The median nocturnal HR was 65 [60–69] bpm at baseline and increased to 69 [64–77] bpm on reb-oxy vs 66 [59–70] bpm on placebo (p = 0.02). The mean 24 h HR from ABPM was not different among treatment groups. Reb-oxy administration was not associated with any modification in HRV or BP. Reb-oxy increased the baroreflex sensitivity and did not induce orthostatic hypotension. In conclusion, administration of reb-oxy did not induce clinically relevant sympathetic overactivity over 1-week and, together with a reduction in OSA severity, it improved the baroreflex function.The combination of noradrenergic (reboxetine) plus antimuscarinic (oxybutynin) drugs (reb-oxy) reduced obstructive sleep apnea (OSA) severity but no data are available on its effects on cardiac autonomic modulation. We sought to evaluate the impact of 1-week reb-oxy treatment on cardiovascular autonomic control in OSA patients. OSA patients were randomized to a double-blind, crossover trial comparing 4 mg reboxetine plus 5 mg oxybutynin to a placebo for OSA treatment. Heart rate (HR) variability (HRV), ambulatory blood pressure (BP) monitoring (ABPM) over 24 h baseline and after treatment were performed. Baroreflex sensitivity was tested over beat-to-beat BP recordings. 16 subjects with (median [interquartile range]) age 57 [51–61] years and body mass index 30 [26–36]kg/m The repetitive collapse of the pharyngeal airway characteristic of OSA leads to intermittent oxygen desaturations and sleep fragmentation with downstream consequences, including an increased risk of cardiovascular disease, daytime sleepiness, and sympathetic nervous system over-activity3. Intermittent hypoxemia and arousals from sleep activate the sympathetic nervous system, being them the major contributors to the blood pressure (BP) and heart rate (HR) elevation, together with the release of inflammatory mediators4. Thus, untreated OSA may lead to cardiovascular, neurocognitive, metabolic, and daytime functional consequences over time, resulting in increased morbidity and mortality5.Obstructive sleep apnea (OSA) is one of the most common sleep disorders affecting one-third of the population aged 30–70 years in Europe7, partially by attenuating sympathetic over-activity9 and improving arterial baroreflex sensitivity, depressed by OSA12. Although OSA is effectively alleviated by this treatment, CPAP is poorly tolerated by many patients, with a consequent very low adherence14. Hence, there is an urgent need for alternative interventions that are safe and well-tolerated17.In the last 40 years, the gold standard for OSA treatment has been nocturnal ventilation through continuous positive airway pressure (CPAP), which acts to pneumatically splint the pharynx open. If regularly employed, CPAP therapy might reduce cardiovascular risk and overall mortality rate19. Responsible for the latter is a loss of noradrenergic drive and muscarinic inhibition to the upper airway muscles21. In the last years, these findings have stimulated research on pharmacological solutions aimed at improving neural control of pharyngeal muscle tone. In such a context, pharmacotherapy for OSA is moving its first steps with promising results provided by single-night studies22. We have recently performed a study aimed at expanding the knowledge on these pharmacological possibilities by conducting a randomized controlled trial to evaluate for the first time the effectiveness of the combination of reboxetine  and oxybutynin (an antimuscarinic compound), administered over a 1-week period, versus placebo on patients with moderate-to-severe OSA with promising results23.Reduced pharyngeal dilator muscle tone and responsiveness during sleep are key contributors to OSA pathogenesis25. On the other hand, the substantial decrease of the apnea-hypopnea index (AHI) with the resulting improvement of nocturnal hypoxemia induced by reb-oxy, might be also associated with beneficial effects on sympathetic over-activity, thus counterbalancing the direct sympathetic stimulation of these noradrenergic and antimuscarinic drugs.As known, noradrenaline is the main neurotransmitter of the sympathetic nervous system and muscarinic receptors are responsible for the vagal activity. Thus, a pending issue, not yet explored, is the possibility that the administration of noradrenergic reboxetine together with antimuscarinic oxybutynin might negatively affect the autonomic control of circulation28.The sympathetic and parasympathetic cardiovascular modulation can be assessed with direct measurements, or thanks to non-invasive reliable tools such as BP by 24 h ambulatory monitoring (ABPM), HR variability (HRV), and baroreceptor sensitivity (BRS)In order to assess the effect of reboxetine plus oxybutynin (reb-oxy) on cardiovascular autonomic modulation in OSA patients, we performed 24 h ABPM and estimated BRS and HRV after 1-week of treatment in the frame of our randomized controlled cross-over trial. The outcomes were evaluated as the change from baseline during the week of reb-oxy administration and compared to placebo.We performed a randomized, double-blind, placebo-controlled, cross-over, single-center study of the combination of reb-oxy in adults with OSA documented by polysomnography (PSG). Participants were enrolled from July 2020 to October 2020 through our sleep clinic  and the trial ended when the previously calculated sample size of 16 patients was reached. Participants were randomized (1:1 ratio) to first receive a 4 mg reboxetine plus 5 mg oxybutynin or a matching placebo, and then to switch to the other treatment arm after a washout of 7–10 days. Study participants matching eligibility criteria performed a one-night inpatient PSG test, which served as the baseline measure for AHI. Subjects started taking the study drug the day after the baseline PSG, immediately before bedtime, and continued for 7 days in total. On the final dosing night of each week, participants performed in-lab PSG. The study was approved by the Ethics Committee on 18/02/2020  and by the Italian drug agency AIFA  on 22/04/2020 (EudraCT n 2019-004917-15) and all methods were performed in accordance with the guidelines and regulations. Informed consent in writing was obtained from all study participants. The study was first registered at ClinicalTrials.gov (NCT04449133) on 26/06/2020.29. All studies were scored by the same specialized sleep clinician, blinded to treatment assignment, according to AASM scoring criteria30.PSG recording and data interpretation was performed in accordance with the American Academy of Sleep Medicine (AASM) scoring manual28. For the frequency-domain analysis, the NNI series was resampled evenly at 5 Hz linearly interpolating possibly missing beats. The Welch periodogram was estimated using 50% overlapped Hanning windows of 120 s length. The powers in the very-low-frequency , low-frequency , and high-frequency  bands, as well as the LF/HF powers ratio, were obtained by integrating the periodogram28. The breathing rate was estimated from the fluctuations of QRS-complex amplitude of the ECG reflecting the respiratory movements of the thorax31. The series of the R peaks resampled at 5 Hz were high-pass filtered at 0.05 Hz to remove oscillations too long to be generated by respiratory movements; the Welch periodogram was calculated and the breathing rate measured as the frequency of the highest spectral peak.The beat-by-beat series of R-R intervals were extracted from 1 ECG channel of each PSG through a derivative-and-threshold algorithm, selecting a segment of at least 10-min duration without respiratory events in the supine position during non-REM stage 2 (N2) sleep for the HRV analysis. Premature beats were visually identified and manually removed, obtaining series of normal-to-normal intervals (NNI). Time-domain indexes of HRV were the root-mean-square of successive differences (RMSSD) and the percentage of beats with NNI value at least 50 ms longer or shorter than NNI of their preceding beat (pNN50)ABPM was performed using a validated oscillometric device  to evaluate blood pressure (BP) changes for 24 h. Blood pressure was evaluated every 20 min during the day and every 30 min during the night. Day and night sub-periods were defined according to the personal logbook. 24 h, daytime and night-time average Systolic BP (SBP), Diastolic BP (DBP) and heart rate (HR), day and night SBP and DBP standard deviations (SD) were quantified to assess BP variability, SBP and DBP nocturnal falls, night/day ratios, average morning (7–11 a.m.) values and morning surge . The ABPM monitoring was assessed in the pre-screening visit at least 2 days before baseline PSG and between the 2nd and the 5th night of the two weeks of treatment to avoid disturbing the PSG night sleep.® device . Patients underwent measurements at rest, without coffee intake in the previous 3 h and at the same time of the day before the PSG. Recordings were performed in a silent room without speaking and without any disturbing elements for 10 min while patients were lying supine, and then for 10 min while they were standing. The beat-by-beat values of SBP and DBP, derived from the continuous BP, recordings, and NNI from the ECG lead, were interpolated evenly at 5 Hz for spectral analysis. The sensitivity of the baroreflex control of heart rate (BRS) was estimated by the sequence technique32 (BRSSEQ), the transfer function technique (HLF)33, and the spectral method (αLF)34. As to BRSSEQ, the beat-to-beat series were scanned in search of sequences of 3 or more consecutive heartbeats in which a progressive SBP increase was followed, with a lag of zero, one or two beats, by a progressive NNI lengthening or, vice versa, in which a progressive SBP reduction was followed by a progressive NNI shortening. The slope of the regression line between SBP and NNI values in each sequence was taken as a local BRS estimate. The local estimates were averaged over the supine and standing periods separately to obtain the final BRSSEQ values. As to the spectral and transfer function estimates, the SBP and NNI power spectra, and SBP-NNI cross-spectrum and coherency spectrum were calculated from the evenly resampled series at 5 Hz using 50% overlapped Hann data windows of 120s length. SBP and NNI powers were calculated over the LF band and the root square of the SBP/ NNI powers ratio evaluated only for spectral lines with squared coherence modulus > 0.3 provided the αLF estimate of BRS. The ratio between the SBP-NNI cross-spectrum and NNI spectrum was calculated considering again only spectral lines with squared coherence modulus > 0.3 and averaged over the LF band, providing the HLF estimate of BRS.ECG and non-invasive BP were measured by a NexfinLF and SBPLF). These indexes measure the power of the 10-s oscillations in arterial BP, which are considered a surrogate measure of sympathetic activity35.The DBP power spectrum was similarly estimated by the Welch periodogram. The baroreflex resonance was quantified by integrating the DBP and SBP power spectra over the LF band  between supine position and standing was also calculated.23. According to study design, a sample size of 16 subjects was powered to detect an AHI reduction with Reb-Oxy than placebo , plus a ≈ 20% dropout{Perger, 2022 #223}.Categorical data were summarized by proportions, while continuous data by median [interquartile range] values. Percent changes in study variables from baseline after 1-week of placebo and after 1-week of reb-oxy were compared as continuous variables by using a two-tailed Wilcoxon matched-pairs signed-rank test. The effect of the drug combination on the cardiovascular autonomic nervous system reported here was a prespecified exploratory outcome, while the primary outcome was AHI change as reported in our previous publicationp-value of <0·05 was considered statistically significant. Statistical analyses were performed using Statistical Analysis Software .A 23.The anthropometric and clinical characteristics of the 16 participants are presented in Table p=0.02 for reb-oxy versus placebo)  during the PSG increased from 65 [60–69] bpm at baseline to 69 [64–77] bpm on reb-oxy and to 66 [59–70] bpm on placebo  and on reb-oxy . The percent changes in HLF from supine to standing were similar on placebo (+ 49% [+ 30 to + 59] %) and on reb-oxy . When considering changes from baseline to treatment, no differences between placebo and reb-oxy were found for BRSSEQ  and reb-oxy .Table + 49% + 3 to + 60 LF and DBPLF were significantly and substantially lower after reb-oxy treatment than on placebo in both postures (Table LF from supine to standing were similar on placebo (− 86% [− 204 to − 28]) and on reb-oxy . This was the case also for the percent changes in DBPLF from supine to standing .Regarding the baroreflex resonance in BP spectral powers, SBPes Table . The perReb-oxy did not induce orthostatic hypotension nor any modification of parasympathetic activity indices. The respiratory frequencies remained in the HF band in all treatment groups.23. Here, we add that, in OSA patients, this treatment is not associated with short-term autonomic dysregulation. Particularly, during indirect evaluations, the tested drug combination does not induce either sympathetic overactivity or orthostatic hypotension as it could be expected by the reboxetine mechanism of action.We recently demonstrated that one-week bedtime administration of reboxetine plus oxybutynin reduces OSA severityOur results show that one-week administration of reboxetine plus oxybutynin: (i) did not increase BP during the day or the night; (ii) did not enhance cardiac sympathetic modulation as reflected by nighttime HRV; (iii) did not impair but rather increased the sensitivity of the baroreflex control of heart rate; and (iv) decreased the baroreflex resonance in BP spectra, a surrogate measure for the vascular sympathetic modulation. To date, this is the first evaluation of the impact of the new OSA pharmacologic therapy on cardiovascular autonomic regulation.36. Reboxetine is prescribed for major depressive diseases, dysthymia, and attention-deficit/hyperactivity disorder, its antidepressant effects being related to the sustained increase in norepinephrine levels in the central nervous system37. As a noradrenergic drug, reboxetine would be expected to increase sympathetic activity. In fact, in previous studies on healthy volunteers, 4 mg of reboxetine has been associated with an increase in HR39. Oxybutynin is an anticholinergic drug used for bladder over-activity. Its effect on muscarinic cardiac receptors determines inhibition of vagal activity with an increase in HR40. HR is indeed primarily modulated by the opposing autonomic influences of parasympathetic and sympathetic activity. Thus, theoretically, the administration of this drug combination would be expected to inhibit cardiac parasympathetic stimulation together with a direct sympathomimetic effect.Reboxetine is highly selective for norepinephrine transporters and has a low affinity with muscarinic, histamine-H1, and adrenergic α1 receptors22. Similarly, in our study, HR during the night only slightly increased (by 3.7 bpm) on reb-oxy versus placebo during PSG. Moreover, the 24 h HR evaluated during the ABPM was similar in the two groups. Previous studies in healthy subjects reported an increase in SBP and DBP after reboxetine administration41, whereas neutral effects on BP have been reported in long-term treatment with reboxetine43. In our patients, BP did not differ between placebo and reb-oxy and we did not observe orthostatic hypotension after 1 week of reb-oxy administration, confirming the neutral effect previously reported even in a population of OSA patients. Morning surge and BP variability, additional markers of sympathetic activity, did not increase during reb-oxy administration, which, again, represents a reassuring clinical result considering the administration of a noradrenergic drug.A previous pharmacological trial for OSA treatment showed that a single-night administration of atomoxetine plus oxybutynin in OSA patients led to a small (2.6 bpm) overnight increase in HR46. This is in line with the demonstration that sympathetic overactivity is a key mediator of adverse cardiovascular consequences in OSA47. In fact, autonomic derangement and sympathovagal imbalance are associated with arrhythmias, which are often observed in patients with OSA, contributing to their cardiovascular mortality48. Previous studies showed that reboxetine influences the autonomic nervous system by reducing the HF power of HRV in healthy volunteers39. Oxybutynin, in turn, showed an anti-cholinergic effect according to HRV indexes40. By contrast, our study points out that in OSA patients one week of reb-oxy did not increase sympathetic activity, as shown by no changes in the HRV spectral index of sympathovagal balance, i.e., the LF/HF power ratio, and had no significant influence on HRV indexes of parasympathetic cardiac control: RMSSD, pNN50, and the HF power.Using HRV analysis, OSA patients were shown to be characterized by a predominance of sympathetic markers and by a reduction in parasympathetic indices49. Our study does not report any worsening of BRS after reb-oxy treatment, as it could be theoretically expected considering the autonomic effects of the noradrenergic reboxetine and anticholinergic oxybutynin. On the contrary, our data show a significantly improved sensitivity of arterial baroreflex modulation of HR, in particular in the LF band (αLF and HLF). It has been shown that αLF and HLF reflect baroreflex modulation of HR through both the sympathetic and the parasympathetic neural influences. Conversely, BRSSEQ mainly reflects the vagal HR modulation50. Thus, our findings of increased αLF and HLF accompanied by no changes in BRSSEQ suggest that one-week treatment with reb-oxy improved BRS mainly through a reduction of cardiac sympathetic modulation, with no evident changes in vagal control of HR.An unbalanced cardiac baroreflex modulation has been shown to favor cardiovascular complications and arrhythmias. Particularly, in OSA patients the known reduction in BRS during both wake and sleep is associated with the development of arterial hypertension and with excessive daytime sleepinessMoreover, our study demonstrates that reb-oxy largely decreased the power of SBP and DBP oscillations at LF, which have been suggested to be an expression of the resonance in the baroreflex loop at a frequency of 0.1 Hz, considered a surrogate measure for sympathetic vascular regulation. Thus, when considering all the above findings, our study suggests the occurrence of a reduction in the overactivity of sympathetic cardiovascular control induced by sleep apneas in OSA patients after one week of reb-oxy treatment. This reduction, however, was not accompanied by major alterations in posture-induced changes in cardiovascular control, as demonstrated by the lack of orthostatic hypotension and other signs of autonomic imbalance.12. Thus, similarly to what happens with CPAP treatment, it might be supposed that the beneficial effect of drug combination on the severity of OSA would have mitigated the sympathetic hyperactivity induced by OSA events51. The reduction of the hypoxic burden, together with a reduced frequency of arousals from sleep determined by reb-oxy, might have determined the beneficial effect on the apnea-hypopnea-related sympathetic overflow53.The improvement in baroreflex cardiac modulation we observed during wake is likely to represent a positive consequence of nocturnal apneas reduction, as previously reported after long-term OSA treatment with CPAPEven if the present study offers unique data on the effects of a novel drug treatment for OSA over the longest administration period tested so far, we acknowledge a few limitations. First, our findings on the short-term impact of Reb-Oxy on cardiac autonomic modulation in OSA patients cannot be generalize to other populations and need to be confirmed over a longer period. Second, the relatively small sample size was powered to detect significant changes in AHI, not in baroreflex or HRV indices, possibly precluding the detection of smaller effects of the treatment. Third, by study design we evaluated cardiovascular autonomic modulations only by indirect measures, as direct measures of sympathetic activity such as norepinephrine spillover or muscle sympathetic nerve traffic were excluded.per se. Being efficacious on OSA severity, these drugs could also positively act to improve the deranged cardiovascular autonomic modulation typical of OSA. Future intervention trials, including a larger number of OSA patients followed over longer treatment periods are needed to assess whether these favorable clinical and pathophysiological effects are also associated with a reduction in cardiovascular morbidity and mortality.We demonstrate for the first time that the combination of the noradrenergic drug reboxetine and the anticholinergic drug oxybutynin could safely be administrated in OSA patients, who are typically characterized by sympathetic overactivity due to sleep apnea Supplementary Information.


In hospitals, catheter acquired urinary tract infection causes significant resource waste and discomfort among admitted patients. An intervention for reducing indwelling catheterisations - No-CAUTI - was trialled across four hospitals in New South Wales, Australia. No-CAUTI includes: train-the-trainer workshops, site champions, compliance audits, and point prevalence surveys. The trial showed reductions on usual care catheterisation rates at 4- and 9-month post-intervention. This result was statistically non-significant; and post-intervention catheterisation rates rebounded between 4 and 9 months. However, No-CAUTI showed statistically significant catheterisation decreases for medical wards, female patients and for short-term catheterisations. This study presents a budget impact analysis of a projected five year No-CAUTI roll out across New South Wales public hospitals, from the cost perspective of the New South Wales Ministry of Health.Budget forecasts were made for five year roll outs of: i) No-CAUTI; and ii) usual care, among all public hospitals in New South Wales hosting overnight stays (n=180). The roll out design maintains intervention effectiveness with ongoing workshops, quality audits, and hospital surveys. Forecasts of catheterisations, procedures and treatments were modelled on No-CAUTI trial observations. Costs were sourced from trial records, the Medical Benefits Scheme, the Pharmaceutical Benefits Scheme and public wage awards. Cost and parameter uncertainties were considered with sensitivity scenarios.The estimated five-year No-CAUTI roll-out cost was $1.5 million. It had an overall budget saving of $640,000 due to reductions of 100,100 catheterisations, 33,300 urine tests and 6,700 antibiotics administrations. Non-Metropolitan hospitals had a net saving of $1.2 million, while Metropolitan hospitals had a net cost of $0.54 million.Compared to usual care, NO-CAUTI is expected to realise overall budget savings and decreases in catheterisations over five years. These findings allow a consideration of the affordability of a wide implementation.ACTRN12617000090314). First registered 17 January 2017, retrospectively. First enrolment, 15/11/2016.Registered with the Australian New Zealand Clinical Trials Registry (The online version contains supplementary material available at 10.1186/s12913-022-08313-7. Waste in healthcare is a significant problem. It is evidenced by unexplained variations in: the prices of interventions and procedures ; the oveCatheter-associated urinary tract infections (CAUTIs) make up 70 - 80% of all hospital-associated urinary tract infections (HAUTIs) , 7. AlsoA trial of such an intervention was conducted over four hospitals in the state of New South Wales (NSW), Australia, between 2017 and 2018: the ‘No-CAUTI’ trial. The intervention aimed to optimise the use of a health technology (indwelling urinary catheters (IDC)) in hospital settings. This intervention has the potential to reduce unnecessary urinary catheterisation procedures and also increase adherence to evidence-based guideline care when urinary catheterisations are warranted. Both can potentially reduce CAUTI, along with the associated and consequential CAUTI-related treatment costs –16.efficiency of various courses of action that decision makers could choose. However, there is growing evidence that these analyses are not well understood by healthcare decision makers so they may not be optimally contributing to decision-making [Economic evaluations  of such interventions and their alternatives are often required as an input to healthcare decision-making. These analyses are typically designed to reflect the relative n-making . Also, en-making .Budget impact analysis (BIA) supports healthcare decisions by informing the relative ‘affordability’ of intervention choices by comparing expected budgets for alternative proposals; both in terms of cash outlays and cash savings. BIA also compares intervention outcomes for alternative services . Unlike To the author’s best knowledge, no previous budget impact analyses have been published on nurse led hospital interventions for reducing catheterisation incidence  No-CAUTI; and b) usual care, both over five years. The costing perspective is that of the New South Wales Ministry of Health .The No-CAUTI trial researched a nurse led multi-faceted intervention conducted in the Australian state of New South Wales (NSW) in 2017-18 , 16, 32.In both LHDs, the intervention required six months for implementation, comprising: three hour ‘Train-the-Trainer’ workshops and ward in-services (over three to four weeks)), which were expected to generate ongoing on-site education in future years; champion meetings for six months post education; compliance audits; and promotion . Further details can be found elsewhere .As noted eslsewhere , the No-p < .01) [First, given catheterisation rates pre-intervention 12%) were lower than rates reported in the literature (15% to 25%) % were lo, the 2% p < .01) .p = .015), but this result was offset by no change among male patients (13% - 13%). The largest specialty group, those in medical wards, showed a statistically significant drop in catheter prevalence from pre-intervention to 4 months intervention  [Second, statistically significant catheter prevalence reductions between pre-intervention and 9-months post-intervention occurred among important sub-groups. Notably this occurred for female patients . Further, catheterisations among patients requiring postsurgical urinary management - which are avoidable – decreased between pre-intervention to 9-month post intervention from 29%–21%. Hence, effectiveness can be confidently predicted for certain major groups in a roll out, albeit with efforts required to gain improvements among others [For the same period, a statistically significant downward change also occurred for patients receiving short-term catheterisations (≤ 3 days) . This duration was advised by author MG, a senior co-ordinator of the No-CAUTI trial, as appropriate for planning purposes. As with ISPOR practice, no discounting was undertaken [This study will analyse and compare five year budget costs for two mutually exclusive scenarios involving the study population for: a) usual care; and b) the No-CAUTI interventionThe main outcome of this BIA exercise is the net cost/saving attributable to the No-CAUTI intervention over the time horizon. Other important outcomes are, the direct budget cost of the No-CAUTI intervention; scenario differences in catheterisations, urine tests and antibiotic administrations.A BIA model was constructed in a Microsoft EXCEL 2016  workbookThe basic method for designing the state-wide roll-out had two parts. First, using hospital data, estimations were made of resources necessary for roll-out of three critical aspects of the No-CAUTI intervention: workshops, compliance auditing and point prevalence surveying  which may be attended by new trainer nurses or qualified No-CAUTI trainers seeking refresher instruction. Intervention staff will continuing liaison with hospitals to encourage maintenance of No-CAUTI practices.Also, in Year 1, each hospital will conduct five compliance audits and two catheterisation point prevalence surveys. In subsequent years there will be one audit and one point prevalence survey. Results will be reported to the program managers and presented to the Ministry of Health.. For the roll out, these materials - already developed in the trial - will exclude badges. This will leave posters and flyers to be distributed by email for printing at the sites. The intervention costs of distributing the materials include the labour time for the administrator to telephone each hospital to confirm that materials have been sent. All annual compliance audits and point prevalence surveys will be conducted by permanent hospital staff. Hence audits and surveys will not require extra budget costs.Workshops will be conducted remotely by intervention staff on electronic media. The number of workshops required per hospital was estimated on an algorithm related to bed capacities shown in Additional file  and associated overheads  are valued with respect to total labour costs respectively at 21.5% and 27.5%. The on-cost rate was estimated from information at a university website . The oveFrom Year 2, the number of workshops would be reduced due to the need to only teach new train-the-trainers or others requiring refresher sessions. Hence, the time budget allows for one annual workshop per local health district (LHD) n=16). Such a task, along with hospital and health authority liaison could be covered by one CNC3 nurse and the administrative officer. Both could be effectively hired at 0.8 FTE. .For its parameters, this budget impact analysis requires estimates of annual rates for hospital catheterisations, urine tests and antibiotic administration for a) one full year post-intervention care; and b) one full year of pre-intervention usual care. The trial data offered only point prevalence parameter estimates, necessitating rate modelling.Analysis rates for a 12-month post intervention period, were modelled with polynomial regressions using trial point prevalence rates as inputs. Rates were generated for catheterisations, urine testing and antibiotic administrations. The modelling can be viewed in Additional file For a year of usual care, the No-CAUTI trial results offered only one set of rates – those collected for ‘pre-intervention’. Hence, in the absence of more data, this analysis will forecast the usual care budget with No-CAUTI trial pre-intervention rates for catheterisations, urine culture testing and antibiotics.All parameter rates were weighted to allow for the distribution of Metropolitan and Non-Metropolitan hospitals in NSW, which differed slightly to that of those within the trial Sensitivity scenarios adjusted parameters and costs that have significant uncertainty including the intervention costs and catheterisation rates. Results indicate the scope of possible budget impact outside the base case. Scenarios 1 and 2 consider possible changes in the intervention costs.The increase of 10% for Scenario 1, is a subjective but possible difference in real budget expenditure. For Scenario 2, the employment of casual nursing staff is a possibility if permanent hospital nurses are not available.3.Increases 10%4.Increases linearly to reach the usual care catheterisation rate by year 6The remaining scenarios are adjustments to the estimated annual intervention catheterisation rate:For Scenario 3, the 10% increase has been chosen subjectively, based on the assumption that over the five-year forecast, the average catheterisation rate could be significantly higher than described in the base case, but without equalling the usual care rate. Scenario 4 assumes that after Year 1, the catheterisation rate could trend back linearly to that of usual care. Such a gradual decay in No-CAUTI’s effect, may occur with decreasing compliance with No-CAUTI practice. Note that changes to catheterisation rates will also drive increases in urine testing and antibiotics administrations with associated cost increases.Modelling was conducted for Metropolitan and Non-Metropolitan hospitals using point prevalence catheterisation, urine testing and antibiotics rates from the trial   and the Central Coast Human Research Ethics Committee (reference no 1016-097C). Individual patient consent was not required for the point prevalence data collection as all data collected was from already routinely collected inpatient clinical data and in line with routine quality control auditing. All clinical data collected during point prevalence was de-identified. This approach was approved by the abovementioned human research ethics committees, Hunter New England Human Research Ethics Committee and the Central Coast Human Research Ethics Committee.The study was also registered retrospectively with the Australian New Zealand Clinical Trials Registry  . The firTable The BIA forecasts five-year reductions for relevant NSW public hospitals of 100,100 catheterisations; 33,300 urine tests; and 6,700 antibiotic administrations. A total estimated budget cost saving over the time horizon is an estimated $640,000 .Scenario 2 costs a change to the intervention where audits and point prevalence surveys are performed by casual nurses, thereby increasing budget costs. This would significantly lower the five-year saving by 84.7% to $98,100.Scenario 3 considers a 10% increase in the estimated five-year catheterisation rate (10.27% to 11.3%) for the intervention. This would eliminate intervention savings and lead to a five-year cost of intervention of $923,600.Scenario 4 considers a linear increase in the intervention catheterisation rate – or a decay in the effect – back to the usual care catheterisation rate by year 6. This is predicted to generate a five-year budget cost of $410,300 .Figure The overall difference in cost/savings between the intervention and usual care is – given the scenarios conducted – most sensitive to changes in the expected catheterisation rate/s. This is partly because changes in catheterisations subsequent drive further changes and costs for urine tests and antibiotics..Non-Metro hospitals showed a five-year saving of $1.2 million, while Metropolitan hospitals registered a loss of $539,000. This difference is mainly due to the greater effectiveness of the intervention in Non-Metropolitan hospitals. Tables can be viewed in Additional file The authors have also conducted an in-trial cost-effectiveness analysis of the No-CAUTI intervention . The resOn its own, decision makers would find this economic analysis necessary but not sufficient for informed decision making. Missing in a pure economic analysis is an understanding of how No-CAUTI will impact on operational budgets. Questions that decision makers might pose are, ‘Will some existing healthcare stop as a consequence of the new model of care?’; ‘Is there a need for more/fewer staff?’; and, ‘Are additional capital purchases required?’. BIA is a means to leverage the economic analysis to provide more targeted information to decision makers and answer questions such as these. A BIA addresses the question of the financial cost, or affordability of intervention implementation. Consistently, the current study shows the projected cash outlays for the intervention in a budget period. Table To the author’s best knowledge, this is the first Australian budget impact study  platform  could reEconomic evaluations for operational health services should be accompanied by information that informs whether a new technology or model of care will be affordable. BIAs provide this information. Currently the guidelines for BIAs are mostly based on the ISPOR recommendations but these are international guidelines and not tailored to individual health systems. In Australia, and NSW specifically, work to customise BIA practice to local health systems is needed. The example of the BIA for No-CAUTI in this paper demonstrates how results and data from a cost effectiveness analysis can be leveraged to generate additional information for decision makers.The study has limitations related to the No-CAUTI trial, from which it took most of its cost and parameter data. The trial was limited to only four hospitals, rather than a random robust sample of hospitals across NSW. The sample had no remote or very large Metropolitan hospitals. The point prevalence outcome measurement approach was not ideal as it failed to accurately summarise cumulative catheterisation rates for the entire 4- and 9-months post interventions periods. This budget analysis therefore required modelling to estimate annual post-intervention catheterisation rates and there is significant uncertainty for the pre-intervention catheterisation rate in its application for this study. It is noted that rollouts are likely to see variations in effect sizes and costs due to differences in quality control and patient mixes across hospitals.The findings demonstrate that an effective No-CAUTI implementation to reduce CAUTI cases and associated treatment costs is within the affordability of the Ministry of Health of NSW if it is can budget approximately $1.5 million for over five years. A roll-out at a state-wide level would be expected to save approximately between $640,000 in budget costs over five years while the base case is forecast to reduce catheterisations by over 100,100. Higher levels of intervention effectiveness would increase budget savings, freeing funds for other health care purposes. Rollouts are likely to see variations in effect sizes and costs due to differences in quality control and patient mixes among NSW public hospitals, but focused intervention management can bring implementation effectiveness within budgets.Additional file 1. Supporting Calculations referred to within the text.


Despite HIV viral load (VL) monitoring being serial, most studies use a cross-sectional design to evaluate the virological status of a cohort. The objective of our study was to use a simplified approach to calculate viraemic-time: the proportion of follow-up time with unsuppressed VL above the limit of detection. We estimated risk factors for higher viraemic-time and whether viraemic-time predicted mortality in a second-line antiretroviral treatment (ART) cohort in Myanmar.We conducted a retrospective cohort analysis of people living with HIV (PLHIV) who received second-line ART for a period >6 months and who had at least two HIV VL test results between 01 January 2014 and 30 April 2018. Fractional logistic regression assessed risk factors for having higher viraemic-time and Cox proportional hazards regression assessed the association between viraemic-time and mortality. Kaplan-Meier curves were plotted to illustrate survival probability for different viraemic-time categories.Among 1,352 participants, 815 (60.3%) never experienced viraemia, and 172 (12.7%), 214 (15.8%), and 80 (5.9%) participants were viraemic <20%, 20–49%, and 50–79% of their total follow-up time, respectively. Few  participants were ≥80% of their total follow-up time viraemic. The odds for having higher viraemic-time were higher among people with a history of injecting drug use , sex workers  and patients treated with lopinavir/ritonavir . Viraemic-time was strongly associated with mortality hazard among those with 50–79% and ≥80% viraemic-time . This association was not observed in those with viraemic-time <50%.Key populations were at risk for having a higher viraemic-time on second-line ART. Viraemic-time predicts clinical outcomes. Differentiated services should target subgroups at risk for a higher viraemic-time to control both HIV transmission and mortality. An increasing number of treatment-experienced people living with HIV (PLHIV) require second-line or third-line antiretroviral treatment (ART) regimens. It has been estimated that by 2030, about 4.6 million people in Sub-Saharan Africa alone will receive second-line ART . For theWorld Health Organization (WHO) guidelines recommend routine monitoring of ART effectiveness and adherence to treatment by performing HIV viral load (VL) testing at 6 months after treatment initiation and then every subsequent 12 months . CoveragDespite serial HIV VL monitoring being implemented in many HIV cohorts, most of the studies use a cross-sectional design to evaluate virological status. However, during HIV treatment, especially when taking second-line treatment with a high genetic barrier , 17, patWe conducted a retrospective cohort analysis of PLHIV aged above 5 years who had received second-line ART for over 6 months and had at least two HIV VL test results during the study period between 01 January 2014 and 30 April 2018.The study used data from the MSF HIV programme in Myanmar, which provided, free of charge, a comprehensive HIV care package to more than 58,000 PLHIV. The secondary use of programme data frequently serves operational research, which has been seen as a tool to improve outcomes of existing medical programmes or evaluate new strategies or interventions in specific contexts. Findings often inform policy change .Xpert® HIV-1 Viral LoadSince 2014, routine HIV VL monitoring twice a year was introduced for PLHIV on second-line ART. Different viral load assays were used during the study period: Cavidi ExaVir version 3.0  and (LLD 40 copies/mL). Management of virological failure in Myanmar relies on a public health approach . For PLHThe study used routine programme data collected from standardised patient forms and encoded in the MSF HIV programme database, FUCHIA (Follow-up and Care of HIV Infection and AIDS). To calculate the viraemic-time, we divided the cumulative unsuppressed time by follow-up time (both in days). Cumulative unsuppressed time was the time during which we assumed that a patient had plasma HIV VL > 200 copies/mL . Cumulative suppressed time was the time during which we assumed that a patient had undetectable (suppressed) HIV VL. Follow-up time was defined as a sum of cumulative unsuppressed and suppressed time. When two consecutive VL tests showed the same result, either viraemia or suppression, the time in between both tests was considered unsuppressed or suppressed, respectively. When two consecutive VL tests showed different results, the time in between both tests was divided in half, adding both unsuppressed and suppressed time. Patients were supposed to have VL tests twice a year; however, if the time between two VL tests was more than 365 days, a maximum of 183 days was added to either unsuppressed or suppressed time . Follow-For assessing the mortality hazard during second-line ART, observation time was calculated as the time between the date of the second VL test and the date of the primary outcome (death). Follow-up started on the date of the second VL test to avoid immortal time bias  since thThe normal distribution of continuous variables was assessed by Skewness/Kurtosis tests for Normality and plotting histograms for each of the continuous variables. When the distribution was not normal, we calculated medians and interquartile ranges (IQR).To calculate the odds ratios (OR) and respective 95% confidence intervals (CI) for having an unsuppressed VL we performed a fractional logistic regression. To compute hazard ratios (HR) and respective 95% CI for mortality we performed a Cox proportional hazards regression. For both regressions, forward stepwise selection was used to construct the final multivariable model. First, variables known for their clinical importance  were included, regardless of their association with the outcome. Additional variables were stepwise included in the multivariable model if a) they were associated with outcome (p<0.10) in the univariate analysis, and b) if they significantly improved the model . The proportional hazards assumption was tested using scaled Schoenfeld residuals. All analyses were carried out using STATA statistical software version 14.0 .a posteriori analyses of routinely collected clinical data—which requires patients in MSF programmes at the time of entering MSF care to have given informed written consent for secondary use of their data, including research—thus did not require MSF ERB review [The study was approved by the Institutional Review Board, Department of Medical Research, Ministry of Health and Sports, Myanmar (Ethics/DMR/2019/153). The study also fulfilled the exemption criteria set by the MSF independent Ethical Review Board (ERB) for B review . All medDuring the study period, 1,448 PLHIV aged >5 years started second-line ART and 1,352 (93.4%) were included in the study . Their mThere were 5,048 VL results recorded during the overall follow-up time of 1,103,817 days for 1,352 participants . In only 244 occasions, the time between two consecutive VL tests was >365 days, resulting in a reduction of 23,338 days, based on the established maximum of allocated time per VL result , sex workers  and patients treated with a second-line lopinavir/ritonavir-based regimen . When compared to married participants, those who were separated had a higher odds for having higher viraemic time . Age, gender and profession were not significantly associated with viremia in our study, as presented in At the end of the study period, 61 (4.5%) participants had died, 565 (41.8%) were transferred-out to the NAP, and 726 (53.7%) were still in care in the MSF programme; 5 participants had a brief history of loss to follow-up but all returned to care in the MSF programme during the study period (after a medium time of 112 days (IQR 65–145)). Twenty-two (1.63%) PLHIV switched to third-line ART during the study period. Patients with viraemic-time >50% had a higher mortality hazard . PLHIV w≥80% viraemic-time (p<0.001), respectively.The cumulative mortality hazard  at two yThe study of our second-line ART cohort in Myanmar demonstrated a close to three-fold increase in mortality hazard in PLHIV who were more than half of their follow-up time viraemic, after controlling for other relevant factors. Those who were viraemic, but less than half of their follow-up time, were not at risk of mortality. HIV is a chronic disease. Being viraemic does not equal immediate symptomatic morbidity and this may explain why mortality increases only when patients are viraemic for a longer period of time . StudiesAs a measure for unsuppressed VL, we used any viraemia that was above 200 cells/mL. The WHO now recommends intensive adherence support and three-monthly VL monitoring for PLHIV with detectable viraemia <1000 copies/mL  and therTo calculate viraemic-time, we used a simplified approach that could be applied in programmatic settings. Multiple studies used VCY as a measure of the proportion of follow-up time with an unsuppressed VL and reported an association between VCY and having an unfavourable outcome, either morbidity , 36, 37 The risk of having higher viraemic-time was double in people with a history of injecting drug use or sex work. Key populations are disproportionately affected by the HIV epidemic and are known to play a fundamental role in HIV transmission in many settings, including Myanmar . In 2019Our results show that PLHIV with higher viraemic-time should benefit from differentiated care, including more frequent clinical visits, better adherence support, HIV drug-resistance monitoring, and eventually an early switch to third-line treatment when resistance to second-line drugs emerges. Additionally, the periodicity of VL monitoring may need to increase. In 2015, Marks et al. demonstrated that when VL monitoring was done less frequently, patients were at risk for longer periods with viraemia. They argued that more frequent virological monitoring might reduce viraemic-time, transmission risk, and improve individual health of PLHIV . In the PLHIV on a lopinavir/ritonavir-based regimen experienced higher viraemic-time in our cohort, consistent with previously reported findings . Long-teOur study identified other hazards for mortality among PLHIV on second-line ART. Our results show an increase in mortality hazard for every year increase in age. The older, the higher risk of NCDs or some type of opportunistic infections. However, careful mortality ascertainment was not done and known causes of death among adults were not included in the regression model. PLHIV who received lopinavir/ritonavir had a higher risk of mortality when compared to those on atazanavir/ritonavir. The association between the type of protease inhibitor and mortality is probably not related to the drug itself, but the underlying indication for its use. Unfortunately, data on such indications (e.g. an episode of tuberculosis during second-line treatment) were not included in the study.Our study represents the reality of a large long-term HIV programme in the Southeast Asian context with an exceptionally high coverage of routine VL testing. However, there are several limitations. Sampling bias caused by irregular VL testing has been discussed as a limitation of cumulative indicators of viraemia . In our Among PLHIV on second-line ART in Myanmar, having less than 50% viraemic-time was not associated with mortality but could be considered as a risk factor for ongoing HIV transmission, especially among key populations. Viraemic-time >50% was associated with mortality. Cross-sectional analysis of VL data does not allow clinicians and programme managers to assess the clinical and public health impact of higher viraemic-time. Cumulative assessments of HIV viraemia might better reflect the health status and the level of HIV control of the entire cohort than cross-sectional indicators. To reduce the risk of HIV transmission and mortality among those who are failing second-line HIV treatment, differentiated services including innovative approaches for the management of viraemia and models of care tailored to the specific needs of at-risk groups should be scaled up.


Kaplan–Meier curves for 30-day survival displayed a statistically significant better survival rate in patients treated with high-dose steroid therapy (p = 0.018). The results of this study highlighted that the use of high-dose methylprednisolone, compared to dexamethasone 6 mg once daily, in hospitalized patients with COVID-19 may be associated with a significant reduction in mortality.The hyperinflammatory phase represents the main cause for the clinical worsening of acute respiratory distress syndrome (ARDS) in Coronavirus disease 2019 (COVID-19), leading to the hypothesis that steroid therapy could be a mainstream treatment in COVID-19 patients. This is an observational study including all consecutive patients admitted to two Italian University Hospitals for COVID-19 from March 2020 to December 2021. The aim of this study was to describe clinical characteristics and outcome parameters of hospitalized COVID-19 patients treated with dexamethasone 6 mg once daily (standard-dose group) or methylprednisolone 40 mg twice daily (high-dose group). The primary outcome was the impact of these different steroid treatments on 30-day mortality. During the study period, 990 patients were evaluated: 695 (70.2%) receiving standard dosage of dexamethasone and 295 (29.8%) receiving a high dose of methylprednisolone. Cox regression analysis showed that chronic obstructive pulmonary disease (HR 1.98, CI95% 1.34–9.81,  SARS-CoV-2 infection can progress to a severe respiratory illness that requires hospital care. In a significant percentage of cases, it can progress to a critical disease, ranging from mild respiratory failure to severe acute respiratory distress syndrome (ARDS).The hyperinflammatory phase, in which an excessive and ineffective immune system activation leads to a massive infiltration of immune cells in the lungs and a systemic overproduction of pro-inflammatory cytokines, represents the main cause for ARDS ,2,3 leadThe RECOVERY trial  demonstrThe aim of this study was to describe clinical characteristics and outcome parameters of hospitalized COVID-19 patients treated with a standard steroid dose (dexamethasone 6 mg once daily) or a higher dose of steroids (methylprednisolone 40 mg twice daily). Since the severity of the disease could impact the actual benefit of increasing steroid dose and could, therefore, act as a major confounder, we stratified patients treated with low-flow oxygen therapy and those treated with high-flow nasal cannula, continuous positive airway pressure or non-invasive ventilation (HFNC/CPAP/NIV); furthermore, possible risk factors for 30-day mortality were investigated.This observational study included all consecutive patients admitted to two Italian University Hospitals: the “Mater Domini” teaching hospital of Catanzaro  and the “Umberto I” teaching hospital of Rome , from March 2020 to December 2021.The Ethics Committees of each participating center approved the study protocol for observational analyses. For the “Umberto I” teaching hospital of Rome, the study was designed as a prospective, and was approved by the local Ethics Committee (n. 5923/2020) with informed consent obtained from each patient included. For the “Mater Domini” teaching hospital of Catanzaro, this study was designed as a retrospective; it was notified to the Ethics Committee of the Calabria Region on 13 May 2020. The study did not require ethical approval by an Ethics Committee as determined by the Italian Drug Agency, note 20 March 2008 . The need for written informed consent was waived for patients owing to the retrospective nature of the study. The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice standard.Inclusion criteria were: (1) a positive SARS-CoV-2 real-time polymerase chain reaction test on nasopharyngeal swab, according to WHO recommendations ; (2) theThe following data were extracted from the patients’ medical databases of each participating center: demographics, clinical and laboratory findings, comorbidities, microbiologic data, COVID-19 diagnosis date, radiological characteristics of pneumonia, therapies administered, need for oxygen or ventilation support during the hospital stay, length of ICU stay, length of hospital stay and outcome. All patients were followed until discharge or death. Non-invasive respiratory support techniques included HFNC, CPAP and NIV. Management of patients at admission and during hospitalization were previously reported  acts/min, p = 0.009) and lower PaO2/FiO2 ratio . In addition, compared to survivors, non-survivors had higher levels of interleukin-6  and D-dimer ; moreover, they were less frequently treated with remdesivir , low-weight molecular heparin , high-dose steroid therapy  and low-flow oxygen ; instead, non-survivors more frequently received HFNC/CPAP/NIV  (see 001) see .p = 0.002), chronic kidney disease , oncologic disease  and HFNC/CPAP/NIV oxygen therapy ; conversely, high-dose steroid therapy was associated with survival .Cox regression analysis (reported in p = 0.018).p = 0.457) or with HFNC/CPAP/NIV (p = 0.842).Kaplan–Meier curves in COVID-19 patients treated with high-dose steroid therapy or standard-dose steroid therapy in the subgroups of those treated with HFNC/CPAP/NIV or low-flow oxygen are reported in This observational real-life study primarily aimed to investigate the clinical impact of the use of two different dosages of steroids on 30-day mortality in a large population of patients hospitalized for COVID-19.In our large cohort, treatment with a high-dose corticosteroid  was significantly associated with a lower 30-day mortality compared to the outcome of treatment with a standard dose  in Cox regression analysis and survival analysis by using Kaplan–Meier curves. However, when the impact on mortality of the two steroid regimens was analyzed in the subgroups of patients treated or not with HFNC/CPAP/NIV, no statistically significant differences were found.The strength of our study is that the effect of high-dose methylprednisolone on survival was significantly higher on the overall population if compared to dexamethasone, and it is possible to hypothesize that methylprednisolone could be at least as effective as dexamethasone in the treatment of COVID-19. This could be also explained by a better penetration of methylprednisolone in the lung tissue, in comparison to dexamethasone ,12,13,14There are some important limitations to our study. First, the retrospective nature of this study involving two heterogeneous populations belonging to different centers; moreover, data are refereed to different waves of the pandemic and therapeutic approach was consistently modified during these years; third, microbiological endpoints, such as time to negative nasal swab or bacterial or fungal co- and super-infections, were not considered in the final analysis; finally, in this cohort, consecutively hospitalized patients were enrolled independently from COVID-19 severity and no data are available about follow-up after discharge.During the first month of the pandemic, several authors recommended prescribing steroids based on anecdotal observations and retrospective uncontrolled series of patients ,16,17,18In July 2020, the RECOVERY Collaborative Group showed in a preliminary report, and confirmed in the definitive publication in February 2021, that in patients with COVID-19, therapy with 6 mg once daily for up to 10 days  of oral or intravenous dexamethasone resulted in significantly lower 28-day mortality among those undergoing oxygen supplementation, but not among those receiving no respiratory support . CurrentIn September 2020, the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group published the results of a prospective meta-analysis that pooled data from seven randomized clinical trials  that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19 . They fo2 saturation of less than 92 in room air on admission) randomly assigned to receive a 10-day course of methylprednisolone (2 mg per kilogram intravenously) vs. dexamethasone (6 mg intravenously) with the standard care, the all-cause 28-day mortality rates were lower in patients treated with methylprednisolone than in those who received dexamethasone, though the difference did not reach statistical significance. Instead, they reported a significantly better clinical status at day 5 and day 10 of admission, lower mean length of hospital stay and need for a ventilator in the intervention group than in the control group [Further studies investigated the efficacy of treatment with methylprednisolone in COVID-19 patients ,6,25,26.A more recent prospective study published on February 2022 by Saeed et al. compared the differences in clinical outcome and laboratory results in mechanically ventilated patients with SARS-CoV-2 radiologically confirmed pneumonia treated for ten days with dexamethasone 6 mg/day (192 patients) vs. those treated with methylprednisolone 2 mg/kg/day . They reIn conclusion, these real-life experience data highlight that the use of methylprednisolone in hospitalized patients with COVID-19 may be associated with a significant reduction in mortality in the global population, but this difference was not observed when stratifying patients undergoing HFNC/CPAP/NIV or not. These results suggest the need to conduct further RCTs to evaluate the impact of different dose and duration of corticosteroid therapy in hospitalized COVID-19 patients at different stages of the disease.


IntroductionThyroid nodules are exceedingly common, occurring in up to 76% of adults. Less than 10% are palpable, and the majority are detected incidentally with an estimated prevalence of 68%, 25%, and 18% using ultrasound (US), CT, and MRI, respectively. The rising use of imaging over the last four decades has led to a significant increase in nodule detection or ‘over-identification,’ fine-needle aspiration (FNA), a higher reported incidence of thyroid cancer, and thyroidectomy. The purpose of this study is to provide a descriptive experience with thyroid nodule FNAs one year prior and one year after the implementation of the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) at a prototypical community hospital.MethodsA total of 104 patients with 114 thyroid nodules underwent US-guided FNA at Bluewater Health from January 1, 2018, to March 31, 2020, with available cytological results (The Bethesda System). The study population was divided into two cohorts  based on the implementation of the ACR TI-RADS guidelines in March 2019.ResultsThe local best practice cohort  comprised 57 thyroid nodules in 52 patients . The ACR TI-RADS cohort  comprised 57 thyroid nodules in 52 patients . There were no statistical differences with respect to age, gender, or thyroid nodule location. Our results show a dramatic decrease in the number of unnecessary FNAs if ACR TI-RADS was implemented from January to December 2018. Thirty (52.6%) of the previously sampled thyroid nodules using the local best practice guidelines would have been followed as per ACR TI-RADS.ConclusionACR TI-RADS is a reliable classification system in routine practice that significantly reduces the number of unnecessary thyroid FNAs with higher specificity compared to local best practice guidelines. Thyroid nodules are exceedingly common, occurring in up to 76% of adults . Less thPapillary carcinoma is the most common malignancy, occurring in 80-90% of all cases, and has a 30-year survival rate of 95% . FollicuMany risk-stratification systems were developed to address the over-diagnosis ‘epidemic,’ particularly given the associated substantial human and financial costs . They inThe purpose of this study is to provide a descriptive experience with thyroid nodule FNAs one year prior to and one year after the implementation of the ACR TI-RADS at a prototypical community hospital.Study settingBluewater Health (BWH) is a dual-site secondary care center with 330 beds serving the county of Sarnia-Lambton, Ontario, Canada, with a catchment area of 150,000 people. Prior to the implementation of the ACR TI-RADS stratification system in March 2019, US-guided thyroid nodule FNAs were performed according to local best practice (LBP) inspired by the ATA guidelines. While the sonographic suspicion categories were the same as outlined in the ATA guidelines, the size criteria for biopsy were more conservative  ,21.The research ethics board approved this study, and the principles of the Declaration of Helsinki were followed. Informed signed consent was not required.Study populationA total of 104 patients with 114 thyroid nodules underwent US-guided FNA at Bluewater Health from January 1, 2018, to March 31, 2020, with available cytological results (The Bethesda System) . PatientImage interpretation and ACR TI-RADS categorizationA total of eight radiologists with between two and 20 years of post-training experience routinely interpret thyroid US exams at Bluewater Health. Recommendations for thyroid nodule FNA prior to the implementation of the ACR TI-RADS criteria were based on local best practice guidelines motivated by ATA guidelines Table , as discAll thyroid nodules that were sampled between January 1, 2018, and December 31, 2018, were reclassified based on their sonographic morphology and maximal size using the ACR TI-RADS algorithm with structured reporting similar to the Cancer Care Ontario (CCO) thyroid ultrasound reporting template and blinded from the cytopathology results . This waStarting from March 1, 2019, all thyroid US assessments and management recommendations were standardized to the ACR TI-RADS guidelines.StatisticsMicrosoft Excel  was used for data tabulation. Categorical data were described as counts. Statistical analysis was performed using GraphPad Prism . The z-score test for two population proportions was used to determine the level of significance between population characteristics for categorical data. A two-tailed t-test was used to compare normally distributed data to determine statistical significance. p≤0.05 was deemed statistically significant.Data related to the study population are presented in Table Thyroid nodules sampled between January 1, 2018, and December 31, 2018, were reclassified according to the ACR TI-RADS guidelines and presented in Table Thyroid nodules sampled between March 1, 2019, and March 31, 2020, according to the ACR TI-RADS guidelines are presented in Table Multiple thyroid nodule classification systems were developed to minimize the number of unnecessary FNAs while maintaining reasonable to high negative predictive values. ACR TI-RADS has been validated and shown to outperform the other classification systems in minimizing unnecessary FNAs with negative predictive values as low as 2.2% -20. StarOur results show a dramatic decrease in the number of unnecessary FNAs if the ACR TI-RADS guidelines were implemented from January to December 2018. Thirty (52.6%) of the previously sampled thyroid nodules using the LBP guidelines would have been followed as per ACR TI-RADS. This is a considerable amount given the amount of resources, costs, and patient anxiety that could have been averted. Our results also show that higher ACR TI-RADS corresponds to higher Bethesda grades. There were significantly more thyroid nodules with Bethesda III  in the ACR TI-RADS cohort versus the LBP cohort , as well as Bethesda IV or above . These findings are consistent with the literature demonstrating that ACR TI-RADS is reliable, specific, and outperforms the other classification systems in reducing unnecessary FNAs -20.There is still room for improvement for ACR TI-RADS. Forty-five point six percent (45.6%) to 61.6% of the sampled thyroid nodules as per ACR TI-RADS showed benign cytology. Interobserver variability among radiologists and sonographers is an important consideration to improve TI-RADS performance. In a retrospective analysis of 127 nodules using ACR TI-RADS, Sahli et al. (2019) showed that while TI-RADS interobserver variability was fair (0.6 to 0.74), shape and margin criteria were the biggest sources of disagreement  . InteresA study suggested that decreasing the point assignment for punctate echogenic foci, particularly for mixed solid and cystic thyroid nodules, can also reduce the number of benign nodules . Teefey Shape is currently a binary criterion in ACR TI-RADS . Grani et al. (2020) showed that applying a more specific AP/T ratio ≥1.2 would decrease unnecessary FNAs by up to 58.2% without a negative impact on sensitivity or diagnostic odds ratio .Real-time tissue elastography can also improve the diagnostic performance of ACR TI-RADS -30. Pei The limitations of this study include the inherent biases of retrospective analysis, small sample size, as well as interobserver variability for both sonographers and radiologists.ACR TI-RADS significantly reduces the number of unnecessary thyroid FNAs compared to local best practice guidelines. A review of the literature suggests that further modifications to ACR TI-RADS may be helpful to improve overall diagnostic performance.


Access-site-related complications are often related to high-risk anatomy and technical pitfalls and impair the outcomes of transfemoral aortic valve implantations (TAVIs). Calcification and tortuosity are widely recognized risk factors, and their impact on procedural planning is left to the implanting experts’ discretion. To facilitate decision-making, we introduced a quantitative measure for iliofemoral tortuosity and assessed its predictive value for access-site-related vascular and bleeding complications.We performed a single-centre prospective cohort study of consecutive, percutaneous transfemoral TAVI performed between April 2019 and March 2020. Medical history and all-cause mortality were extracted from the electronic patient files. Arterial anatomy and calcifications were evaluated using 3mensio Structural Heart software. The primary outcome was access-site-related vascular or bleeding complications.P = 0.012), as was maximal angulation median  were higher. Both variables had a significant effect on our primary outcome, with odds ratios (OR) of 3.1  and 2.6 . The degree of angulation was a predictor of major complications too .In this elderly, intermediate-risk population, we registered the primary outcome in 43 patients (39%), and major access-site complications in 10 patients (9.2%). Complete hemostasis was achieved in 77 patients (70.6%), by the application of the MANTA plug alone. In the group with access-site-related adverse events, compared with the group without, the tortuosity index was higher median (26% interquartile range [IQR 18%-33%] vs median 19% [IQR 13%-29%], respectively; Steeper angles and greater arterial elongation increase the risk of vascular and bleeding complications after femoral TAVI with the utilization of a plug-based closure device. Transcatheter aortic valve implantation (TAVI) is a well-accepted, truly minimally invasive method to treat severe symptomatic aortic valve stenosis.We performed a single-centre prospective cohort study of consecutive, percutaneous TF TAVIs performed between April 2019 and March 2020. The only inclusion criterion was that access-site closure had to be attempted with a plug-based device . Relevant medical history and all-cause mortality data were extracted from the electronic patient files. The study was approved by the ethical committee of Maastricht University and Maastricht UMC+; approval number: METC 2019-1253.Congestive Heart Failure, Hypertension, Age (≥ 75 Years) (doubled), Diabetes Mellitus, Stroke (doubled), Vascular Disease, Age (65-74) Years, Sex Category  (CHA2DS2-VASc) score ≥ 8; mechanical heart valves (not in aortic position); and venous thromboembolism for ≤ 3 months. Bridging was carried out using low-molecular-weight heparin until the day of the procedure. Compression bandage was not routinely placed.In a dedicated hybrid operating theatre, all TF valve implantations were performed with patients under conscious sedation. At least one of the operators was highly experienced . Echo-guided arterial puncture was left to the operator’s discretion. Patients were treated with either a balloon-expandable  or a self-expandable  valve. Per protocol, valves were advanced via their manufacturer-dedicated sheaths (e-sheath [Edwards Lifesciences] or InLine sheath [Medtronic] / sheathless). If the usual preoperative assessment suggested significant tortuosity, then the self-expandable valves were advanced via a guiding-sheath from Cook Medical . Per protocol, a plug-based vascular closure device was used (MANTA). Device deployment depth was based on the stop-flow measurement. Until December 2019, 2.0 cm was added to the measured depth; after December 2019, this depth was reduced to 1 cm per a change in the manufacturer instructions.Arterial closure was scored with a semi-subjective classification: complete arterial hemostasis ; manual compression for > 10 minutes; and pressure bandage or surgical intervention required. Vascular and bleeding complications of the TAVI access site were closely monitored and registered until the fourth postoperative day. Complications of the adjunctive arterial access sites were not included in this analysis, including daily inspection and palpation of the inguinal area and monitoring of hemoglobin levels. An ultrasound examination was done in cases of suspicion of a possible pseudoaneurysm. Pseudoaneurysms were treated according to the advice of vascular surgeons . At 6 weeks of regular follow-up, patients were asked if they had any access-site-related problems, which were then examined and/or treated by a medical professional.,All patients who were accepted for TAVI were screened with multidetector computed tomography angiography to assess the access routes and determine appropriate valve sizes. These images were analyzed using 3mensio Structural Heart software . Tortuosity index, angulation, and calcification index were determined for the iliofemoral tract of the access site. We adapted 2 quantification methods to adequately measure tortuosity and calcification. To acquire a tortuosity index, the true arterial length (centreline of flow) and the direct distance between the aortic bifurcation and the femoral bifurcation were measured, and their relation was determined: ([centreline of flow / direct distance] - 1) ∗ 100).3) was quantified using an individual Hounsfield unit (HU) threshold to compensate for the contrast-agent density. The HU of 3 noncalcified sections in the selected area was measured and averaged, and an additional 200 HU was added to this number, and a volume filter for lesions smaller than 5 mm3 was applied.,Calcification was measured between the aortic bifurcation and the femoral bifurcation, as this trajectory corresponds well to the length of sheath used for the introduction of the delivery device, and both locations are easily and reproducibly identified. Calcium volume -2 criteria.t test or the Mann-Whitney U test. Categorical variables are presented as frequencies with percentages, and were compared with the χ2 test. The correlation of calcification index and calcium score was tested with bivariate correlation and described with the Pearson coefficient. Binary logistic regression analysis was used to identify variables associated with access-site-related vascular or bleeding complications after MANTA closure. Cutoff values for tortuosity index and angulation were selected by visual analysis of their empirical receiver operating characteristic curves (vascular and bleeding complications registered). Both variables were added as categorical variables to the univariable regression model. For the multivariable model, the tortuosity index and angulation were merged as one categorical variable with 3 categories—high TI, high angulation, or both. A P value < 0.05 was considered statistically significant.Statistical analysis was performed using SPSS version 26.0 . All continuous variables are presented as mean ± standard deviation (SD), or median with interquartile range (IQR), depending on the distribution. Normality was tested with normality plots and the Shapiro-Wilk test, and group comparisons were done with the Student Within the study period, 109 eligible patients consented to participate in our registry. Their baseline characteristics are summarized in In almost all patients (97%), a right-sided approach was used, and in 23%, femoral arterial access was obtained under ultrasound guidance. In 8.7%, more than one arterial puncture attempt was required. Interventional cardiologists performed 76% of the procedures. Balloon-expandable valves were implanted in 60% of the patients. Operators closed all TAVI access sites with an 18 Fr-sized MANTA. Patients with vs without TAVI access-site-related vascular and bleeding complications (major and/or minor) had comparable 30-day and 1-year mortality rates . PatientP = 0.012) as well as maximal angulation of the access site . Calcification index, calcium score, and minimal arterial lumen diameter across the iliofemoral system on the TAVI side were comparable between groups  had one or more primary access-sited-related vascular or bleeding complications. Ten of these patients had a major complication, 8 had a significant drop in their hemoglobin level , and 1 had a perforation at the access site. The remaining 34 patients had minor complications, hematomas or a pseudoaneurysm .Table 4AP = 0.020). After discharge, we did not register any major access site-related vascular and bleeding complications.Direct arterial hemostasis was achieved in 77 patients (70.6%). Additional manual compression for over 10 minutes was necessary for 5 patients (4.6%). Pressure bandage was required in 25 patients (22.9%), and surgical intervention was required in 2 patients (1.8%). Postoperative hospitalization was longer for patients with access-site-related complications  and 2.8 (P = 0.012), respectively. The effect of other, traditional risk factors remained insignificant .After visual assessment of their respective receiver operating characteristic curves, a cutoff value of 49.5 degrees was chosen for the maximal angulation , and 22.8% was chosen for the tortuosity index . Univariable binary regression analysis showed that only maximal angulation and tortuosity index could have had a significant effect on TAVI access-site related vascular and bleeding complications (major and minor), with odds ratios (ORs) of 3.4 ,,10,The incidence of major vascular and bleeding complications and unplanned vascular repairs has decreased within the intermediate- and lower-risk population, compared to that in the first high-risk TAVI trials. Yet, both our data and the available literature show that these events still affect short- and long-term outcomes in up to 4%-7.5% of the TAVI population.,,,Proper preprocedural planning, taking patient- and device-related factors into account, is crucial to minimalize the incidence of periprocedural bleeding and vascular complications. The interaction of anatomy and closure devices is especially interesting, as these devices have unique learning curves, usability, and applicability. To these ends, several predictors of adverse events have been proposed.,,Our most important and novel finding is the unfavourable influence of arterial elongation, measured by the tortuosity index and angulation, on the efficacy of a plug-based vascular closure device (MANTA). We have shown that a tortuosity index of 22.8 and an angle > 49.5 are important and synergistic predictors of VARC-2 vascular and bleeding complications. These findings connect well to the findings of Mach et al., who published similar findings (a tortuosity score of 21.2) in a population treated with suture-based closure devices and clinical experience with endovascular aneurysm repair.We believe that objective tortuosity measurements should be incorporated into the preprocedural screening process to improve procedural outcomes. Both measurements could help with closure-device selection and in predicting access-site-related vascular and bleeding complications, although further studies are warranted to determine and validate the most relevant cutoff values.The strength of the study was its prospective design, with predefined access-site evaluation immediately after and during hospitalization. Patients were treated with one type of closure device. Access-site assessment was scored by the ward doctors. We faced a limited follow-up after hospital discharge due to pandemic measurements (COVID-19)—from March 2020 onward, patients could not be physically present in the outpatient clinic for the 6-week follow-up appointment and instead received a telephone consultation. Some of the vascular complications  may have been missed, as no routine echocardiographic control of the access site was performed. No information is available on circumferential calcifications. Due to the small sample size, information on the influence of complications or other procedural factors on patient survival remains limited.Steep angles and greater elongation, as measured by the tortuosity index of the iliofemoral tract, increase the risk of vascular and bleeding complications after utilization of plug-based closure devices in TAVI patients. Integrating these measurements into the TAVI workup could help improve TAVI outcomes.


Hematological and hemorheological parameters are known to be altered in COVID-19; however, the value of combined monitoring in order to deduce disease severity is only scarcely examined. A total of 44 acute SARS-CoV-2-infected patients (aCOV) and 44 age-matched healthy controls (Con) were included. Blood of aCOV was sampled at admission (T0), and at day 2 (T2), day 5 (T5), day 10 (T10), and day 30 (T30) while blood of Con was only sampled once. Inter- and intra-group differences were calculated for hematological and hemorheological parameters. Except for mean cellular volume and mean cellular hemoglobin, all blood cell parameters were significantly different between aCOV and Con. During the acute disease state (T0–T5), hematological and hemorheological parameters were highly altered in aCOV; in particular, anemic conditions and increased immune cell response/inflammation, oxidative/nitrosative stress, decreased deformability, as well as increased aggregation, were observed. During treatment and convalescence until T30, almost all abnormal values of aCOV improved towards Con values. During the acute state of the COVID-19 disease, the hematological, as well as the hemorheological system, show fast and potentially pathological changes that might contribute to the progression of the disease, but changes appear to be largely reversible after four weeks. Measuring RBC deformability and aggregation, as well as oxidative stress induction, may be helpful in monitoring critically ill COVID-19 patients. It has been almost three years since the coronavirus disease 2019 (COVID-19), induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first described. Still, and possibly caused by diverse mutations, infected individuals exhibit new and highly diverse symptoms. After infection, some individuals may remain asymptomatic or suffer from mild upper respiratory symptoms, whereas others develop life-threatening symptoms such as severe acute respiratory distress syndrome (ARDS), pneumonia, cardiac, vascular, and organ damage, or neurological diseases  .1/2 (sec)  and Shear Rate at disc min (1/s) (minimum change in back-scatter intensity found during the iteration procedure) were obtained from the syllectrogram.In addition, TIn syllectometry, blood was illuminated and subjected to shear stress, causing the cells to deform and align in the direction of the flow, while the change in backscattered light was measured after the driving mechanism stopped. In the resulting time-dependent intensity plot, the so-called syllectogram, four RBC-behavioral stages were distinguished: (1) The initial plateau during the disaggregation stage originates from the light that is backscattered by the elongated RBCs that are aligned in the direction of the flow. (2) The shape-recovery stage that follows immediately after cup cessation. (3) Aggregation state that starts during the shape-recovery stage when external shear forces fail to keep the RBCs dissociated (rouleaux formation). (4) So-called 3D aggregate formation following rouleaux formation during which rouleaux connect end-to-end as well as side-to-end, creating larger 3D aggregates .Published immunostaining protocols were used to investigate RBC-NOS activation by analysis of the serine 1177 phosphorylation and to investigate nitrotyrosine staining. First, RBCs from whole blood were immediately treated with 4% formaldehyde in order to be able to detect changes within the sample. Blood smears were prepared, and two areas were marked on the slide using a grease pen; a smaller area (=control area) and a larger area (=test area). Both areas were treated identically unless otherwise described. Samples were washed twice using tris buffered saline  prior to permeabilization of the RBCs using 0.1% trypsin. After another washing procedure, peroxidase activation was blocked using a methanol-hydrogen peroxide solution, followed by a third washing protocol. Unspecific binding sites were blocked using a 3% skim milk solution prior to application of the primary antibody to the test area only (one antibody per slide): Rabbit anti Human NOS III Serine1177  or anti-nitrotyrosine . The control area was incubated using an antibody control solution. Slides were washed, unspecific binding sites were blocked using a 3% Normal Goat Serum, and samples were incubated with the secondary goat anti-rabbit antibody . The staining was developed using 3,3-diaminobenzidine-tetrahydrochloride solution  containing ammonium chloride, Nickel (II)-sulfate hexahydrate, ß-D-Glucose monohydrate, and glucose-oxidase. Slides were then dehydrated using increasing alcohol solutions, mounted using Entellan™ , and covered.Slides were placed in a transmitted-light microscope , and a resolution of at least 200-fold was adjusted. The microscope was coupled to a camera  and attached to a computer to take pictures of the stained RBCs and to process images taken. Staining intensity was expressed as gray values, which were analyzed using the software ImageJ 1.52a . For staining intensity analysis, mean grey values were measured from the slide background, the control RBCs, and the RBCs of the test area. The net immunostaining intensity was calculated as previously described .2. Comparisons between the control group and patients were conducted using ANOVA with trimmed means  and robust linear regression . The change over time in blood parameters, aggregation parameters, and deformability was modeled with linear growth models using time as a polynomial predictor  and a random intercept. Due to the non-normality and heteroscedasticity of the residuals, robust procedures were applied (R package: robustlmm ). To ass robust,  with timGraphPad Prism software  was used for visualizing the data. Due to blood volume restrictions, no measurements could be made for ferritin and CRP in Con.Since the beginning of the pandemic, the effective treatment for COVID-19 patients and its versatile underlying molecular actions are still under discussion. Rapid diagnosis and subsequent recovery without long-term adverse health effects are of paramount interest. Improved insight and a better understanding of rheological properties, as well as alterations in RBC morphology and activation and their effects on oxygen transport, may lead to new therapeutic strategies and could possibly improve the monitoring and evaluation of COVID-19 patients. Therefore, hemorheological assessment, in combination with hematological profiling, in particular, may be an asset in determining severe courses as well as a potential  target.In the present study, we observed that besides an increased immunological and nitrosative stress response, both hematological and hemorheological variables were negatively affected in hospitalized COVID-19 patients compared to healthy individuals. Moreover, we showed that alterations in deformability and aggregation recovered during the course of the infection, respectively, within 30 days after hospitalization, whereas anemia may persist even longer.RBC and its associated Hb, Hct, and MCHC values were already lower compared to control at hospital admission T0, which persisted during the whole study monitoring of 30 days. These results confirm existing evidence showing lower Hb, RBC count, higher ferritin, and RDW in severely ill COVID-19 patients . Anemic Interestingly, RDW increased at the end of the study period, indicating a more diverse RBC population. Altered RDW in COVID-19 was already observed by other groups, associating elevated RDW with all-cause mortality  and RDW max, SS1/2, as well as the ratio of SS1/2/EImax—which is assumed to be a robust value in reflecting alterations of deformability when reporting and comparing various populations of RBCs during different clinical states [In terms of RBC deformability, our results showed that aCOV patients had lower RBC deformability than Con, especially in the acute disease state (T2-T10). This is consistent with the findings of other groups, who identified lower RBC deformability in their studies ,19. In gl states —showed dl states ,14. The A decrease in RBC morphology could be a further reason for lower deformability, as deformability is dependent on the shape and volume of the RBCs. Kubánková et al. reported that COVID-19 patients had significantly more heterogeneous size and deformation of RBCs than healthy controls, and Gérard et al. reported mushroom-shaped phenotypes ,42. In aInterestingly, there was no difference in aCOV’s MCV compared to Con and no change in MCV over time. It is known that too high or too low MCV can negatively affect RBC deformability ,49, but Although the increased fibrinogen levels at hospital admission T0 gradually decreased over time, the inflammatory state during the infection could be one factor causing the observed fibrinogen levels and, thus, a potential source of RBC hyper-aggregation . Virus-dThe assessment of leukocytes and neutrophils confirmed the activated immune system response in aCOV, showing highly increased values until T10. Conversely, the relative proportion of eosinophilic cells was highest at T30, suggesting an autoimmune reaction after one month. Although it was observed that eosinophilia reduced severity and symptoms in COVID-19-positive individuals , the obsIn addition to this, increased D-Dimer concentrations in aCOV, already proposed as a biomarker for monitoring SARS-CoV-2 infected individuals , confirm1/2, which represents the kinetics of the aggregation, indicates that aCOV RBC aggregates form rouleaux at a shorter time after their disaggregation compared to Con. This result reflects a higher tendency for aggregation among aCOV, especially after the incubation period with SARS-CoV-2. The shear rate at disc min represents the minimal shear rate needed to prevent RBC aggregation. An elevated shear rate indicates a higher tendency for aggregation and aggregate stability in aCOV over the first ten days. This implies that an increased shear rate was needed for complete disaggregation in these SARS-CoV-2 infected individuals, which, in turn, possibly contributes to blood clotting and elevated thrombosis risk frequently observed in COVID-19 [The shortening of aggregation half-time TCOVID-19 ,64.Our findings show that initially increased aggregation index (AI) values of COVID-19 patients decreased over the duration of the study, particularly from T0 to T5. Reduced aggregation is the result of lower AI, which is advantageous for patients . The defAdditionally, altered RBC structural proteins may play a role in the thromboembolic and coagulopathic issues faced by certain critically ill patients . Even afIn addition to mechanical stress, oxidative stress may have an impact on RBCs as well. Increased RBC intracellular reactive oxygen/nitrogen species (iROS) levels have been shown to reduce RBC deformability in sepsis: a similar mechanism could possibly reduce deformability in COVID-19 as a result of increased oxidative stress . It has Beside hemorheological assessment, other cell-based prognostic markers are under examination or already established in COVID-19 inflammation monitoring. Both increased monocyte distribution width (MDW) ,73 and hAs a result, therapeutic approaches to reduce oxidative stress and immune response may be capable of minimizing RBC damage during COVID-19 infection and may result in better RBC deformability and improved oxygen supply. Downregulation of the immune response and therapeutic medications could also affect the potential regeneration of RBC deformability with subsequent reduction of persistent symptoms. There are some limitations that have to be mentioned. One limitation is the small number of participants in the study population and the reduction in sample size over time when patients had already left the hospital before T10 or T30, which resulted in partly incomplete data sets of blood samples and associated measures for each patient. In addition, admission of clinically ill patients at night led to the necessity to collect and measure hemorheological and hematological variables after some hours of blood storing at 4 °C resulting in variability in duration from collection to measurement. However, results suggest that this factor was unlikely to cause any discrepancies in the measured values. Vaccination status could not be obtained in the majority of aCOV due to language skills or rapid inpatient release/death, whereas all individuals in CON were vaccinated. The possible influence of vaccination before hospital admission and concomitant disease severity with regard to the present parameters have still been determined with no possible conclusion at the moment.Due to their significant impact on microcirculation and oxygen supply, rheological properties such as RBC deformability and aggregation could play a significant role in the treatment of COVID-19 and the possible prevention of severe Long-/Post-COVID cases.We observed that RBC hematological and hemorheological variables are pathologically affected in hospitalized COVID-19 patients compared to healthy controls especially impaired during acute infection. Because of their close relationship with the immune response and intracellular stress, they may be sufficient indicators for severe COVID-19 cases and may provide another additional asset to monitor COVID-19 severity and therapy in combination with hematological assessment. Both deformability and aggregation appear to be usable for appropriate severity parameters because they are, on the one hand, validly measurable, with moderate material and time requirements, and, on the other hand, directly influenced by the effects of COVID-19 infection. In addition, examining RBC deformability and aggregation as well as ROS/RNS stress induction in relation to both vaccination status and patient outcome, as well as to any long-term COVID symptoms, may be beneficial in addition to established inflammatory parameters like CRP or ferritin.


Clinical studies demonstrated the efficacy of rTMS treatment in major depressive disorder. However, the results of meta-analyses are contradictory due to the heterogeneity of the included studies.The aim was to analyse the effectiveness of rTMS for treatment-resistant major depression.A systematic literature review of English-language articles published in the last 10 years was performed on PubMed and Scopus databases according to PRISMA guideline principles. To assess the effects of rTMS on response and remission rates, random-effects model and inverse variance method were used.2analysis showed no considerable heterogeneity in the combined effect sizes neither for remission studies (I2=23.36%) nor for response studies (I2=0.00%).23 randomized double-blind sham-controlled studies met the inclusion criteria for quantitative analysis for response (n= 1020 patients) and 12 studies for remission (n= 846 patients). The relative risk for response and remission were 2.19  and 2.65 , respectively using rTMS as add on treatment (in patients after two antidepressant treatment failures) compared to standard pharmacotherapy. ITranscranial magnetic stimulation became an evidence-based, effective treatment for treatment-resistant major depressive disorder, either as a monotherapy or as an augmentation of pharmacotherapy. However, because of the lack of standardized protocol, a substantial methodological heterogeneity exists. According to our results, rTMS was significantly more effective than sham rTMS in both response and remission outcomes, which is consistent with previous meta-analyses, but the effect size was a bit smaller than what was reported previously.No significant relationships.