Search Results (356)

Background: Static cold storage is the standard method of kidney preservation following donation after circulatory death (DCD). A previous study on rodent models demonstrated the efficacy of storing DCD kidneys at 22 °C in an extracellular-type solution (ETK). We evaluated the efficacy of storing warm-ischemic kidneys at 22 °C in MHC-inbred miniature swine. Methods: After 2 h warm ischemia, the kidneys were preserved in ETK for one hour at either 4 °C or 22 °C and then subjected to ex vivo normothermic machine perfusion (NMP) for 2 h (n = 3 in each group). The same warm-ischemic kidneys, preserved in ETK (n = 3 in each group) or intracellular-type solution (UW; n = 2 in each group) at either 4 °C or 22 °C, were transplanted into MHC-matched recipients. Results: Compared with kidneys preserved at 4 °C, those preserved at 22 °C showed significantly better physiological and metabolic indices during ex vivo NMP. Furthermore, renal function was significantly higher in transplanted kidneys, and graft biopsies on postoperative day 4 showed more localized necrosis in the renal tubules when kidneys were stored at 22 °C. In contrast, recipient animals with kidneys stored in UW solution did not survive for more than 7 days. Conclusions: Two-hour warm-ischemic kidneys from miniature swine showed improved preservation at 22 °C than at 4 °C when an extracellular-type solution was used. Full article

Background: The perfusion of viscera, kidney, and spinal cord represents one of the main concerns during open repair (OR) of Thoraco-Abdominal Aortic Aneurisms (TAAAs). Passive shunting (PS) has been historically used for intraoperative distal aortic perfusion but has been progressively replaced almost entirely by partial left-sided heart or total cardiopulmonary bypass with extra-corporeal circulation (ECC). Despite several advantages of these methods, PS still has potential in mitigating some drawbacks of long extracorporeal circuits connected with centrifugal or roller pumps, such as the need for cardiac and great vessels cannulation, priming and large intravascular fluid volume shifts, high heparin dose, immunosuppressive effects, and systemic inflammatory response syndrome. Methods: This study prospectively analyzed data of a cohort of patients who underwent TAAA OR using a PS in a single institution. Outcomes of interest were mortality, rate of mesenteric, renal and spinal cord ischemia, cardiac complications, and intraoperative hemodynamic stability achieved in this setting. Our institutional bundle and a comprehensive literature review about the different configurations and applicability of PS for TAAA OR is also reported. The search was performed based on three databases (PubMed, EMBASE, and Cochrane Library) by two independent reviewers (LS and AA) from inception to 31 December 2023, and the reported clinical results (visceral, renal, and spinal cord complications and mortality) using PS during TAAAs OR were analyzed. Results: Between March 2021 and December 2023, 51 TAAA repairs were performed and eleven patients (n = 8, 73% male; mean age 67 years, range 63–79) were operated using a PS for a total of one (9%) type I, one (9%) type II, two (18%) type III, five (45%) type IV, and two (18%) type V TAAA. In our early experience, PS was indicated for limited staff resources during the COVID-19 pandemic to treat five non-deferable cases. The sixth and seventh patients were selected for PS as they already had a functioning axillo-bifemoral bypass that was used for this purpose. For the most recent cases, PS was chosen as the primary perfusion method according to a score based on clinical and anatomical factors with ECC as a bailout strategy. Selective renal perfusion with cold (4 °C) Custodiol solution was the method of choice for renal protection in all cases while antegrade perfusion of the coeliac trunk and the superior mesenteric artery was assured by PS through a loop graft (8–10mm) proximally anastomosed to the axillary artery (10 patients, 90.9%) or the descending thoracic aorta (one patient, 9%) and distally anastomosed to the infrarenal aorta (3), common iliac (3), or femoral vessels (5). In-hospital mortality was 9% as one patient died on the 10th postoperative day from mesenteric ischemia following hemodynamic instability; permanent spinal cord ischemia rate was 0% and the rate of AKI stage 3 was 9% (one patient). Bailout shifting to ECC was never required. No cardiac complications, nor a significant increase in serum CK-MB were reported in any patient. No prolonged severe intraoperative hypotension episodes (Mean Arterial Pressure < 50 mmHg) were assessed using the Software Acumen Analytics (Edwards LifeSciences, Irvine CA, USA). No peri-operative coagulopathy nor major bleeding was reported. Conclusions: Our experience showed satisfactory outcomes with the use of PS in specifically selected cases. Current data indicate that PS may represent an alternative to ECC techniques during TAAAs OR in high volume centers where assisted extracorporeal circulation could eventually be applied as a bailout strategy. However, due to the small sample size of this and previously published series, more data are needed to clearly define the potential role of such approach during TAAA OR. Full article

Background: Regional cerebral blood flow (rCBF) is a putative biomarker for neuropsychiatric disorders, including major depressive disorder (MDD). Methods: Here, we show that rCBF can be predicted from resting-state functional MRI (rsfMRI) at the voxel level while correcting for partial volume averaging (PVA) artifacts. Cortical patterns of MDD-related CBF differences decoded from rsfMRI using a PVA-corrected approach showed excellent agreement with CBF measured using single-photon emission computed tomography (SPECT) and arterial spin labeling (ASL). A support vector machine algorithm was trained to decode cortical voxel-wise CBF from temporal and power-spectral features of voxel-level rsfMRI time series while accounting for PVA. Three datasets, Amish Connectome Project (N = 300; 179 M/121 F, both rsfMRI and ASL data), UK Biobank (N = 8396; 3097 M/5319 F, rsfMRI data), and Amen Clinics Inc. datasets (N = 372: N = 183 M/189 F, SPECT data), were used. Results: PVA-corrected CBF values predicted from rsfMRI showed significant correlation with the whole-brain (r = 0.54, p = 2 × 10⁻⁵) and 31 out of 34 regional (r = 0.33 to 0.59, p < 1.1 × 10⁻³) rCBF measures from 3D ASL. PVA-corrected rCBF values showed significant regional deficits in the UKBB MDD group (Cohen’s d = −0.30 to −0.56, p < 10⁻²⁸), with the strongest effect sizes observed in the frontal and cingulate areas. The regional deficit pattern of MDD-related hypoperfusion showed excellent agreement with CBF deficits observed in the SPECT data (r = 0.74, p = 4.9 × 10⁻⁷). Consistent with previous findings, this new method suggests that perfusion signals can be predicted using voxel-wise rsfMRI signals. Conclusions: CBF values computed from widely available rsfMRI can be used to study the impact of neuropsychiatric disorders such as MDD on cerebral neurophysiology. Full article

Neurologic complications remain a major cause of morbidity in patients undergoing surgical repair of acute type A aortic dissection (ATAAD). Near-infrared spectroscopy (NIRS) is used for continuous, noninvasive monitoring of cerebral oxygenation during cardiopulmonary bypass; however, its utility in predicting perioperative stroke remains inadequately defined. A retrospective cohort study was conducted in 175 patients who underwent ATAAD repair between 2015 and 2023. Patients were stratified by the occurrence of perioperative stroke (n = 47, 26.9%). Intraoperative NIRS data, including cerebral regional oxygen saturation (crSO₂) values at key procedural timepoints and signal variability with band power and crest factor, were analyzed in conjunction with demographic, anatomic, and postoperative variables. Patients with stroke exhibited significantly lower minimum NIRS values during deep hypothermic circulatory arrest (DHCA) (left: 46.7 (15.7–69.4) vs. 52.2 (22.0–81.6); right: 47.0 (23.3–78.5) vs. 56.3 (20.2–85.0); p = 0.03 and p < 0.01). Within the stroke group, NIRS signal variability was significantly greater (crest factor and standard deviation; p < 0.05) and showed blunted recovery post-DHCA. crSO₂ values below 50% were more frequent in the stroke group (p = 0.04). Right common carotid artery dissection was more prevalent in the stroke group (40% vs. 23%, p = 0.04). ICU length of stay was significantly increased in patients with stroke. Cerebral desaturation and NIRS signal instability during DHCA are significantly associated with perioperative stroke in ATAAD repair. These findings support the prognostic value of intraoperative cerebral oximetry in detecting critical ischemic thresholds and identifying at-risk perfusion patterns. Full article

This study aimed to evaluate the effect of combined supplementation of MSG with glycerin, a glucogenic precursor, on ovarian function in sheep. Twenty-four ewes had estrus and follicular waves synchronized using three prostaglandin injections at 7-day intervals. The ewes were grouped: baseline TMR diet (Control; n = 8); glutamate diet (MSG; n = 8), receiving MSG (1 g/kg of body weight/day) for 16 days; and MSG plus glycerin (MSGLY; n = 8), which received MSG plus 150 mL of glycerin during the eight days prior to ovulation induction. MSG showed lower dry matter intake, while the MSGLY group showed increased heart and respiratory rates and skin temperature. Rectal temperature was higher in MSG and MSGLY. MSGLY also showed reduced triglyceride and urea levels. MSG and MSGLY exhibited decreased cholesterol and creatinine. MSGLY exhibited a higher number of large follicles and greater intraovarian blood perfusion after ovulation induction and larger corpus luteum perfusion. Ovulation rate increased by 64% in the supplemented groups vs. control. MSG supplementation led to greater SCL1A1, GRIA1, and GLUD1 genes expression. Thus, the combined supplementation of MSG and glycerin effectively enhances ovarian function in sheep, representing a viable nutritional strategy to improve reproductive outcomes. Full article

Background/Objectives: Invasive coronary angiography (ICA) is the gold standard for the diagnosis of coronary artery disease (CAD), with various non-invasive imaging modalities also available. Machine learning (ML) methods are increasingly applied to overcome the limitations of diagnostic imaging by improving accuracy and observer independent performance. Methods: This meta-analysis (PRISMA method) summarizes the evidence for ML-based analyses of coronary imaging data from ICA, coronary computed tomography angiography (CT), and nuclear stress perfusion imaging (SPECT) to predict clinical outcomes and performance for precise diagnosis. We searched for studies from Jan 2012–March 2023. Study-reported c index values and 95% confidence intervals were used. Subgroup analyses separated models by outcome. Combined effect sizes using a random-effects model, test for heterogeneity, and Egger’s test to assess publication bias were considered. Results: In total, 46 studies were included (total subjects = 192,561; events = 31,353), of which 27 had sufficient data. Imaging modalities used were CT (n = 34), ICA (n = 7) and SPECT (n = 5). The most frequent study outcome was detection of stenosis (n = 11). Classic deep neural networks (n = 12) and convolutional neural networks (n = 7) were the most used ML models. Studies aiming to diagnose CAD performed best (0.85; 95% CI: 82, 89); models aiming to predict clinical outcomes performed slightly lower (0.81; 95% CI: 78, 84). The combined c-index was 0.84 (95% CI: 0.81–0.86). Test of heterogeneity showed a high variation among studies (I² = 97.2%). Egger’s test did not indicate publication bias (p = 0.485). Conclusions: The application of ML methods to diagnose CAD and predict clinical outcomes appears promising, although there is lack of standardization across studies. Full article

Diabetes-related pathophysiological processes contribute to endothelial dysfunction, arterial stiffening (AS), hypertension, vascular remodeling, and impaired myocardial perfusion. This study aimed to assess the relationship between arterial wall parameters and sST2 concentration as potential risk factors in type 2 diabetes (T2DM) and investigate sex-related differences. To achieve this, we enrolled 100 patients with suspected or exacerbated coronary artery disease (CAD) and divided them into a T2DM group (n = 58) and a control group (n = 42). Endothelial reactivity (lnRHI), ABI, sST2 levels, and carotid–femoral (cfPWV) and carotid–radial pulse wave velocity (crPWV) were assessed. Coronary angiography was performed in every patient, and epicardial flow and myocardial perfusion were evaluated using QuBE and FLASH. Our results showed that the coronary angiographic findings were similar in both groups. However, T2DM patients had a significantly higher central AS (cfPWV 10.8 ± 2 vs. 9.9 ± 2.7 m/s, p < 0.05) and vascular age (70.0 ± 12.3 vs. 61.3 ± 15.4 years, p < 0.05), while peripheral AS, RHI, and ABI showed no differences. CfPWV correlated with renal function; higher HbA1c and sST2 levels were additionally associated with advanced vascular age. Notably, central AS and vascular age were higher in men with T2DM but not in women. These findings indicate that T2DM patients exhibit increased central AS and vascular aging, influenced by sST2 levels, suggesting fibrosis as a target for precision medicine in T2DM. Full article

Fluid resuscitation after thermal injury is paramount to avoid burn shock and restore organ perfusion. Both over- and under-resuscitation can lead to unintended consequences affecting patient outcomes. While many studies have examined systemic effects, limited data exist on how fluid resuscitation impacts burn wound progression in the acute period. Furthermore, the mechanisms underlying burn wound progression remain not fully understood. This study used a swine model to investigate how varying resuscitation levels affect peri-burn wound dynamics. Twenty-seven female Yorkshire pigs were anesthetized, subjected to 40% total body surface area burn and 15% hemorrhage, then randomized (n = 9) to receive decision-support-driven (adequate, 2–4 mL/kg/%TBSA), fluid-withholding (under, <1 mL/kg/%TBSA), or high-constant-rate (over, >>4 mL/kg/%TBSA) resuscitation. Pigs were monitored for 24 h in an intensive care setting prior to necropsy. Laser Doppler Imaging (LDI) was conducted pre-burn and at 2, 6, 12, and 24 h post burn to assess perfusion. Biopsies were taken from burn, peri-burn (within 2 cm), and normal skin. RNA was isolated at 24 h for the qRT-PCR analysis of IL-6, CXCL8, and IFN-γ. At hour 2, LDI revealed increased peri-burn perfusion in over-resuscitated animals vs. under-resuscitated animals (p = 0.0499). At hour 24, IL-6 (p = 0.0220) and IFN-γ (p = 0.0253) were elevated in over-resuscitated peri-burn skin. CXCL8 showed no significant change. TUNEL staining revealed increased apoptosis in over- and under-resuscitated peri-burn skin. Differences in perfusion and cytokine expression based on resuscitation strategy suggest that fluid levels may influence burn wound progression. Full article

Background/Objectives: The Pleth Variability Index (PVI) is a non-invasive parameter used to guide fluid management by reflecting respiratory-induced variations in the plethysmographic waveform. While PVI’s reliability in various positions has been studied, data on its behavior in geriatric patients undergoing transurethral resection of the prostate (TUR-P) in the lithotomy position remain limited. This study aimed to evaluate the effect of the lithotomy position on PVI in geriatric versus non-geriatric patients under spinal anesthesia. Methods: This prospective observational study included 90 patients undergoing elective TUR-P in the lithotomy position under spinal anesthesia. Patients were divided into geriatric (≥65 years, n = 48) and non-geriatric (<65 years, n = 42) groups. PVI and Perfusion Index (PI) were recorded at baseline, in the supine position, and in the lithotomy position. Fluid and vasopressor requirements, along with hemodynamic parameters, were also analyzed. Results: PVI values at the 5th minute in the lithotomy position were significantly higher in the geriatric group compared to the non-geriatric group (p = 0.019). No significant differences were observed in PI values or intraoperative hypotension rates between the groups. Neurological comorbidities were more prevalent in the geriatric group (p = 0.025). Conclusions: PVI appears to be a more sensitive indicator of fluid responsiveness in elderly patients under spinal anesthesia in the lithotomy position. Its age-dependent variability suggests clinical utility in guiding fluid management in geriatric populations, while the stable hypotension rates support the effectiveness of PVI-guided goal-directed therapy. Full article

Background/Objectives: Ellagic acid (EA) is a polyphenol found in several fruits and vegetables, including pomegranate, nuts and berries. It exhibits significant health benefits, mainly cardio- and vaso-protective; indeed, EA protects the myocardium against infarction and inhibits cardiac fibrosis. These beneficial effects may be, at least in part, promoted by calcium release from and uptake by the sarcoplasmic reticulum, which are crucial events for cardiac relaxation and contraction. Regardless, the exact mechanism is currently unclear. Methods: A deeper investigation of the role of EA in cardiac contractility and the underlying mechanism has been carried out by using an ex vivo model of isolated and perfused rat heart. Results and Discussion: EA perfusion (100 nM–10 µM) did not influence the coronary flow (CF), suggesting the absence of a vasoactivity, but significantly increased contractility parameters (LVDP and dP/dt). Interestingly, a more marked effect of EA on LVDP and dP/dt values was observed when it was perfused in the presence of AngII. Cyclopiazonic acid (CA) and red ruthenium (RR), specific antagonists of SERCA and RyRs, respectively, were used to explore the contribution of EA when the intracellular calcium handling was altered. In the presence of CA, EA, perfused at increasing concentrations, showed a very modest positive inotropism (significant only at 1 µM). Instead, RR, which significantly compromised all functional parameters, completely masked the effects of EA; furthermore, a marked reduction in CF and a dramatic impact on the positive inotropism occurred. Conclusions: These results demonstrate the positive inotropism of EA on isolated and perfused hearts and suggest that the RyRs may be a main target through which EA plays its effects, since inhibition with RR almost completely blocks the positive inotropism. Full article

Background/Objectives: Despite extensive research, the underlying causes of amyotrophic lateral sclerosis (ALS) remain unclear. This umbrella review aims to synthesize a vast body of evidence from advanced magnetic resonance imaging (MRI) studies of ALS, encompassing a wide range of neuroimaging techniques and patient cohorts. Methods: Following the PRISMA guidelines, we conducted an extensive search of four databases (PubMed, Scopus, Web of Science, and Embase) for articles published until 3 December 2024. Data extraction and quality assessment were independently performed using the AMSTAR2 tool. Results: This review included 18 studies that incorporated data from over 29,000 ALS patients. Structural MRI consistently showed gray matter atrophy in the motor and extra-motor regions, with significant white matter (WM) atrophy in the corticospinal tract and corpus callosum. Magnetic resonance spectroscopy revealed metabolic disruptions, including reduced N-acetylaspartate and elevated choline levels. Functional MRI studies have demonstrated altered brain activation patterns and functional connectivity, reflecting compensatory mechanisms and neurodegeneration. fMRI also demonstrated disrupted motor network connectivity and alterations in the default mode network. Diffusion MRI highlighted microstructural changes, particularly reduced fractional anisotropy in the WM tracts. Susceptibility-weighted imaging and quantitative susceptibility mapping revealed iron accumulation in the motor cortex and non-motor regions. Perfusion MRI indicated hypoperfusion in regions associated with cognitive impairment. Conclusions: Multiparametric MRI consistently highlights widespread structural, functional, and metabolic changes in ALS, reflecting neurodegeneration and compensatory mechanisms. Full article

Background/Objectives: Challenges in normothermic machine perfusion (NMP) remain, particularly concerning the duration for which individual organs can be safely preserved. We hypothesize that optimal preservation can be achieved by perfusing organs together in a multivisceral block. Therefore, our aim was to establish a platform for ex situ multivisceral organ perfusion. Methods: Multivisceral grafts containing the liver, kidneys, pancreas, spleen, and intestine were obtained from Yorkshire pigs. Three generation (gen) set-ups were tested during the iterative design process, and minor changes were made throughout. Gen 1 (n = 4) used a custom-designed single perfusion circuit. Gen 2 (n = 3) employed a dual perfusion circuit. Gen 3 (n = 4) featured a single perfusion circuit with an optimized basin and reservoir. Grafts underwent NMP using an autologous blood-based perfusate, while hemostatic parameters and function were assessed. Results: Comparing Gen 1 versus Gen 3, the mean aortic flow improved (1.018 vs. 2.089 L), resistance decreased (0.224 vs. 0.038), urine output increased (51.90 vs. 271.3 mL), oxygen consumption rose (43.56 vs. 49.52 mL O₂/min), perfusate lactate levels dropped (10.44 vs. 3.10 mmol/L), and the pH became more physiological (7.27 vs. 7.30). Cellular injury trended lower in Gen 3. Histological evaluation demonstrated minimal differences in Gens 2 and 3. Conclusions: We demonstrate the feasibility of abdominal multivisceral NMP for up to 8 h. Adequate arterial flow, stable perfusate pH, and high oxygen consumption in setup 3 indicated organ viability. Multivisceral perfusion may serve as a plat-form for long-term NMP. Full article

Background: PP-007 (SANGUINATE^®, PEGylated carboxyhemoglobin, bovine) is under development to treat conditions of ischemia/hypoxia. Hemorrhagic/hypovolemic shock (H/HVS) becomes a life-threatening comorbidity due in part to hypotension and hypoxia. Blood transfusions are indicated, but supply and compatibility issues may limit subject access or when blood is not an option due to religious restriction or concern for clinical complications. PP-007 is universally compatible with an effective hydrodynamic radius and colloidal osmotic pressure facilitating perfusion without promoting extravasation. Methods: A review of previous clinical trials was performed and revealed an Open-Label Phase 1 safety study of acute severe anemia (hemoglobin ≤ 5 g/dL) in adult (≥18 y) patients unable to receive red blood cell transfusion (NCT02754999). Primary outcomes included safety events with secondary efficacy measures of organ function and survival at 1, 14, and 28 days. Additionally, a retrospective review of published, peer-reviewed case reports was performed, evaluating the administration of Sanguinate for Expanded Access in those patient populations where blood was not an option over the past 12 years. Results: A total of 103 subjects were enrolled in the Phase I safety study with significant co-morbidities that most commonly included hypertension (n = 43), acute and chronic kidney disease (n = 38), diabetes mellitus (n = 29), gastrointestinal bleeds (n = 18), and sickle cell disease (n = 13). Enrollment characteristics included decreased hemoglobin and severe anemia (mean baseline hemoglobin of 4.2 g/dL). Treatments included an average of three infusions [range 1–17]. Secondary efficacy measures were mean Hb levels, respiratory support, and vasopressor requirements, all demonstrating clinically relevant improvements. Fourteen additional cases were identified in the literature. Though one patient died due to pre-treatment conditions, all patients but one were discharged home in stable condition. Conclusion: Collectively, these observations are encouraging and provide support for the continued evaluation of PP-007 in advanced clinical trials in severe anemia including H/HVS. The review of published case reports underscored the potential of Sanguinate to reduce early mortality. Adverse effects included transient hypertension, lethargy, dizziness, and troponin elevation. These findings highlight the need for continued research and funding of blood alternatives to improve outcomes when standard blood transfusions are unavailable or contraindicated. Full article

Objectives: This study aimed to evaluate the impact of cannulation site preference—femoral versus axillary—on postoperative complications and in-hospital mortality in patients undergoing peripheral venoarterial extracorporeal membrane oxygenation (VA ECMO) due to cardiogenic shock. Methods: In this single-center, retrospective study, 85 patients who received peripheral VA ECMO support between January 2013 and July 2023 were analyzed. Patients were divided into two groups based on arterial cannulation site: femoral cannulation (FC, n = 47) and axillary cannulation (AC, n = 38). Preoperative, intraoperative, and postoperative variables were compared. Cannulation-related complications were categorized as vascular, neurological, or pulmonary. The primary endpoints were postoperative complications and in-hospital mortality. Results: There were no statistically significant differences between the FC and AC groups in terms of demographics, comorbidities, surgical procedures, or ECMO weaning times. Rates of vascular, neurological, and pulmonary complications were similar between groups. Mortality and postoperative dialysis rates did not differ significantly. The low rate of ischemic complications in the FC group may be explained by the use of distal perfusion catheters, which are considered the standard approach to prevent leg ischemia. Both cannulation techniques demonstrated comparable safety and efficacy profiles. Conclusions: Both femoral and axillary cannulation sites can be safely used for peripheral VA ECMO when selected based on individual patient conditions and institutional experience. Cannulation strategy should be tailored according to the urgency of the clinical situation, anatomical feasibility, and anticipated duration of support. Further prospective, randomized studies are required to establish the optimal cannulation approach. Full article

Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and concomitant interstitial lung disease (ILD) are particularly challenging to manage due to concerns about ventilation–perfusion mismatch with systemic vasodilators. In this case series, we evaluated the effects of selexipag in eight prostacyclin-naïve CTD-PAH patients with concomitant ILD. Clinical, functional, and laboratory data were collected at baseline and after 16 weeks of treatment. After 16 weeks of treatment, the mean six-minute walk distance increased by 101.75 m (p < 0.05), and the mean estimated right ventricular systolic pressure decreased significantly (p < 0.05). Mean N-terminal pro b-type natriuretic peptide levels declined by 63%, though this reduction did not reach statistical significance. Importantly, supplemental oxygen requirements trended downward (p < 0.05) and pulmonary function tests remained stable. Pulmonary vasodilators have long been unsuccessfully studied in PH-ILD patients until the INCREASE trial. While other systemic agents used in PAH have not shown as much success as inhaled treprostinil in treating PH-ILD, our case series highlights the potential role of selexipag in patients with concomitant CTD-PAH and ILD. Further investigation of selexipag in pure Group 3 PH-ILD patients is warranted. Full article