Efficacy and safety of a fourth dose of the COVID-19 vaccine in kidney transplant recipients: A systematic review and meta-analysis

BackgroundKidney transplant recipients (KTRs) who become infected with SARS-CoV-2 are at greater risk of serious illness and death than the general population. To date, the efficacy and safety of the fourth dose of the COVID-19 vaccine in KTRs have not been systematically discussed.MethodsThis systematic review and meta-analysis included articles from PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, and Wanfang Med Online published before May 15, 2022. Studies evaluating the efficacy and safety of a fourth dose of the COVID-19 vaccine in kidney transplant recipients were selected.ResultsNine studies were included in the meta-analysis, with a total of 727 KTRs. The overall pooled seropositivity rate after the fourth COVID-19 vaccine was 60% (95% CI, 49%–71%, I² = 87.83%, p > 0.01). The pooled proportion of KTRs seronegative after the third dose that transitioned to seropositivity after the fourth dose was 30% (95% CI, 15%–48%, I² = 94.98%, p < 0.01).ConclusionsThe fourth dose of the COVID-19 vaccine was well tolerated in KTRs with no serious adverse effects. Some KTRs showed a reduced response even after receiving the fourth vaccine dose. Overall, the fourth vaccine dose effectively improved seropositivity in KTRs, as recommended by the World Health Organization for the general population.     

Humoral Response After SARS-CoV-2 Vaccination in Kidney Transplant Recipients: Role of Immunosuppression Therapy

BackgroundMessenger RNA vaccination against COVID-19 has been shown to produce an immune response with sufficient efficacy to prevent natural infection in immunocompetent recipients. However, the response in kidney transplant recipients is low. We aimed to evaluate the specific humoral response to SARS-CoV-2 after vaccination in a population of kidney transplant recipients and assess the main factors associated with a lack of response.MethodsWe undertook a prospective study of 105 kidney transplant recipients and 11 recipients of a combined kidney-pancreas transplant. We analyzed immunoglobulin G and immunoglobulin M antibodies after the patients received their second and third doses of the messenger RNA 1273 (Moderna) or BNT162b1 (BionTECH-Pfizer) vaccinations between February and November 2021.ResultsMean (SD) age of the 116 patients was 50 (16) years, and 65% were men. They had their transplants for 40 months (IQR, 15-123 months), with 14% undergoing retransplant and 11% sensitized. The maintenance immunosuppression regimen was steroids + tacrolimus + mycophenolate (MMF) in 68% of the patients and any combination with mammalian target of rapamycin inhibitor (mTORi) in 28%. A humoral response developed in 40% of the patients 6 weeks (IQR, 4-10 weeks) after receiving the second dose of the vaccine. Of the 67 patients with no response to the second dose, 51 had an analysis of the humoral response after the third dose, which was positive in 16 (31%). A total of 80% received the Moderna vaccine and 20% the BionTECH-Pfizer. No patient experienced major adverse effects after the vaccination.Factors associated with a lack of humoral response to the vaccine were recipient age (odds ratio [OR], 1.02; 95% CI, 1.001-1.05; P = .04), diabetes (OR, 2.8; 95% CI, 1.2-6.9; P = .02), and treatment with MMF (OR, 2.6; 95% CI, 1.08-6.8; P = .03). Treatment with mTORi was associated with a better response to vaccination (OR, 0.3; 95% CI, 0.1-0.9; P = .04).ConclusionsThe humoral response to the COVID-19 vaccine in kidney transplant recipients is poor. Factors related with this lack of immunity are recipient age and diabetes, plus MMF therapy, whereas mTORi therapy was associated with a better response to vaccination.     

Predictor factor for worse outcomes in kidney transplant recipients infected with coronavirus disease 2019: A systematic review and meta-analysis

IntroductionThe pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a massive impact on the health sector, especially in patients with pre-existing comorbidities. This study aims to define the predictor factors for worse outcomes in kidney transplant patients infected with SARS-CoV-2 and affected by coronavirus disease 2019 (COVID-19). We have analyzed in these patients their prior medical history, their clinical symptoms, and their laboratory results.MethodWe assessed outcomes of kidney transplant patients with confirmed COVID-19 until July 2021 from PubMed, Medline, Science Direct, Cochrane databases, EMBASE, Scopus, and EBSCO. We performed meta-analyses of nine published studies to estimate predictor factors. The analysis was analyzed by the Newcastle-Ottawa Scale (NOS) and then using the Review Manager 5.4 software.ResultOur analysis demonstrated that the most significant risk factors for the worse COVID-19 outcomes for kidney transplant patients included: age of 60 and older [MD 9.31(95% CI, 6.31–12.30), p < 0.0001, I2 = 76%], diabetic nephropathy [OR 2.13 (95% CI, 1.49–3.04), p < 0.0001, I2 = 76%], dyspnea [OR 4.53, (95% CI, 2.22–9.22), p < 0.0001, I2 = 76%], acute kidney injury (AKI) [OR 4.53 (95% CI, 1.10–5.21), p = 0.03, I2 = 58%], and some laboratory markers. Many patients had two or multiple risk factors in combination.ConclusionAge and several comorbidities were the most significant factors for COVID-19 outcomes for kidney transplant recipients.     

Humoral response to natural influenza infection in solid organ transplant recipients

The humoral immune response of transplant recipients to influenza vaccination has been studied in detail. In contrast, the hemagglutinin inhibiting (HI) antibody response evoked by natural influenza infection and its impact on viral kinetics is unknown. In this prospective, multicenter, cohort study of natural influenza infection in transplant recipients, we measured HI antibody titers at presentation and 4 weeks later. Serial nasopharyngeal viral loads were determined using a quantitative influenza A polymerase chain reaction (PCR). We analyzed 196 transplant recipients with influenza infection. In the cohort of organ transplant patients with influenza A (n = 116), seropositivity rates for strain‐specific antibodies were 44.0% (95% confidence interval [CI] 31.5‐53.2%) at diagnosis and 64.7% (95% CI 55.4‐72.9%) 4 weeks postinfection. Seroconversion was observed in 32.8% (95% CI 24.7‐41.9%) of the cases. Lung transplant recipients were more likely to seroconvert (P = .002) and vaccine recipients were less likely to seroconvert (P = .024). A subset of patients (n = 30) who were unresponsive to prior vaccination were also unresponsive to natural infection. There was no correlation between viral kinetics and antibody response. This study provides novel data on the seroresponse to influenza infection in transplant patients and its relationship to a number of parameters including a prior vaccination status, virologic measures, and clinical variables.     

Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients

The protective capacity and duration of humoral immunity after SARS-CoV-2 infection are not yet understood in solid organ transplant recipients. A prospective multicenter study was performed to evaluate the persistence of anti-nucleocapsid IgG antibodies in liver transplant recipients 6 months after coronavirus disease 2019 (COVID-19) resolution. A total of 71 liver transplant recipients were matched with 71 immunocompetent controls by a propensity score including variables with a well-known prognostic impact in COVID-19. Paired case–control serological data were also available in 62 liver transplant patients and 62 controls at month 3 after COVID-19. Liver transplant recipients showed a lower incidence of anti-nucleocapsid IgG antibodies at 3 months (77.4% vs. 100%, p < .001) and at 6 months (63.4% vs. 90.1%, p < .001). Lower levels of antibodies were also observed in liver transplant patients at 3 (p = .001) and 6 months (p < .001) after COVID-19. In transplant patients, female gender (OR = 13.49, 95% CI: 2.17–83.8), a longer interval since transplantation (OR = 1.19, 95% CI: 1.03–1.36), and therapy with renin–angiotensin–aldosterone system inhibitors (OR = 7.11, 95% CI: 1.47–34.50) were independently associated with persistence of antibodies beyond 6 months after COVID-19. Therefore, as compared with immunocompetent patients, liver transplant recipients show a lower prevalence of anti-SARS-CoV-2 antibodies and more pronounced antibody levels decline.     

Serologic response to a third dose of an mRNA-based SARS-CoV-2 vaccine in lung transplant recipients

Lung transplant recipients have an increased risk for severe coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A third dose of a SARS-CoV-2 vaccine has been recommended for all solid organ transplant recipients, but data from lung transplant recipients specifically are scarce. In this study, the serologic response to a third dose of an mRNA-based SARS-CoV-2 vaccine was measured in 78 lung transplant recipients. Sixty-two percent (n = 48) had a serological response to vaccination, which was significantly higher than after the second vaccine dose (27 patients (35%); p = 0.0013). A positive serologic response was associated with having had COVID-19 (p = 0.01), and higher serum IgG level and complement mannose binding lectin pathway activity prior to vaccination (p = 0.04 and p = 0.03, respectively). Serologic response was not associated with the dose of mycophenolate mofetil or prednisone or other immune status parameters. Eleven patients (14%) developed COVID-19 after the second or third vaccine dose, but this did not associate with serologic response after the second vaccine dose (9% in patients who developed COVID-19 versus 39% in patients who did not develop COVID-19 (p = 0.09)), or with serologic response above cut-off values associated with clinical protection in previous studies. In conclusion, the response to mRNA-based SARS-CoV-2 vaccines in lung transplant recipients improves significantly after a third vaccine dose. Factors associated with a positive serologic response are having had COVID-19 prior to vaccination, and serum IgG and complement mannose binding lectin pathway activity prior to vaccination. Serologic response did not associate with clinical protection against COVID-19 in this study.     

Analysis of Risk Factors for a Low Immune Response to Messenger RNA COVID-19 Vaccine in Kidney Transplant Recipients and Differences Between Second and Third Dose

BackgroundThe efficacy of the response to SARS-CoV-2 vaccination in kidney transplant recipients is low. The aim of our study was to evaluate the risk factors correlated with the low antibody response and whether there was an improvement between the second and the third dose.MethodsA prospective study was conducted on 176 kidney transplant recipients who received the second and the third dose of the anti-SARS-CoV-2 mRNA Comirnaty vaccine. We evaluated the seroconversion process after administration of the second and the third dose and assessed a possible correlation with age, time between transplant and vaccination, and type of immunosuppressive therapy.ResultsA total of 98 of the 176 patients (55.7%) responded positively after the inoculation of the second dose and according to the multivariable logistic regression analysis the lack of seroconversion was independently associated with patient age ≥60 (P = .025; odds ratio [OR], 2.094), time since transplant of 1 to 3 months (P = .032; OR, 2.118), and triple therapy (P = .044; OR, 2.327). After the vaccine third dose, the seroconversion increased to 62.5%, and it was negatively influenced by calcineurin inhibitor use (12/21, 57.1% vs 71/78, 91.0%, P = .0006) and triple therapy (13/21, 61.9% vs 72/78, 92.3%, P = .0014). The median of antispike antibody response significantly increased from 18.5 IU/mL after the second dose to 316.9 IU after the third dose (P < .0001).ConclusionsWe demonstrated a correlation between older age and shorter distance from the transplant and triple immunosuppressive therapy with the lack of seroconversion. We noticed a significant improvement in antibody response by a third dose of messenger RNA vaccine.     

Physical modalities with eccentric exercise are no better than eccentric exercise alone in the treatment of chronic achilles tendinopathy: A systematic review and meta-analysis

BackgroundTo investigate the available evidence and conduct a systematic review with meta-analysis to determine the effectiveness of physical modalities combined with eccentric exercise (PMEE) with eccentric exercise (EE) alone for improvements in pain and function in individuals with chronic Achilles tendinopathy (AT) at short-term (4 weeks) and long-term (12–16 weeks) follow-ups.Materials and methodsA systematic literature review identified 8 papers (from 6404 possible inclusions) that allowed the comparison of PMEE with EE alone, in the treatment of chronic AT. We extracted the mean and standard deviations for Victorian Institute of Sports Assessment Achilles Tendinopathy (VISA-A), Numerical Pain Rating Scale (NPRS), and load-induced pain (NRS). Standardized mean difference (SMD) of the included variables was presented, and all the studies had low risk of bias.ResultsNon-significant results were achieved for short-term (pooled SMD = 0.03; 95% CI= −0.46 to 0.53, p = 0.89, I2 = 60%) and long- term follow-ups (pooled SMD =0.43; 95% CI= −0.05 to 0.92, p = 0.08, I2 = 82%) of VISA-A. Short-term (pooled SMD = −0.16; 95% CI= −0.72 to 0.40, p = 0.57, I2 = 40%) and long-term (pooled SMD = −0.39;95% CI= −1.11 to 0.32, p = 0.28, I2 = 62%) follow-up analysis of NPRS and long-term(pooled SMD = −0.46; 95% CI= −1.08 to 0.15, p = 0.14, I2 = 74%) follow-up of load induced pain also demonstrated non-significant improvements when comparing two groups.ConclusionMeta- analysis of the results published in the 8 papers that met theinclusion criteria showed no significant differences between PMEE and EE, in terms of load-induced pain (NRS) and numerical pain rating scales (NPRS) at 4 and 12–16 weeks. Thus, the meta-analysis reflects the other cited published work that PMEE shows no greater advantage than EE in the treatment of Chronic Achilles Tendinopathy.     

Association of Inflammatory Biomarkers with Immunosuppression Management and Outcomes in Kidney Transplant Recipients with COVID-19

BackgroundKidney transplant recipients with coronavirus disease 2019 (COVID-19) are at increased risk for adverse outcomes, such as acute kidney injury (AKI), intensive care unit (ICU) admission, and death. The association of inflammatory biomarkers with outcomes and the impact of changes in immunosuppression on biomarker levels are unknown.MethodsWe investigated factors associated with a composite of AKI, ICU admission, or death, and whether immunosuppression changes correlated with changes in inflammatory biomarkers and outcomes in kidney transplant recipients with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction.ResultsOf 59 patients, 50% had estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m². Patients who discontinued calcineurin inhibitors (CNIs) had higher peak high-sensitivity C-reactive protein (hs-CRP) than those who maintained the same dose (median, 344; interquartile range [IQR], 145-374 vs median, 41; IQR, 22-116 mg/L, P = .03). Of the patients, 73% were hospitalized, 22% had admissions to the ICU, and 20% died. Of the 56% with AKI, 35% required dialysis. All patients with AKI but without pulmonary manifestations recovered to 10% of baseline creatinine levels. Factors associated with the composite outcome were eGFR <60 mL/min/1.73 m² (odds ratio [OR], 5.833; 95% confidence interval [CI], 1.880-18.099; P = .002), hs-CRP (OR, 1.011/unit increase; 95% CI, 1.002-1.021; P = .019), white blood cell count (OR, 1.173/unit increase; 95% CI, 1.006-1.368; P = .041), and decreased or discontinued CNI (OR, 4.286; 95% CI, 1.353-13.572; P = .013). eGFR<60 mL/min/1.73 m² (OR, 11.176; 95% CI, 1.581-79.001; P = .016), and peak hs-CRP (OR, 1.010/unit increase; 95% CI, 1.000-1.020; P = .049) remained associated with the composite in the multivariable model.ConclusionsKidney transplant recipients with COVID-19 have high rates of ICU admissions, AKI, and death. Those with eGFR<60 mL/min/1.73 m² are at highest risk. CNI reduction is associated with higher inflammatory biomarkers, correlating with worse outcomes. More studies are needed to determine if this association should drive clinical management.     

Perioperative supplemental oxygen and oxidative stress in patients undergoing moderate- to high-risk major abdominal surgery – A subanalysis of randomized clinical trial

Study objectiveOxidative stress plays a pivotal role in the development and aggravation of cardiovascular diseases. The influence of intraoperative inspired oxygen concentrations on oxidative stress is still not entirely known. Therefore, we evaluated in this sub-study if supplemental oxygen affects the oxidation-reduction potential in patients at-risk for cardiovascular complications undergoing moderate- to high-risk major abdominal surgery.DesignSub-study of a prospective parallel-arm double-blinded single-center superiority randomized trial.SettingOperating room and postoperative recovery area.InterventionAdministration of 0.8 FiO₂ versus 0.3 FiO₂ throughout surgery and for the first two postoperative hours.MeasurementsThe primary outcome was the static oxidation-reduction potential (sORP) and the oxidation-reduction potential capacity (cORP) between both groups. The secondary outcome was the trend of sORP and cORP in the overall study population. We assessed sORP and cORP before induction of anesthesia, 2 h after induction of anesthesia, within 2 h after surgery and on the first and third postoperative day.Main results258 patients were analyzed. 128 patients were randomly assigned to the 80% oxygen group and 130 patients were randomly assigned to the 30% oxygen group. Postoperative sORP values did not differ significantly between the 80% and 30% oxygen group (effect estimate: −1.162 mV,95% CI: −2.584 to 0.260; p = 0.109). On average, we observed a change in sORP of 5.288 mV (95% CI:4.633 to 5.913, p < 0.001) per day. cORP values did not differ significantly between the 80% and 30% oxygen group (effect estimate: −0.015μC, (95%CI: −0.062 to 0.032; p = 0.524). On average, we observed a change in cORP values of −0.170μC (95%CI: −0.194 to −0.147, p < 0.001) per day.ConclusionIn contrast to previous reports, we could not find any evidence of an association between intraoperative supplemental oxygen and perioperative oxidative stress assessed by sORP and cORP.Trial registrationclinicaltrials.gov: NCT03366857 https://clinicaltrials.gov/ct2/show/NCT03366857?term=vienna&cond=oxygen&draw=2&rank=1     

Interstitial lung disease in patients treated with Cyclin-Dependent Kinase 4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials

BackgroundCyclin-Dependent Kinase (CDK) 4/6 inhibitors have shown significant clinical activity in cancer patients. However, some concerns regarding rare adverse events (AEs) have occurred including interstitial lung disease (ILD)/pneumonitis, for which data are deficient. The aim of this study was to evaluate the overall incidence and risk of ILD/pneumonitis related to CDK4/6 inhibitors in randomized controlled trials (RCTs).MethodsElectronic databases and ClinicalTrials.gov were searched from inception to October 1, 2021 for RCTs reporting the occurrence of LD/pneumonitis in cancer patients treated with CDK4/6 inhibitors. Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs) were used to pool the study.Results12 RCTs with a total of 16,060 patients were eligible. The overall incidence of all-grade ILD/pneumonitis was 1.6% (131/8407) in the treatment group compared with 0.7% (50/7349) in the control group. CDK4/6 inhibitors significantly increased the risk of all-grade ILD/pneumonitis with a pooled Peto OR of 2.12 (95% CI [1.57, 2.86], P < 0.00001) with no heterogeneity (I² = 0%, χ² P = 0.98). A higher incidence of grade 3 or higher ILD/pneumonitis was also observed in the treatment group (0.2%, 16/7087) compared with the control group (0.05%, 3/6617) with a Peto OR of 3.22 (95% CI [1.28, 8.09], P = 0.01) with no heterogeneity (I² = 0%, χ² P = 0.62). Two grade 5 pneumonitis were reported in the included studies. Subgroup analyses did not show any significant difference.ConclusionsThe risk of all-grade and grade 3 or higher ILD/pneumonitis was higher in patients treated with CDK4/6 inhibitors compared to controls. The awareness for these rare AEs in the application of CDK4/6 inhibitors should be enhanced. Further studies are required to validate the mechanisms and the risk factors of ILD/pneumonitis with CDK4/6 inhibitors.     

Efficacy and safety of PARP inhibitors in patients with BRCA-mutated advanced breast cancer: A meta-analysis and systematic review

ObjectiveThis meta-analysis aimed to investigate the efficacy and safety of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors in BRCA-mutated advanced breast cancer patients comprehensively.MethodsWe conducted a systematic literature research through PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, China National Knowledge Infrastructure (CNKI), wanfang, China Biology Medicine disc (CBMdisc), and ClinicalTrials.gov from inception to January 2021. Randomized controlled trials (RCTs) with available data comparing PARP inhibitors versus control therapy in BRCA-mutated advanced breast cancer were eligible for analysis. Statistical analyses were performed with Review Manager (RevMan) version 5.4 and R version 4.0.3.Results1706 studies were retrieved in total, and 4 RCTs with 1540 patients were eligible for meta-analysis finally. The results showed that progression-free survival (PFS) and overall survival (OS) were significantly improved in germline BRCA-mutated breast cancer patients with PARP inhibitors (HR 0.64, 95% CI [0.56–0.74]; HR 0.86, 95% CI [0.74–0.99], respectively) with no significant heterogeneity across studies (I² = 22%, χ² p = 0.28; I² = 0%, χ² p = 0.70, respectively). There was no significant difference in the overall adverse events (AEs), grade≥3 AEs and AEs leading to treatment discontinuation between PARP inhibitor arms and control arms (RR 1.01, 95% CI [0.99–1.02]; RR 0.95, 95% CI [0.83–1.09]; RR 1.17, 95% CI [0.87–1.57], respectively). Based on the available data, PARP inhibitors provided comparable or better results than control arms in improving the quality of life in BRCA-mutated advanced breast cancer patients.ConclusionsPARP inhibitors prolonged PFS and OS among patients with BRCA-mutated advanced breast cancer with tolerable safety and improved quality of life.     

Calcium chloride for the prevention of uterine atony during cesarean delivery: A pilot randomized controlled trial and pharmacokinetic study

Study objectiveTo assess the feasibility, patient tolerance, pharmacokinetics, and potential effectiveness of a randomized controlled trial protocol investigating intravenous calcium chloride for the prevention of uterine atony during cesarean delivery.DesignDouble-blind, randomized controlled pilot trial with nested population pharmacokinetic analysis.SettingThis study was performed at Lucile Packard Children's Hospital, from August 2018 to September 2019.PatientsForty patients with at least two risk factors for uterine atony at the time of cesarean delivery.InterventionsOne gram of intravenous calcium chloride (n = 20 patients) or a saline placebo control (n = 20 patients), in addition to standard care with oxytocin, upon umbilical cord clamping.MeasurementsThe primary efficacy-related outcome was the presence of uterine atony defined as the use of a second-line uterotonic medication, surgical interventions for atony, or hemorrhage with blood loss >1000 mL. Blood loss, uterine tone numerical rating scores, serial venous blood calcium levels, hemodynamics, and potential side effects were also assessed.Main resultsThe study protocol proved feasible. The incidence of atony was 20% in parturients who received calcium compared to 50% in the placebo group (relative risk 0.38, P = 0.07, 95% CI 0.15–1.07, NNT 3.3). Calcium recipients tolerated the drug infusion well, with no adverse events and an equal incidence of potential side effects in the calcium and placebo groups. Ionized calcium concentration rose significantly in all patients who received calcium infusion, from baseline 1.18 mmol/L to peak levels 1.50–1.60 mmol/L. One-compartment population pharmacokinetics established clearance of 0.93 (95% CI 0.63–1.52) L/min and volume of distribution 76 (95% CI 49–94) L.ConclusionsIn this pilot study, investigators found that intravenous calcium chloride was well-tolerated by the 20 patients assigned to receive the study drug and may be effective in prevention of uterine atony. A 1-g dose was sufficient to substantially increase calcium levels without any critically elevated lab values or concern for adverse side effects. These encouraging findings warrant further investigation of calcium as a novel agent to prevent uterine atony with an adequately powered clinical trial.Clinical trial registry NCT03867383 https://clinicaltrials.gov/ct2/show/NCT03867383     

Remote transmission monitoring for postoperative perineural analgesia after major orthopedic surgery: A multicenter,randomized, parallel-group,controlled trial

Study objectiveAfter surgery, patients reported the delay in receiving help as the primary factor for poorly controlled pain. This study aimed to compare the effectiveness of patient management through two communication modalities: remote transmission (RT) versus bedside control (BC). We hypothesized that using remote technology for pump programming may provide the best postoperative infusion regimen for the patient's self-assessment of pain and adverse events.DesignA multicenter, randomized, parallel-group, controlled trial.SettingAnesthesiology department and orthopedic surgery ward at three university hospitals.PatientsEighty patients undergoing orthopedic surgery with postoperative perineural patient-controlled analgesia were included.InterventionsTwo groups (n = 40 for each group) were formed by randomization. In the postoperative period, perineural analgesia was followed up via an RT system or BC for 72 h.MeasurementsA nurse assessed daily pain, sensory and motor blocks and adverse events. Patients completed a questionnaire three times a day and alerted for any problem according to the group (RT system or nurses' follow-up). On the third postoperative day, the nurse removed the catheter, completed the final assessment, and collected the historical data from the pump. A physician's shorter response time to change the patient control analgesia (PCA) program was the primary endpoint.ResultsOf the 80 patients, 71 were analyzed (34 were randomized to the RT group and 37 to the BC group). Fifty-eight pump setting changes were noted. Analysis of repeated evaluations shows that mean time (SD) to change the PCA pump settings was significantly lower in the RT group (20 min (22.3 min)) than in the BC group (55.9 min (71.1 min)); mean difference [95% CI], −35.9 min [−74.3 to 2.4]); β estimation [95% CI], −34 [−63 to −6], p = 0.011). Pain relief, sensory and motor blocks did not differ between the groups: β estimation [95% CI], 0.1 [−0.4 to 0.6], p = 0.753; 0.5 [−0.4 to 1.4], p = 0.255; 0.9 [−0.04 to 1.8], p = 0.687, respectively. β = −34 [−63 to −6], p = 0.011). The consumption of ropivacaine, nurse workload and the cost of the analgesia regimen decreased in the RT group. No differences were noted in satisfaction scores or complication rates.ConclusionsThe response time for the physician to change the PCA program when necessary was shorter for patients using RT and alerts to the physician were more frequent compared with spot checks by nurses. RT helps to decrease nurses' workload, ropivacaine consumption, and costs but did not affect postoperative pain relief, complication rate, or patient-reported satisfaction score.IRB contact informationComité de Protection des Personnes, Sud Méditerranée III, Montpellier-Nîmes, France, registration number EudraCT A01698-35.Clinical trial numberClinicalTrials.gov ID:NCT02018068ProtocolThe full trial protocol can be accessed at Department of Anesthesiology and Critical Care Medicine, Medical Research and Statistics Unit, Lapeyronie University Hospital, Avenue Doten G Giraud, Montpellier, France. s-bringuierbranchereau@chu-montpellier.fr     

Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus

COVID-19 is associated with increased morbidity and mortality in transplant recipients. There are no efficacy data available regarding these patients with any of the available SARS-CoV-2 vaccines. We analyzed the humoral response following full vaccination with the BNT162b2 (Pfizer-BioNTech) in 136 kidney transplant recipients, and compared it to 25 controls. In order to exclude prior exposure to the virus, only participants with negative serology to SARS-CoV-2 nucleocapsid protein were included. All controls developed a positive response to spike protein, while only 51 of 136 transplant recipients (37.5%) had positive serology (p < .001). Mean IgG anti-spike level was higher in the controls (31.05 [41.8] vs. 200.5 [65.1] AU/mL, study vs. control, respectively, p < .001). Variables associated with null humoral response were older age (odds ratio 1.66 [95% confidence interval 1.17–2.69]), high-dose corticosteroids in the last 12 months (1.3 [1.09–1.86]), maintenance with triple immunosuppression (1.43 [1.06–2.15]), and regimen that includes mycophenolate (1.47 [1.26–2.27]). There was a similar rate of side effects between controls and recipients, and no correlation was found between the presence of symptoms and seroconversion. Our findings suggest that most kidney transplant recipients remain at high risk for COVID-19 despite vaccination. Further studies regarding possible measures to increase recipient's response to vaccination are required.     

Transcutaneous electrical acupoint stimulation before surgery reduces chronic pain after mastectomy: A randomized clinical trial

Study objectiveDespite multiple interventions, the incidence of chronic pain after mastectomy could be as high as 50% after surgery. This study aimed to determine the efficacy of transcutaneous electrical acupoint stimulation (TEAS) before anesthesia induction in reducing chronic pain and to compare the effect of combined acupoint TEAS with that of single acupoint TEAS.DesignA multicenter randomized clinical trial.SettingThe study was conducted at six medical centers in China from May 2016 to April 2018. Final follow-up was on October 26, 2018.ParticipantsEligible patients were women scheduled for radical mastectomy under general anesthesia.InterventionsPatients were randomly and equally grouped into sham control (n = 188), single acupoint (PC6, n = 198), or combined acupoints (PC6 and CV17, n = 190) TEAS groups using a centralized computer-generated randomization system. TEAS was applied for 30 min before anesthesia induction. The sham-operated control group received electrode attachment but without stimulation. Anesthesiologists, surgeons, and outcome assessors were blinded to the interventions.MeasuresThe primary endpoint was the incidence of chronic pain 6 months after surgery. Incidences were compared among the groups using the unadjusted χ² test.ResultsOf the 576 randomized patients, 568 completed the trial. In the intention-to-treat analysis, post-mastectomy pain at 6 months was reported in 42 of 190 patients (22.1%) in the combined acupoints group, 65 of 188 patients (34.6%) in the sham-operated group (P = 0.007; relative risk [RR], 95% confidence interval [CI]: 0.68, 0.52–0.89), and 72 of 198 patients (36.4%) in the single acupoint group (P = 0.002; RR, 95% CI: 0.72, 0.55–0.93). Remifentanil consumption during surgery and postoperative nausea and vomiting at 24 h after surgery were lower in the combined acupoint group than that in the sham-operated group.ConclusionTEAS at combined acupoints before surgery was associated with reduced chronic pain 6 months after surgery.Trial registration: Clinicaltrials.gov identifier: NCT02741726. Registered on April 13, 2016.     

Post-Transplantation Anemia and Risk of Death Following Lung Transplantation

BackgroundPost-transplantation anemia (PTA) is frequent among solid organ transplant recipients and has been associated with increased morbidity and mortality. However, the prevalence and impact of PTA in lung transplant recipients is still not elucidated.MethodsWe performed a retrospective cohort study of adult Danish lung transplant recipients between January 2010 and December 2019. The prevalence and severity of PTA were determined during the first three years post-transplantation. Associations between PTA and selected risk factors were established using uni- and multivariate logistic regression models.ResultsA total of 278 patients were included. At one and three years post–lung transplantation the prevalence of PTA was 75% and 52%, respectively. Male sex was associated with increased odds of PTA at all time points (aOR ranging from 2.3, 95% CI 1.1-4.6, P = 0.02 to 5.9, 95% CI 2.6-14, P < .001). Cystic fibrosis was also associated with anemia at one-year post-transplantation (aOR 4.3, 95% CI 1.2-17, P = 0.03). We found no strong associations between PTA and renal function or viral infections. Excess mortality in recipients with moderate or severe anemia compared to patients with mild or no anemia was borderline statistically significant at one-year post-lung transplantation (aHR 2.0, 95% CI 0.9-4.4, P = 0.07).DiscussionPost-transplantation anemia is very common in Danish lung transplant recipients. Male sex and cystic fibrosis are independent risk factors for development of anemia. Further investigation on PTA, the underlying mechanisms, and its clinical impact is needed.     

Postoperative opioid administration characteristics associated with opioid-induced respiratory depression: Results from the PRODIGY trial

Study objectiveOpioid administration for pain in general care floor patients remains common, and can lead to adverse outcomes, including respiratory compromise. The PRODIGY trial found that among ward patients receiving parenteral opioids, 46% experienced ≥1 respiratory depression episode. The objective of this analysis was to evaluate the geographic differences of opioid administration and examine the association between opioid administration characteristics and the occurrence of respiratory depression.DesignProspective observational trial.Setting16 general care medical and surgical wards in Asia, Europe, and the United States.Patients1335 patients receiving parenteral opioids.InterventionsBlinded, alarm-silenced continuous capnography and pulse oximetry monitoring.MeasurementsOpioid-induced respiratory depression, defined as respiratory rate ≤ 5 bpm, SpO₂ ≤ 85%, or ETCO₂ ≤ 15 or ≥ 60 mmHg for ≥3 min; apnea episode lasting >30 s; or any respiratory opioid-related adverse event.ResultsAcross all patients, 58% received only long-acting opioids, 16% received only short-acting (<3 h) opioids, and 21% received a combination of short- and long-acting (≥3 h) opioids. The type and median total morphine milligram equivalent (MME) of opioid administered varied significantly by region, with 31.5 (12.5–76.7) MME, 31.0 (6.2–99.0) MME, and 7.2 (1.7–18.7) MME in the United States, Europe, and Asia, respectively (p < 0.001). Considering only postoperative opioids, 54% (N = 119/220) and 45% (N = 347/779) of patients receiving only short-acting opioids or only long-acting opioids experienced ≥1 episode of opioid-induced respiratory depression, respectively. Multivariable analysis identified post-procedure tramadol (OR 0.62, 95% CI 0.424–0.905, p = 0.0133) and post-procedure epidural opioids (OR 0.485, 95% CI 0.322–0.731, p = 0.0005) being associated with a significant reduction in opioid-induced respiratory depression.ConclusionsDespite varying opioid administration characteristics between Asia, Europe, and the United States, opioid-induced respiratory depression remains a common global problem on general care medical and surgical wards. While the use of post-procedure tramadol or post-procedure epidural opioids may reduce the incidence of respiratory depression, continuous monitoring is also necessary to ensure patient safety when receiving postoperative opioids.Registration numberwww.clinicaltrials.gov, ID: NCT02811302     

Evaluation of the Correlation Between Responders and Non-Responders to the Second Coronavirus Disease Vaccination In Kidney Transplant Recipients: A Retrospective Single-Center Cohort Study

BackgroundThe immune response to COVID-19 vaccination in kidney transplant (KTx) recipients is significantly lower than that in healthy controls. We evaluated immune responses after the COVID-19 vaccine and their possible relationship with other cofactors in KTx recipients.MethodsThis retrospective single-center cohort study included 29 KTx recipients 2-8 weeks after receiving 2 doses of the Pfizer-BioNTech SARS-CoV-2 messenger RNA vaccine. Anti-SARS-CoV-2 spike (S) immunoglobulin (Ig)-G levels were evaluated to define cofactors influencing the immune response between the responder (anti-SARS-CoV-2 IgG level ≥0.8 U/mL) (n = 16) and nonresponder groups (anti-SARS-CoV-2 IgG level <0.8 U/mL) (n = 13). The kinetics of antibodies between 2 and 6 months after the second vaccination was also compared between the groups.ResultsKTx recipients with IgG levels ≥0.8 U/mL were younger (54 [interquartile range {IQR}, 46.5-61] years vs 65 [IQR, 55-71.5] years; P = .01), had been transplanted for a longer median time (1588 [IQR, 1382-4751] days vs 1034 [IQR, 548.5-1833] days; P = .02), and were more often treated with a lower mycophenolate mofetil dosage (765.6 ± 119.6 vs 1077 ± 76.9 mg; P = .04) than KTx recipients with IgG levels <0.8 U/mL. There was no significant difference in antibody titers between time periods after the second dose in the responder group. At the 6-month follow-up, a serologic response against the SARS-CoV-2 S was observed in 44.4% of KTx recipients in the nonresponder group.ConclusionsMore than 50% of KTx recipients developed a higher antibody response after the second dose of COVID-19 vaccination.