hypometabolic patterns in patients with HH and the third pattern may be associated with poor prognosis; thus, more studies are needed to confirm these data in the future.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Ethic committee of Xuanwu Hospital of Capital Medical University, Beijing, China. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.Y-FY contributed to the data acquisition and analysis of the manuscript. Y-ZS and G-GZ contributed to the data acquisition, analysis and redaction of the manuscript, and also the interpretation of the data. P-HW, Y-HW, and L-KR contributed to the data acquisition and analysis. YA, FM, and DW contributed to data acquisition. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Following the introduction of fully endoscopic techniques for the resection of pituitary tumors, there was a rapid expansion of the indications for endonasal endoscopic surgery to include extrasellar tumors of the skull base. These techniques offer significant advantages over traditional open surgical approaches to the skull base, including improved tumor resection, and better post-operative neurological outcomes. Following their introduction, however, the initial rate of post-operative CSF leak was unacceptably high. Post-operative CSF leak following skull base surgery is a major source of morbidity, and can lead to the development of life-threatening intracranial infection. The use of vascularized naso-septal flaps transformed the management of these patients, significantly reducing the rate of post-operative CSF leak and increasing the number of patients that could benefit from this less invasive treatment modality. Adequate repair of iatrogenic defects in the skull base is of crucial importance for patients with skull base tumors, as the development of a post-operative CSF leak, and the associated complications can significantly delay the administration of the adjunctive oncological therapies these patients require. In this review, we provide an overview of the latest evidence regarding skull base reconstruction following endoscopic skull base surgery, and describe the skull base repair technique in use at our institution. The endoscopic endonasal approach to the skull base was initially introduced as an adjunct to the microscope in the resection of pituitary tumors in 1979, with fully endoscopic approaches described in the early 1990s . The endThe advantages of these extended endonasal approaches (EEA) to skull base tumors are that they provide a direct trajectory to lesions of the ventral skull base, avoiding the parenchymal retraction and the traversal of cranial nerves inherent to transcranial approaches for these tumors. This less invasive approach is associated with better neurological outcomes and a shorter length of stay than more traditional open approaches , 16. WheThe resection of pituitary adenomas is often an extra-arachnoidal procedure, with a small dural defect created to access the pathology and is therefore associated with a low rate of CSF leak that was not observed to increase following the introduction of the endoscopic technique . EEA to The development of the naso-septal flap (NSF) in by Hadad et al. in 2006 revolutionized the field of endoscopic endonasal skull base surgery and has facilitated the expansion of this treatment modality . Prior tThis technique was widely adopted soon after its introduction, and Kassam et al. published their experience of NSF utilization in 75 patients following EEA to a variety of skull base tumors. A large dural defect with high flow intra-operative CSF leak was noted in 55 patients. In similar fashion to that reported by Hadad et al. the authors combined the nasoseptal flap with the use of an inlay synthetic dural graft, secured using a biological glue or Foley catheter. In the first 1/3 of the series, the authors noted a post-operative CSF leak rate of 33% in cases with a high-flow intra-operative CSF leak rate, which dropped to 5.4% in the latter 2/3 of the series . With crAlthough the development of the NSF was a significant advance in skull base surgery, the technique itself is subject to some limitations. Although it is a rare occurrence, the flaps are subject to necrosis due to compromise of the vascularized pedicle: this is reported to occur in <1% of cases, but these patients will often require revisional surgery for alternative skull base reconstruction , 37. TheThe NSF is an effective, versatile technique that has gone on to form the basis of skull base reconstruction protocols in a number of high-volume skull base centers the world over, with some modifications which will be explored in the sections that follow. Long-term outcomes from a series of 46 patients who underwent EEA and skull base reconstruction using the gasket seal technique were published by Garcia-Navarro et al. in 2013 . This teThis technique, originally described by Luginbuhl et al. in 2010 utilizes a bilayer fascia lata graft, in conjunction with a NSF. In this method, the authors suture an onlay fascia lata graft slightly larger than the bony defect onto a much larger piece of fascia lata that goes on to act as an inlay graft. The inlay graft is directly opposed to the dura, with the appropriately sized onlay graft acting to prevent graft migration from the dural defect. This fascial construct was then covered in 16/20 cases by a NSF, secured with a fibrin glue. Using this technique, the authors noted a decrease in the rate of post-operative CSF leak in patients with large dural defects from 45 to 10% . AlthougCavallo et al. recently published a modification to their skull base reconstruction technique following EEA, having previously employed a modification of the gasket seal technique combined with a NSF . In this®  acellular matrix in combination with a free mucosal flap  sponges . A NSF flap is harvested at the beginning of the procedure, and stored in the posterior nasopharynx/maxillary sinus until completion of the tumor resection. Our technique is different from the Gasket-seal technique, insofar as an inlay rather than an onlay fascia lata graft is used, and is more similar to the bilayer button technique and indeed that originally described by Hadad et al. in that respect , 42, 43.trans-sphenoidal approaches to pituitary tumors (Identification of patients at higher risk of post-operative CSF leak following EEA allows the surgeon to ensure particularly meticulous skull base reconstruction following tumor resection, as well as considering the pre-emptive insertion of a lumbar drain. A number of studies have been performed to identify these risk factors, and BMI ≥ 30 has frequently been identified as being associated with an increased risk of post-operative CSF leak , 68, 69.y tumors .There is also evidence to suggest that posterior fossa defects have a higher proclivity for post-operative CSF leak, which may not be surprising given their dependent location and the requirement for any vascularized nasoseptal flap to be transposed to a greater extent than if they were being used for an anterior fossa or sellar defect , 70. TheEffective closure of the large osteodural defects created by EEA to skull base tumors is of vital importance in the prevention of post-operative CSF leak and meningitis. The addition of the NSF to multi-layered closure has been transformative in this regard, and as demonstrated in CH and MJ drafted and reviewed the manuscript. EK created the medical illustrations. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Treatment fidelity, defined as ensuring that the recipient receives the intended intervention, is a critical component for accurate estimation of treatment efficacy. Ensuring fidelity and protocol adherence in behavioral trials requires careful planning during the design phase and implementation during the trial. The Tinnitus Retraining Therapy Trial (TRTT) randomized individuals with severe tinnitus to tinnitus retraining therapy  and sound therapy (ST) using conventional sound generators (SGs)); Partial TRT (TC and placebo SGs); or standard of care (SOC), using a patient-centered care approach. Study audiologists administered both types of counseling in the TRTT, creating a challenge for managing protocol adherence.We developed methods to enhance treatment fidelity including training, competency assessment, scripts, visual aids, and fidelity monitoring. Protocol monitors identified critical topics and content to be addressed for each type of counseling session, prepared corresponding scripts, and developed training aids and treatment-specific checklists covering those topics. Study audiologists’ competency assessment required submission and review by the protocol monitors of an audiotape of one TC and one SOC counseling session. Treatment-specific aids included scripts, a 3-D model of the ear, handouts, and for TC, an illustrated flip-chart with talking points that followed the scripted content. During the trial, audiologists completed treatment-specific checklists during each counseling session, indicating topics covered/discussed and submitted audiotapes of counseling sessions. Protocol monitors reviewed audiotapes using corresponding treatment-specific checklists. Results for individual checklist items were tabulated and proportions calculated.Twenty-five audiologists were certified for TC and/or SOC counseling and 24 completed at least one counseling session. Adherence to each of 33 critical items on the TC checklist as assessed by the protocol monitor ranged from 70 to 100% across 37 counseling sessions (median 97%), with no difference between adherence for TRT  and partial TRT . Adherence to each of 44 critical items on the SOC checklist across 30 SOC counseling sessions ranged from 42 to 100% .The TRTT used multiple methods to address treatment fidelity. The close adherence to each treatment type was critical for evaluating the efficacy of the study interventions in this randomized trial.NCT01177137. Registered on 5 August 2010.clinicaltrials.gov  Adherence or fidelity is a critical component of randomized trials. Importantly, treatment fidelity impacts the ability of investigators to estimate accurately the treatment effect; poor adherence to the treatment protocol may result in enhancement of either type I or type II errors. When the intervention is not a drug, but a behavioral intervention, treatment fidelity allows for the identification of the critical elements of the experimental and comparator interventions for replication in future studies or in practice. Ultimately, poor adherence can lead to inaccurate translation of trial findings to clinical practice.Design: strategies to enhance fidelity in delivery of treatment . Design addresses the question “What steps can be taken to make sure that the participant receives the intended intervention?”Training: training of providers who will deliver the intervention . Training addresses the question “Are the providers adequately trained to deliver the intervention?”Delivery: processes to monitor and improve delivery of the intervention . Delivery addresses the question “Do the providers deliver the intervention as intended?”Receipt: processes to monitor and improve ability of participants to understand and implement the intervention . Receipt addresses the question “Do the participants understand the intervention and are they able to use it?”Enactment: processes to monitor and improve ability of participants to implement intervention in real-life settings . Enactment addresses the question “Are the participants implementing the intervention following the intervention?”In medication trials, adherence monitoring may involve counting unused tablets or pills or measurement of a biochemical marker. However, when the intervention involves a counseling or behavioral component, measures to assess adherence are less well-developed. Treatment fidelity for behavioral interventions is defined as ensuring that the recipient receives the intended intervention. Measures to enhance treatment fidelity in trials aim to confirm that individuals take the medication or receive the type of counseling or other intervention assigned at randomization. These measures also aim to prevent errors due to contamination of the treatment. Typically, treatment fidelity involves a number of steps, as recommended by the National Institutes of Health (NIH) Behavior Change Consortium and described by Bellg et al. . These sThoughtful pre-planning is required to implement these adherence steps to achieve consistency and accuracy for most behavioral interventions. The details of these steps often varies across trials. For example, some recent reports described fidelity steps for a variety of interventions, including music therapy for people with dementia , best prTinnitus, the perception of sound in the absence of a corresponding external stimulus for which there is no apparent cause is a debilitating condition for some individuals. Various options for management exist, including tinnitus retraining therapy (TRT). TRT involves non-psychiatric tinnitus-specific educational counseling (TC) and low-level sound therapy (ST), typically achieved using sound generators (SGs) and/or enriched environmental sound, to habituate the individual’s associated negative emotional reactions  and perception (awareness) of the tinnitus, and ultimately its impact on the patient’s life . The oveα of 0.05, 80% power, standard deviation of 12.5, and a two-sided test and 10% attrition. The primary outcome, mean change in TQ score from baseline to follow-up, was assessed longitudinally at 3, 6, 12, and 18 months’ follow-up using intention-to-treat longitudinal data analyses. End-of-treatment and longitudinal changes in scores on the sub-scales of the TQ were secondary outcomes; other outcomes include the total and subscale scores of the Tinnitus Functional Index [The TRTT protocol has been previously described . Brieflyal Index , Tinnitual Index , and chaal Index .The TRTT received ethical approval from institutional review boards at the University of Alabama, the Johns Hopkins Bloomberg School of Public Health, and participating clinical sites. No study participant was enrolled in the study before informed consent was obtained and documented by a signed informed consent statement.We summarize the steps we used to match the NIH Behavior Change Consortium model  in TableAdherence design involves “strategies to enhance fidelity in delivery of treatment ”. Steps we implemented to address adherence design included engagement of experts to develop standardized protocols, development of checklists, and decisions regarding the number of audiologists and how they were expected to administer treatment within the trial. The TRTT engaged two audiologic experts, one each in TC  and SOC Training involves “training of providers who will deliver the intervention ”. Audiologists for the TRTT were required to have completed at least 1 year of clinical experience  as an audiologist. No audiologist was permitted to administer either counseling intervention within the trial before completing training and certification specific to the TRTT and to the TC and/or SOC counseling administration.  described the talking points related to that illustration. The TC presentation started with a diagram of the ear, including the gross anatomy of the components of the ear. The audiologist simultaneously used the first illustration in the flip chart and the three-dimensional model of the ear to describe the anatomy and physiology of the outer, middle, and inner ear and to discuss possible sites of any associated hearing loss and origins of tinnitus. Instructions to the audiologist were to spend enough time on this section to educate a patient about the inner ear and relevant neural pathways so that the presentation of the Jastreboff neurophysiological model of tinnitus would be a logical next step . AltogetIt should be emphasized here that the material provided for both the TRT counseling and the SOC counseling sessions allowed reasonable flexibility and that each session was expected to be tailored for the individual participant. The theoretical concepts on which TRT is based were requisite aspects of the TC; an empathic response from the study audiologist and shared decision making regarding treatment goals and options were considered essential in the SOC protocol. In both approaches, audiologists were encouraged to listen to and build a relationship with the participant.The other aspect of delivery involved monitoring. We incorporated two approaches for monitoring. The protocol monitors developed separate checklists for TC and SOC counseling sessions. Each comprised a list of topics that were essential to cover during the counseling session. The SOC checklist also included an option to indicate that a specific symptom  was not a problem for an individual and, while asked, was not covered in depth. Checklists were completed either during the session or immediately following the session and submitted to the protocol monitors for subsequent review.In addition to the checklist, counseling sessions were audiotaped, provided that the study patient gave permission. Audiologists submitted their recordings of the first two study counseling sessions of each type. Protocol monitors reviewed the audiotape by completing a separate identical checklist to verify topics covered, checking whether topics were adequately covered during the counseling session. If no deficiencies were noted, then subsequent recordings were randomly selected for review. Whenever deficiencies were noted, the protocol monitor communicated with the audiologist in writing or by phone to discuss the deficiency, and the next two counseling sessions were submitted for review. Continued non-adherence would have resulted in de-certification; however, no audiologists were de-certified during the trial.In the NIH Behavior Change Consortium model for treatment fidelity, receipt of the intervention encompasses processes to monitor and improve the ability of participants to understand and implement the intervention . To faciEnactment includes processes to monitor and improve the ability of each participant to implement the assigned intervention in real-life settings. Enactment is not the equivalent of treatment efficacy, because although a participant may have received the intervention as assigned, he or she may be unwilling or unable to act on that intervention . NeverthTwenty-five audiologists were certified for TC and/or SOC counseling and 24 completed at least one counseling session.Twenty-five audiologists submitted audiotapes for TC. Of these, 22 (88%) demonstrated competency for TC. An additional 2 (8%) audiologists demonstrated partial competency requiring a telephone call with the protocol monitor regarding some deficiencies in the recordings. One of these two audiologists re-submitted an audiotape demonstrating full competency. The other audiologist did not submit an acceptable audiotape and chose not to re-submit a second one.Twenty-five audiologists submitted audiotapes for SOC. Of these, 15 (60%) demonstrated competency for SOC, with 2 audiologists demonstrating adequate competency but requiring a telephone call with the protocol monitor. The remaining 8 (32%) audiologists did not submit an acceptable audiotape, and 2 of these chose not to submit a second audiotape. Of 6 audiologists who submitted a second audiotape, 2 were classified as acceptable and 3 as partially acceptable. The remaining audiologist re-submitted another two audiotapes with the fourth classified as acceptable.Audiologists submitted 101 checklists comprised of 33 items for TC . The primary challenge we faced was that the same audiologist might be called upon to administer both interventions due to cost and personnel constraints. As noted by others, we needed to consider the nature of each intervention, the study design, and the relevant outcome measurements . Our goaDevelopment of a standardized protocol for TRT was challenging for the TRTT. Typically, training in TRT had been offered through a 2 or 3-day course by Jastreboff, the TRT developer. His course also covered hyperacusis and misophonia, conditions that may accompany tinnitus. To our knowledge, Jastreboff used no specific measures to assess quality control by professionals within the course. For implementation in the TRTT, we had to operationalize and standardize the practice of TRT, which we modeled based on the delivery of TC and ST at the University of Maryland Tinnitus and Hyperacusis Center  and descDevelopment of the protocol for SOC was even more of a challenge than that for TC. In contrast to the structured TC protocol, SOC engaged the participant and was more fluid from individual to individual, a known barrier to implementing treatment fidelity with patient-focused interventions . It was Another challenge was training the audiologists. For some audiologists, TRT and SOC provided new concepts in tinnitus care. Most audiologists are used to taking the lead in delivering care for tinnitus, so it was difficult for some to move from the usual clinician-patient interaction in a position of authority towards collaboration decision-making and elicitation of the patient’s personal story while administering SOC. Associated with the SOC approach was the need to show empathy, which was challenging for some audiologists. This difficulty may be reflected in the lack of agreement between the audiologist and protocol monitor on items related to the patient-centered approach on the SOC checklist. For both interventions, audiologists needed to learn how to use scripts effectively—not reading them verbatim, but placing the critical concepts in their own words while still engaging with the study patient. Most audiologists were able to present the counseling content effectively in the case of TC because they were aided by the talking points on the back of the flip-chart.The implementation of treatment fidelity in the TRTT had some limitations. We had only a single protocol monitor for each type of counseling. Most experts recommend that two monitors should be involved and inter-rater scoring completed. With only one protocol monitor, there could be some bias in selection of the critical components to include in the protocol and review of the audiotapes, leading to some error in absolute measurement of adherence. However, there was high agreement between audiologists and protocol monitors when scoring the checklists. Agreement in scores between 80 and 100% typically indicates high integrity of the intervention with the protocol . AnotherOne major strength of the TRTT treatment fidelity measures was the development of standardized protocols that can readily be adapted to clinical settings for either type of counseling. By describing the steps required to implement each of the two types of counseling in detail, other audiologists or clinicians can provide these types of treatments for individuals with tinnitus. In fact, the protocols developed by the TRTT are currently in use in some of the clinics participating in the TRTT. The high turnover of audiologists and constant training had the unintended effect of resulting in a large number of audiologists trained in these two interventions. The viewpoint expressed anecdotally by participating audiologists was that the TRTT and associated treatment fidelity steps served to strengthen their professional skills, which we used originally as a selling point to promote the trial to the military commands at each site in the TRTT.In conclusion, the TRTT ensured treatment fidelity to two types of counseling interventions, TC and SOC, for the management of severe tinnitus, following the guidelines of the NIH Behavior Change Consortium . AlthougAdditional file 1.


The impact of mechanical ventilation on the daily costs of intensive care unit (ICU) care is largely unknown. We thus conducted a systematic search for studies measuring the daily costs of ICU stays for general populations of adults (age ≥18 years) and the added costs of mechanical ventilation. The relative increase in the daily costs was estimated using random effects meta regression. The results of the analyses were applied to a recent study calculating the excess length-of-stay associated with ICU-acquired (ventilator-associated) pneumonia, a major complication of mechanical ventilation. The search identified five eligible studies including a total of 54 766 patients and ~238 037 patient days in the ICU. Overall, mechanical ventilation was associated with a 25.8% (95% CI 4.7%–51.2%) increase in the daily costs of ICU care. A combination of these estimates with standardised unit costs results in approximate daily costs of a single ventilated ICU day of €1654 and €1580 in France and Germany, respectively. Mechanical ventilation is a major driver of ICU costs and should be taken into account when measuring the financial burden of adverse events in ICU settings. Intensive care consumes a large proportion of healthcare resources. Days in intensive care are substantially more costly than general ward days in hospitals due to increased resource utilization and labour intensity. One major driver of these costs is mechanical ventilation.Adverse events occurring during hospitalization add a substantial further burden to the healthcare system. The most prevalent hospital-onset conditions are hospital-acquired infections, which absorb substantial resources in hospitals and often require costly treatment . For patThe major aim of this review is to determine the relative impact of mechanical ventilation on the daily costs of intensive care unit (ICU) care. We believe that this information is crucial in a number of contexts but has been neglected given the unavailability of reliable estimates.We therefore conducted a systematic review regarding the costs of an ICU day and the proportion of these costs attributable to mechanical ventilation and quantified the relative increase in the daily costs using meta regression. In order to illustrate the practical relevance of these findings, we then determine the economic burden of VAP using recent cost information from France and Germany.On 24 March 2017 we searched MEDLINE via Wolters Kluwer's search interface Ovid (indexed and non-indexed databases), Web of Science via Thomson Reuters, , CINAHL via EBSCOhost and the NHS Economic Evaluation Database (NHS EED) via Centre for Reviews and Dissemination, University of York. We performed the searches restricted to the English language and publication year 2000 to the update status at date of search (2017).The search strategies varied by the database used. For details of the search strategies in all databases, see Supplementary material (Appendix). The searches returned 2839 studies of potential interest. After elimination of duplicates, 2072 studies remained.Studies were eligible if they gave data for the daily costs of ICU stays for general populations of adults (age ⩾ 18 years) and the added costs of mechanical ventilation. Screening of titles and abstracts found 257 potentially relevant papers. We were able to access full-texts of all articles of interest. Of these, 14 articles provided data on the daily costs of ICU stays, but only five articles  fulfilleTwo authors (KK and PH) checked the titles and abstracts of all potentially relevant English articles, and the full text of these was obtained. The same authors independently checked all the full-text articles for eligibility, and author KK extracted clinical data from the full texts. Details on the number of patients, ICU days, daily ICU costs and corresponding measures of uncertainty  were derived from the studies for ICU patients currently under mechanical ventilation or not. If necessary, patient days were derived from the proportion of patients ventilated and mean/median length of ICU stay (LoS). In the case of no reported variances, a standard deviation of 20% was imputed. In two cases  it was at-tests based on summary data (command ttesti in Stata) were applied on log transformed daily costs. As the latter costs were used in all analyses, resulting coefficients were exponentiated in order to show the relative effect of ventilation on the daily ICU costs. Please note that the relative increase is always taking place within a country and year, therefore making adjustment for inflation and/or currency exchange rates unnecessary.Daily ICU costs were log transformed along with their standard errors and analysed using random effects meta regression  was used.The selection of studies is summarised in et al. [Bluhmki et al.  reportedet al. [The study of Lefrant et al.  providedet al.   for patients hospitalised in German ICUs [Bock man ICUs . Assuminman ICUs  (3.52 daIntensive care absorbs a large proportion of health care spending in industrialised countries . ReliablThe results of the systematic review and meta regression analysis showed that mechanical ventilation is associated with a substantial increase in the daily costs of ICU care. Moreover, we observed a strong variability in the relative effect of mechanical ventilation across studies. However, the number of appropriate studies was rather limited and we were unable to find relevant more recent studies. As technology, procedures and indications for ventilation have changed in the meantime, our findings may be limited in scope and further studies on this topic are needed.et al. were aware of this fact and correctly estimated the excess LoS associated with VAP using multistate models accounting for the time-dynamics of ventilation status and VAP. At the same time, Bluhmki et al. [In the estimation of the additional LoS of adverse events during hospitalization, it is crucial to treat the exposure as time-varying to avoid a time-dependent bias 12. Thisi et al.  consideri et al. –22.Our cost calculations were based on the simplifying assumption that the entire excess LoS can be attributed to ventilation; thus, we may have slightly overestimated the costs. However, we refer to the result that this excess seems to be mainly triggered by ventilation . While LOur study contributes to a more detailed understanding and measuring of the costs of intensive care and mechanical ventilation by providing first estimates and discussing methodological particularities. Being an area with relatively little empirical evidence to date, more studies on the daily costs of mechanical ventilation and intensive care are duly needed.


Limited research to date has defined the nature and extent of foot involvement in a psoriatic arthritis-specific population in Australia and the scale of the problem remains unclear. Survey research provides the ideal opportunity to sample a large population over a wide geographical area. Although quality criteria for survey research have been developed, research shows that adherence is low and that survey studies are poorly reported in peer-reviewed survey articles, which limits the ability to inform future survey design. The objective of this paper was to develop a national survey about foot involvement in people with psoriatic arthritis using a best practice approach. This is a methods paper for the development of survey research.A systematic, multi-stage process of survey development was undertaken, which comprised 3 phases: 1) the generation of the conceptual framework and survey content; 2) the development of the survey and pre-testing and 3) development of the survey dissemination strategy. A survey best practice approach was adopted using iterative pre-testing techniques, which included; cognitive debriefing, cultural sensitivity review, survey design expert validation, subject expert validation and pilot testing. Targeted postal and online survey dissemination strategies were developed a priori to optimise the response rates anticipated.n = 649), high data completeness (83% of respondents reached the end of the survey) and low rates of missing data (below 5% for 95% of respondents). Extensive survey pre-testing among the target population, health professionals and experts improved the overall quality, content validity, functioning and representativeness of the survey instrument, which optimised potential response rates. Clear audit trails that mapped the analytical process at each stage substantiated the rigour of the survey development methods. Robust strategies for sampling, survey dissemination and community engagement were deemed to have made a powerful contribution to response rates and the scale of information collected.A 59-item survey with 8 sections was developed. Findings demonstrated a high survey response (Robust patient-centred methods in survey design were used to create a novel, high-quality survey to comprehensively evaluate psoriatic arthritis-related foot involvement. Transparent and precise description of the survey design and dissemination methods provides useful information to other researchers embarking on survey design in healthcare. Psoriatic arthritis (PsA) is well recognised as a distinct clinical entity with a high disease burden –4. TypicSurvey research provides the opportunity to sample a large population over a wide geographical area and to measure a broad range of constructs with sufficient granularity , 18. HowA cross-sectional observational study design was used to develop a self-administered paper-based and web-based survey Fig. . QualitaPeople with PsA and rheumatology health professionals involved in phases 1 and 2 were recruited using a convenience sampling technique with attention to ensuring diversity across health sectors and regions. A total of six sites across Australia and New Zealand were included, comprising three rheumatology public hospital outpatient departments, two university-based podiatry departments and a multidisciplinary rheumatology private practice with ethical approval granted for each participating site . Written informed consent was provided by all participants prior to data collection.Demographic and clinical information were collected from people with PsA for the purpose of describing the sample and have been previously reported for Phase 1 , 35 and Detailed descriptions of the preliminary work involved in phase 1 have been previously reported , 35, 36.Paper and online formats of survey administration were developed with the aim to increase response rates and reduce potential selection bias. Throughout the pre-testing phase survey content remained the same irrespective of the method of completion, with adaptions to survey item content reflected in both versions of the paper and web-based survey. The online version of the survey was developed using Qualtrics software .focus groups with health professionals in rheumatology,cognitive debriefing interviews of people with PsA,cultural sensitivity review with New Zealand-based health professionals,survey design expert validation,content expert validation,pilot testing among people with PsA.Pre-testing is the process of collecting validity evidence to support and ensure the content, cognitive and usability standards of the final survey , 38. A cQualitative feedback from pre-testing sessions was used to make inclusion, exclusion and revision decisions for individual items, with data tabulated and examined for patterns in responses to each question . A clearMultidisciplinary rheumatology focus groups systematically evaluated the survey content in order to make improvements to the overall quality and representativeness of the items. Health professionals experienced in the management of people with PsA were recruited. A total of 2 focus groups (participant number range 9–17) were conducted, which is in accordance with recommended numbers needed to generate consensus on proposed scale items . Health In-depth cognitive debriefing interviews of people with PsA were used to determine how respondents comprehend questions, process and recall information and decide what answers to give, which identified potential sources of error, such as with the interpretation of items and response anchors –45. An iThe patient pre-testing was valuable for managing concerns raised by health professionals on terminology complexity and the belief that people with PsA would need simpler alternatives to some medical terms in order to aid understanding. Indeed, comprehension and interpretation concerns were continually raised during survey item revisions by health professionals. Whilst some items were simplified to account for varying levels of understanding, the majority of people with PsA were familiar with technical language such as plantar fasciitis, dactylitis and pitting nails and the cognitive debriefing interviews supported the respondents’ understanding of each item.As part of the cognitive debriefing interviews for the web-based survey, usability pre-testing involved participants completing the survey on their own mobile devices (smartphone or tablet) or other electronic devices (home computer or laptop). The evaluation of the web-based survey included all the elements of the paper version, but participants were additionally asked to comment on the online layout and design of the survey items and navigation features. Web-based design modifications were introduced as a result in order to optimise the user experience and ensure response options would display correctly on different types of electronic devices , 48.The original research intention was to conduct the survey in both Australia and New Zealand. However, challenges related to ethical requirements, logistical management and time restrictions, resulted in the New Zealand arm of the study being postponed. However, for completeness, the cultural sensitivity review is presented. For both national and international multicentre studies, cultural sensitivity reviews are required to identify and correct for any cultural differences in the interpretation of survey items . In Austn = 2) in the development and evaluation of healthcare surveys and patient-centred outcome research reviewed the draft design of the paper and web-based survey. Feedback was provided in the form of detailed free-text annotations on the survey and written comments to specific questions on how to optimise the look, flow and design of the survey. Consequently, survey items were re-grouped, streamlined and survey sections were numbered to improve consistency in navigation and layout between the paper and online versions of the survey.Experts , reviewed the final survey items and response scales. The panel members were selected based on a priori criteria, which included having recent publications in PsA-specific foot involvement research, a track record of special interest in PsA and current specialised clinical practice in PsA. An innovative online collaborative platform was used to facilitate the instant recording of responses, while web-conferencing allowed real-time audio/visual communication between panel members across 3 countries including the UK, Australia and New Zealand. Panel members independently rated the relevance and importance of each item to its assigned construct; demographics, pain and musculoskeletal disease, skin and toenail disease, function and participation, footwear, treatment burden and emotional well-being. The review process was moderated (SW) in order to ensure that all panel members had rated and commented on each survey construct and progressed as a group. Following independent, real-time completion of the data form, results were presented to all members for open discussion in order to reach a consensus on the final survey items. To ensure face and content validity, the revised items were then re-reviewed by the experts to confirm that they were acceptable for inclusion. The expert panel recognised the need for all items given the heterogeneity of disease expression and potential impact.Pilot testing is a ‘dry run’ of the entire survey administration; the target population completes the survey in the planned delivery mode and final revisions to the survey process are made ready for full-scale administration . Six proReporting survey implementation and dissemination is crucial in order to determine the generalisability of study results . Survey With PsA prevalence in Australia unknown a priori and in the absence of national databases to estimate the potential target population and response rate, the sampling strategy was to identify target estimates from the major sites for dissemination in order to establish the potential reach of survey to people with PsA. The estimated total target population was 6000 people with PsA in Australia. Targeted sites and organisations for dissemination of the survey were pre-identified. The survey was promoted by; 13 patient support organisations, 5 social media support groups, 7 health professional associations, 6 specialist clinical services and 2 research centres. Both the web-based and paper-based versions of the survey were run concurrently to optimise data collection. In total, 650 paper surveys were posted to the targeted patient community groups and specialist clinical services in Australia, as well as 2000 flyers and 300 posters. Consent was implicit by the return/submission of the completed survey and participants were informed of this at the start of the paper and online survey.A study website, Facebook page, video and animation were created to generate research interest through online health social networks and communities, and to provide ongoing engagement through the survey dissemination phase. This targeted approach to survey dissemination was followed by snowballing and crowdsourcing sampling techniques, where participants informed other potential participants of the research by liking posts and sharing links about the survey. Monthly progress and reminder emails were sent to all target sites and organisations during the dissemination phase (6-months).The final 59-item self-administered survey was developed based on feedback from each of the stages involving people with PsA, health professionals and experts. Despite the substantial length of the survey, the majority of people with PsA interviewed during survey pre-testing suggested that it was acceptable, which contrasted with the view that most health professionals had that the survey length would be prohibitive to potential participants. Reasons for this included 1) having a desire to share their experience of foot problems that they felt had been neglected and/or poorly understood, and 2) resonance of patient-derived statements throughout the survey, which reportedly had a positive effect on encouraging survey completion. Key survey domains included demographic (10%) and socioeconomic data (10%), global disease information (18%), foot and ankle characteristics (18%), and the impact of foot problems on daily life including daily routine, footwear choice, family life, work and accessing health care (44%). The percentage coverage of items directly reflects the dominant concerns of people with PsA-related foot problems and health professionals in rheumatology.Quantity-related success outcomes included a total of 606 survey completions (10% response rate) that comprised 559 (92%) online survey completions and 47 (8%) completed paper surveys Fig. . Of the This paper provides an overview of the development of a survey on foot involvement in PsA based on best practice methods in survey design. Extensive pre-testing among key relevant stakeholder groups improved the overall quality, functioning and representativeness of the survey instrument. Although there is limited empirical evidence and few universal best practice recommendations for survey design and conduct –29, compn = 400 target sample) [n = 400 target sample) were received from people with systemic lupus erythematous [Sample size requirements of this study were difficult to estimate in the absence of national patient databases and with unknown PsA prevalence in Australia. The total target population was estimated from the major sites for dissemination to be 6000 people with PsA (10% response rate). Similar New Zealand-based podiatry surveys received 197 web-survey completions from people with inflammatory arthritis   and 131 hematous . Althoughematous , 51, thePatient self-report is increasingly used to assess the impact of PsA, to gain insight into the patient experience and to formulate new questions for investigation –54. In aLimitations of the survey development process (phase 1 and 2) include a potential sampling bias with all research participants chosen by convenience sampling, meaning those who volunteered to take part in the survey development may not be representative of all people with foot involvement in PsA or the health professionals who manage this patient group. However, participants were recruited from multiple sites in order to achieve a diverse cross-section of the sample and recruitment continued until qualitative data saturation was reached. A limitation to the study generalisability is that the multiple iterations of pre-testing and pilot testing required to develop a high-quality survey are resource and time intensive, which may be prohibitive for some research teams. Future work will involve adaption and implementation of the survey in the UK. The findings from the programme of survey research will also be used to inform the development of an evaluative PsA foot-specific patient-reported outcome measure for use in clinical practice and research.This paper describes a robust survey development protocol using best practice methods in survey design and conduct, with the intent that this could be utilised as a framework for survey development in other areas of clinical practice. Involvement of people with PsA, health professionals and experts throughout the survey development process was a central component that ensured the survey functioned properly and yielded successful survey outcomes. Focus on high-standards of reporting survey research permits wider application of the protocol beyond the intended target population of the survey. Whilst the survey has not been used in a clinical setting with the purpose to better direct assessment and targeted care, future work is planned to determine the feasibility of its use to support assessment in clinical practice.Additional file 1. Survey item revisions and refinements audit trail.


A questionnaire with validated Urdu translation was filled by each participant that included socio-demographic data, pre-Covid and Covid-19 era health seeking behaviors and the impact of the pandemic on the utilization of healthcare facilities. Data was analyzed using SPSS V.19.A total of 393 patients were enrolled with a male preponderance (72%) and a median age range of 31-45 years. Fifty-eight percent of the study population was unemployed and 47.3% were seeking follow up care. The frequency of ER and multiple (>4 times) OPD visits were significantly decreased in the Covid-19 times whereas, the laboratory and radiology services were largely unaffected. A significant number of patients were not satisfied with the current healthcare facilities that was seen irrespective of the socio-demographic status. Emergency Room and radiology services were largely unaffected whereas, elective procedures and laboratory facilities were reported to be severely affected or delayed in relation to socio-demographic variables.Healthcare inequalities have widened and depression has shown a sharp rise during this pandemic. The over-burdened healthcare facilities at the verge of collapse may miss out on the chronic non-Covid patients which would ultimately lead to increased morbidity and mortality. Due to the unprecedented conditions secondary to Covid-19 pandemic, the hospitals and emergency departments are overwhelmed with critically ill patients. The already fragile health care system of many developing as well as the developed countries has collapsed, making preventive techniques and effective infection control the major facets of clinical care.2Social distancing, frequent prolonged lockdowns, unemployment, lack of social support systems, fear of getting infected and overwhelmed hospitals have contributed adversely to the health seeking behavior of the community. An analysis from the United States showed a 40% reduction in STEMI presentation in Rhodes Island and a similar study reported a 50% reduction in emergency department visits (other than respiratory symptoms).4Things might not be this simple for many low and middle income countries where the socio-demographic discrepancy has a significant effect on the availability of quality health careThis is one of the few studies conducted at the community level to explore the possible impact of the pandemic on the health seeking behavior of patients and the delays the community has to suffer in the face of the over-burdened heath care facilities. Also, the discrepancy in availability of the health services faced in relation to socio-demographics was studied within the limitations.This cross-sectional study was conducted by enrolling all patients, aged 15 years or more and freely consenting to participate in the study, visiting the OPDs of three large hospitals of the country namely Pak Emirates Military Hospital, Bahria Town International Hospital and Armed Forces Institute of Dentistry Rawalpindi after taking ethical committee approval from the concerned department (A/28/EC/196/2020 dated 01-07-2020). The patients were enrolled using convenience sampling and the sample size was calculated using OpenEpi sample size calculator with 5% margin of error, 95% confidence interval and frequency of outcome factor set at 50%.The questionnaire was translated in to Urdu language and was back translated in to English by a translator completely blind to the study. This translation was then validated by two sources before putting to test.To measure the internal consistency of the instrument, Cronbach’s alpha was calculated which produced a value of 0.78. Qualitative data was expressed as frequencies and percentages. Relation of health-seeking behavior with socio-demographic variables was seen using multinomial logistic regression. A value of <0.05 was considered statistically significant All analysis was done using SPSS V.19.A total of 393 patients, of age ≥15 years, attending the OPD were enrolled with male preponderance (72%) and the age range of 31-45 years representing the majority (38%). Fifty-eight percent (58%) of the study population was unemployed and majority hailed from urban residency (77.6%). Almost half of the study sample (47.3%) was seeking follow up care .The frequency of multiple (>4 times) OPD visits was significantly decreased in the Covid times either due to non-availability of services for follow up of chronic illnesses or deliberate avoidance whereas, the laboratory and radiology services were largely unaffected . PatientA significant number of patients were not satisfied with the current healthcare facilities and relayed that improvements are necessary. Also the need for non-Covid hospitals or at least a separate waiting area in the OPD, ER and laboratory after a thorough triage was strongly advocated. Majority of the patients were depressed and were facing financial constraints . ER and Delay in seeking or providing medical attention may lead to morbidity and mortality more devastating than the Covid-19 pandemic itself.10Since our study set-up was urban with two public and one welfare hospital, patients belonging to low and middle social classes were the main representatives. Unemployed patients were venturing out more to seek health care probably because of more time at hand, increased psychosomatic symptoms or fear of getting worse. The pandemic didn’t significantly affect the OPD visits as a whole, showing that the people were eager to get healthcare, although refusal of OPD services was statistically related to the social status of the population. ER and radiology services were largely unaffected by socio-demographics but the elective procedures and services were significantly affected or delayed with socially affluent population being able to get appointments in private set ups. The residence also did not affect the health seeking behavior and the presence of psychological distress significantly, as people could travel in and out of the cities following SOPs.Socio-economically under-privileged people with larger families were avoiding OPD and ER visits probably due to overburdened set ups and refusal of services at public hospitals. The health-related inequalities, though prevalent in our community, have widened further and would tremendously affect the basic human right to quality care.11The lack of satisfaction towards healthcare facilities was also seen to be related to the socio-demographic status in our study. There was a statistically significant relation between the presence of depression secondary to quality-of-health-care provision and social and employment status which was studied in a similar study showing a sharp rise in depression and stress scores for younger, unemployed population confined to homes.These unprecedented conditions have transformed all the aspects of medical and surgical patient care. Telemedicine is emerging as a safe alternative for in-person consultations and a significant number of patients in our study showed their willingness towards telemedicine by sitting in the confines of their homes in contrast to a study that showed poor public acceptance.14Also an effective system of triaging patients at ER or a designated area isolated from the rest of the hospital, into low and high risk patients for COVID-19 infection would minimize the number of trainees/consultants exposed.16To mitigate the impeding collapse of health care, mobile health care services, mobile pharmacies with prescription refills, preliminary triaging at the community dispensaries and small hospitals should be encouraged.The study set up comprised of public and welfare hospitals which might have led to sample bias in relation to socio-demographics. Also the Obstetric and Gynae clinic and specialized surgical units were not a part of the study due to logistics and allocation of different buildings to these services.While robust research is going on for Covid-19 management, literature lacks the effective ways to mitigate the impeding healthcare disaster for non-Covid emergency and non-emergency situations. Healthcare inequalities have widened leading to depression and financial taxation. The over-burdened health care facilities at the verge of collapse may miss out on the chronic non-Covid patients which would ultimately lead to increased morbidity and mortality.LA: Contributed to the idea, design and drafting of the manuscript, data collection, statistical analysis and literature review.KHK: Contributed to data collection.MA: Contributed to data collection and literature review.VF: Contributed to data collection.All authors take equal responsibility for the accuracy and integrity of the work.


Toscano et al.). Bioactive compounds in fruit and vegetables are of consumer interest for their potential benefit to the health, especially in counteracting several diseases related to aging and stress. However, the bioactive molecules also have preservation properties that extend the shelf life of the produce. Postharvest technologies and storage conditions can reduce the degradation of bioactive compounds and some industrial operation can even promote their accumulation.Fruit and vegetables are considered to be among the most important sources of bioactive compounds with proven beneficial effect on human diet. Tomato has been evolved as a model crop to study both fruit ripening pattern as well as for understanding how different environmental and agricultural factors can enhance the accumulation of bioactive compounds. The concentration of bioactive compounds is highly dependent on the crop species, cultivar/genotype, agronomic management, preharvest environmental conditions, and postharvest management practices . The availability of advanced molecular tools allows fast and accurate transcriptome profiling that can help in the identification of the main gene clusters that are activated or repressed under different conditions. Such information coupled with the big data from metabolomics studies will be useful both for preharvest and postharvest management of produce with high nutritional value.The systematic screening of key bioactive compounds with high content in a wide range of germplasm and the restoration of key genes and gene clusters from wild species and/or landraces both are important for reducing the loss of agro-biodiversity and the creation of a “gene pool” that can be exploited in future breeding programs toward the release of new cultivars with added nutraceutical value . FurtherSolanum lycopersicum L.) grown in Tuscany showed higher polyphenols, flavonoids, and carotenoids compared with commercial ones . Similar results have been reported in onion (Allium cepa L.) and sweet cherry . In the meantime, breeding projects are targeting toward the release of new cultivars with enhanced bioactive content, as this is the case for tomatoes . These compounds are also substrates for volatile biosynthesis, contributing to fruit aroma with direct effect on produce quality .Bioactive compounds show wide variations among different species. Several studies have reported that ancient or old varieties accumulate higher concentration of bioactive compounds that have been linked to their adaptation to different environmental conditions . The acctomatoes . Recentlenotypes . A compaMoles et al.).Environmental conditions can positively or negatively affect the concentration of bioactive molecules in different horticultural produce. Tomato fruits obtained from plants exposed to high salinity conditions (60 or 120 mM NaCl) showed a reduction of antioxidant capacity and several secondary metabolites such as lycopene and phenols (Vaccinium corymbosum L.) grown in different altitudes, was shown that lower altitudes induced an early ripening and a higher anthocyanin accumulation .Environmental conditions including altitude, temperature, and light can influence bioactive compound accumulation. A study carried out on blueberry (Prunus persica L.), UV-B treatments applied for 1 or 3 h enhanced several phenolic compounds. The employment of UV-B was also studied as priming for preventing the development of Monilinia fructicola fungus . Treatments applied for different durations indicated that 1 and 3 h of UV-B treatments increased the phenolics in the fruit except near the inoculation point, while around the inoculation point the effect of UV-B treatments were not always consistent depending also on the effects of fungus, the wounding and their interaction .Light quality can induce the biosynthesis of different secondary metabolites that can have protective functions against biotic and abiotic stresses. Plants exposed to UV-B treatments have increased phenolic compounds in a dose-response manner. In a study performed in peaches .There are plant hormones that have bioactive molecules as precursors such as abscisic acid (ABA), auxin, salicylic acid (SA), and melatonin. ABA biosynthesis is derived from the catabolism of carotenoids, while the auxins, SA, and melatonin are synthetized from the chorismite as their precursor. The connecting molecules may explain the cross-talks among them and their roles in the modulation of the growth and the ripening process of both climacteric and non-climacteric fruits . However, the concentration and composition of these molecules in the cuticular waxes varies among species and within cultivars of the same species. Tomato mutants such as NON-RIPENING (nor) and RIPENING INHIBITOR (rin) have different cuticular waxes . In particular, the MADS-RIN transcription factor TDR4/FUL1 and its homolog MBP7/FUL2 have high similarity with FRUITFULL of Arabidopsis. This TDR4 transcription factor has been reported to be involved in pigment biosynthesis in tomato fruit. A functional analysis of this gene using virus-induced gene silencing technology (VIGS) demonstrated that the TDR4 gene is effectively involved in the biosynthesis of bioactive molecules. In fact, TDR4-silenced tomatoes showed a strong reduction of amino acids and α-tomatine .The protection of plant cells from external environments and biotic or abiotic stresses is partly provided by the cell wall and, in several species, by the cuticular waxes. The major components of cuticular wax are very long chain fatty acids and derived compounds (ar waxes . These fThe collection of articles in this Research Topic demonstrates that the accumulation of bioactive compounds in produce can derive from different environmental, genetic, and agronomic factors.All authors planned the structure of the editorial, contributed in its writing, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


No significant correlations were found concerning patient demographic characteristics. bIMGA demonstrated a substantial degree of anatomical variability, rendering its consistent identification in the surgical field challenging. Conclusions: Given the observed variability and the associated difficulty in its identification, the use of the bIMGA as a dependable anatomical reference during ACL graft harvesting is not recommended. This study confirms the inconsistency of bIMGA as a traditional landmark, underscoring the need for research aimed at identifying more consistent and reliable anatomical references to enhance the precision of surgical interventions in ACLR.Background: The identification of the branch of the inferior medial genicular artery (bIMGA) in anterior cruciate ligament reconstructions (ACLRs) has previously been considered a landmark by some surgeons, but its consistency remains debated. The aim of this investigation was to evaluate the variability in the appearance and location of bIMGA and to assess its validity as a reliable landmark during hamstring tendon harvesting procedures. Methods: This prospective, single-center study comprised 213 patients who underwent ACLR over a period of two years. The surgical procedures were conducted by the same surgical team, maintaining uniformity in the approach. The study sought correlations between patient demographics, level of activity, and the potential for successful identification of the bIMGA. Results: A statistically significant association between patient activity levels and successful identification of the bIMGA ( The anterior cruciate ligament (ACL) is essential for knee stability and function. Injuries to the ACL can impair mobility and necessitate surgical intervention, making ACL reconstruction (ACLR) a common and vital orthopedic procedure, particularly in the context of sports-related injuries ,2.Over the years, surgical techniques and graft choices have evolved considerably, offering a wider array of options to orthopedic surgeons and patients alike ,4. A sucA comprehensive understanding of the pes anserinus anatomy is paramount in the ACLR graft harvesting procedure. Significant insights into the vascularity and neuroreceptors of this notable landmark were provided in a comprehensive study conducted two decades ago . Any inaRecently, a novel vascular anatomical reference, frequently named the “sentinel vessel” or the inferior medial geniculate artery branch (bIMGA), has been brought to the forefront of ACLR surgical planning, with studies suggesting its potential to enhance procedural predictability and decrease harvest-related complications ,12,13. TThey are primarily responsible for supplying blood to the knee joint, complementing the contributions from their superior genicular counterparts . HoweverThe main objective of the present study is to investigate the anatomical variability of this vascular structure in the context of ACLRs. Insight is sought on its incidence and implications for surgical planning and procedure standardization. A secondary aim is to augment the state-of-the-art and assist in the refinement of ACLR surgical techniques.The conduct of this study was in full compliance with ethical standards, having received formal approval (No. 2023334) from the local ethical review board at Regina Maria Hospital’s ethics committee, located in Timisoara. This process included a thorough review of the research protocols to ensure the safeguarding of participant rights, adherence to the principles of informed consent, and compliance with relevant regulatory standards. Furthermore, all research procedures strictly adhered to the principles of the Declaration of Helsinki.A prospective study was conducted involving 213 consecutive patients who underwent ACLR with an HT autograft. The study participants had experienced an isolated knee trauma leading to an ACL tear, which was confirmed via magnetic resonance imaging (MRI) and clinical examination. The surgical procedures were conducted by the same surgical team, led by a senior orthopedic surgeon. Assisting him were two junior orthopedic surgeons. The combined expertise of this team ensured uniformity and precision in the approach over a period of approximately 24 months.The study included patients who had experienced an isolated knee trauma resulting in an ACL tear, confirmed by MRI and clinical examination (Lachman and anterior drawer tests). Both male and female patients aged between 18 and 65 years were considered for inclusion. Additionally, the patients had to range from very low to very high on a physical activity scale from 1 to 5. Patients were excluded from the study if they had multiple ligament injuries in the knee or had undergone previous surgeries on the affected knee. We also excluded those with systemic diseases or conditions that could interfere with the surgery or post-operative recovery, such as diabetes, rheumatoid arthritis, or any form of immunodeficiency. Patients who were unable or unwilling to follow post-operative care instructions or to attend follow-up appointments were not considered for the study.Surgical procedures were performed with patients in a supine position, with the knee flexed and placed in a leg holder, under regional anesthesia. A tourniquet was uniformly used, inflated at 275 mmHg following vascular drainage of the leg and prior to skin incision. Prophylactic antibiotic therapy and tranexamic acid were administered during surgery.A small incision was made over the pes anserinus, where the tendons insert on the medial side of the tibia, just below the knee joint line. Identification of the pes anserinus was achieved by palpating 1.5 cm medial and below the lower margin of the tibial tubercle. The skin incision typically ranged from 2 to 3 cm in length, positioned slightly oblique from medial and proximal to lateral and distal. Subsequent to meticulous dissection of the subcutaneous tissues, a Langenbeck retractor was placed medially and the presence or absence of the ‘sentinel vessel’ was noted and documented .The HT harvesting continued with a horizontal incision of the fascia and identification of the gracilis and semitendinosus tendons at their insertion points on the pes anserinus. A closed tendon stripper was utilized to strip the grafts proximally, and the HT preparation proceeded with muscle tissue stripping and quadruple stitching of the graft. The process culminated with a standard, single-bundle graft ACL reconstruction.® 26 Suite . Descriptive analyses were conducted to determine frequencies and correlations. Both the Student’s t-test and the chi-square tests were used, and statistical significance was established for each variable. The t-test was selected as the statistical analysis method due to its efficacy in comparing means between two independent groups, which in this case were the patient groups. Before the implementation of the t-test, a Shapiro–Wilk test was conducted to ascertain the normality of the data distribution. Additionally, the homogeneity of variances was confirmed using Levene’s test, another assumption for the t-test, to ensure the reliability of the analysis outcomes. Sensitivity analyses were conducted to explore the robustness of the findings, providing added confidence in the results. All findings were presented with a confidence interval of 95%, reflecting the level of certainty in the statistical conclusions drawn from the study.Data processing was performed with the SPSSt-test to compare these mean proportions between males and females. This test was chosen because it allows the comparison of means between two independent groups and our data met the assumptions of normality and equal variances.In conducting our analysis, we first segregated the dataset into two groups based on the gender of the patients: male and female. The variable of interest was the proportion of patients presenting with bIMGA in each group. For each gender, we calculated the mean proportion of patients with bIMGA across all age groups. We then employed the independent samples In the study population, 135 individuals (63.4%) were male, exhibiting a mean age of 30.2 years, with an age range of 15–46 years, and were predominantly involved in active sports or physical occupations. Patient characteristics and demographics, including details about their social determinants of health, are illustrated in Preoperative data were collected at the time of study enrollment by a study nurse and are meticulously presented in A diminished degree of consistency was encountered in the identification of the bIMGA within the patient cohort when utilizing the described surgical procedure. Patient subgroups were established based on the presence or absence of the specified blood vessel. The data associated with these groupings were systematically accumulated and are presented in The results of the t-test indicated that there was no statistically significant difference between the mean proportion of males and females presenting with bIMGA across all age groups . As a rep-value was 0.035, which was less than the significance threshold of 0.05. Both genders exhibit a statistically significant correlation between activity level and the presence or absence of bIMGA.The chi-square test was used for data pertinent to specific levels of activity. The calculated The main discovery in this investigation is the correlation between the patient’s activity levels and the successful identification of the bIMGA. The observed association suggests that there may be underlying factors related to activity levels that coincide with the identification of the bIMGA It is essential to note that this finding does not imply a causal relationship between physical activity and the detectability of this vascular structure during ACL graft harvesting. The complexities associated with the identification and obtaining appropriate length tendons from the pes anserinus are well documented . PrecisiThe presence of tendon anatomical variations demands significant consideration. Numerous research studies have identified a variety of anomalies, including accessory fascial bands, supernumerary muscles, and additional tendon slippage, thereby posing difficulties in the precise procurement of tendons for grafting ,19,20. TRecent research by de Lima Lopes and colleagues  revealedBased on an examination of four cadaveric specimens, Zaffagnini et al. provided a detailed description of the neurovascular anatomy . Our ownShahid and colleagues examined 20 cadaveric knees in detail, concentrating on the branching and vascular anatomy of the geniculate arteries . In thisThe inconsistency of bIMGA as a reliable anatomical reference during graft harvesting procedures was observed in our study. This can be explained and highlighted by a number of factors. Initially, the bIMGA’s small caliber vessel size and patient-specific anatomical characteristics make it easy to overlook during surgical procedures. The absence of detection during our surgical procedures does not necessarily indicate that the vessel does not exist. Second, inherent vascular variability poses a difficult obstacle and directly contributes to the third possible explanation, which is the difficulty of precisely locating a small vascular structure via a less invasive surgical approach in a manner that can be replicated and standardized. This observation necessitates additional research to refine existing methods or identify more reliable anatomical landmarks that could improve the efficacy and predictability of graft harvesting techniques.Obviously, the utility of prominent anatomical landmarks for various interventions and comprehensive approaches cannot be contested or changed, as they serve as navigational aids for surgeons during the procedure . Our datDespite the fact that the current study provides important insights into the interaction between age groups, gender, activity levels, and the detection of the bIMGA during ACLR, it is important to acknowledge our limitations. The reduced sample size, which is common in single-center research, is a restriction that may have reduced statistical power and the capacity to identify significant changes. In the design of this study, no power analysis or specific sample size calculation was conducted. The decision to omit these analyses was made in consideration of the exploratory nature of the investigation and the limited existing literature on the bIMGA in ACL reconstructions. The sample size of 213 patients was determined based on the clinical volume over a two-year period, ensuring a diverse and representative cohort for the evaluation of bIMGA. While this approach may limit the generalizability of the statistical findings, it enabled in-depth and nuanced insights into the state-of-the-art of this specific anatomical feature.Furthermore, the study was restricted to a specific patient cohort, which may not be indicative of the broader population. Additional multicenter research with larger sample sizes and more diverse patient populations is required to validate and expand the current study’s findings.Our study provides new insights into the challenges of identifying bIMGA in ACL graft harvesting, emphasizing the significant variability in its presence and its correlation with patient activity levels. Derivatively, we have underscored the importance of individualized approaches and meticulous preoperative evaluations highlighting the thoroughly described importance of personalized evaluations prior to surgery ,24,25. OA better understanding and appreciation of these anatomical variances can help to optimize surgical methods, lowering the chance of unfavorable outcomes. Our findings highlight the necessity of individualized surgical and therapeutic approaches based on thorough preoperative evaluations.Based on our examination of the studied sample, bIMGA demonstrated a high degree of anatomical variation, thereby posing substantial challenges in its consistent identification within the surgical field. Our analysis did not establish a significant correlation between the variability of the bIMGA and the demographic characteristics of patients. Considering these observations, we advise against the utilization of the bIMGA as a reliable anatomical landmark during ACL graft harvesting procedures due to its marked inconsistency and the potential to compromise surgical precision.


Technologies with high throughput have fundamentally altered medical research . In receSingh et al., 2022). Despite these benefits, the article also points out that employing an integrated omics approach has limitations as well. The complexity of the data generated, which necessitates sophisticated bioinformatics tools and methodologies, is one of the key problems. Another issue is that using various omics technologies could result in data that needs to be carefully validated to assure its accuracy .An article on this Research Topic has extensively discussed the importance of integrated omics approaches in decoding virulence and fitness of Gram-negative bacteria, which is the possible outcome of host-pathogen interaction. An integrated omics technology, which enables researchers to identify the crucial genes, proteins, and metabolites involved in the network of interactions between hosts and infections, is highlighted as one of the most advantageous strategies in the paper . Furthermore, another article has used whole genome sequencing to assess the virulence potential of Shiga toxin-producing Escherichia coli (STEC) O121 . The reduction in the number of genes associated with the Type III Secretion System is primarily responsible for the diversity in the virulence gene repertoire that was shown by the results. The findings showed diverse evolutionary lineages among the strains and revealed that some STEC strains had less pathogenicity potential.Genome-wide screens are another omics technique used in this context to produce significant, high-quality data sets that can be utilised immediately to determine the genes that are involved in a certain process. The contributed article in this Research Topic has utilised genome-wide screening tool TraDIS (Transposon Directed Insertion-site Sequencing) to identify Staphylococcus aureus isolates from a large cohort of French patients with severe community-acquired staphylococcal pneumonia. The results indicated that the level of virulence components expressed in vitro by S. aureus may be correlated with the severity of the infection .In a related study, research paper on targeted proteomics was used to compare the quantitative virulomes of Chen et al., 2023 explored the function of duodenal ulcer-promoting gene A (DupA) in gastropathy induced by Helicobacter pylori. They utilised 16S rRNA metagenome amplicon sequencing to analyse the microbiota DNA of the gastric mucosa and confirmed the expression of DupA from isolated H. pylori strains using PCR and qRT-PCR. According to their findings, high DupA expression in H. pylori is associated with a higher risk of erosive gastritis and a lesser degree of disruption to the gastric microbiota, demonstrating that DupA as a risk factor for erosive gastritis rather than gastric cancer . Therefore, measurements of functional activity for certain genes by RT-PCR are more powerful when integrated with traditional omics technologies that better capture genome and metabolome alterations, transcriptome perturbations, as well as proteome dynamics and post translational modifications (PTMs). Moreover, the combined knowledge from 16S rDNA and various omics approaches may enable better elucidation of the impact of the microbiota community on the corresponding hosts, paving the way to build support for new biological hypotheses.Furthermore, another genomics study by In conclusion, the articles in this Research Topic have provided valuable perspectives using omics approaches that revolutionized the field of host-pathogen interactions. A thorough understanding of host-pathogen interactions is critical for the development of infectious disease therapies and prevention strategies.ARA prepared and wrote the editorial manuscript. KB and NR reviewed and edited the editorial manuscript. All authors contributed to the article and approved the submitted version.