Background and aimEndovascular aneurysm repair (EVAR) has revolutionized the management of abdominal aortic aneurysm (AAA). The re-intervention rate following EVAR has been a subject of debate in many studies. The study aims to evaluate the short-term outcomes in terms of the early (four-year) re-intervention rate following EVAR at our centre and compare it to the average re-intervention rate of the main studies assessed by the National Institute of Health and Care Excellence (NICE).MethodsThe EVAR procedures performed over two years (2015 and 2016) were retrieved using the operation codes. The clinical portal and PACS systems were used to review the discharge summaries, clinic and multidisciplinary team (MDT) letters, as well as the scans and interventional radiology procedures to assess the patients’ adherence to follow-up and identify any re-intervention procedure done to correct underlying problems related to the EVAR performed. Patients who switched their follow-up to another hospital were contacted and interviewed about any re-intervention undergone. ResultsA total of 108 patients underwent EVAR during the two-year study period. Twenty EVAR-related re-interventions (18.5%) were recorded, irrespective of the cause or the type of intervention. This is slightly higher than the average rate by NICE (16.89%). Type 1 endoleak represented the leading cause for re-intervention (30%). Most of the cases of re-intervention were done endovascularly (60%). Forty-five percent of the patients had a re-intervention during the first year and 35% in the third year.ConclusionThis study shows that although our re-intervention rate following EVAR was slightly higher than the international average, EVAR is still a safe method for the repair of AAA with relatively low peri-operative morbidity and mortality. However, long-term follow-up of these patients is mandatory as re-interventions are frequently required. Nonetheless, the majority of re-interventions can be done with minimal morbidity to the patient. The first endovascular repair of infra-renal abdominal aortic aneurysm (AAA), which was reported by Parodi et al. in 1991, revolutionized the management of AAA . This isThe study aims to evaluate the short-term outcomes in terms of the early (four-year) re-intervention rate following EVAR at our centre and compare it with the average re-intervention rate of the main studies assessed in the evidence review of AAA: diagnosis and management by NICE guidelines. A secondary aim is to evaluate the different devices used in EVAR regarding the rate and causes of re-intervention. The four-yearly re-intervention rate following EVAR in ACE , EVAR-1 and OVER (Open versus endovascular repair) trials is 16.89%; these trials combined a total of 1220 EVAR cases .The EVAR procedures performed from 1st of January 2015 till the 31st of December 2016 were retrieved using the operation codes. The clinical portal and PACS systems were used to review the discharge summaries, clinic and multidisciplinary team (MDT) letters, as well as the scans and interventional radiology procedures to assess the patients’ adherence to follow-up and identify any re-intervention procedure done to correct underlying problems related to the EVAR performed. Patients who switched their follow-up to another hospital were contacted and interviewed about any re-intervention undergone. A total of 108 patients underwent EVAR during the two-year study period. The study included 93 males (86.1%) and 15 female (13.9%) patients. The average age of the patients was 75.6 years ranging from 57 to 89 years old. Only two repairs were done urgently for ruptured AAA, while the rest were done as an elective procedure following detailed discussion in the vascular MDT. The patients' co-morbidities are illustrated in Table Twenty EVAR-related re-interventions (18.5%) were recorded, irrespective of the cause or the type of intervention. Although 30 patients 27.8%) developed a type of endoleak post-operatively which required close follow-up, only 17 patients (15.7%) had a re-intervention to further investigate or treat this endoleak. Type 1 endoleak represented the main cause for re-intervention (30%), other causes are summarized in Table 7.8% deveOur experience with the Gore excluder device yielded the best results, as no re-intervention was recorded for the 10 patients who underwent the EVAR using it. Although The Nellix device was one of the devices least used, it showed a high rate of re-intervention at 37.5%, which included postoperative mortality following open repair for Type I endoleak. The re-interventions with the Nellix device were caused by device migration/Type I endoleak, which contributed to half of Type 1 endoleak cases in our study.The Ovation device was used in just over half of the cases, followed by the Zenith in 18.5%, the re-intervention rates in both are roughly around the percentage of our average re-intervention figure. The Ovation device re-intervention was related in the majority of patients to Type II endoleak; four cases needed either embolization or ligation of the Inferior Mesenteric Artery (IMA) for Type II endoleak. While three cases developed Type I endoleak, which required a cuff/stent, it is worth noting that the aneurysm neck measurements were within the Instructions for Use (IFU). The rest of the cases were divided between revascularization procedures for acute lower limb ischemia and open repair for Type V endoleak. Seventy-five percent of the re-interventions for the Zenith devices were endovascular repair for Type I endoleak which were contributed to short neck (<12 mm), while one case required a revascularization procedure for acute lower limb ischemia owing to extremely tortuous iliac arteries with tight angles. The only re-intervention case related to the Powerlink device recorded was Fluoroscopic guided embolization using Onyx™ for a Type II endoleak. Types and frequency of devices used and re-intervention rate per device are summarized in Table It is evident that we have a slightly higher re-intervention rate than the international average rate, however, most cases were managed with minimally invasive approaches as endovascular or laparoscopic (70%) and less than a third required either open repair or bypass graft (30%). It is noted that eight patients underwent an additional planned procedure at the time of the primary EVAR, either in the form of embolization or a fem-fem crossover bypass. Although it can be a coincidence that only one of these patients underwent a re-intervention , it is encouraged to extensively assess the scans prior to the primary EVAR to ascertain the requirement for an additional procedure done at the same setting to decrease the incidence of re-intervention, and ultimately improve the efficiency of utilization of resources. While rupture of sac following EVAR is considered rare, it has been reported, and so patients who develop persistent endoleak need close and continuous surveillance .Nordon et al. stated that the main bulk of re-interventions are done within one month following EVAR. They stressed the importance of supplementary procedures intra-operatively to evaluate the perfectness of the exclusion of the AAA with the graft, and thus, a precautionary strategy will help to cut down the number of re-interventions and the overall need for close follow-up . This isThe re-intervention rate following EVAR has been a subject of debate in many studies -8; ConraIn contrast to most studies that examined the re-intervention rate after EVAR ,4,6,7, tThe gold standard management for Type II endoleak remains a subject of debate. It is the most commonly occurring endoleak in 10% to 25% of patients following EVAR -11. On fOn the other hand, more recent studies like that published by Axelrod et al. reported less persistent endoleaks and a greater shrinkage of sac in patients who underwent preoperative embolization of the IMA when compared to those who did not . In our The main principle of EVAR is the total exclusion of the aneurysmal sac and depressurization, to eliminate the risk of aneurysm rupture. It is well documented that the rupture rate following EVAR is minimal; Conrad et al. reviewed 4291 patients who underwent EVAR from the EUROSTAR registry and only identified 34 patients (0.8%) who had a rupture following EVAR . The maiThe limitations of this study are primarily being a retrospective study, and variations in case selection and device use as well as follow-up plan by individual surgeons involved in the management of patients, though all cases are discussed in a formal MDT before surgery and any re-intervention.This study shows that although our re-intervention rate following EVAR was slightly higher than the international average, EVAR is still a safe method for repairing AAA with relatively low peri-operative morbidity and mortality. However, long-term follow-up of these patients is mandatory as re-interventions are frequently required. Nonetheless, the majority of re-interventions can be done with minimal morbidity to the patient.


ObjectiveThe aim of this study was to evaluate the effect of botulinum toxin A (BTX-A) injection on patients with chronic low back pain (CLBP).DesignIn this open-label prospective study, patients with CLBP who satisfied inclusion and exclusion criteria received 100 units of BTX-A injection. Patients were followed up at four weeks, three months, and six months after injection. Pain and function were assessed with visual analog scale (VAS), Roland-Morris Disability Scale (RMS), and Oswestry Disability Index (ODI) at baseline and subsequent visits.ResultsA total of 19 participants with a mean age of 41.11 years completed the study. Compared to baseline, a significant improvement in all scores was observed that persisted up to six months post-injection (P<0.001). Only two patients reported transient injection site pain that improved over two to three days without any treatment.ConclusionBTX-A injection is safe and improves pain and function in patients with resistant CLBP. The effects are more beneficial when the population is more homogenous in diagnosis and devoid of negative predictors for the outcome. Low back pain (LBP) is a major public health problem worldwide and is a significant cause of morbidity and reduced quality of life ,2. AmongDespite several available treatment options, relief is often inadequate and adverse effects of analgesics and opioid medications limit their chronic use. The lumbar erector spinae muscles have become an important therapeutic target as an increased contraction of these muscles has been linked to lumbar stiffness hence the intensity of LBP . Many thBTX-A is one of the most potent neurotoxins which is produced by Clostridium botulinum. It is a potent inhibitor of acetylcholine (Ach) release from presynaptic vesicles. BTX-A effectively treats spasticity, dystonia, and several other forms of muscle spasm, including blepharospasm . LiteratThis prospective open-label study was conducted in the Department of Physical Medicine and Rehabilitation, in a tertiary care institute of India. The ethical approval has been taken from Institutional Research Cell, AIIMS, Bhubaneswar (Registration no- ECR/534/Inst/OD/2014/RR-17) on 23rd January 2018. The IRB approval number was AIIMS/BBSR/RC/130/2017, dated 23rd January 2018. After ethical approval, we started recruiting patients  for our study. Inclusion criteria were: (1) chronic and stable LBP for at least six months; (2) age 18-70 years; (3) failure of medical and/or surgical treatments. Exclusion criteria were: (1) chronic LBP attributable to acute and/or serious pathologies including fracture, infection, and neoplasm; (2) systemic inflammation; (3) pregnancy (current or planned) and/or breastfeeding; (4) history of neuromuscular junction disorders; (5) primary muscle weakness; (6) known allergy or sensitivity to BTX-A; (7) history of any psychiatric illness; (8) any history of injection to paravertebral muscles in last six months and (9) patients who were not motivated to undergo the treatment. Patients were advised against any change in the current treatment regimen for LBP. All patients who satisfied the inclusion and exclusion criteria were explained about the study and included in the trial after signing the informed consent form.All patients were evaluated at baseline, at four weeks, at three months, and at six months post-injection. During each evaluation, patients were assessed with visual analog scale (VAS) for pain, Roland-Morris Disability Scale (RMS), and Oswestry Disability Index (ODI) for disability. Participants rated their average perception of LBP during the past one month on VAS having a 10-cm linear axis with a left end-point of “no pain” and right end-point of “worst pain ever”. The pain was recorded by measuring the distance on the 10-point scale . ParticiBTX-A , with a concentration of 50 units/mL, was prepared by reconstitution of the frozen-dried toxin (100 units) with normal saline (2 ml) and was drawn in a 1-cc tuberculin syringe. The injection was performed with a 25 gauze needle and the needle size was selected depending upon the body habitus of the subject. The intervening physician injected the solution of 12.5 units each at 4 sites per side (L1 to S1) either by locating points of maximum tenderness or at equidistant sites to encompass the whole length of the lumbar paraspinal muscle. The injection was performed without any guidance as to the superficial location and the adequate size of the target muscle made it easily accessible. The total injected dose of BTX-A in a single participant didn’t exceed 100 units. Patients were advised to report any adverse events during the study period and to follow-up at four weeks, three months, and six months post-injection as per study protocol.The statistical analysis was done with the help of SPSS software version 20.0 . The categorical variables were presented as n (%) and continuous data as mean and standard deviation (SD). The significance of outcome measures  at follow-up visits compared to baseline was determined by the paired t-test.A total of 21 patients were included in the study but only 19 patients completed the study with a mean age of 41.11 years. Among them, 10 were male and nine were female patients. The mean duration of CLBP was 38.58 months. Radiation of LBP into lower limbs was present in five patients (26.32%) with three of them having both limb pain and two patients having only single limb pain. Rest 14 patients (73.7%) had isolated LBP without any radiation. LBP was unilateral in four patients and bilateral in 15 patients. Fifteen patients took one or more non-opioid pain medications, and four patients used heat modalities for pain relief. None of them were using any opioid pain medications. MRI of the lumbosacral spine was abnormal in 12 patients with common findings being degenerative changes, disc herniation, lumbar spinal stenosis, spondylolisthesis, or a combination of these abnormalities. Five patients were diagnosed with myofascial pain syndrome (MPS) with palpable trigger points. No patients were having any neurologic deficits, any history of back surgery, any red flag or yellow flag signs. Table At baseline, the mean average VAS score was 6.89, the mean RMS score was 12.63, and the mean ODI score was 47.70. Among all participants, 18 patients significantly reduced all scores at subsequent follow-ups that persisted up to 6 months post-injection. The percentage reduction in scores from baseline was also significant across all subsequent visits. Only one patient didn’t respond to injection which might be attributed to the presence of multiple etiology. In all responders, the beneficial response to BTX-A occurred within 24-72 hours of injection. No patient reported worsening in pain and/or function after administration of BTX-A. Only two patients reported side effects as local injection site pain which subsided without treatment in two to three days. Comparison of outcome scores with baseline at all follow-ups has been summarized in Figure Paraspinal muscle hyperactivity has been implicated as an important contributor to CLBP. The source of the pain can be the ischemic muscle itself due to the accumulation of metabolic waste products or from the adjacent tissues such as ligaments, tendons, and joints which are under continuous stress by the hyperactive muscles. Also compared to subjects without pain, patients with CLBP demonstrated increased electrical activity of the paraspinal muscles in electromyographic studies . This prBTX-A has demonstrated a mild to moderate analgesic effect in various chronic musculoskeletal pain conditions besides its well-known tone reducing effect. In a recent meta-analysis, it has been found to be particularly efficacious in plantar fasciitis, tennis elbow, and back pain -14. MPS According to the American Pain Society Clinical Practice Guidelines , there wNey et al , conductIn contrast, our study's improvement in pain and function persisted up to 6 months post-injection and can be attributed to a couple of the following important factors. Firstly, participants were devoid of certain conditions that might have negatively affected the outcome including failed back surgery syndrome, yellow and red flag signs, any acute or serious pathology, and lack of motivation to undergo the intervention. Similar studies in the past have not considered excluding the above factors which might have contributed to the short-term effects of BTX-A. Secondly, all participants were aware of the high cost of BTX-A and the interventional nature of the treatment before giving their consent for participation. This may have led to a positive pre-conception about the treatment outcome and possibly could have contributed to a placebo response alone, or in combination with the actual therapeutic response.The analgesic effect of BTX-A can be attributed to its effect on various nociception-inducing mechanisms. It inhibits the release of a number of neurotransmitters (NTs) from presynaptic vesicles which include acetylcholine, substance P, bradykinin, calcitonin gene-related peptide, and glutamate . This inSimilar to our findings, a favorable safety and tolerability profile has been shown across a wide spectrum of therapeutic uses with focal weakness being the only reported adverse event . Two parThis study despite having encouraging results is not without limitations. First, the sample size was small which prevents the generalizability of the results. Second, the lack of a control group and non-blinding may reduce the study's internal validity and causal inference cannot be established. Nevertheless, the number of patients receiving BTX-A is similar to that in past trials, which also reported a significant positive effect on CLBP. Our study adds to the findings of previous trials by showing a superior effect of BTX-A on CLBP when the population subset is more homogenous in their diagnoses. Therefore we encourage future trials on a larger cohort with a superior study design to further support our results.This study demonstrated a more beneficial and persistent effect of BTX-A injection on CLBP when the patient group is more homogenous in their diagnoses. Also, BTX-A appears like a safer alternative to manage chronic and refractory LBP with only very few and transient side effects. However, further good quality trials with a larger sample size are needed to support this conclusion. Also, future trials should focus on the cost-benefit analysis of BTX to warrant its wider clinical application.


Case Presentation. A 74-year-old man was referred to our hospital for treatment of bilateral vision loss. The best-corrected visual acuity was 20/100 in the right eye and 20/200 in the left eye. His electroretinogram (ERG) showed a reduced b-wave and a normal dark-adapted a-wave in both eyes. Optical coherence tomography (OCT) revealed loss of the interdigitation zone in both eyes. We strongly suspected MAR based on the markedly reduced b-wave in the ERG and a history of intranasal melanoma. The diagnosis was confirmed after autoantibodies against TRPM1 were detected in his blood serum. Fifteen months later, his ERG remained unchanged, and OCT showed bilateral cystic changes in the internal nuclear layer. The visual acuity in both eyes also remained unchanged.  We report the clinical features and clinical course of melanoma-associated retinopathy (MAR), in which autoantibodies against the transient receptor potential cation channel subfamily M member 1 (TRPM1) were detected.  Anti-TRPM1 autoantibodies were detected in a patient diagnosed with MAR who had negative flash ERG and retinal microstructural abnormalities, and the impairment did not recover during the follow-up period. Identification of anti-TRPM1 antibodies was helpful in confirming the diagnosis of MAR. Melanoma-associated retinopathy (MAR) is a disease associated with melanoma that causes dysfunction of retinal ON-bipolar cells . It is aA 74-year-old Japanese man gradually developed visual disturbances in both eyes. He was referred to our department four months after his symptoms emerged due to an unknown cause. At his first hospital visit, the best-corrected visual acuities of the right and left eyes were 20/100 and 20/200, respectively. Intraocular pressure was normal. Slit-lamp examination and fundus photography yielded normal results in both eyes . Swept-sFifteen months later, the best-corrected visual acuity of both eyes remained unchanged. OCT demonstrated obscuration of the interdigitation lines and cystic changes in the internal nuclear layer (INL) in both eyes Figures . The cysWe present a case of MAR with negative flash ERG and retinal microstructural abnormalities. Identification of the anti-TRPM1 antibody was helpful in confirming the diagnosis of MAR. The patient was followed up for 15 months, and his visual acuity in one eye was preserved, although it deteriorated slightly in the contralateral eye.According to previous reports in which changes in visual function were analyzed, visual acuity, color perception, and central visual field were generally preserved in most patients with MAR. However, in this case, the visual acuity of the patient was severely impaired at the initial visit and did not improve during the next 15 months. At the initial visit, SS-OCT was able to detect an irregularity in the interdigitation line, indicating photoreceptor damage, which did not recover during the follow-up period. This damage seemed to correlate with visual disturbances. TRPM1 was originally identified as a specific protein against melanocytes and has also been reported to be expressed in ON-bipolar cells as a binding protein against mGluR6 , and thePreviously, our team reported a correlation between the detection of anti-TRPM1 antibodies and the clinical characteristics of paraneoplastic retinopathy with ON-bipolar cell dysfunction . In thisThe differences in the clinical courses of each patient can be explained by the variability of recognition sites in anti-TRPM1 antibodies. Some recognition sites can bind to only one specific site, and the binding possibly causes only transient dysfunction of retinal ON-bipolar cells, while other recognition sites can cause severe damage to retinal ON-bipolar cells , 13.In conclusion, this study shows the clinical course of a patient diagnosed with MAR who tested positive for anti-TRPM1 antibodies. In this case, both visual disturbance and retinal microstructural abnormalities at the initial visit did not recover for 15 months. Anti-TRPM1 antibodies may be useful for confirming the diagnosis of MAR; however, it is important to know the variety of clinical courses in each case with anti-TRPM1 antibodies.


Many patients with chronic obstructive pulmonary disease (COPD) are treated in general practice only and have never received specialist care for COPD. They are seldom included in COPD cost studies but may account for a substantial proportion of the total costs.To estimate and specify the total healthcare costs of patients who are treated for COPD in Denmark comparing those who have- and have not had specialist care for COPD.Denmark, population 5.7 million citizens.Via national registers, we specified the total healthcare costs of all + 30-years-old current users of respiratory pharmaceuticals. We identified the patients with COPD and compared those with at least one episode of pulmonary specialist care to those with GP care only.Among totally 329,428 users of respiratory drugs, we identified 46,084 with specialist-care- and 68,471 with GP-care-only COPD. GP-care-only accounted for 40% of the two populations’ total healthcare costs. The age- and gender-adjusted coefficient relating the individual total costs specialist-care versus GP-care-only was 2.19. The individual costs ranged widely and overlapped considerably . Hospital treatment accounted for most of the total cost , pharmaceuticals , and primary care costs . The total costs of primary care pulmonary specialists were negligible.Healthcare policy makers should consider the substantial volume of patients who are treated for COPD in general practice only and do not appear in specialist statistics. In developed countries, chronic obstructive pulmonary disease (COPD) is among the diseases that poses the highest economic burdens on the healthcare systems . In DenmIn Denmark, virtually all subjects are listed with a general practice, being the primary caregiver for COPD. Specialist care for COPD requires a referral from the GP . There aThis study aims to estimate and specify the total healthcare costs for patients who are treated for COPD in Denmark comparing those who have- and have not had pulmonary specialist care for COPD.Register-based nation-wide cohort study.Denmark is a north European country with 5.7 million citizens, each with a unique identification number allowing linkage between national registers. The tax-funded public healthcare system provides almost all primary- and secondary care services free of charge. Outpatients’ pharmaceutical expenses are substantially reimbursed. The Danish National Prescription Registry keeps record of all fillings of prescriptions including the pharmaceutical’s Anatomical Therapeutic Chemical code (ATC) and the price of the purchase . The NatSpecialist-care: Patients who had had at least one episode of pulmonary specialist care for COPD were identified in NPR as those who during the past five years had at least one episode of in- or outpatient care in any Danish hospital diagnosis coded with ICD-10 code DJ44 or subgroups (COPD) as primary diagnosis or secondary to J13-18 (pneumonia) or J96 (respiratory insufficiency). The Danish Register of COPD uses this validated algorithm .GP-care-only: Patients who were treated for COPD in general practice and had had no pulmonary specialist treatment for COPD were identified among the remaining patients as those who on at least two different dates during the years 2015 and 2016 had redeemed a prescription with indication code 379 or 464 (COPD) or on a pharmaceutical with ATC code R03AC18, R03AC19, R03AL02-06, R03BB04-07, or R03DX07 (long-acting muscarinic antagonists (LAMA) in 2016 in Denmark, approved only for treatment of COPD). The Danish Register of Chronic Diseases (RUKS) uses this algorithm to identify COPD outside hospitals , except GP care LABA (Asthma or COPD): Remaining patients who at least twice had redeemed a prescription on long-acting beta-2-agonist (LABA) alone or in combination with inhaled corticosteroids (ICS/LABA).GP care other R03 (Asthma or COPD): Remaining patients who at least twice had redeemed a prescription on any respiratory drug (ATCR03) being the same or two different drugs.In the Danish population, we identified all patients aged 30 years and above who redeemed a prescription for a drug for obstructive lung disease (ATC R03) during year 2015 or 2016. This cohort was subsequently split into four mutually exclusive populations ).We included all the secondary care, primary care, and pharmaceutical costs of the patients in 2016 not requiring any direct link to COPD. We did not include the municipalities’ costs of nursing and rehabilitation, and any indirect costs e.g., welfare expenses and income lost due to sick leave. The secondary care costs were calculated based on the patients’ individual data in the NPR using diagnosis-related-group (DRG) tariffs updated on an annual basis. All in- and outpatient hospital services were included. The primary care costs were based on the Danish National Health Service Registry, including services rendered by GPs, primary care specialist physicians, physiotherapists, chiropractors, psychologists, dentists, and foot therapists. The pharmaceutical costs were based on the retail price of each purchased drug including the dispensing costs.The total and age- and sex-adjusted individual costs were compared across all four groups, but in the following specified analyses, in order to secure a high specificity of the COPD diagnoses in general practice, only population 2) GP-care-only was compared to population 1) specialist-care.The secondary care costs were divided into the major ICD-10 diagnosis groups based on the primary diagnosis of each episode of care, the primary care costs into the different provider types, and the pharmaceutical costs into the major ATC groups. For each type of cost, the costs per patient year were compared between the two COPD populations. The reported age- and sex-adjusted coefficients indicate the relative difference in annual cost per patient between specialist-care and GP-care-only patients. In the calculations of costs per patient year, each patient only contributed with their time being alive and resident in Denmark.A sensitivity analysis was conducted expanding the GP-care-only COPD population to also include the patients in population 3) and 4).All analyses were performed using STATA 14.0 .We identified 329,428 users of respiratory drugs, among those 46,084 with specialist-care- and 68,471 with GP-care-only COPD. The total health care costs for patients with specialist-care or GP-care-only COPD were €852 million corresponding to €7,436 per patient per year. GP-care-only comprised 60% of the COPD population and accounted for 40% of the total costs. In the GP-care-only population 81% were included due to use of LAMA and 19% used another ATCR03 pharmaceutical specifically targeted at COPD (data not shown). Many users of respiratory drugs did not fulfil our GP-care-only criteria and were thus not included in the specified comparing analyses   and 4), the adjusted total cost ratio between specialist-care and GP-care-only was 2.58.The highest total costs were for hospital services, followed by pharmaceuticals, and primary care services. The costs for hospital services were primarily for respiratory diseases, cardiovascular diseases, and cancers. Except for pregnancy- and birth related conditions, the adjusted costs in all ICD-10 diagnosis groups were higher if the patient had been treated in specialist care compared to GP-care-only Table .Table 2AThe distribution of pharmaceutical costs on ATC-groups varied little between specialist-care and GP-care-only. More than half of the pharmaceutical costs were for respiratory drugs Table .Table 3CMost primary care costs were for services in general practice. Compared to GP-care-only patients, specialist care patients had 2.57 times higher per patient costs for general practitioner home visits in daytime and 3.3 times after hours. Also, specialist care patients had higher costs for all other types of GP services and for physiotherapists, psychologists, and foot therapists, but lower cost for all types of primary care specialist physicians, chiropractors, and dentists. The costs of primary care pulmonary specialists were negligible as they only account for a (not distinguishable) share of the very low total costs of all services provided by primary care specialists in internal medicine Table .Table 4AWe found that at least 60% of all patients who are treated for COPD in Denmark have never been treated for COPD in pulmonary specialist care. The average individual total health care cost of a patient who have had specialist care treatment for COPD is between 2,19 and 2,58 times higher than that of a patient who have only been treated for COPD in general practice, and the range of individual costs is very wide and highly overlapping between the specialist care- and GP-care-only populations.Specialist care patients have higher individual costs than GP-care-only for most types of pharmaceuticals and services in both primary and secondary care. It follows the intentions of the Danish health care system that severe cases are referred to specialist care and though the study lacks clinical characteristics of the patients  our results, especially the higher costs for GP home visits, indicates a higher overall severity among specialist-care patients than GP-care-only . This diAs confirmed by our findings, in Denmark almost all COPD treatment in primary care is delivered by the GPs. Shortly after the present study period and among other reasons to save hospital resources, the Danish Regions and the GPs agreed that the GPs should take responsibility for treating a larger proportion of the COPD population and therefore receive a capitation fee (€247 per year) replacing the previous fees for daytime consultations, telephone calls, and E-mails used in this study . NotablyPrior studies, including two from Denmark, have found that patients with COPD have three to five times higher health care costs compared to age- and gender matched control persons without COPD , 10, 15.Lack of spirometry data lowers the validity of the COPD diagnoses in our study. We used the RUKS’ COPD algorithm that was developed by Sundhedsdatastyrelsen [The Danish Board of Health Data] to identify patients with COPD in the national registries. The algorithm intentionally favours specificity over sensitivity. For specialist care it means that the diagnoses used to define COPD are highly specific, but some hospital treatments of COPD are falsely coded as pneumonia or other not COPD diagnoses leading the patient to be misclassified as GP-care-only or not even included in the study . Also, t€ versus 1950 €) but considerably higher costs for primary- (729 € versus 564 €) and secondary health care (8717 € versus 6954 €) [Despite its known limitations, we used the RUKS’ algorithm partly to concur with the approach of Danish authorities but mostly to optimise the specificity of the COPD diagnoses, acknowledging that in general practice the COPD diagnoses may be less accurate than in specialist care. Even with this very restrictive approach we identified a large cohort of patients with GP-care-only COPD accounting for much of the total costs. RUKS provides sufficient case severity and accuracy of the COPD diagnoses to rely on the shown differences in resource allocation. For example, that patients with specialist care COPD are more likely than GP-care-only patients to use GPs and psychologists, but less likely to use primary care specialists and dentists. Intuitively, one could mistakenly assume that specialist-care patients would use the GP less often, but this is not the case. The specialist-care patients were identified via episodes of hospital care during the past five years, some of these episodes only lasting few days. However, COPD is a chronic progressive disease and therefore it is reasonable and customary to classify patients based on knowledge of prior rather than only current need for treatment. Inclusion of patients in the specialist-care COPD group based on only brief historic need for hospital treatment may explain why a substantial proportion of the specialist-care patients had lower costs of healthcare than the median of the GP-care-only patients. Also noteworthy, most likely some of the specialist-care classified patients were not directly treated by a fully trained pulmonary specialist. Our assumption that hospital-based treatment for COPD equals pulmonary specialist level is however the usual approach and our specialist care cost estimates are generally consistent with previous findings. A study based on the same Danish registries as this study estimated the total costs of healthcare for patients with COPD in specialist care during the period from 1998 to 2010. Compared to that study (and adjusted to 2016-prices) the present study found somewhat lower individual costs for pharmaceuticals (1794  6954 €) . GeneralOur findings are probably generalisable to other health care systems with a strong general practice sector e.g., the UK, the Netherlands, and Scandinavia.The cost data from Danish registries used in this study are highly complete and valid . All ATCOur findings imply that health care planners and researchers doing population- and cost studies of COPD in countries with a strong general practice should be aware that most patients who are treated for COPD are solely treated for the disease in general practice. These patients appear frequently in the secondary healthcare system but not directly with COPD. They account for a large share of the total health care costs of patients with COPD and should not be overlooked when comparing and/or prioritizing disease-related health care resources.Future studies should aim to further characterize and differentiate patients with COPD in different parts of the health care systems exploring the wide and overlapping range of individual costs. Healthcare professionals, politicians, and patients think, plan, agree on, and draw pyramids where the few most resource demanding COPD patients are supposed to be treated in specialist care and only milder cases in general practice , 24. How


To meet the unprecedented requirement of diagnostic testing for SARS-CoV-2, a large number of diagnostic kits were authorized by concerned authorities for diagnostic use within a short period of time during the initial phases of the ongoing pandemic. We undertook this study to evaluate the inter-test agreement and other key operational features of 5 such commercial kits that have been extensively used in India for routine diagnostic testing for COVID-19. The five commercial kits were evaluated, using a panel of positive and negative respiratory samples, considering the kit provided by National Institute of Virology, Indian Council of Medical Research (2019-nCoV Kit) as the reference. The positive panel comprised of individuals who fulfilled the 3 criteria of being clinically symptomatic, having history of contact with diagnosed cases and testing positive in the reference kit. The negative panel included both healthy and disease controls, the latter being drawn from individuals diagnosed with other respiratory viral infections. The same protocol of sample collection, same RNA extraction kit and same RT-PCR instrument were used for all the kits. Clinical samples were collected from a panel of 92 cases and 60 control patients, who fulfilled our inclusion criteria. The control group included equal number of healthy individuals and patients infected with other respiratory viruses . We observed varying sensitivity and specificity among the evaluated kits, with LabGun COVID-19 RT-PCR kit showing the highest sensitivity and specificity (94% and 100% respectively), followed by TaqPath COVID-19 Combo and Allplex 2019-nCoV assays. The extent of inter-test agreement was not associated with viral loads of the samples. Poor correlation was observed between Ct values of the same genes amplified using different kits. Our findings reveal the presence of wide heterogeneity and sub-optimal inter-test agreement in the diagnostic performance of the evaluated kits and hint at the need of adopting stringent standards for fulfilling the quality assurance requirements of the COVID-19 diagnostic process. Since the overwhelming majority of the infected cases are asymptomatic4 widespread testing has been advocated to be critical for the early diagnosis of cases and containment of the pandemic.The ongoing COVID-19 pandemic has spread globally infecting approximately 90 million individuals and has led to 1.9 million deaths within a year since the first declaration of the outbreak in Wuhan, China on 31st December 20196.The availability of whole genome sequencing of the SARS-CoV-2 virus, within 2 weeks of the declaration of the outbreak, enabled the development of a wide range of RT-qPCR kits by several commercial manufacturers within a relatively short span of time. To cope with this urgency and huge demand for testing, regulatory agencies like United States Food and Drug Administration (USFDA) adopted the procedure of Emergency Use Authorization (EUA) for clinical use of these kits in contrast to the customary process of granting full approval or clearance for diagnostic assays8. These kits target a wide range of viral genes, including RNA-dependent RNA polymerase (RdRp), open reading frame (ORF1ab), envelope (E), nucleocapsid (N), and spike (S) proteins9. However, there have been limited studies that have compared these kits relative performances via inter-test agreement of these kits using a robust panel of clinical samples within the operational settings of a diagnostic virology laboratory14.Consistent with this worldwide trend of rapid ramp-up of diagnostic capacity, in India over a period of nine months 1260 diagnostic laboratories have been approved by the Indian Council of Medical Research (ICMR), which is spearheading the country’s response to the pandemic. To perform the diagnostic RT-qPCR tests, ICMR has approved 145 commercial kits till dateSince this exercise constitutes a critical part of the total quality management of a diagnostic set-up, we undertook this study to evaluate the analytical and clinical performance of 5 commercial SARS-CoV-2 molecular diagnostic assays that have been granted EUA by the FDA. These kits included Allplex 2019–nCOV assay, Lab Gun COVID-19 RT-PCR Kit, TaqPath COVID-19 combo kit, BGI Real Time Fluorescent RT-PCR Kit and TRUPCR SARS-CoV-2 RT qPCR KIT assays and their performance was compared with 2019-nCoV Kit, provided by National Institute of Virology (NIV) under the aegis of ICMR.Since the study was done on anonymized samples after they have been used for routine diagnostic processing; involved less than minimal risk to the participants as there was no additional sampling involved; was integrated with the quality audit of the institute and the programmatic requirement of evaluating the operational performance of the commercial diagnostic kits, it qualified for exemption from ethical review and waiver of informed consent according to ICMR’s “National Ethical Guidelines for Biomedical and Health Research involving Human Participants”.We created a panel of positive samples from individuals having suggestive clinical features, identifiable history of contact with known cases of COVID-19 and positive laboratory report in ICMR-approved 2019-nCoV Kit, provided by National Institute of Virology, Pune. Similarly, a panel of healthy control samples was created from asymptomatic individuals without any known contact with cases of COVID-19. Furthermore, a panel of disease controls was created from individuals diagnosed with five other respiratory viruses like Influenza A H1N1 pdm09, Influenza A H3N2, Influenza B and Respiratory Syncytial virus, Human Metapneumo virus.Nasopharyngeal and oropharyngeal swab samples were collected from individuals belonging to each of the three groups mentioned above. Sterile nylon, dacron or rayon swabs with flexible plastic shafts were used to collect nasopharyngeal specimens (NPS) from symptomatic patients. After collection, swabs were placed in sterile Virus Transport Medium (VTM). Before testing, samples were vortexed for 3–5 s and a calibrated pipette was used to transfer the specimen volume specified by the kit manufacturer for RNA extraction. To simulate actual testing conditions in a COVID-19 diagnostic laboratory, the samples were not tested in replicates.RNA extraction from the collected samples was done using HiPurAViral RNA purification kit manufactured by HiMedia Laboratories Pvt. Ltd., India as per the kit instructions, after removing all patient identifiers. Briefly, 200 µl of patient sample was added to 460 µl of lysis buffer mixture. It was mixed well and incubated at room temperature for 10 min. The magnetic beads in the buffer were separated from the suspension using the magnetic stand, followed by washing with buffer MW1, MW2 and with absolute ethanol. RNA was eluted by incubating the beads with RNase free water at 56 The volume of extracted RNA sample, specified by the respective kit manufacturers, was subjected to diagnosis using 2019-nCoV Kit (ICMR-NIV Pune), Allplex 2019–nCOV assay, Lab Gun COVID-19 RT PCR Kit, TaqPath COVID-19 combo kit, BGI Kit Real Time Fluorescent RT-PCR Kit and TRUPCR SARS-CoV-2 RT qPCR KIT assays for detecting SARS-CoV-2 as per the manufacturer’s protocol on a ABI7500 thermal cycler (Applied Biosystem).The target genes, performance characteristics and operational aspects of the evaluated genes are depicted in Supplementary table-1, based on the information provided in the respective kit inserts. The PCR mix and thermal profiles were also used according to the kit protocols (Supplementary tables 2 & 3).As recommended by the manufacturers, a sigmoidal curve with a specific Ct value was considered as the criterion for considering a sample as positive for SARS-CoV-2. The criteria provided by the manufacturers of the respective kits were used for interpretation of the results (Supplementary table 1). All the required controls namely no-template control, extraction control and positive control were tested simultaneously with every set of samples, as part of the quality control of the procedure. The data was entered in MS Excel. The descriptive summarization of variables of interest was done by median and IQR for ordinal and interval data and counts for nominal data. Sensitivity and specificity were determined, as per convention, using confirmed COVID-19 cases and healthy and diseased control panels. To check the proportion of agreement, Cohen’s kappa test was used. Lin’s Concordance correlation coefficient of Ct values was also estimated and Bland Altman plots were used for understanding agreement in Ct values among different methods.18 and 'Bland Altman Leh'packages19.All the analyses were done by using base R version 4.0.3, tidyverse, epi-RIn absence of a gold standard assay, we considered a combination of clinical, epidemiological and laboratory criteria as indicator of COVID-19 infection. Accordingly, a panel of 92 clinical samples were collected from equal number of cases who were symptomatic for respiratory infection, had history of contact with diagnosed cases of COVID-19 and were RT-qPCR positive by 2019-nCoV kit provided by National Institute of Virology, under the aegis of Indian Council of Medical Research (ICMR), which is the apex national agency for COVID-19 testing. Similarly, a panel of 60 control samples was created, including healthy individuals and patients infected with other respiratory viruses .We observed varying sensitivity and specificity among the evaluated kits, with LabGun COVID-19 RT-PCR kit showing the highest sensitivity and specificity (94% and 100% respectively), followed by TaqPath COVID-19 Combo and Allplex 2019-nCoV assay . The comparative distribution of Ct values, as observed on testing with the evaluated kits, is depicted in Table We estimated inter-test agreement between the NIV kit and the five other evaluated kits. Of the panel of 92 positive samples, 52 tested positive by all the kits. Furthermore, an additional set of 34, 28, 29, 22 and 15 samples tested positive by LabGun, TaqPath, Allplex, BGI and TRUPCR kits respectively. The best inter-test agreement with NIV kit was shown by LabGun. Considering kappa value of 0.8 to be an indicator of ‘strong’ inter-rater agreementInterestingly, the degree of agreement was not dependent on the number of gene targets that were similar between the kits. To illustrate, TaqPath and Allplex kits showed identical kappa values though they had 1 and 2 gene targets in common with NIV kit respectively. Inter-test agreement was also compared between samples with low and high viral loads by restricting analysis to samples showing Ct values ≤ 35 (n = 28) and ≤ 30 (n = 64) in the reference kit. We did not observe improved concordance between the kits, in samples with relatively higher viral load.21. Lin’s Concordance Correlation Coefficient (CCC) is used to examine agreement between two continuous measurements. Like Pearson’s correlation coefficient, CCC ranges from − 1 to + 1. However, if one method of measurement differs systematically from other method then we will get higher value of correlation coefficient but concordance is not ensured. Therefore, Lin’s CCC is better measurement when our aim is to assess agreement or concordance. Lin’s CCC was estimated between the evaluated kits and the reference kit for E, RdRP and ORF1ab genes  for this analysises Figs. . Lin’s CWe also evaluated the kits for several operational features including turn-around time, instrument compatibility, reagent cost and input volume of RNA. All the five kits except TaqPath COVID-19 Combo kit were compatible with ABI7500, Bio-Rad CFX96 and Cobas z 480 ROCHE real time PCR machine. TaqPath was only compatible with ABI7500 machine. PCR duration was maximum for LabGun COVID-19 RT-PCR kit and minimum for BGI kit (Supplementary table 2).When we create a scatter plot showing measurement by one method on X-axis and by other on Y-axis, then their values should be clustered near 45-degree diagonal line if there is high agreement. Solid line indicates this 45-degree line. Dashed line is fit line for linear regression analysis.In this study we report a comparative assessment of five commercially available RT-qPCR kits that have been recently validated for COVID-19 diagnostics in India. Using a panel of anonymised samples, curated on the basis of clinical, epidemiological and laboratory criteria, we observed significant heterogeneity in the clinical performance and operational efficiency of the different commercial kits compared to the reference kit provided by the national agency of India. The wide variability in performance spanned across the range of viral load in the clinical samples and was not dependent on the number of gene targets that were shared between the evaluated kits and the reference kit. While LabGun COVID-19 RT PCR kit showed the highest sensitivity, specificity and inter-test agreement with the comparator kit, two of the five kits demonstrated sub-optimal concordance with the reference kit (kappa < 0.8). There was poor correlation between the Ct values obtained from the same sample and the same gene target in different kits.Lack of concordance between different commercial kits tends to be a major cause of irreproducible test results in clinical practice. This implies the need for enforcement of comprehensive quality management practices for kit manufacturers. Availability of a panel of reference standards, containing pre-determined copy numbers of various target genes, could help in resolving such heterogeneity and improving performance standards of the marketed kits. In absence of quality-assured kits, the purpose of containing the pandemic by widespread diagnostic testing cannot be fully achieved.22. While our selection of cases were based on the WHO definition of a “confirmed” case of COVID-19 23, our selection of controls enabled us to evaluate the specificity of these kits in discriminating between COVID-19 and other simulating clinical conditions. Evaluating the relative performance of 5 most common diagnostic kits, against a robust panel of clinically and RT-qPCR confirmed cases and other healthy and disease controls, is one of the main strengths of this study.Though RT-qPCR constitutes the cornerstone in the diagnosis of COVID-19, no kit has been declared to be the gold standard by any regulatory agency till date. The usual samples of nasopharyngeal and oropharyngeal swabs have been reported to deliver sensitivity of only 70% in COVID-1924.Our study on delineating the clinical sensitivity and specificity of the evaluated kits assumes significance in view of the fact that the grant of EUA is irrespective of the determination of these performance characteristics. The data considered for EUA comprises of analytical sensitivity  and analytical specificity . Owing to the novelty of the pathogen and the lack of both reference methods and a clearly defined disease state, establishment of clinical sensitivity and specificity are not required under EUA 25. However, despite the use of Ct values in comparing viral loads between samples collected and tested under similar conditions, the clinical diagnosis and management of COVID-19 is based on the qualitative results of RT-qPCR assays. Hence, categorical agreement can be considered as the yardstick of kit comparability and lack of such agreement between some of the approved commercial kits is worrisome.On comparing the relative diagnostic performance of the evaluated kits, we observed the highest diagnostic accuracy with LabGun COVID-19 RT-PCR kit, in terms of clinical sensitivity and specificity. Strong agreement with the reference kit was observed in case of three of the evaluated kits for dichotomous outcomes, i.e. positive and negative results. In addition to this categorical agreement, we also evaluated the extent of correlation between Ct values obtained on amplifying the same target gene using different commercial kits. In agreement with a previous study, we too observed poor correlation between the Ct values obtained on using the different kitsThe inter-test agreement was not associated with the number of gene targets that were similar between the kits or with the Ct value of the samples. Poor correlation between Ct values of PCR assays targeting the same gene hints at the variable efficiency of primers, probes and master mix components included in the different kits. The variation in efficiency of PCR amplification was found to be irrespective of the viral load, since the inconsistency in inter-test agreement was similar between samples with Ct values above and below 30 or 35.2, the operational aspects of such comparison have not been reported till date. Since the number of RT-qPCR instruments in a particular lab is usually limited, the adaptability of the diagnostic kits to a wider range of instruments is a useful advantage. The LabGun COVID-19 RT -PCR kit performed the best in terms of versatility. Similarly, the turn-around time of the assay becomes important in view of the increasing challenges of space limitation in holding areas for COVID-19 suspects. Though the assay time for LabGun COVID-19 RT -PCR kit was the longest (140 min) among the evaluated kits, still the higher agreement and versatility of this kit over-shadows this apparent disadvantage.Though diagnostic performance of COVID-19 RT-qPCR assays have been compared in several earlier studiesOur study suffered from several limitations. Firstly, the limit of detection of the different kits could not be determined in absence of a suitable RNA standard. Secondly, we could not assess the cross-reactivity of these kits with commonly circulating coronaviruses due to want of samples known to be positive for these viruses. Thirdly, the kit evaluation was done following the thawing of archived frozen samples which may have impacted the performance of the kits. Lastly, though we attempted to select the most widely used kits, we understand that this is a relatively minor proportion of the total number of kits that are approved for diagnostic use in India.To conclude, the present study advocates stringent verification of a kit’s diagnostic performance and due consideration of its operational aspects before adopting it for clinical use and also highlights the limited inter-test agreement between assays irrespective of the target genes amplified and the viral load present in the samples.Supplementary Information.


The objective of this review was to critically and systematically appraise the available evidence regarding the effectiveness of high-energy laser therapy (HELT) with flapless corticotomy in accelerating orthodontic tooth movement and the associated untoward effects.We searched eight databases electronically in August 2021: PubMed®, Medline®, Google Scholar, Cochrane Library, Scopus®, Web of Science™, Trip, and PQDT OPEN from ProQuest. Another search was done in the reference lists of the included studies. Randomized controlled trials (RCTs) were included in which patients had received fixed orthodontic treatment combined with HELT-assisted corticotomy in comparison with traditional orthodontic treatment. Cochrane’s risk of bias (RoB2) tool was used to assess the risk of bias.Five RCTs and one CCT were included in this review (155 patients). The HELT-based corticotomy around the upper canines led to a greater canine retraction at the first and second months (P < 0.001). In the third month, no statistically significant differences were noticed. In one RCT focusing on incisor intrusion, the irradiated upper incisors showed a greater intrusion speed than that of the control group . No significant side effects associated with the application of HELT were reported. According to the GRADE  approach, the quality of evidence supporting these findings was low to moderate.Although the acceleration of tooth movement appeared to be significant at least in the first two months, there was low to moderate evidence concerning the efficacy of HELT-based flapless corticotomy in the acceleration of orthodontic tooth movement. There is a need for more well-conducted high-quality RCTs. Traditional orthodontic treatment for moderate to severe malocclusions usually takes several years when fixed appliances are used , and thiIn an attempt to accelerate orthodontic tooth movement, several approaches have been studied, including surgical approaches, such as corticotomy , distracDental lasers are generally divided into high-energy laser and low-level laser devices . High-enRecently, HELT has been suggested to be used in performing alveolar corticotomy to induce the so-called 'regional acceleration phenomenon' (RAP) -14. ErbiDespite the importance of high-energy laser therapy and its widespread use in medical centers and teaching hospitals, few clinical trials have evaluated its efficacy as an adjunctive procedure for conducting corticotomies for accelerating tooth movement . There aMaterials and methodsA scoping PubMed search was performed to confirm the existence of similar systematic reviews and to investigate potentially relevant papers prior to writing the final systematic review protocol. No systematic review was found in the literature evaluating the effectiveness of high-energy laser therapy with flapless corticotomy in accelerating orthodontic tooth movement.Eligibility CriteriaExclusion and inclusion criteria were established according to the PICOS  framework:Study design: Randomized controlled trials (RCTs) of any design: parallel-group design, split-mouth design, or compound design  and non-randomized controlled trials (CCTs) were included, without time-of-publication or language restrictions.Participants: Healthy patients of all ages and malocclusions, both males and females, of all ethnic groups who received orthodontic treatment using a fixed orthodontic appliance were included.Type of interventions: All types of treatment using fixed orthodontic appliances (with or without extraction) assisted by HELT-based corticotomies for accelerating orthodontic tooth movement were included.Comparisons: Patients receiving traditional orthodontic treatment  using fixed orthodontic appliances (with or without extraction).Outcomes: The primary outcome was the rate of orthodontic tooth movement (RTM) or any measure indicating the effectiveness of high-energy lasers in accelerating teeth movements . The secondary outcomes were patient-reported outcomes , loss of anchorage, and unwanted tooth movements. In addition, the other secondary outcomes were gingival and periodontal problems , iatrogenic harm to teeth , or stability of treatment in the long term.Search StrategyThe following databases were electronically searched in August 2021: PubMed®, Medline®, Google Scholar, Cochrane Library databases, Scopus®, Web of Science™, Trip, and PQDT OPEN (to identify dissertations and theses).The following terms and their derivatives were used: (Orthodontic) AND (Acceleration) AND (high-energy laser). Table Study Selection and Data ExtractionTwo reviewers (RIS and MYH) independently assessed the articles for suitability according to the selection criteria; a third reviewer (GM) was asked to decide in case of disagreement. Initially, the titles and abstracts of articles were checked by the two reviewers during the search by using the eligibility criteria. Then, the same two reviewers evaluated the full text of all articles that might be included in the review or if the title or summary was ambiguous to reach a clear judgment. If any article did not fulfill one or more of the eligibility criteria, it was discarded from the review. Finally, the same two authors (RIS and MYH) conducted data extraction in the piloted and predefined data extraction tables. The data extraction sheet contained the following elements: general information ; method ; participants , mean age, malocclusion); interventions ; outcomes (primary and secondary outcomes); and results (the main finding). Other information about orthodontic aspects  was also included.Assessing the Risk of Bias of the Included StudiesThe two reviewers (RIS and MYH) independently assessed the risk of bias of all included studies using Cochrane’s risk of bias tool for randomized trials (RoB2) and the risk of bias in non-randomized studies of interventions (ROBINS-I) tool for non-randomized controlled trials -22. ThenResultsLiterature Search Flow and the Retrieved StudiesA total of 2780 references were found in the electronic search. Five hundred ninety-seven citations were carefully checked after duplicate references were removed. The titles and abstracts were checked for eligibility and all papers that did not meet the selection criteria were discarded. As a result, six studies were left for full-text assessment. No studies were excluded. Finally, six studies were included in the systematic review ,18,23-25Characteristics of the Included StudiesAn overview of the characteristics of the six included studies is given in Table Extraction treatment (maxillary first-premolar extraction followed by a canine retraction) was performed in five studies ,16,23-25A pre-adjusted orthodontic appliance (MBT 0.022 × 0.028-inch slots) was used in the five trials to investigate the effects of HELT on tooth movement ,18,23-25Two types of erbium laser were evaluated  ,18,23-24Different laser parameters were also used by researchers; Al-Jundi et al. used 400 mJ/10 Hz/4W for gingival perforations, then 400 mJ/15 Hz/6W for alveolar bone perforations . HoweverOn the other hand, Mahmoudzadeh et al. used Er, Cr: YSGG laser to accelerate canine retraction movement. In this study, the Waterlase iPlus Biolase device  was used with the following parameters: 3.5 W, 30 Hz, H’ mode 40% air and 80% water, using the MZ5 tip (500 μ diameter) .The primary outcome was the rate of canine movement in three studies ,24-25, tThe follow-up lasted until the completion of the intended tooth movement in four studies and ranged from two to four months ,18,23-24Risk of Bias in the Included StudiesThe summary of the overall risk of bias of the included RCTs is shown in Figures Effects of InterventionsPrimary outcome: Rate of tooth movement. Out of the six included trials, four trials assessed the effect of erbium lasers on canine retraction speed after premolar extraction ,16,24-25The effect of erbium lasers in accelerating upper canine retraction: three split-mouth trials ,24-25 anThe amount of maxillary canine retraction at the first month was assessed by 3 trials ,24-25, cThe study by Salman and Ali also found that the canine in the laser side moved twice the amount of that in the control side after six weeks of observation . Two triThe degree of retraction at the third month was assessed by two trials ,24, compEffect of Er: YAG laser in accelerating upper incisors intrusion. One trial conducted by Al-Jundi et al. evaluated the acceleratory effect of using the Er: YAG laser in flapless corticotomy at the anterior regions of the maxilla for incisor intrusion . This stSecondary Outcomes Four trials evaluated the levels of pain and discomfort associated with erbium laser radiation [Pain and discomfort:adiation ,23-25. HAlfawal et al.  evaluateA five-item questionnaire was used by Jaber et al.  to assesAnchorage loss and undesirable tooth movements: Only two trials evaluated these variables ,25. AlfaFor molar anchorage loss, the differences between the experimental and control sides were not significant during the observation time . The observation time in the study of Mahmoudzadeh et al.  was onlyThe rates of canines’ rotation were greater in the experimental sides compared to the control sides in both trials. However, these differences were insignificant (p>0.05) after four months of observation in the Alfawal et al. trial . There wPeriodontal problems: These problems were evaluated in two studies ,25. SalmDiscussionTo our knowledge, this is the first systematic review in the literature evaluating the effectiveness of high-energy lasers therapy (HELT) with flapless corticotomy in accelerating orthodontic tooth movement. The present review performed an overall qualitative assessment of the currently available studies, which comprised 155 patients from six trials. In order to minimize bias and possible confounders, only randomized and non-randomized controlled trials were included. The six trials that evaluated HELT were judged to be at unclear risk of bias; Participant blinding was the most problematic field. So this has affected the level of certainty of the achieved results.Four trials investigated the efficacy of erbium lasers irradiation in accelerating canine retraction after premolar extraction ,24-25. TWith erbium lasers, the peak of the RAP was after a month and decreased at the end of the second month. However, Wilcko et al. reported that the RAP phenomenon starts within a few days following injury, reaches its peak after four to eight weeks, and lasts for two to four months ,29. ThisAl-Jundi et al. evaluated the effectiveness of flapless corticotomy with Er: YAG laser in accelerating incisors intrusion (non-extraction treatment) and reported a significant difference in the overall treatment time; the mean increase in the rate of tooth movement was 38.4%  . When coOne hundred fifty-five participants were included in the six studies. The six trials included only adult patients. The previously included trials evaluated a variety of flapless corticotomy protocols with variations in the design and size of the cortical bone cuts. Therefore, future studies must test the effect of these differences on the amount of acceleration and the adverse side effects of each individual intervention.The levels of pain and discomfort associated with HELT were higher at the experimental sides than those at the control sides on the first day only -24. The Although no important levels of pain and discomfort associated with laser-assisted flapless corticotomy were reported in the evaluated trials, the evidence is weak. Therefore, further trials should investigate this outcome as well as other patient-reported measures.Only two included trials investigated the undesirable tooth movements  associated with laser-assisted flapless corticotomy ,25. InsiHigher canines’ rotation rate was reported on the surgical side compared to the control side ,25. HoweThe included trials did not report any adverse effects of laser-assisted flapless corticotomy on the periodontal tissue . Salman LimitationsA lack of large, high-quality studies investigating HELT-based flapless corticotomy in the acceleration of tooth movement is evident. Altogether, most of the included studies were at unclear risk of bias and had small sample sizes. Most studies evaluated part of the provided orthodontic treatment and not the entire treatment duration. Adverse effects are investigated in a limited number of studies, and there have been no attempts to assess the interventions in terms of cost-benefit analysis. Long-term follow-up of the response to these interventions was also lacking among the included studies.The efficacy of HELT with flapless corticotomy in accelerating tooth movement appeared to be significant at least in the first two months according to this review. However, the evidence has been found low to moderate according to the GRADE approach. More well-conducted studies are needed, with more attention paid to the size of the sample, the overall follow-up period, the surgical protocol , the type of orthodontic treatment (extraction vs. non-extraction), side effects, and cost-benefit ratios.


Understanding the risk factors associated with hospital burden of COVID-19 is crucial for healthcare planning for any future waves of infection.An observational cohort study is performed, using data on all PCR-confirmed cases of COVID-19 in Regione Lombardia, Italy, during the first wave of infection from February-June 2020. A multi-state modelling approach is used to simultaneously estimate risks of progression through hospital to final outcomes of either death or discharge, by pathway  and the times to final events (lengths of stay). Logistic and time-to-event regressions are used to quantify the association of patient and population characteristics with the risks of hospital outcomes and lengths of stay respectively.Risks of severe outcomes such as ICU admission and mortality have decreased with month of admission  and increased with age (odds ratio of ICU admission in 45–65 vs 65 + age group is 0.286 [0.201–0.406]). Care home residents aged 65 + are associated with increased risk of hospital mortality and decreased risk of ICU admission. Being a healthcare worker appears to have a protective association with mortality risk  and length of stay. Lengths of stay decrease with month of admission for survivors, but do not appear to vary with month for non-survivors.Improvements in clinical knowledge, treatment, patient and hospital management and public health surveillance, together with the waning of the first wave after the first lockdown, are hypothesised to have contributed to the reduced risks and lengths of stay over time.The online version contains supplementary material available at 10.1186/s12879-021-06750-z. Since the start of the coronavirus disease 2019 (COVID-19) pandemic, understanding the severe burden on healthcare, particularly hospitals, and the risk factors associated with severe events has been a crucial question. Note that by “risk factors” we mean covariates significantly associated with the outcome. Initial research  demonstrThe first Italian individual confirmed positive for the novel SARS-CoV-2 virus was identified on 20th February 2020 in Codogno, Regione Lombardia. Confirmed cases of COVID-19 rapidly increased to 403 in just one week , peakingThe aims of this study are to assess: the magnitude of the burden of the COVID-19 pandemic on Lombardia secondary healthcare in terms of risks of severe outcomes and lengths of stay in hospital; and how this burden varies across demographic and health groups. Use of the subset of cases in the COVID-19 Regional Database who were hospitalised allows quantification of the within-hospital burden using a multi-state modelling approach  to accouThe Lombardia COVID-19 Regional Database, as of 5th August 2020 and covering the period 1st December 2019 to 17th July 2020, contains detailed pseudo-anonymised retrospective individual-level data on the cohort of all individuals in Regione Lombardia diagnosed with COVID-19 via polymerase chain reaction (PCR) during the first wave. This dataset is described in full elsewhere , 14  , the pro , the prThe type of multi-state model considered is a “mixture model” , 16, comIn the dataset considered, outcomes are missing for < 1% of individuals in the Hospital and ICU states, and for 15% of individuals in the Post-ICU state. It is unknown whether the missing outcomes had not happened by the end-date of the data, 17th July, ("right-censoring"), or whether the outcome had happened, but was not recorded ("missing data/loss to follow-up"). Grosso, Presanis et al.  considerThe factorised models are fitted using a covariate selection procedure, as detailed in the following sections. Point estimates and 95% confidence intervals (CIs) are reported for each probability of interest, as well as for the median and interquartile ranges (IQRs) of each time-to-event distribution. The confidence intervals represent parameter uncertainty, whereas the median and IQRs summarise the heterogeneity across individuals in the time-to-event distributions.flexsurv package  relative to non-care-home residents), resulting in the predicted probabilities shown in Fig. –3.419 reCare home residence among 65 + year-olds was significantly associated with LoS Fig. , substanBeing a healthcare worker aged 45–65 was slightly associated with a lower risk of death from hospital without ICU, particularly in the earlier months of admission Fig. a. It is Being a healthcare worker shortened the median LoS in hospital amongst survivors aged under 65 and not admitted to ICU (Fig. Having at least one co-morbidity was significantly associated with probabilities of next events among 65 + year-olds, although with small effect sizes: reducing the risk of ICU admission, but increasing the risk of death, from either a hospital ward or ICU Fig. . There wGrosso, Presanis et al.  found hoThis analysis is one of the first to demonstrate the association of key risk factors with hospital burden of COVID-19 in Regione Lombardia during the first wave, while correctly accounting for confounders, censoring and the competing risks of different pathways through hospital. To our knowledge, similar studies have been conducted in England, investigating trends in severe outcomes for hospitalised COVID-19 cases , 7. TheiConsistently with other studies , risks oAlthough risk of being infected with SARS-CoV-2 is three-fold higher for healthcare workers than in the general population , and thith-31st March 2020 [COVID-19 outbreaks in care homes have been hotspots of the pandemic in Lombardia. In April, hospitals overwhelmed with in-patients, and required to provide more and more beds, were allowed to discharge patients still in need of low-intensity care to suitable care homes . Debate rch 2020 . Burton rch 2020  reportedrch 2020  reportedThe multi-state modelling approach employed allows comprehensive and simultaneous estimation of all hospital case-severity risks and lengths of stay of interest, under some assumptions. The dataset used is relatively complete and is a comprehensive census of confirmed cases hospitalised during the first wave, so is thought to be representative of hospitalised cases in the region. We have, however, assumed missingness is ignorable for some key covariates and for final outcomes  and thatFurther work is underway to apply a similar multi-state model to the subset from the Milano Local Healthcare Agency district, where good information is available on symptom onset dates, to understand the burden in the community, such as the proportion of symptomatic cases that are hospitalised or who die in the community, as well as the corresponding distributions of times to these events. Such an analysis, combined with the within-hospital analysis here, will provide further crucial evidence on the burden of COVID-19 in Lombardia, in particular the overall symptomatic case-fatality risk.Additional file 1. Additional figures and tables.


Recently, it has been sustained that only surgeons skilled in minimally invasive radical hysterectomy (MI-RH) could provide valuable oncological outcomes in early-stage cervical cancer. Still, literature lacks data correlating surgeon experience with patient survival rate.To investigate the impact of surgeon training patient survival rate following MI-RH for early stage cervical cancer.This was a retrospective study of 243 early-stage cervical cancer treated with MI-RH. Multiple regression analyses were undertaken to investigate the impact of the surgeons learning curve, according to the number of MI-RH, on patients prognosis.A steady trend of reduction in disease recurrence risk is associated with increased surgeon experience. The peak of the learning curve was shown at the 19th MI-RH . The 3 years disease-free survival that a surgeon could provide to patients is significantly lower at the beginning of his/her learning path comparing to what he/she could guarantee once adequate experience had been achieved . Surgeon experience appears to be an independent prognostic factor.The experience that a surgeon can achieve practicing in MI-RH significantly influences oncological outcomes of early-stage cervical cancer patients. Future studies comparing minimally invasive and open surgery should take this into account. It would be advisable that the scientific community precisely establishes the minimum training required in the field of MI-RH for early-stage cervical cancer. Radical hysterectomy with pelvic lymphadenectomy is the main treatment for women suffering from early-stage cervical cancer  and has During the last decades, minimally invasive radical hysterectomy (MI-RH) for early-stage cervical cancer patients became increasingly popular on the basis of several retrospective studies  and two Recently, a multicenter phase III prospective, randomised study comparing MI-RH vs O-RH failed to achieve the primary end-point , due to the documentation of a fourfold increase of hazard ratio for recurrence of disease, leading to the premature closure of the study for safety issues .These unexpected results rapidly led to contrasting reactions within the scientific community, modifying current ideas regarding the best surgical approach in early-stage cervical cancer and, at the same time, causing still ongoing controversial opinions, including the potential role of gynaecological oncology surgeon (GOS) learning of the minimally invasive approach, which must require specific skills .It has been argued that minimally invasive procedures performed by surgeons who are not adequately skilled could have affected survival results of MI-RH . It is sThe aim of this study is to investigate whether the surgeon learning curve for MI-RH, evaluated in terms of number of performed procedures, might have an impact on early-stage cervical cancer patient survival.This is a single centre, retrospective study including patients affected by histologically confirmed cervical cancer from Gynaecologic Oncology Units of Fondazione Policlinico-Universitario A. Gemelli-IRCCS, Università Cattolica, Roma. All data were retrospectively collected and then analysed. All women had a histologically confirmed cervical cancer diagnosis and also subscribed a written informed consent about data collection and their processing for scientific purposes. The Institutional Review Board approved the study (IRB number: DIPUSVSP-03-04-2051).Patients demographics, surgical, pathological, and follow-up data were obtained from an electronic database. Preoperative staging was performed through gynaecologic examination under anaesthesia, pelvic ultrasound, and magnetic resonance imaging. All patients with clinical 2009 FIGO stage  from IA1Patients were primarily treated with radical hysterectomy codified according to the Querleu– Morrow classification  and systAll surgical specimens were evaluated by dedicated pathologists. Adjuvant treatment was recommended according to international guidelines .The complete learning paths of 11 surgeons were available since all MI-RH procedures for early- stage cervical cancer patients performed during their own careers were traced and recorded. All the 11 surgeons completed their residency in our institution, focusing their training on the field of gynaecologic oncology surgery. Once they became consultants, they performed surgery autonomously. In our institution surgery is generally performed by a consultant as first surgeon, a senior resident as first assistant and a junior resident as second assistant. At least one senior consultant (with more than 10 years of experience as first surgeon) is always available for consultation in case of the less experienced consultant needs.MI-RH procedures were checked on the basis of the standard guidelines . If the Disease free survival (DFS) was defined as the time elapsed between surgery and recurrence or date of the last follow-up. Overall survival (OS) has been defined as the time elapsed between surgery and death for cervical cancer or date of the last follow up. The χ2 test or Fisher’s exact test for proportion were used to analyse the distribution of clinical and pathological variables between the two groups. Medians and life tables were computed using the product limit estimate by Kaplan–Meier method  and the From January 1998 to December 2018, 685 consecutive cases of early-stage cervical cancer patients were retrieved from the electronic database. We began to implement the minimally invasive approach in our clinical practice for cervical cancer from 2010 and from 2012 it became the most used. An increase in the rate of patients treated with open surgery was recorded in 2018 . From thTwo hundred and forty-three were treated by surgeons who completed all their learning path in our institution, while 120 were treated by external consultants.Main analyses were conducted on these 243 cases with complete pathological and surgical information .Median age was 47 years (range 25-80). Most patients underwent type B hysterectomy according to Querleu-Morrow classification. One hundred ninety-six (80.7%) underwent systematic pelvic lymphadenectomy while 47 (19.3%) underwent sentinel lymph node biopsy. Aortic lymphadenectomy was performed in 84 (34.6%) cases. The majority of patients had a pathological FIGO stage IB , a squamous histotype  and a tumor diameter < 2 cm . Adjuvant therapy was performed in 103 (42.3%) cases.As of September 2019, the median follow-up was 38 months (range: 3-111); 35 (14.4%) patients relapsed and 11 (4.5%) died from disease.Surgeons learning path was retraced classifying patients according to the progressive number of MI-RH for early-stage cervical cancer performed by each GOS .Not all surgeons started their career as first operator at the same time and 6 of them became consultants after 2010.The 11 surgeons included in the analysis performed a median of 17 MI-RHs for early-stage cervical cancer (range: 6–47). Four of them (36.3%) performed more than 30 procedures as first surgeon. The mean number of MI-RHs performed for early- stage cervical cancer per year by each surgeon was 6.2 (range: 2.8 – 7.1).Multiple, sequential survival analyses were conducted according to the number of MI-RHs per GOS in order to assess the impact of experience on patient survival improvement . Excluding the range of the first 4 procedures, each unitary increment in MI-RHs performed by a surgeon provided a reduction of patients’ risk of recurrence (hazard ratio: from 0.974 to 0.321).In particular, the experience, measured by evaluating the number of performed procedures, showed a statistically significant impact on patients’ prognosis starting from the 14th MI-RH performed . This statistical significance lasted until the 21st MI-RH performed . The peak of reduction of the recurrence risk was shown when the surgeon performed the 19th MI-RH . Data details are shown in th and the 21st performed MI-RHs. Subsequently, as the number of performed MI-RHs increased, a stable, small effect on the patient prognosis was observed.The comprehensive GOS learning curve showed only a very small impact of the experience on patients’ prognosis during the first procedures . A substAccording to these results, patients were divided in two groups regarding the operators experience at the time of surgery. The first one included patients managed by a gynaecologic oncologist at the beginning of the learning path in MI-RH for early- stage cervical cancer (<18 procedure performed), while the other group included patients treated by a physician who gained enough experience (>19MI-RH performed).There was no difference between the two groups according to the main pathological risk factors and the adjuvant treatment administered .The survival outcomes of patients treated by a gynaecologic oncologist once he/she had gained experience in MI-RH were significantly better than those of patients treated at the beginning of the learning path .Figure 5 shows that the GOS learning curve had a relatively relevance in cases with <2 cm tumor size . On the other hand, the GOS experience was statistically relevant when the tumor dimension was >2 cm .This study demonstrates that there is a strict relationship between GOS experience and early- stage cervical cancer patient prognosis based on the number of MI-RH procedures and that it is independent of other, well known, prognostic factors of cervical cancer . In the The present analysis showed that the increase of GOS experience allowed better results in terms of oncological outcomes. Furthermore, surgeon experience affected patient prognosis following the typical trend of a learning curve. At the beginning, a steady recurrence-risk reduction trend was associated with the increase of number of MI-RHs performed. Subsequently, there was a phase of steep growth of the curve. This could be considered the most significant period of the learning process since each procedure performed improves the surgeon outcomes and has a strong impact on the patient prognosis. Lastly, once a surgeon achieved a certain level of experience, further practice gave only a small and stable improvement on patient survival.In addition, we showed that the survival related results in the laparoscopic group were in accordance with the primary analysis. On the other hand, the sample of patients treated with the robotic approach was too small to draw any relevant conclusion (data not shown). The experience appeared as having a greater impact among high-risk cases, since the difference between the different phases of a learning curve was significant especially in cases of tumor > 2 cm.In our series the peak of recurrence risk reduction was represented by 19th MI-RHs. One could argue that the identified cut-off could not be generalised to other series due to the limitations inherent to a retrospective study , and even to a single-centre patient series. We had planned at the beginning to exclude in the present analysis other institutions because the homogeneity of surgical procedures, equipment/facilities and the standardised selection criteria for recruitment shared by all surgeons could be better guaranteed by a single-institution series.As far as the identified cut-off, we acknowledge that the absolute number of performed procedures without the referral to a specific time interval could have introduced a bias in the evaluation of the surgeon skillfulness. However, although we could have had details relative, for instance, to the number of MI-RHs performed by per month, this ratio would have not been sufficiently reliable given the heterogeneity of time frames and modalities of individual learning path.Moreover, in the present series, we failed to identify a significant difference in terms of OS according to surgeon learning path. However, one could consider that, while DFS could be strictly related to basic treatment and pathological tumor features, the OS may also be influenced by other factors such as the site  and manaPresent findings should be evaluated in the current clinical context. After publication of the LACC trial, some international guidelines and statements of the Scientific Societies generally accept and recommend implementing the trial evidence in clinical practice  while otLiterature is constantly enriched with studies comparing MIS to open surgery for early-stage cervical cancer  also in Recently, the European Society of Gynecological Oncology Group developed quality indicators for surgical treatment of cervical cancer . It is rThe main conclusion of the present study is that the experience that a gynaecological oncologist can achieve by practice in MI-RH is an independent prognostic factor for early-stage cervical cancer patients.Although other non-measurable data, such as the individual comprehensive surgical skill and the competence regarding the disease, the pelvic anatomy etc., may influence the GOS skillfulness, a disease-specific training under the supervision of an expert surgeon should be required prior to perform MI-RH safely in cases of early-stage cervical cancer.A prospective trial is advisable to confirm our findings and we strongly believe that these results could encourage Scientific Societies to define better the minimum level of training required for gynaecologic oncologic surgeons, not only in the field of early-stage cervical cancer, in order to provide high, standardised care to our patients.