In patients with chronic kidney disease (CKD), there is an unmet need for novel biomarkers that reliably track kidney injury, demonstrate treatment-response, and predict outcomes. Here, we investigate the potential of retinal optical coherence tomography (OCT) to achieve these ends in a series of prospective studies of patients with pre-dialysis CKD (including those with a kidney transplant), patients with kidney failure undergoing kidney transplantation, living kidney donors, and healthy volunteers. Compared to health, we observe similar retinal thinning and reduced macular volume in patients with CKD and in those with a kidney transplant. However, the choroidal thinning observed in CKD is not seen in patients with a kidney transplant whose choroids resemble those of healthy volunteers. In CKD, the degree of choroidal thinning relates to falling eGFR and extent of kidney scarring. Following kidney transplantation, choroidal thickness increases rapidly (~10%) and is maintained over 1-year, whereas gradual choroidal thinning is seen during the 12 months following kidney donation. In patients with CKD, retinal and choroidal thickness independently associate with eGFR decline over 2 years. These observations highlight the potential for retinal OCT to act as a non-invasive monitoring and prognostic biomarker of kidney injury. In patients with CKD, there is an unmet need for biomarkers that reliably track kidney injury. Here, in a series of prospective studies, the authors show that retinal OCT metrics reflect kidney injury, are modified by treatments for kidney disease and can predict future decline of kidney function. CKD is strongly associated with incident cardiovascular disease. Indeed, patients with pre-dialysis CKD are more likely to die from cardiovascular disease than develop kidney failure1. Kidney transplantation is the only treatment that reduces cardiovascular risk and prolongs the survival of patients with kidney failure but these patients remain at a 3–5-fold greater cardiovascular risk than the matched general population and cardiovascular disease is their leading cause of death2.Chronic kidney disease (CKD) is a global health problem the prevalence of which increased by 30% worldwide between 1990 and 20173, and as eGFR declines these risks increase4. However, eGFR lacks sensitivity and specificity. For example, substantial renal tissue damage has to occur before eGFR is impaired5. It is also recognized that the focus on eGFR-related outcomes is unidimensional, poorly reflecting complex disease pathology6. Microvascular changes are important in CKD development and progression. Currently, these can only be assessed reliably through kidney biopsy, which is invasive. Interval kidney biopsy, to assess microvascular changes over time and in response to therapies, is also impractical. Thus, there is an urgent unmet need for novel biomarkers that will sensitively and specifically track kidney injury, reliably demonstrate response to treatments, and predict longer-term outcomes.A reduced estimated glomerular filtration rate (eGFR) is strongly associated with adverse cardiovascular and renal outcomes8 meaning that diseases may present similarly and via common pathways in both organs. For example, Bruch’s membrane in the eye and the glomerular basement membrane (GBM) both contain a network of α3, α4 and α5 type IV collagen chains10. Thus, inherited diseases of type IV collagen manifest with co-existent nephropathy and retinopathy as seen in Alport syndrome11. The microcirculation of the retina can be subdivided into retinal and choroidal circulations. The choroidal capillary (choriocapillaris) endothelium has ~80 nm fenestrations allowing fluid exchange within the subretinal space12 similar to the glomerular endothelium for ultrafiltration into the urinary space13. In addition, the eye and kidney have matched chorioretinal and corticomedullary oxygen gradients, respectively, and excessive activation of the renin-angiotensin-aldosterone and endothelin systems are implicated in the development and progression of both retinopathy and CKD17. The choroidal circulation receives ~80% of ocular blood flow and passively oxygenates key visual apparatus including the pigment epithelium and photoreceptors particularly within the avascular fovea, suggesting a critical role in maintaining global retinal health18. Choroidal vascular change may therefore predate the onset of overt retinopathy and, if detectable, might allow earlier identification of incipient disease.The kidney and eye are structurally and functionally similar19. Optical coherence tomography (OCT) is a non-invasive and rapid method to cross-sectionally image the eye that is available in most high street opticians20. Recent advances have enabled the identification of specific cell layers within the retina in high resolution, as well as deeper structures such as the choroid, an exclusively vascular bed, in a way only previously possible histologically. Recently, we demonstrated, for the first time, that patients with CKD have choroidal and retinal thinning compared to matched healthy volunteers21. Here, in a series of prospective studies, we show that OCT metrics reflect circulating and histological measures of kidney injury, are modified by treatments for kidney disease and can predict future decline of kidney function. OCT metrics, therefore, have the potential to act as a non-invasive monitoring and prognostic biomarkers of kidney injury.The transparency of the ocular media offers a unique opportunity to directly visualize the microvasculature within the eye which may be affected in systemic diseases such as CKDi) patients with pre-dialysis CKD, (ii) patients with kidney failure undergoing kidney transplantation, (iii) living kidney donors, and (iv) healthy volunteers into a series of prospective cross-sectional and longitudinal studies as shown in Fig. We enrolled —and heavier proteinuria than kidney transplant recipients, and patients with a kidney transplant had received their transplant on average ~7 years prior to OCT imaging.   Fig. . In keep01) Fig. . Recipie01) Fig. . In CKD p < 0.01 for each). Conversely, patients with a kidney transplant had choroidal thicknesses similar to healthy levels, suggesting reversal of this thinning  and lower eGFR such that those patients with a lower eGFR had a thinner choroid , and this continued to improve over the 12-month study follow-up. We observed early thickening of the choroid in the post-transplant period with a ~5% increase by 1 week at each of locations I, II and III. At 1 month after transplant, choroidal thickness had increased by ~10% at each location   Fig. . This in2 to 62 ± 14 ml/min/1.73 m2 in the first week post-donation and these remained stable over the 12-month follow-up period. Following this acute loss of functional kidney mass, the choroid thickened in the first week post-kidney donation before showing a tendency to thinning over the longer term at each of locations I, II and III . Across all patients (n = 262), the mean macular volume was 8.3 ± 0.4 mm3 and mean choroidal thicknesses were 203 ± 81 μm, 276 ± 85 μm and 257 ± 77 μm at locations I, II and III, respectively.Finally, we determined whether macular volume  and choroidal thickness associated with eGFR decline in patients with stable CKD. OCT images were available for 289 subjects with CKD. Five (2%) patients were excluded as their OCT scans were of insufficient quality, 16 (6%) were excluded because of eye disease identified at the time of imaging, and 6 patients (2%) were excluded due to insufficient follow-up , whilst the odds of eGFR declining by ≥20% at 2 years increased by 3.75 . Of the three choroidal locations assessed, only location III demonstrated a significant association with each primary outcome. Indeed, for every 10 μm decrease in choroidal thickness at location III, the odds of an eGFR decline of ≥10% at 1 year and ≥20% at 2 years increased by 1.04  and 1.06 , respectively.The primary outcomes of an eGFR decline of ≥10% at 1 year and ≥20% at 2 years occurred in 38% (100/262) and 23% (60/262) of patients, respectively. The results of unadjusted analyses evaluating the relationship between each OCT metric and these outcomes are summarized in Supplementary Table 3 decrease in macular volume , and for every 10 μm decrease in choroidal thickness at location III   and more modest increases for every 10 μm decrease in choroidal thickness at locations I  and III   is a more reliable metric of kidney disease severity and prognosis23, its use in routine clinical practice is impractical. Retinal imaging offers an attractive route to non-invasively assess microvascular remodelling in chronic systemic disease. In these prospective studies, we assessed the potential for retinal OCT metrics to report kidney function during CKD progression, and in response to treatment. Our major findings are that: (1) retinal and choroidal thinning occurs in CKD and progresses as kidney function declines; (2) these changes in OCT metrics are reversed when kidney function is restored by kidney transplantation; (3) healthy individuals who donate a kidney and lose kidney function, gradually develop choroidal thinning and, (4) in those with CKD, a thinner retina and choroid seen on a single point-in-time OCT scan independently associate with future eGFR decline. These observations highlight the potential for OCT metrics to act as a non-invasive monitoring and prognostic biomarker of kidney injury.Estimated glomerular filtration rate is a key indicator of kidney function in patients with CKD. However, it is insensitive, only becoming abnormal once >50% of functional kidney mass has been lost24. We also found that the retinal thinning in patients with CKD was more marked in the central retina, compared with the peripheral scan regions. The central retina is reliant on the choroidal circulation for oxygen supply8, which may make it more vulnerable to microvascular injury. Indeed, choroidal thickness was reduced by ~15% in CKD across the three locations examined and related directly to kidney scarring even after adjusting for important confounders. This relationship was stronger than that between choroidal thickness and eGFR, suggesting the potential for non-invasive OCT to convey important clinical information about patients with kidney disease. We found that choroidal thinning was particularly evident in the subfoveal region (location II), which might account for the exaggerated retinal thinning observed centrally around the fovea. From a biomarker perspective, a focus on these central areas may further improve sensitivity of OCT metrics to report microvascular injury in CKD.The greater the severity of kidney disease (reflected by a lower eGFR), the thinner the retina and choroid. Notably, this was independent of age, a recognized, important contributor to chorioretinal thinningtoward values observed in health and so may not portend the same pathological significance as increases observed in age-related macular degeneration or diabetic macular oedema that are deviations away from health driven by underlying vasculopathy. The implications of these increases for the ocular health of kidney transplant recipients are beyond the scope of our study but will be an important part of future work as ocular disease is common in these patients25.One of the main aims of our study was to examine if the OCT changes seen in CKD are dynamic and modifiable. Two complementary paradigms show these to be the case. First, we show that patients with kidney failure receiving a kidney transplant undergo rapid thickening of the retina and choroid, an effect that begins as early as 1 week following transplant and continues for at least 12 months. Our data suggest a generalised increase in retinal thickness and thus macular volume, rather than focal accumulation of intra or sub-retinal fluid, which appears more evident in central regions. The ~2% increase in macular volume represents a deviation 2. Nevertheless, cardiovascular disease remains the leading cause of death in transplant recipients26. Conventional cardiovascular risk factors, such as hypercholesterolemia and proteinuria, are poor predictors of cardiovascular events in this setting27 and OCT imaging may offer a route to robustly assess cardiovascular risk in this high-risk population. Further support of a link between choroidal thickness and vascular function is provided by our data showing a strong association between tacrolimus exposure and choroidal thickness. Tacrolimus, a calcineurin inhibitor and a standard component of post-transplant immunosuppression, is well recognized to promote vasoconstriction, endothelial dysfunction, and arterial hypertension; those patients with a greater tacrolimus burden had thinner choroids28.The most impressive increase in thickness was observed in the choroid, suggesting that the changes here are reporting improving vascular flow and/or function. This is an important finding; kidney transplantation is the only treatment that reduces cardiovascular risk in patients with kidney failure30. Currently, we are unable to identify kidney donors most at risk of these complications. Recently, we showed the potential utility of OCT-angiography (OCT-A)—which defines retinal vascular density and geometry—in discriminating kidney donors with normal kidney function from matched healthy volunteers31. The phenotype of the donors’ retinal vasculature evolved over time following donation to resemble that of patients with CKD. The current data suggest that OCT, which provides complementary data to OCT-A, may also have a role in long-term risk stratification of kidney donors, especially if future studies link OCT metrics to cardiovascular disease risk.The second key observation came from serial OCT scans in living kidney donors, a group in whom GFR is rapidly lost. Living kidney donors demonstrated choroidal thinning over a 12-month period even though eGFR remained within the normal reference range during this follow-up period. Kidney donation is associated with important longer-term risks of developing both chronic kidney and cardiovascular disease2) but those with CKD had thinner choroids than transplant recipients. Patients with a kidney transplant had received their transplant on average ~7 years prior to OCT imaging. Notably, CKD patients had greater degrees of systemic inflammation and proteinuria than kidney transplant recipients at the time of imaging, and their underlying causes for developing CKD were more ‘inflammatory’ than those of transplant patients . We have previously shown that both inflammation and proteinuria associate with choroidal thinning21, and these two important contributors to endothelial dysfunction and cardiovascular risk32 may partly explain the findings here. Indeed, the relationship between changing choroidal thickness and potential modification of cardiovascular risk remains to be defined and future prospective studies should aim to modulate inflammation and proteinuria in patients with CKD and examine the effects on OCT metrics.Importantly, our data suggest that factors other than eGFR influence OCT metrics in the longer-term. In our cross-sectional study, patients with CKD were matched to transplant recipients in terms of age, sex and eGFR  and retinal nerve fibre layer (RNFL) thickness, and this is in line with our previous work2), with both BP and proteinuria controlled to current guidelines . Thus, this was a cohort at low risk of disease progression. Despite this, our fully adjusted models show that for every 1 mm3 fall in macular volume , the likelihood of an eGFR decline of ≥10% at 1 year increased 2.5-fold. Choroidal thickness was also independently associated with eGFR decline, although the effect was more modest (~10% increased risk of a ≥10% decline in eGFR at 1 year). We speculate that these effects may be even more impressive in patients at higher risk of disease progression. Notably, reduced macular volume showed a stronger association with risk of eGFR decline that then observed with choroidal thinning. The vascular nature of the choroid means that choroidal thickness is potentially subject to influence by blood pressure, sympathetic nervous system activation, volume status and vasoactive medications. These factors serve to increase the heterogeneity of choroidal thickness in any given population, and it would be impractical to consider and adjust for of all these in our analyses given our study size. Despite this, we still found an important association between choroidal thickness and eGFR decline which strengthens the utility of choroidal thickness as a biomarker for adverse kidney disease outcomes.Finally, we have shown that OCT metrics associate with eGFR decline in those with CKD. Currently, baseline eGFR, BP and proteinuria are the only reliable predictors of kidney function decline in CKD on a population scale. Using these parameters to individualize risk is not part of current standard of care. Here, we studied a cohort of patients that had modestly impaired kidney function at baseline  would confound interpretation of changes related to kidney disease per se. Indeed, choroidal thickening has been reported in diabetics even in the absence of overt retinopathy39 and the need for renal transplants far outstrips organ supply.Kidney disease is common, progressive, and inextricably associated with cardiovascular disease. 60,000 people die prematurely in the UK every year because of CKD and its associated cardiovascular disease. CKD costs the NHS ~ £2 billion per year. Half this cost is for provision of dialysis for ~2% of patients. Currently, 64,000 patients are on dialysis in the UK40. OCT metrics may plausibly be even more useful given the high-fidelity, granular nature of the images acquired, particularly if coupled with modern deep learning image analysis. OCT metrics have already been incorporated into clinical trial outcome measures in multiple sclerosis41 and our data introduce the exciting possibility that these metrics might be included alongside eGFR and proteinuria to individualize cardiovascular risk and the risk of kidney disease progression in future trials in CKD.Incorporating metrics from the analysis of retinal photographs improves the accuracy of risk stratifying patients with CKD for disease progression and incident cardiovascular risk by ~10%Between September 2016 and August 2020, we enrolled (1) patients with pre-dialysis CKD, (2) patients with kidney failure undergoing kidney transplantation, (3) living kidney donors, and (4) healthy volunteers into a series of prospective cross-sectional and longitudinal studies  and then 1 week, 1-, 3-, 6- and 12-months following surgery. Study 4 was a prospective cohort study and examined whether OCT metrics associate with future decline in kidney function as determined by estimated glomerular filtration rate (eGFR) . Creatinine clearance, as an estimate of GFR, was calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation43. Tacrolimus exposure was estimated from the area under the curve of consecutive trough plasma tacrolimus concentrations against time in days since starting tacrolimus up to the date of the OCT study for each recipient of a kidney transplant and expressed as ng/L*days. Tacrolimus is a calcineurin inhibitor used as part of post-transplant immunosuppression.All studies were performed in a quiet, temperature-controlled room. Systolic and diastolic blood pressure (BP) were recorded in duplicate, with an appropriately sized cuff, using a validated oscillometric sphygmomanometer, the Omron HEM-705CP, and values are presented as the average of two recordings44. Images were acquired using proprietary TruTrack active eye tracking and Automatic Real-Time (ART) software, which averages the image over 100 scans, to generate a single high-resolution image.All subjects underwent examinations of both eyes using the Heidelberg SPECTRALIS Spectral-Domain OCT machine . Images of the right eye were used for analysis wherever possible. Our protocol included three scans for each eye: (1) a horizontal line scan through the macula, centred over the fovea, with enhanced depth imaging (EDI) enabled for greater choroidal visualization; (2) a macular volume scan consisting of 61 horizontal B-scans with a separation of 120 μm covering the whole area of the macula; (3) a peripapillary circular line scan centred over the optic disc, with Nsite Axonal Analytics software automated segmentation of the RNFL45. The ETDRS map divides the macula into 9 subfields. The circular grid is centred over the fovea and consists of three concentric rings of diameters 1, 3, and 6 mm, respectively. The inner and outer rings are further divided into quadrants: temporal, nasal, superior, and inferior. Retinal thickness, RNFL thickness, and macular volume were measured using the automatic segmentation values of the SPECTRALIS OCT. Choroidal thickness was measured manually by two independent, blinded operators, on the horizontal EDI line scan, in three separate locations: 2 mm nasal to the fovea (location I), subfoveal (location II), and 2 mm temporal (location III) to the fovea. The measurement was taken in a vertical line from the outer hyper-reflective line corresponding to the base of the retinal pigment epithelium (RPE/basement membrane complex), to the choroidal-scleral junction , choroidal thickness and RNFL thickness  classification46, were recruited from the general renal outpatient clinics at the Royal Infirmary of Edinburgh. Patients were well and had not been started on any new medications in the 4 weeks leading up to the study. Kidney transplant recipients & donors: patients with a functional kidney transplant and living kidney donors were recruited from the transplant inpatient and outpatient services. For recipients, both those who had received a living and deceased donor (donation after both brain and circulatory death (DBD and DCD)) kidney transplant were included into the study. Healthy volunteers: were recruited from local, ethically approved databases. Subjects with any eye disease, previous eye surgery, refractive error greater than ±6 dioptres and those with diabetes mellitus were excluded from the study.48. To detect a difference of 10% in choroidal thickness between healthy controls and patients with CKD, or in those with a functional kidney transplant, with 80% power and a two-sided significance of 5%, we calculated that we would need to recruit 82 participants in each group. To detect a similar magnitude of change in RNFL thickness, we would require 63 subjects in each group.The primary endpoint of this study was difference in choroidal thickness between CKD patients and healthy controls. Secondary endpoints included difference in retinal and RNFL thickness. This study was powered on the basis of a healthy subfoveal choroidal thickness of 289 ± 52 μm and a healthy temporal RNFL thickness of 79 ± 16 μmThe primary endpoint of this study was association between choroidal thickness and kidney scarring reflected by extent of glomerulosclerosis and interstital fibrosis and tubular atrophy. This study was powered based on our previous work, with 40 patients providing 80 percent probability to detect a relationship between kidney scarring and choroidal thickness at two-sided significance of 5%, assuming a standard deviation of choroidal thickness of ±50 um.Kidney transplant recipients: our previous work in patients with kidney failure showed a choroidal thickness of 241 ± 50 μm and an RNFL thickness of 48 ± 11 μm21. To detect a 15% change in choroidal thickness in patients with kidney failure undergoing kidney transplantation, we would need 24 subjects. To detect the same change in RNFL thickness, 19 subjects would be required. Kidney donors: to detect a 15% change in choroidal thickness in a healthy subject pre- and post-kidney donation, we needed to recruit 21 subjects. To detect a similar magnitude of change in RNFL thickness, 20 subjects were needed.The primary endpoint was a difference in OCT metrics 12 months after surgery compared to pre-surgery. The studies were designed to detect differences in OCT metrics with 80% power and with a two-sided significance of 5%. VitalData. The ‘index’ or baseline eGFR was defined as the first test result available within 6 months of the OCT scan. One-year outcomes were calculated based on the first available measure of eGFR during a 6-month window 1 year following the index eGFR. Two-year outcomes were calculated based on the first available measure of eGFR during a 6-month window 1 year following the result used to define the 1-year outcome. The study endpoints were selected based on the results of a meta-analysis of >1.7 million patients, which demonstrated that reductions in eGFR such as these were frequently and robustly associated with subsequent risk of kidney failure in patients with and without renal impairment at baseline49. From our previous work50, we estimated that the standard deviation of baseline eGFR in our population would be ~25 mL/min/1.73 m2 and that the difference in mean eGFR at 1 year would be ~5 mL/min/1.73 m2. Therefore, with a sample size of ~220 and an alpha of 0.05, our study would have a power of at least 80% to detect our pre-specified endpoints at 1 and 2 years.For this study, our primary outcomes were a decline in eGFR of ≥10% at 1 year and ≥20% at 2 years. Linked, routinely collected, individual-level biochemistry data were accessed from our regional registry of renal patients, Studies 1 and 2, choroidal, retinal and RNFL thicknesses at all locations were compared between groups by two-way ANOVA with Tukey correction for multiple comparisons. Macular volume was compared using one-way ANOVA. Stepwise linear regression was used for multivariable analysis of variables showing linear relationship with choroidal thickness. For Study 3, within group thicknesses at all locations and macular volumes were compared at each timepoint by two-way ANOVA with Tukey correction for multiple comparisons or a mixed effects analysis where appropriate. Statistical analysis was performed using Prism version 8.2.1 (GraphPad Software Inc) and R version 3.6.1 (R Foundation). Data are presented as mean ± standard deviation. Parametric and non-parametric tests were used as appropriate to compare the differences between groups. For Study 4, unadjusted, univariable logistic regression models were used to examine the simple relationships between OCT metrics  and choroidal thickness) and the pre-specified study outcomes. Then, multivariable logistic regression models were constructed to further investigate the relationship between each OCT metric and both study outcomes. These models were adjusted for important confounders which were identified a priori, and included: patient age, sex, baseline eGFR, systolic BP and urine protein:creatinine ratio. Confounding variables were added sequentially; the relative performance of each model was assessed by examining the likelihood ratio test statistic, whilst the goodness-of-fit of each model was evaluated by reviewing its associated Akaike Information Criterion (AIC) value. The variance inflation factor (VIF) was used to evaluate the degree of multicollinearity present in each model. A VIF of ≥2 was considered significant. The results of both univariable and multivariable logistic regression models were presented as odds ratios (ORs) and 95% confidence intervals (CIs).For Further information on research design is available in the Supplementary InformationPeer Review FileReporting SummarySource Data


Endotracheal intubation and mechanical ventilation are prevalent interventions in the operating room and intensive care unit. Recently, the complications of endotracheal tube cuff pressure have been a topic of interest. Therefore, this study compared the effect of pressure control and volume control ventilation modes on the endotracheal cuff pressure rate in patients undergoing general anesthesia and mechanical ventilation.In this triple-blinded randomized clinical trial, 50 patients undergoing open limb surgery and inguinal hernia were allocated to two groups of 25 based on inclusion criteria. After intubation, one group underwent ventilation on the pressure control ventilation mode, and the other underwent ventilation on the volume control ventilation mode. In both groups, using a manometer, the cuff’s pressure was first adjusted in the range of 25–30 cm of water. Then, the cuff pressure was measured at 10, 20, and 30 min intervals. The data were statistically analyzed using independent t-test, and two-way repeated measures ANOVA.F = 117.7, P < 0.001). However, a repeated measures ANOVA with a Greenhouse-Geisser correction showed no interaction between time and groups . The two groups had no significant difference in cuff pressure .The present study’s findings showed that cuff pressure has significantly decreased over time in both study groups . Many patients are admitted to intensive care units, and almost all surgeries requiring general anesthesia need respiratory support by mechanical ventilation, which may cause ventilator-induced lung injury by various mechanisms. A proper artificial airway should be provided for this device to have adequate ventilation, often supplied by the endotracheal tube , 2. EndoRecently, much attention has been paid to the complications of endotracheal cuff pressure (ETCP), especially the need to monitor ETCP in the operating room during surgery. Immediate side effects on the endotracheal and larynx were reported 15–94% after intubation. Voice violence and sore throat are 15% and 80%, respectively . An exce2O [Many factors can affect complications and problems in the endotracheal tube for patients who use mechanical ventilation. Some of these factors are lack of sufficient airway moisture, high content of inhalation oxygen, inadequate heat of administered gases, improper values, and pressure changes of the endotracheal tube cuff. Insufficient pressure of the endotracheal cuff causes damage to the endotracheal wall (at higher than standard cuff pressure). It also causes ventilation air leakage and the risk of aspiration of gastric contents and pneumonia caused by mechanical ventilation  subsequently . In this2O .One of the affecting factors of the ETCP is positive pressure mechanical ventilation . In voluThis study determined and compared the effect of pressure control and volume control ventilation modes on the pressure rate inside the endotracheal cuff in patients undergoing general anesthesia and mechanical ventilation.This parallel randomized clinical trial with the registration number IRCT20181018041376N1 was registered in the Iranian Registry of Clinical Trial on 23/02/2019. It was conducted on patients undergoing open limb surgery and inguinal hernias referred to Imam Hussein Hospital relevant to Shahroud University of Medical Sciences from April 2019 to February 2020.Fifty patients were selected from the study population in two groups (intervention and control) based on the desired characteristics. Inclusion criteria in this study included: 18–40 years old Patients who were ready for open limb or inguinal hernia surgery in the supine position, ASA 1 & 2 (patients of class 1 & 2 of anesthesia surgery assortment), and BMI = 18–24 . Also, eThis study was conducted on 50 patients undergoing open limb surgery or inguinal hernia who met the inclusion criteria. After obtaining verbal and written informed consent from the patient, participants were randomly assigned to intervention and control groups based on quadrigeminal blocks. The patients were intubated and connected to the ventilator in the operating room. In the intervention group, pressure control ventilation was used; in the control group, volume control ventilation was used for mechanical ventilation of patients during anesthesia.Pre-intervention patient preparation: Both groups received the same general anesthesia. Pre- anesthesia drug was Fentanyl (2 µg/kg), to start the anesthesia was Propofol (1.5 mg/kg), muscle relaxant was Atracurium (0.5 mg/kg), The continuance of anesthetic was propofol-remifentanil and Ventilation, was with an equal mixture of oxygen and air (no N2O) [(no N2O) . IntubatInitially, the German VBM Aneroid Manometer (with a measuring range of 0-120 cm) adjusted the cuff pressure for both groups in the standard range (25 to 30 cm). The endotracheal tube was then fixed on the right side of the mouth of the patients using a band on the number 21 for 7-7.5 tubes and 23 on the 8-8.5 tubes. The correct location of the endotracheal tube was confirmed by pulmonary auscultation. The temperature and blood pressure of the patient and the percentage of received oxygen were recorded at the research’s beginning.Any complication of intubation, anesthesia, patient ventilation, cardiovascular system, and routine surgical procedure caused the patient to be excluded from the study.Intervention: In group P (intervention), PCV was used for mechanical ventilation during anesthesia after the patient was connected to the ventilator. This mode was activated on the ventilator, and airway pressure was adjusted to 7 ml/kg to reach the current volume.Control: In group V (control) routine system was used for the mechanical ventilation of patients during the anesthesia. VCV, which is routine ventilation, was activated on the device for this group of patients, and the current volume was adjusted to 7 ml/kg on the ventilator.In both study groups, respiratory rate was selected ten times per minute on the ventilator. In both groups, endotracheal tube cuff pressure was measured 10, 20, and 30 min after mechanical ventilation.N = 50).According to the Tyagi et al. 2011) study and the mean score of peak airway pressures in the VC and PC groups, type 1 error was 0.05, and power was 80%; the sample size in each group was determined to be 20 [ study anAlpha = 0.05 Power = 0.8 Delta=-3.1.1 = 18.7 M2 = 15.6M1 = 3.6 SD2 = 3.2SD1 = 20 N2 = 20NIn this study, participants, the assessor of the study variables, and the analyst were blinded.Patients were selected according to the inclusion and exclusion criteria and randomly allocated to two groups of p and v using the randomly permuted blocks method. For this method, a table of 50 sequences of groups A and B was presented by consulting with a statistical consultant and using software (block number 13 and block size of 4). To ensure the concealment, each letter was placed in a sealed envelope. After closing each envelope, they were numbered based on the initial table. After selecting the eligible patient for the study, the envelope corresponding to the patient was opened, and based on the letters inside, the patient was assigned to one of two groups. The statistical consultant determined random sequence allocation. The first researcher enrolled the participants. According to the letters in each envelope written based on the specified sequence, participants were assigned to the intervention by an anesthesiologist. Data were collected and recorded by a trained individual blinded to the type of intervention performed during anesthesia . Inferential statistics such as independent t-test (to compare quantitative variable between two groups), and repeated measure ANOVA (for the correlated data) using SPSS software version 22. The significance level of the tests was considered to be 0.05.The study participants included 50 patients undergoing open limb surgery and inguinal hernia. The mean age of the patients under study was 34.84 ± 6.626 years in the test group and 32 ± 8.411 years in the control group, and most of the participants were male (60%). The evaluation of demographic characteristics, such as age, sex, and BMI, showed no significant difference between the two groups in terms of demographic variables . A Greenhouse-Geisser correction showed that mean cuff pressure did not differ significantly between the two groups . In both volume control and pressure control groups, the cuff pressure significantly decreased over time   comparing volume control and pressure control ventilation in patients undergoing laparoscopic cholecystectomy demonstrated that airway pressure was significantly lower in pressure control mode than in volume control mode  comparin. In the Based on the current study results, the passage of time significantly reduced cuff pressure in both volume control and pressure control groups. So, both groups had the lowest cuff pressure at 30 min after ventilation.According to the results of the study by Sole et al. (2011), which evaluated an intervention to maintain cuff pressure in patients undergoing mechanical ventilation, the passage of time reduced cuff pressure significantly . In theiThe results of this study demonstrate the importance of continued control of endotracheal tube cuff pressure in patients undergoing mechanical ventilation. Therefore, it is suggested to maintain the cuff pressure within the recommended range to prevent complications resulting from cuff pressure reduction, such as aspiration and ventilation decrease.In this study, patients undergoing mechanical ventilation in ICU were initially considered study patients. Still, since ICU patients are generally elderly patients with numerous underlying problems that may affect the results of the study, young patients undergoing mechanical ventilation in the operating room who were classified under ASA I and II anesthesia were used for sampling to obtain the most negligible effect (other factors affecting cuff pressure) and remove these limitations in the study results.


P = 0.003), maintenance oral corticosteroid doses (P = 0.027), and exacerbation frequency (P = 0.017) were significantly improved, while prebronchodilator-forced expiratory volume in 1 second (% predicted) did not significantly change (P = 0.19). When we grouped the patients into 2 groups according to their body mass index levels, the AQLQ scores were more improved in patients with overweight/obesity than those with normal weight (P = 0.01). This study showed that patients with non-controlled severe asthma exhibiting overweight/obesity and low quality of life had potential benefits from BT.Bronchial thermoplasty (BT) is effective in some severe asthma patients; however, the specific asthma phenotypes that produce a good response to BT are not fully understood. Clinical data were retrospectively reviewed in severe asthma patients who underwent BT at a single institution in Japan. At the follow-up assessment, the Asthma Quality of Life Questionnaire (AQLQ) scores ( To the Editor,2.Bronchial thermoplasty (BT), which improves asthma-specific quality of life (QOL) and asthma exacerbation,In this retrospective and observational cohort analysis, we used data from patients with severe asthma who underwent BT at a single institution in Japan between September 2017 and October 2019. BT was indicated by pulmonologists for adult patients with severe persistent asthma who did not achieve good control despite optimized treatment and who agreed to receive BT treatment. We collected clinical data recorded at the last visit before BT (baseline assessment) and at 12 months after BT (follow-up assessment). Exacerbation was defined as worsening in asthma control, thereby requiring systemic corticosteroids or doubling or more the daily doses of baseline maintenance oral corticosteroid (mOCS) for at least 3 days. The Asthma Quality of Life Questionnaire (AQLQ) consists of 32 items scored on a seven-point Likert scale. In this study, the average of total scores was used. The minimal clinically important difference was a 0.5-point increase.t-test or Wilcoxon rank-sum test, or χ2 test, as appropriate. Correlations between 2 variables were examined using Pearson's correlation coefficient. Baseline and follow-up assessments were compared by paired t-test or Wilcoxon signed-rank test. Furthermore, changes in paired data between two groups were compared by Multivariate Analysis of Variance (MANOVA). We considered P < 0.05 as statistically significant.All statistical data were analyzed using JMP version Pro 15 . Data are described as means ± SD or median (interquartile range). In comparing between groups, we used Student's n = 21). We found that 28.6% (n = 6) were >65 years, 57.1% (n = 12) had blood eosinophil counts <150/μL, and 38.1% (n = 8) had prebronchodilator-forced expiratory volume in 1 second (FEV1) (% predicted) < 60%. Additionally, all the patients received Global Initiative for Asthma Step 5 treatments.n = 3, omalizumab over 3 years; n = 1, mepolizumab for 5 months; n = 2, benralizumab less than 3 months). At the follow-up assessment of the overall population, the AQLQ scores (points) , mOCS doses (mg/day) , exacerbation frequency (/1 year) , and forced vital capacity (FVC) (% predicted)  (1 (% predicted) did not significantly change  , exacerbations were reduced , and the mOCS doses decreased . The baseline AQLQ scores were inversely associated to the delta AQLQ   signific = 0.19) . In mostlta AQLQ .Table 1B2, n = 11) and overweight or obesity . BMI of 25 kg/m2 was used as cut-off value according to the Japan Society for the Study of Obesity (JASSO).1/FVC and lower AQLQ scores than those with normal weight (n = 5) exhibited a decrease in BMI of at least 3%n = 2; overweight/obesity, n = 3; P = 0.53). Changes in BMI (kg/m2) were not significant in either group . The AQLQ scores were significantly improved in patients with overweight/obesity (P = 0.01); these scores improved more in patients with overweight/obesity than those with normal weight. Meanwhile, the exacerbation frequency  (P = 0.56), FEV1 values (% predicted) (P = 0.83), or FVC values (% predicted) (P = 0.48). None of the groups exhibited a significant decrease in the mOCS doses  with a smoking history of 10 pack-years or more and FEV1/FVC ratio below 0.70, our main findings remained similar; the AQLQ scores were significantly improved in the overweight/obesity group alone . The normal weight group included patients who switched biologics during the study period (n = 3). This switch might have affected the outcomes; hence, these patients were excluded from the analysis. After the exclusion, the exacerbation frequency , FEV1 (% predicted) , and FVC (% predicted)  were no longer significantly improved in the normal weight group. Furthermore, 1 values (%predicted). Baseline BMI values were significantly associated with delta AQLQ even after adjustment with baseline (1) AQLQ (P = 0.038), (2) the presence of OCS (P = 0.023), (3) FEV1/FVC ratio below 0.70 (P = 0.005), or (4) at least four episodes of exacerbations in the past year (P = 0.023). When the analysis was confined to patients not taking any biologics in this study, the association remained significant between baseline BMI and the change in AQLQ scores . Baseline characteristics of patients with early-onset asthma and adult-onset asthma exhibiting overweight/obesity are shown in Next, we grouped the patients into 2 groups according to their BMI levels: normal weight  c, and FVedicted) d were siCS doses e, probab1/FVC had more asthma symptoms.3This study identified a phenotype as the potential target for BT treatment to improve asthma QOL scores. This phenotype is characterized by female dominance, late-onset, overweight/obesity, low AQLQ, low-eosinophilic state under optimal treatment, and preserved pulmonary function. Its characteristics were overlapped with previously identified phenotypes of females with asthma and late-onset obesity1/FVC, or exacerbations. These results suggested the importance of BMI in the effectiveness of BT on patients with severe asthma. Meanwhile, baseline BMI values correlated with neither delta blood eosinophil counts nor delta FEV1 values (%predicted). These findings imply that improvements in AQLQ scores are not due to weight loss, suppression of eosinophilic inflammation, or improved lung function. The precise mechanism of BT effects in patients with severe asthma exhibiting overweight/obesity remains unknown, however, reduction of neuroendocrine epithelial cells, submucosal nerves, and airway smooth muscle-associated nerves may be involved.via BT may contribute to favorable responses in patients with severe asthma exhibiting overweight/obesity. Otherwise, other potential mechanisms may be involved, including increased glucocorticoid receptor expression and heat shock protein expression.The impact of BMI on clinical effects after BT is discussed. While BMI values did not change significantly pre- and post- BT in either group, AQLQ scores significantly increased for patients with overweight/obesity than those with normal weight. Furthermore, in this study, baseline BMI values positively correlated with delta AQLQ, which remained significant after adjustment with baseline AQLQ, OCS, FEV1 values after excluding patients with biologics switch. The reason for the non-significant improvement of exacerbation frequency is probably because of the small sample size. Further studies are warranted to confirm the relevance of our findings. Further insight is required by accumulating evidence from large populations to select patients for BT treatment. In conclusion, BT treatment may obtain favorable QOL scores in patients with asthma exhibiting overweight/obesity with low QOL scores.Currently, females with asthma exhibiting obesity are often steroid-resistant, and weight loss is considered to be the only optimal treatment for such patients.1, forced expiratory volume in 1 second; FVC, forced vital capacity; MANOVA, Multivariate Analysis of Variance; mOCS, maintenance oral corticosteroid; QOL, quality of life.AQLQ, the Asthma Quality of Life Questionnaire; BMI, body mass index; BT, bronchial thermoplasty; FEVThe authors would like to thank Professor E. Juniper for allowing us to use the AQLQ Japanese translation for Japan. There is no funding for this study.There is no funding for this study.The data analyzed during the current study are not publicly available because we did not obtain prior consent from the participants, but are available from the corresponding author on reasonable request.KN collected, analyzed and interpreted the data and wrote the draft. CY and KM conceived and designed the study, collected, analyzed and interpreted the data. RI and ET collected and analyzed the data. TN wrote and edited the manuscript. HM revised the work critically. YN provided overall supervision and critically revised the manuscript.This study was approved by The Ethics Committee of Osaka Red Cross Hospital . Informed consent was obtained in the form of opt-out on the web-site.All authors have approved the submission of this manuscript.The authors declare that they have no competing interests.


Septic shock is a common condition associated with hypotension and organ dysfunction. It is associated with high mortality rates of up to 60% despite the best recommended resuscitation strategies in international guidelines. Patients with septic shock generally have a Mean Arterial Pressure below 65 mmHg and hypotension is the most important determinant of mortality among this group of patients. The extent and duration of hypotension are important. The two initial options that we have are 1) administration of intravenous (IV) fluids and 2) vasopressors, The current recommendation of the Surviving Sepsis Campaign guidelines to administer 30 ml/kg fluid cannot be applied to all patients. Complications of fluid over-resuscitation further delay organ recovery, prolong ICU and hospital length of stay, and increase mortality. The only reason for administering intravenous fluids in a patient with circulatory shock is to increase the mean systemic filling pressure in a patient who is volume-responsive, such that cardiac output also increases. The use of vasopressors seems to be a more appropriate strategy, the very early administration of vasopressors, preferably during the first hour after diagnosis of septic shock, may have a multimodal action and potential advantages, leading to lower morbidity and mortality in the management of septic patients. Vasopressor therapy should be initiated as soon as possible in patients with septic shock. Septic shock is a common condition associated with hypotension and organ dysfunction . It is aSeptic shock is a type of distributive shock, more particularly vasoplegic, produced by the activation of inducible NO synthetase, which leads to vasodilation and hyperpolarization of vascular smooth muscle cells, making them less responsive to alpha-adrenergic stimulation. This combination usually causes systemic hypotension, with consequent impairment of organ perfusion . HypotenAccording to Ohm's law, the pressure drops across a circuit as a function of flow and resistance; in general, we do not measure or take into account the back pressure on organ blood flow. Under normal conditions, the flow to the periphery stops as its small arteries and arteriole tone exceeds the intralumenal pressure. The critical closing pressure (Pcc) is different across vascular beds, but as the lumped vascular parameter in healthy individuals is approximately 40 mmHg. This is important because MAP-Pcc represents the actual organ input pressure. At very low-pressure states, such as sepsis, Pcc is often the same or slightly higher than the tissue or venous pressure in those specific beds. Importantly, organ perfusion pressure may be independent of MAP if the Pcc varies widely, as is the case in sepsis. Regrettably, it is very difficult to measure Pcc routinely at the bedside during resuscitation. However, back pressure is rarely central venous pressure (CVP), nor does increasing CVP artifactually, as occurs with the institution of positive pressure ventilation, cause blood flow to decrease for a constant MAP.Nevertheless, measures of systemic pressure are useful for differentiating the causes of hypotension. Under most conditions, hypotension is associated with decreased cardiac output. However, in fluid resuscitated septic patients with vasoplegia, cardiac output is often elevated even though arterial pressure is decreased.The physician must know what determinant we should act on to improve MAP in patients with septic shock, and the two initial options that we have are 1) administration of intravenous (IV) fluids and 2) vasopressors [For many years, the administration of IV fluids has been used to improve MAP in hypotensive patients. In 2001, Dr. Rivers proposed a septic shock management protocol to administer 30 ml/kg of crystalloid solution to achieve initial hemodynamic stabilization as part of early goal-directed therapy . HoweverThe devices and maneuvers to monitor fluid responsiveness remain elusive even after decades of research. Various monitoring techniques have been tested and applied in clinical settings to assess and monitor the accurate or near-accurate amount of fluid to be administered . With thOccasionally, hypovolemia and always reduced peripheral vascular tone are the two predominant pathophysiological mechanisms responsible for septic shock . With thIn patients with septic shock and dehydration, there is no doubt that fluid deficits must be replenished. For example, patients who may have been vomiting, diarrhea, advanced capillary leak, large burns, acute kidney injury in the polyuric phase, diabetic ketoacidosis, hyperosmolar states, among others, will all demand some level of fluid resuscitation. The situation becomes more complex when a patient appears normovolemic. The idea is to use a maneuver that allows us to know if he could benefit from the administration of fluids as soon as possible, since this hemodynamic property of responding to the administration of fluids decreases with the passage of time, even when patients seem to respond to fluids when performing different maneuvers . Many tiIn the CLOVERS trial, all-cause mortality at 90 days was similar between the fluid restrictive and fluid liberal groups. However, the patients were randomized to either group after they received 1–3 litres of fluid. The incidence of serious events was similar in both groups . RegrettThe only reason for administering IV fluids in a patient with circulatory shock is to increase the mean systemic filling pressure in a patient who is volume-responsive, such that cardiac output also increases. However, the mean systemic pressure increases in all patients administered fluids. Guerin et al. showed that fluid increases the mean systemic pressure in all patients regardless of whether or not cardiac output also increases; they also found that the venous return pressure gradient increased only in preload responsiveness patients ,34. On tAt the outset of resuscitation from sepsis-induced hypotensive shock, the use of vasopressors seems to be a more appropriate strategy since patients with septic shock have an alteration in vascular tone and, in theory, by improving the vascular tone with the use of either catecholamine or non-catecholamine vasopressors, it could be restored. At least macrohemodynamics, it has been shown in multiple studies, including CENSER , that thThe very early administration of vasopressors, preferably during the first hour after diagnosis of septic shock, may have a multimodal action. It can cause an increase in preload and cardiac output, reduce preload dependency, and help to improve parameters such as central venous pressure, end-diastolic area of the left ventricle, global end diastolic volume, and E wave, all of them preload parameters . This isp < 0.001) and during the first 8 h of resuscitation , although the development of acute renal failure and/or the need for renal replacement therapy requirements were not dissimilar. However, VE-VPs were related to a significantly lower net fluid balance 8 and 24 h after VPs. VE-VPs were also associated with a significant reduction in the risk of death compared with D-VPs  at day 28. Such an association was also maintained after including patients receiving vasopressors for <6 h [On the other hand, the early administration of vasopressor takes the MAP to a certain value that is variable according to each patient, but that could recruit collapsed capillaries and thus not only improve hemodynamics but also favor organ flow and, therefore, tissue oxygen saturation of different organs . All of for <6 h .In support of these recent findings, the recent SSG hour-1 bundle now recommends applying vasopressors within the first hour when fluid administration is insufficient to achieve hemodynamic resuscitation goals . In a reThere are important reasons for starting norepinephrine as soon as possible in hypotensive patients with septic shock.–Septic shock showed that the time to achieve MAP >65 mmHg was significantly shorter when NE was initiated together with fluid infusion than when NE was initiated only if 30 mL/kg crystalloids failed to achieve the target MAP ,49,51,59–Early NE infusion could augment cardiac output through several mechanisms as previously mentioned ,54,55,59–Early NE administration may potentially recruit microvessels and improve microcirculation in cases of severe hypotension through an increase in organ perfusion pressure and decreased sympathetic tone ,59.–Early NE administration should prevent fluid overload ,57,58,59–Thus, early NE administration should improve outcomes in patients with hypotensive septic shock ,59.p < 0.001). Shock control rate by 6 hours was significantly higher in the early norepinephrine group . No differences in mortality between the groups were found at 28 days. A lower incidence of cardiogenic pulmonary edema and new-onset arrhythmia were found in the early norepinephrine group [Permpikul et al.  found that in the early use of norepinephrine in septic shock, the median time from emergency room arrival to norepinephrine administration was significantly shorter in the early norepinephrine group , aortic aneurism, aortic valve regurgitation, medications  among some others, and even in some patients with septic shock these conditions can also be present and they have to make us think that perhaps the blood pressure target is lower than usual.The SSC guidelines recommend starting a vasopressor after fluid administration if hypotension has not been corrected or even during fluid infusion , but we The disadvantage of starting fluids and vasopressors at the beginning of resuscitation to achieve a target MAP of 65 mmHg early may “hide” an underlying fluid deficit, promoting further tissue hypoperfusion despite increasing the MAP. Such a strategy of early NE may hide coexisting low cardiac output (CO) values. The intravascular volume needs to be adequate to sustain venous return for increased vasomotor tone to increase MAP without inducing tissue hypoperfusion. However, excessive fluids during and after the resuscitative phase are well-known harmful situation ,16.The early combination of fluids and norepinephrine, most likely during the first hour, has potential advantages in the management of patients with septic shock of rapidly increasing mean systemic filling pressure more than fluids alone would, thereby achieving better CO in volume-responsive patients in the setting of a higher MAP; corrects hypotension and perfusion better than fluid or vasopressor alone; decreases the possibility of fluid overload; may improve tissue oxygenation, although this has not been substantiated; and leads to lower morbidity and mortality in the management of septic patients ,61 Figu.. Vasopressin is usually started when the dose of norepinephrine is in the range of 0.25–0.5 μg/kg/min. For adults with septic shock and inadequate MAP levels despite norepinephrine and vasopressin, we suggest adding epinephrine ” [The SSC guidelines 2021 mention this regarding norepinephrine use in settings where it is not available. “Epinephrine or dopamine can be used as an alternative, but we encourage efforts to improve the availability of norepinephrine. Special attention should be given to patients at risk for arrhythmias when using dopamine and epinephrine. For adults with septic shock on norepinephrine with inadequate MAP levels, we suggest adding vasopressin instead of escalating the dose of norepinephrine idence)” .However, when norepinephrine is available, the use of epinephrine or dopamine in patients with septic shock is reserved for those patients who, in addition to low blood pressure, have low cardiac output not associated with hypovolemia, but altered cardiac performance.The effect of early vasopressin initiation on clinical outcomes in patients with septic shock remains uncertain. A meta-analysis of early initiation of vasopressin in patients with septic shock showed that its use was not associated with decreased short-term mortality, new-onset arrhythmias, shorter ICU length of stay, or length of hospitalization, but it did reduce the use of RRT . Gordon Although there is no conclusive evidence that the routine use of glucocorticoids in patients with septic shock improves survival, a recent meta-analysis showed that it can help shorten the reversal time of septic shock. Hydrocortisone is the one glucocorticoid, that has showed the best results. There is still no consensus regarding the best time for administration, vasopressor dose, administration time, or whether the dose should be personalized . HoweverFor adults with septic shock, the SSC suggest starting vasopressors peripherally to restore MAP rather than delaying initiation until central venous access is secured ,68,69,70Many questions regarding the use of early vasopressors remain unanswered. First, it is not clear whether it is better to administer vasopressors first in a hypotensive septic patient followed by fluids, or whether fluids and vasopressors should be administered simultaneously. We prefer to give them simultaneously, but give the fluid in bolus form and then assess its effects 15 min later. Second, it is unclear which vasopressors should be used. Norepinephrine is the primary vasopressor, but vasopressin, dopamine, and angiotensin-2 are potent vasopressors with different vascular bed vasopressor profiles. This leads us to another two fields: the personalized use of vasopressors and broad-spectrum vasopressor therapy as part of the initial management of septic shock . PerhapsBased on current evidence, the very early use of norepinephrine and its combination with smaller amounts of IV fluids in fluid-responsive hypotensive septic shock patients seems to be a safe strategy with better management results compared to large-volume fluids before vasopressor initiation. Vasopressor therapy should be initiated as soon as possible in patients with septic shock.


IntroductionSevere uncontrolled asthma is challenging to manage and impacts lung function and symptoms. Biologic agents targeting inflammatory pathways have transformed asthma management. This retrospective chart review aimed to assess biologic therapy in severe uncontrolled asthma patients and evaluate outcomes.MethodsThe study analyzed medical records of 30 patients receiving biologic therapy for severe asthma at a tertiary care center in Peshawar, Pakistan, from December 2022 to Jun 2023. Ethical approval was obtained, and patient demographics, biologic agent usage, and clinical parameters were collected. Clinical outcomes were evaluated after six months, including forced expiratory volume in the first second (FEV1), eosinophil count, IgE levels, and exacerbation rates.ResultsAfter six months, biologic treatment significantly improved FEV1 (48.7% to 62.4%), reduced eosinophils (540 cells/μL to 290 cells/μL) and IgE levels (410 IU/mL to 280 IU/mL), and decreased exacerbations (4.6 to 1.9). Subgroup analysis based on age and sex showed consistent lung function improvements.ConclusionBiologic agents effectively targeted inflammatory pathways, improving asthma control in severe uncontrolled asthma patients. This study provides valuable insights into biologic therapy for severe asthma, offering new possibilities for patient outcomes. Larger studies are needed to validate findings and optimize personalized treatment strategies. Severe uncontrolled asthma is a complex and challenging condition characterized by persistent symptoms, frequent exacerbations, and poor lung function despite optimal standard therapy and advances in asthma management, leading to a significant burden on their quality of life and healthcare resources . The manBiologic agents, such as monoclonal antibodies, have shown promise in improving asthma control, reducing exacerbations, and enhancing lung function in select patient populations . These aThe efficacy of biologic agents has been demonstrated in clinical trials and real-world studies, highlighting their potential as a valuable addition to the asthma treatment armamentarium . HoweverIn this retrospective chart review, we aimed to assess the use of biologic agents in patients with severe uncontrolled asthma at a tertiary care center in Peshawar, Pakistan. By examining the demographic characteristics, baseline clinical parameters, and clinical outcomes of 30 patients who received biologic therapy for their asthma, we sought to gain insights into the effectiveness of these agents in this specific population. The primary outcomes of interest included changes in forced expiratory volume in the first second (FEV1), eosinophil levels, IgE levels, and exacerbation rates after six months of biologic therapy. The findings from this study contribute to the growing body of evidence on the use of biologic agents in severe uncontrolled asthma, with potential implications for treatment decision-making and patient care. Study design and participantsThis retrospective study involved a meticulous review of electronic medical records of patients with severe uncontrolled asthma who had received biologic therapy for at least six months. The study was conducted at Hayatabad Medical Complex, Peshawar, Pakistan, between December 2022 and June 2023. Ethical approval was obtained from the Institutional Review Board of Hayatabad Medical Complex, Peshawar, and all patient data were anonymized to maintain confidentiality.Patient selection criteriaInclusion CriteriaPatients were included in the study if they met the following criteria: age between 18 and 65 years, a confirmed diagnosis of severe uncontrolled asthma based on the Global Initiative for Asthma (GINA) guidelines, and a minimum of six months of continuous treatment with biologic therapy. Biologic therapies included anti-interleukin (IL)-5, anti-IL-4 receptor alpha, and anti-IL-13 monoclonal antibodies.Exclusion CriteriaPatients with incomplete medical records, overlapping treatments with other biologics, or a history of non-compliance were excluded from the analysis.Incomplete medical records: Patients with incomplete medical records lacking crucial information required for the study analysis, such as spirometry data, eosinophil counts, or IgE levels, were excluded to ensure data integrity and robustness.Overlapping treatments: Patients who had received multiple biologic therapies simultaneously or sequentially during the study period were excluded to eliminate potential confounding effects from overlapping treatment regimens.Non-compliance: Patients with a documented history of non-compliance with prescribed biologic therapy, evidenced by missed or irregular dosages, were excluded to ensure a homogeneous patient population with consistent treatment adherence.Non-severe asthma: Patients with mild-to-moderate asthma or those who did not meet the GINA criteria for severe uncontrolled asthma were excluded, as the study focused specifically on this subset of patients requiring biologic therapy.Age outliers: Patients below 18 years or above 65 years of age were excluded to maintain consistency within the defined age range and enhance the relevance of the study results to the target population.Data collectionElectronic medical records were meticulously screened to identify eligible patients meeting the inclusion criteria while ensuring the exclusion of patients who did not meet the defined criteria. The data extraction process was performed by trained researchers using a standardized data collection form. Patient demographics, including age and sex, were recorded. Additionally, clinical characteristics such as smoking history, duration of asthma, and concurrent medications were noted.Assessment of biologic therapyThe dosages and administration frequencies of biologic therapies, including IL-5, anti-IL-4 receptor alpha, and anti-IL-13 monoclonal antibodies, were documented for each patient. Clinical outcomes were evaluated before and after six months of biologic therapy for each patient, including FEV1, BMI, eosinophil count, IgE levels, and exacerbation rates.Statistical analysisDescriptive statistics were used to summarize the demographic and clinical characteristics of the patient cohort. Continuous variables were expressed as mean ± standard deviation or median (interquartile range (IQR)) depending on their distribution. Categorical variables were presented as frequencies and percentages. Paired t-tests or Wilcoxon signed-rank tests were used to compare pre- and post-treatment values for continuous variables, as appropriate. Statistical significance was set at p<0.05.The study included a total of 30 patients, comprising 17 males (56.7%) and 13 females (43.3%). The mean age of the cohort was 48.2 years, with a range of 32-67 years. The average BMI of the patients was 28.9, ranging from 22.1 to 35.4    Table .The average number of exacerbations per patient prior to initiating biologic therapy was 4.6, ranging from 3 to 7. After six months of biologic treatment, the average number of exacerbations decreased to 1.9, with a range of 0-4. This reduction in exacerbation rates was statistically significant (p < 0.001).Subgroup analysis based on age revealed that patients aged 40 years or younger (n=12) experienced a mean FEV1 improvement of 16.5% (p < 0.001), while patients older than 40 years (n=18) had a mean FEV1 improvement of 13.8% (p < 0.001) after six months of biologic therapy. Similarly, when stratified by sex, males (n=17) showed a mean FEV1 increase of 14.6% (p < 0.001), while females (n=13) demonstrated a mean FEV1 improvement of 15.3% (p < 0.001) after six months of biologic treatment.The findings of this retrospective chart review provide valuable insights into the use of biologic agents in the management of severe uncontrolled asthma. Our study demonstrated significant improvements in lung function, eosinophil levels, IgE levels, and exacerbation rates after six months of biologic therapy.Consistent with previous research , our stuThe reduction in eosinophil levels post-biologic therapy is consistent with the mechanism of action of these agents, which specifically target eosinophilic inflammation . The aveSimilarly, the average post-biologic IgE level decreased by 183 IU/mL, indicating successful IgE-targeted therapy in specific cases. Elevated IgE levels are often observed in patients with allergic asthma, and reducing IgE can help control allergic inflammation and prevent exacerbations ,15. The The reduction in exacerbation rates (mean decrease of 2) further supports the positive impact of biologic agents on asthma control and the potential to prevent exacerbations in this high-risk population. Exacerbation reduction is a critical outcome in severe uncontrolled asthma, as frequent exacerbations are associated with increased healthcare utilization, decreased lung function, and reduced quality of life. By reducing exacerbation rates, biologic agents can alleviate the burden of severe uncontrolled asthma and improve long-term outcomes for patients .These findings should be interpreted in the context of certain limitations, including the retrospective nature of the study and the relatively small sample size. Retrospective studies are subject to inherent biases, and larger prospective studies are needed to validate our findings. Further research with larger cohorts and longer follow-up periods is warranted to confirm these observations and provide more comprehensive insights into the long-term effectiveness and safety of biologic agents in severe uncontrolled asthma.This retrospective chart review provides evidence supporting the effectiveness of biologic agents in improving outcomes for patients with severe uncontrolled asthma. The findings demonstrate significant improvement in lung function, reduction in eosinophil levels, decrease in IgE levels, and a decrease in exacerbation rates after six months of biologic therapy. These results suggest that biologic agents play a crucial role in managing severe uncontrolled asthma by targeting specific inflammatory pathways and providing personalized care. Subgroup analysis based on age and sex showed consistent improvements in lung function, highlighting the potential benefits across different patient populations.However, it is important to acknowledge the limitations of this study, including its retrospective design and small sample size. Larger prospective studies with longer follow-up periods are needed to validate these findings and provide more comprehensive insights into the long-term effectiveness and safety of biologic agents in severe uncontrolled asthma. Overall, biologic therapies offer a promising treatment option for improving asthma control and reducing the burden of severe uncontrolled asthma on patients' lives.


Hypertension exhibits sex-related differences in its causes, symptoms, and complications. In this study, we aimed to confirm the efficacy of hypertension intervention by applying a patient-centered approach based on sex differences. We enrolled 95 hypertensive patients in this prospective quasi-experimental pretest–posttest study. The patient-centered lifestyle intervention included penalized nutrition and exercise education in 30-min one-on-one sessions. Before the intervention, we conducted a pretest to evaluate physical examination, behavioral status, quality of life (QoL), blood pressure (BP) measurements, and routine blood tests. The same evaluations were conducted again in a posttest after 3 months. After 3 months of patient-centered intervention, all patients showed a decrease in systolic BP by 2.87 mmHg and diastolic BP by 1.04 mmHg. However, there was no significant difference in BP between men and women after the 3-month follow-up. There were differences in lipid profiles based on sex, with total cholesterol and low-density lipoprotein cholesterol levels decreasing in men and increasing in women. Behavioral and QoL scores improved after the intervention; however, there was no significant difference based on sex. A patient-centered lifestyle intervention for hypertensive patients can effectively lower BP, and sex-specific risk factors affecting its efficacy have been identified. According to the fact sheet released by the Korean Society of Hypertension in 2021, hypertension is gradually increasing among adults aged 30 years and older; 31.1% of men and 22.8% of women were found to have hypertension2. It has been revealed that sex-specific etiologies, signs, and risk factors for cardiovascular complications are associated with hypertension; specifically, awareness, treatment, and adherence to hypertension management differ between men and women3. According to the fact sheet released by the Korean Society of Hypertension, the proportion of patients with controlled hypertension was < 48%. The hypertension control rate for women was higher than that for men (49% vs. 47%) before the age of 60. After the age of 60, the hypertension control rate for men was higher than that for women (66% vs. 51%), indicating a clear sex difference2. However, despite the sex differences in the prevalence and control rate of hypertension, previous studies have shown conflicting results regarding risk factors, cardiovascular complications, treatment, and interventions for hypertension based on sex; thus, the differences in hypertension management by sex have not been established5. Furthermore, only a few studies have investigated the factors that influence the treatment and control of hypertension following nursing interventions based on sex.Hypertension is a common chronic disease and a significant risk factor that increases the risk of severe complications, such as cardiovascular disease and stroke8. Lifestyle modification through nursing interventions integrates patient-centered care by considering individual preferences, needs, and values9. It emphasizes collaboration between patients, caregivers, and healthcare providers, and encourages patient engagement in treatment planning and lifestyle changes10. Specifically, interventions focused on healthy eating habits and exercise can be considered the most cost-effective methods for patients with hypertension11. Considering that patients with hypertension were less likely to practice healthy lifestyles12, the need for interventions that specifically focus on diet and exercise is strongly emphasized. Providing patient-centered interventions that reflect the individual patient’s lifestyle and characteristics using nutrition and exercise can enhance the relationship between patients and nurses, share information and knowledge, and increase the performance of physical intervention activities14. In patient-centered nursing intervention studies targeting hypertensive patients, there have been results where the effectiveness of BP reduction was reported by applying patient-centered intervention programs17. Such programs are customized, considering individual physical, emotional, and social factors, and help promote patient participation and cooperation, leading to active intervention.The importance of lifestyle modifications in treating hypertension has been continuously emphasized in domestic and international guidelines, in addition to the pharmacological treatment of hypertensive patients. Previous studies have reported positive changes in physical, behavioral , and psychological , self-efficacy) aspects, and the effects on blood pressure (BP) control, through lifestyle modification using nursing interventionsStudies that focus on sex differences in hypertension are limited, and in particular, no study has applied patient-centered interventions to hypertensive patients to confirm the sex-specific effects. In this study, we aimed to apply a patient-centered lifestyle improvement intervention (PLI) that includes education on nutrition and exercise to manage BP in hypertensive patients and evaluate its effects on physical and behavioral changes and quality of life quality of life. We equally aimed to analyze whether there were any differences based on sex.Table p − 3.64 ± 20.31 mmHg vs. − 1.83 ± 14.83 mmHg, p = 0.633; DBP − 1.95 ± 13.97 mmHg vs. 0.20 ± 10.86 mmHg, p = 0.420).Figure p = 0.018) (Table p = 0.007)  Table C, which 7) Table D,E.Tablep = 0.501).Among the 95 patients, 37 (38.9%) responded to patient-centered interventions Table . A changp = 0.012) after adjustment for all of the possible confounding factors using regression analysis. In men, an increased creatinine level of 1 mg/dL or more showed an independent association with a 5.21-fold increased hazard . In women, living alone and receiving calcium channel blockers (CCB) tended to be associated with BP non-response in univariate analysis. After adjustment for all possible confounding factors, living alone was independently associated with an 8.61-fold increased hazard for BP non-response to patients centered intervention .According to the univariate analysis by sex Table , old agep = 0.147), diet behavior (p = 0.173), or exercise behavior (p = 0.699) between men and women in terms of their behavioral status (Supplementary Table p = 0.005).No significant differences were observed in the baseline total behavior score (p = 0.014). However, there were no significant differences between men and women in the 3-month exercise and medication behaviors scores. In addition, although behavioral scores increased after the intervention, there were no significant differences in behavioral status scores between men and women after 3 months (p = 0.923). When examined in each area, there were no significant differences in the 3-month score changes for diet behavior (p = 0.834), exercise behavior (p = 0.470), and medication behavior (p = 0.069) between men and women.After 3 months, the behavioral status scores increased after intervention by 24.98 ± 4.16 for men and 19.38 ± 3.73 for women. In each area, men scored 7.87 ± 1.99 in diet behavior, and women scored significantly higher at 8.78 ± 1.31 (p = 0.666) after the intervention.The baseline QoL scores did not differ significantly between men and women. The QoL scores equally increased after the intervention; however, there were no significant differences between the sexes after 3 months. No significant differences were observed in the QoL scores between men and women  were required to test whether there was a difference of 5 mmHg in SBP between men and women after 3 months of patient-centered education with a power of 80% and a significance level of 5%. Considering a dropout rate of 10%, the total number of participants was 140 (70 women and 70 men). After excluding 20 patients who refused to participate, 16 who dropped out during the study, and nine who did not complete the survey, these data of participants were excluded from the final analysis to maintain data integrity. Therefore, 95 patients, including 55 men and 40 women, were analyzed finally  patients aged 19 years or older. (2) patients who had been diagnosed with hypertension and were receiving antihypertensive medication or patients who had newly diagnosed hypertension and were receiving antihypertensive medication. Patients who met any of the following criteria were excluded from the study: (1) those diagnosed with malignant tumors, (2) those receiving dialysis due to end-stage renal failure. According to a previous study, BP significantly decreased by 3–5 mmHg after lifestyle improvement intervention in patients with hypertensionThe study protocol complied with the Declaration of Helsinki and was reviewed and approved by the Institutional Review Board of Hanyang University Guri Hospital (No. GURI 2021-06-027). All patients provided written informed consent before participating in the study.The hypothesis of this study asserts that PLI will bring about significant improvements in blood pressure control among hypertensive patients. Specifically, the study aims to identify the differences in systolic and diastolic responses, physical and behavioral changes, and quality of life between male and female participants over a 3-month period of patient-centered education.2), medical history, including diabetes, hyperlipidemia, coronary artery disease, and heart failure, and social history, including smoking status, alcohol consumption, and medication use were among the clinical features we obtained. Using the UA-767 device from A&D Co., Ltd., Tokyo, Japan, which meets the standards set by the European Hypertension Society, we gauged office BP across all facilities. After a 5-min relaxation period for the patient, we took two BP readings a minute apart and determined the office BP as the average of these two measurements26. Blood tests included white blood cell count, hemoglobin, sodium, potassium, blood urea nitrogen (BUN), creatinine, aspartate aminotransferase, alanine aminotransferase, glucose, C-reactive protein, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol.We conducted a medical history and physical examination, including BP measurements and routine blood tests, on patients with hypertension after the provided consent. Age, sex, height, weight, BMI , exercise management (two items), and medication adherence (two items), comprising six questions. Each item is rated on a 6-point Likert scale, and detailed information on each item is provided in Supplementary Table 27. It was developed by the World Health Organization and comprised five positive statements: “I have felt cheerful and in good spirits,” “I have felt calm and relaxed,” “I have felt active and vigorous,” “I woke up feeling fresh and rested,” and “My daily life has been filled with things that interest me.” Respondents were asked to rate their experience with these statements over the past 2 weeks on a 6-point Likert scale ranging from 0 (not present) to 5 (constantly present). The score was transformed from 0 (worst possible well-being) to 100 (best possible well-being). Scores below 50 indicate poor emotional well-being, and 28 or below indicate depression28.The WHO-5 Well-Being Index, a one-dimensional quality-of-life instrument, was used29. PLI consisted of nutrition and exercise education for hypertensive patients and was conducted through a 30-min one-on-one in-person education based on a booklet developed by the researchers. First, education was provided on dietary management and eating habits that are helpful for hypertensive patients using a booklet. A hypertension management diet was planned to focus on the patient's preferred diet. For example, for patients who prefer salty flavors, soy sauce is recommended instead of salt when cooking, and flavoring vegetables and spices, such as vinegar, lemon, walnuts, peanuts, ginger, garlic, and green onions, have been suggested as alternatives to salty flavors. For those who enjoy eating carbohydrates, a plan was made to switch to buckwheat, gluten-free bread, or mixed-grain rice. A personalized diet plan was designed for patients who preferred fish to meat, teaching them how to make low-salt fish dishes.PLI was developed by a nurse researcher based on patient-centered intervention, which concentrates on the patient’s unique circumstances and preferencesNext, we educated the patients about exercise management, and together, we created an exercise plan based on their favorite activities. For patients who enjoyed walking, we planned to walk briskly or jump rope for 30 min thrice weekly. Additionally, we created exercise plans that included stretching and aerobic exercises for swimming, cycling, badminton, and golf. We encouraged the patients to record their daily exercise activities at the back of the booklet to motivate them to exercise independently.Figure BP responders to the patient-centered intervention were defined as those with differences of 10 mmHg or more than 10 mmHg for SBP or differences of 10 mmHg or > 10 mmHg for DBP. BP non-responders had differences of < 10 mmHg for SBP or < 10 mmHg for DBP.t-test was used to compare normally distributed continuous variables, Pearson’s chi-squared test was used to compare categorical variables, and the Mann–Whitney U test was used to compare non-normally distributed continuous variables. The Wilcoxon signed-rank test was used to compare the variables measured at baseline and 3 months later. Furthermore, univariate and multivariate regression analyses were performed to assess the predictors of non-response to patient-centered interventions after adjustment for individual risk factors. Variables with predictive significance (p < 0.1) for non-response to patients centered intervention in the univariate analysis were included in the regression analysis. A p-value < 0.05 was considered statistically significant. All analyses were performed using the SPSS software .All categorical data are presented as frequencies and percentages, and continuous variables are expressed as means and standard deviations. For continuous variables, the Shapiro–Wilk test was used to confirm the normal distribution of each dataset. The Student’s Supplementary Information.