An Emulation of Randomized Trials of Administrating Antipsychotics in PTSD Patients for Outcomes of Suicide-Related Events

Post-traumatic stress disorder (PTSD) is a prevalent mental disorder marked by psychological and behavioral changes. Currently, there is no consensus of preferred antipsychotics to be used for the treatment of PTSD. We aim to discover whether certain antipsychotics have decreased suicide risk in the PTSD population, as these patients may be at higher risk. A total of 38,807 patients were identified with a diagnosis of PTSD through the ICD9 or ICD10 codes from January 2004 to October 2019. An emulation of randomized clinical trials was conducted to compare the outcomes of suicide-related events (SREs) among PTSD patients who ever used one of eight individual antipsychotics after the diagnosis of PTSD. Exclusion criteria included patients with a history of SREs and a previous history of antipsychotic use within one year before enrollment. Eligible individuals were assigned to a treatment group according to the antipsychotic initiated and followed until stopping current treatment, switching to another same class of drugs, death, or loss to follow up. The primary outcome was to identify the frequency of SREs associated with each antipsychotic. SREs were defined as ideation, attempts, and death by suicide. Pooled logistic regression methods with the Firth option were conducted to compare two drugs for their outcomes using SAS version 9.4 (SAS Institute, Cary, NC, USA). The results were adjusted for baseline characteristics and post-baseline, time-varying confounders. A total of 5294 patients were eligible for enrollment with an average follow up of 7.86 months. A total of 157 SREs were recorded throughout this study. Lurasidone showed a statistically significant decrease in SREs when compared head to head to almost all the other antipsychotics: aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone (p < 0.0001 and false discovery rate-adjusted p value < 0.0004). In addition, olanzapine was associated with higher SREs than quetiapine and risperidone, and ziprasidone was associated with higher SREs than risperidone. The results of this study suggest that certain antipsychotics may put individuals within the PTSD population at an increased risk of SREs, and that careful consideration may need to be taken when prescribed.

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An Emulation of Randomized Trials of Administrating Benzodiazepines in PTSD Patients for Outcomes of Suicide-Related Events

Journal of Clinical Medicine ◽

10.3390/jcm9113492 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3492

Author(s):

Michael Gilbert ◽

Andrew Dinh La ◽

Noah Romulo Delapaz ◽

William Kenneth Hor ◽

Peihao Fan ◽

...

Keyword(s):

Previous History ◽

Careful Consideration ◽

P Value ◽

Post Traumatic Stress ◽

Regression Methods ◽

Increased Risk ◽

History Of ◽

Post Traumatic ◽

Or History

Benzodiazepines is a class of medications frequently prescribed to patients with post-traumatic stress disorder. Patients with PTSD have a notable increased risk of suicide compared to the general population. These medications have been theorized to increase suicidality and pose a risk when used in this patient population. Previous research has found little utility of using benzodiazepines in the PTSD population. However, benzodiazepines are still commonly prescribed by some clinicians for their symptomatic benefit. This study aims to identify the comparative efficacy of commonly prescribed benzodiazepines including midazolam, lorazepam, alprazolam, clonazepam, diazepam and temazepam in relation to suicide-related behaviors (SRBs). A total of 38,807 patients who had an ICD9 or ICD10 diagnosis of PTSD from January 2004 to October 2019 were identified through an electronic medical record database. Inclusion criteria include patients that initiated one of the above benzodiazepines after PTSD diagnosis. Exclusion criteria include previous history of benzodiazepine usage or history of SRBs within the last year prior to enrollment. For patients enrolled in this study, other concomitant drugs were not limited. The primary outcome was onset of SRBs with each respective benzodiazepine. SRBs were identified as ideation, attempt, or death from suicide. We emulated clinical trials of head-to-head comparison between two drugs by pooled logistic regression methods with the Firth option adjusting for baseline characteristics and post-baseline confounders. A total of 5753 patients were eligible for this study, with an average follow up of 5.82 months. The overall incidence for SRB was 1.51% (87/5753). Head-to-head comparisons identified that patients who received alprazolam had fewer SRBs compared to clonazepam (p = 0.0351) and lorazepam (p = 0.0373), and patients taking midazolam experienced fewer relative incidences of SRBs when compared to lorazepam (p = 0.0021) and clonazepam (p = 0.0297). After adjusting for the false discovery rate (FDR), midazolam still had fewer SRBs compared to lorazepam (FDR-adjusted p value = 0.0315). Certain benzodiazepines may provide a reduced risk of development of SRBs, suggesting careful consideration when prescribing benzodiazepines to the PTSD population.

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Vitamin D status and risk of type 2 diabetes in the Norwegian HUNT cohort study: does family history or genetic predisposition modify the association?

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001948 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001948

Author(s):

Marion Denos ◽

Xiao-Mei Mai ◽

Bjørn Olav Åsvold ◽

Elin Pettersen Sørgjerd ◽

Yue Chen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Family History ◽

Genetic Predisposition ◽

Effect Modification ◽

P Value ◽

Family History Of Diabetes ◽

Increased Risk ◽

History Of

IntroductionWe sought to investigate the relationship between serum 25-hydroxyvitamin D (25(OH)D) level and the risk of type 2 diabetes mellitus (T2DM) in adults who participated in the Trøndelag Health Study (HUNT), and the possible effect modification by family history and genetic predisposition.Research design and methodsThis prospective study included 3574 diabetes-free adults at baseline who participated in the HUNT2 (1995–1997) and HUNT3 (2006–2008) surveys. Serum 25(OH)D levels were determined at baseline and classified as <50 and ≥50 nmol/L. Family history of diabetes was defined as self-reported diabetes among parents and siblings. A Polygenic Risk Score (PRS) for T2DM based on 166 single-nucleotide polymorphisms was generated. Incident T2DM was defined by self-report and/or non-fasting glucose levels greater than 11 mmol/L and serum glutamic acid decarboxylase antibody level of <0.08 antibody index at the follow-up. Multivariable logistic regression models were applied to calculate adjusted ORs with 95% CIs. Effect modification by family history or PRS was assessed by likelihood ratio test (LRT).ResultsOver 11 years of follow-up, 92 (2.6%) participants developed T2DM. A higher risk of incident T2DM was observed in participants with serum 25(OH)D level of<50 nmol/L compared with those of ≥50 nmol/L (OR 1.72, 95% CI 1.03 to 2.86). Level of 25(OH)D<50 nmol/L was associated with an increased risk of T2DM in adults without family history of diabetes (OR 3.87, 95% CI 1.62 to 9.24) but not in those with a family history (OR 0.72, 95% CI 0.32 to 1.62, p value for LRT=0.003). There was no effect modification by PRS (p value for LRT>0.23).ConclusionSerum 25(OH)D<50 nmol/L was associated with an increased risk of T2DM in Norwegian adults. The inverse association was modified by family history of diabetes but not by genetic predisposition to T2DM.

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COLORECTAL CANCER (CRC)

The Professional Medical Journal ◽

10.29309/tpmj/2016.23.04.1490 ◽

2016 ◽

Vol 23 (04) ◽

pp. 364-369

Author(s):

Hafiz Mughees Ather ◽

Muhammad Sarfraz ◽

Touseef Anwaar

Keyword(s):

Colorectal Cancer ◽

Abdominal Pain ◽

Previous History ◽

Abdominal Distension ◽

P Value ◽

Obese Patients ◽

Increased Risk ◽

History Of ◽

Bleeding Per Rectum ◽

Artery Disease

Colorectal cancer (CRC) is a common cancer. It has got significant morbidity andmortality. It is a common malignancy. Obesity is defined as BMI equal or above 25.1 kg/m2.Obesity is associated with an increased risk of developing CRC and poor prognosis in patientswith colorectal cancer. We conducted a study on 414 patients to look for correlation of obesitywith T, N, M and DUKES stage and frequency of obesity in CRC patients. Period: It involvedall CRC cases presented between 2004 to 2009. Methods: It was a single center retrospectivechart review. Total patient were 414. Data was collected on Performa and analyzed on SPSSversion 19. Results: Out of 414 patients males were 243 (58.7%) and females were 171 (41.3%).Mean age was 56 years. It was 57.7 years for males and 54.6 years for females. 221 patientswere obese. 123 patients presented in advanced DUKES stage. Mean BMI was 26 and meanCEA level was 76.60. 134 patients presented in advanced T stage (T3 and T4). 20% patientswith positive polyp history were obese while 80% patients with positive polyp history were nonobese. Majority of patients with family history of CRC, previous history of IBD, smoking andprevious colonoscopy were non obese. Abdominal pain, abdominal distension, constipation,bleeding per rectum and fever were more common in obese patients but this difference was notstatistically significant. About 56% of patients with abdominal pain and abdominal distensionwere obese and about 59% of patients with constipation and bleeding per-rectum were obese.About 65% of diabetic and hypertensive patients were obese (P value 0.01, 0.01) while 70%patients with coronary artery disease were obese. Conclusion: CRC affects more males andadvanced age group. Obese CRC patients are more than non-obese patients but obesity is notassociated with advanced stage of disease. Co-morbidities like diabetes mellitus, hypertensionare more common in obese CRC patients.

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Suicide among Scottish military veterans: follow-up and trends

Occupational and Environmental Medicine ◽

10.1136/oemed-2021-107713 ◽

2021 ◽

pp. oemed-2021-107713

Author(s):

Beverly P Bergman ◽

Daniel F Mackay ◽

Jill P Pell

Keyword(s):

Older Women ◽

Military Veterans ◽

Female Veterans ◽

Veterans Health ◽

Post Traumatic Stress ◽

Increased Risk ◽

History Of ◽

Post Traumatic

ObjectivesThe risk of suicide among UK military veterans remains unclear. Few recent studies have been undertaken, and most studies found no clear evidence of increased risk. We used data from the Trends in Scottish Veterans Health cohort to investigate suicides up to 2017 in order to examine whether there have been any changes in the long-term pattern of veteran suicides since our earlier study to 2012, and to compare trends in the risk of suicide among veterans with matched non-veterans.MethodRetrospective cohort study of 78 000 veterans and 253 000 non-veterans born between 1945 and 1995, matched for age, sex and area of residence, using survival analysis to examine the risk of suicide in veterans in comparison with non-veterans overall and by subgroup, and to investigate associations with specific mental health conditions.ResultsUp to 37 years of follow-up, 388 (0.5%) veterans and 1531 (0.6%) non-veterans died from suicide. The risk of suicide among veterans did not differ from non-veterans overall. Increased risk among early service leavers was explained by differences in deprivation, and the previously reported increased risk in female veterans is now confined to older women. Suicide was most common in the fifth decade of life, and around 20 years postservice. A history of mood disorder or post-traumatic stress disorder was non-significantly more common in veterans.ConclusionsVeterans are not at increased risk of suicide overall. The highest risk for both men and women is in middle age, many years after leaving service.

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Multizonal anogenital neoplasia in women: a cohort analysis

BMC Cancer ◽

10.1186/s12885-021-07949-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Andreia Albuquerque ◽

Michelle A. L. Godfrey ◽

Carmelina Cappello ◽

Francesca Pesola ◽

Julie Bowring ◽

...

Keyword(s):

Anal Canal ◽

Cohort Analysis ◽

Previous History ◽

Immunosuppressive Drugs ◽

High Grade ◽

Lack Of Information ◽

Increased Risk ◽

History Of ◽

Intraepithelial Lesions

Abstract Background There is currently a lack of information on full anogenital evaluation of women with a previous history of anogenital neoplasia. Methods Retrospective analysis of the Homerton Anogenital Neoplasia Service records from January 2012 to March 2017, to identify all new referrals of women with previous anogenital neoplasia, who had had at least one complete examination of all anogenital sites. Multizonal anogenital disease (MZD) was defined as the presence of high-grade squamous intraepithelial lesions (HSIL)/carcinoma concurrently at two or more of the following sites/zones: perianus, anal canal, vulva, vagina or cervix. Results 253 women were included, mean age was 47 (SD=15) years and median duration of follow-up was 12 (IQR=21) months. Fifty-six women (22%) were diagnosed with MZD at first assessment and/or during follow-up. Current smokers (RR=1.84, 95% CI 1.21–2.79, p=0.004) and women on immunodulators/immunosuppressive drugs (RR=2.57, 95% CI 1.72-3.86, p<0.001) had an increased risk for MZD. The risk was lower for women without a previous history of anogenital high-grade lesions/cancer compared to those with this history (RR=0.06, 95% CI 0.01-0.45, p=0.006). Conclusions Multizonal assessment was important to diagnose occult areas of disease and should be especially considered in current smokers, pharmacologically immunocompromised and those with a previous history of anogenital HSIL/cancer.

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Weight change and risk of cardiovascular disease among adults with type 2 diabetes: more than 14 years of follow-up in the Tehran Lipid and Glucose Study

Cardiovascular Diabetology ◽

10.1186/s12933-021-01326-2 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Seyyed Saeed Moazzeni ◽

Reyhane Hizomi Arani ◽

Niloofar Deravi ◽

Mitra Hasheminia ◽

Davood Khalili ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Weight Gain ◽

Weight Change ◽

P Value ◽

Increased Risk ◽

History Of ◽

The Impact

Abstract Background To examine the impact of weight change on incident cardiovascular disease and coronary heart disease (CVD/CHD) among an Iranian population with type 2 diabetes mellitus (T2DM). Methods The study population included 763 participants with T2DM aged ≥ 30 years without a history of CVD and cancer at baseline. Two weight measurements done at baseline and about 3 years later. Based on their weight change, they categorized into: > 5% loss, 3–5% loss, stable (± < 3%), 3–5% gain, > 5% gain. Participants were then followed for incident CVD/CHD annually up to 20 March 2018. Multivariable Cox proportional hazard models, adjusted for age, sex, body mass index, educational level, current smoking, glucose-lowering drug use, family history of CVD, hypertension, hypercholesterolemia, chronic kidney disease, and fasting plasma glucose (FPG) were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of weight change categories for incident CVD/CHD, considering stable weight as reference. Results After the weight change measurement, during a median follow-up of 14.4 years, 258 CVD and 214 CHD occurred. Over 5% weight gain was associated with reduced risks of CVD and CHD development by the HRs of 0.70 [95% CI 0.48–1.01; P-value: 0.058] and 0.61 [0.40–0.93], respectively, in multivariable analysis. After further adjustment for FPG change, the HRs of weight gain > 5% were attenuated to 0.75 [0.51–1.10; P-value: 0.138] and 0.66 [043–1.01; P-value: 0.053] for incident CVD and CHD, respectively. The effect of weight loss > 5% was in opposite direction among those older versus younger than 60 years; with suggestive increased risk (not statistically significant) of incident CHD/CVD for the older group. Moreover, weight gain > 5% significantly reduced the risk of CHD only among those older than 60 years (P-value for interaction < 0.2). Furthermore, weight gain > 5% had an association with lower risk of CVD and CHD among sulfonylurea users (0.56 [0.32–0.98] for CVD and 0.54 [0.29–0.99] for CHD). Conclusions Our results with a long-term follow-up showed that weight gain > 5% was associated with better CVD/CHD outcomes among Iranian participants with T2DM, especially older ones. Moreover, we did not find an unfavorable impact on incident CVD/CHD for sulfonylurea-induced weight gain.

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Parenchymal mucinous cystadenoma of the kidney: a case report and literature review

African Journal of Urology ◽

10.1186/s12301-021-00203-4 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Mahmoudreza Kalantari ◽

Shakiba Kalantari ◽

Mahdi Mottaghi ◽

Atena Aghaee ◽

Salman Soltani ◽

...

Keyword(s):

Renal Cyst ◽

Left Kidney ◽

Previous History ◽

Mucinous Cystadenoma ◽

Single Layer ◽

Renal Cysts ◽

Cystic Mass ◽

Flank Pain ◽

History Of

Abstract Background Mucinous cystadenoma (MC) of the kidney is exceedingly rare. We found 22 similar cases in the literature. These masses are underdiagnosed due to radiologic similarities with simple renal cysts. Case presentation A 66-year-old man with a previous history of hypertension and anxiety was referred to our tertiary clinic with left flank pain. Ultrasound revealed a 60 mm-sized, complex cystic mass with irregular septa in the lower pole of the left kidney (different from last year's sonographic findings of a simple benign cyst with delicate septa). CT scan showed the same results plus calcification. Due to suspected renal cell carcinoma, a radical nephrectomy was performed. Postoperative histopathologic examination revealed a cyst lined by a single layer of columnar mucin-producing cells with small foci of pseudo-stratification, consistent with the MC’s diagnosis. The first follow-up visit showed normal blood pressure without medication and no flank pain and anxiety after a month. Conclusion It is quite challenging to distinguish the primary MC of the kidney from a simple renal cyst based on clinical and imaging findings. The radiologic features of these entities overlap significantly. Thus, complex renal cyst and renal cysts with mural nodules should be followed closely to detect malignancy earlier.

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Association between digoxin use and sudden cardiac death in individuals with the rs10494366 variant of the NOS1AP gene

European Heart Journal ◽

10.1093/ehjci/ehaa946.3394 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

N Soroush ◽

A Aarnoudse ◽

F Shokri ◽

M Van Den Berg ◽

F Ahmadizar ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Cardiac Death ◽

Smoking Status ◽

Adaptor Protein ◽

Therapeutic Window ◽

P Value ◽

Qtc Interval ◽

Total Study Population ◽

Increased Risk

Abstract Background Digoxin is one of the oldest cardiovascular medications still used to treat heart failure and atrial fibrillation. Due to its narrow therapeutic window, it is associated with life threatening intoxication and arrhythmias, and with QTc-shortening. Common genetic variation in the nitric oxide synthase-1 adaptor protein (NOS1AP) has been associated with QTc interval prolongation. Purpose We investigated whether the rs10494366 variant of the NOS1AP gene modified the risk of SCD in patients using digoxin. Methods In a prospective population-based cohort study, we included data of the three cohorts, started as of January 1st, 1991 until January 1st 2014. Digoxin current use on the date of cardiac death in cases and the same day of follow-up in the remainder of the cohort was a time-dependent exposure. The main outcome was SCD defined as sudden and unexpected death as a result of cardiac causes, according to international criteria. Identification and adjudication of SCD was performed independently, before the start of this study. We used Cox proportional hazard regression analysis to investigate the associations between NOS1AP rs10494366 variant and incident SCD among digoxin users compared to non-users. Associations were adjusted for age, sex (model 1) in addition to BMI, prevalent diabetes, myocardial infarction, baseline hypertension and smoking status (past, current, never) (model 2). Results We included 14,594 individuals, with a mean age of 65.3 (SD 10.3) years. Almost 59% were female. The cumulative incidence of SCD was 9.5% (609 cases) by the end of follow up. Among them, 98 (16%) individuals were exposed to digoxin at the time of death. In model 1, NOS1AP rs10494366 variant was not associated with SCD in the total study population. However, an interaction term of the gene with the daily dose of digoxin was significantly associated with increased risk of SCD (p-value 0.0001). In model 2, the risk of SCD in current users of digoxin was 4.2 [95% CI 1.3–13.8] for the GG genotype; 2.1 [95% CI 1.1–4.2] for the GT genotype, and 1.5 [95% CI 0.7–3.2] for the TT genotype. Conclusion NOS1AP rs10494366 variant modified the risk of sudden cardiac death in users of digoxin. Our study suggests that individuals with the homozygous minor GG allele have a fourfold increased risk of sudden cardiac death. Funding Acknowledgement Type of funding source: None

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Impact of atrial fibrillation pattern on outcomes after left atrial appendage closure: lessons from the prospective LAARGE registry

Clinical Research in Cardiology ◽

10.1007/s00392-021-01874-3 ◽

2021 ◽

Author(s):

Shinwan Kany ◽

Johannes Brachmann ◽

Thorsten Lewalter ◽

Ibrahim Akin ◽

Horst Sievert ◽

...

Keyword(s):

Atrial Fibrillation ◽

Left Atrial Appendage ◽

Systemic Embolism ◽

Long Term Outcomes ◽

Increased Risk ◽

History Of ◽

One Year ◽

The One

Abstract Background Non-paroxysmal (NPAF) forms of atrial fibrillation (AF) have been reported to be associated with an increased risk for systemic embolism or death. Methods Comparison of procedural details and long-term outcomes in patients (pts) with paroxysmal AF (PAF) against controls with NPAF in the prospective, multicentre observational registry of patients undergoing LAAC (LAARGE). Results A total of 638 pts (PAF 274 pts, NPAF 364 pts) were enrolled. In both groups, a history of PVI was rare (4.0% vs 1.6%, p = 0.066). The total CHA2DS2-VASc score was lower in the PAF group (4.4 ± 1.5 vs 4.6 ± 1.5, p = 0.033), while HAS-BLED score (3.8 ± 1.1 vs 3.9 ± 1.1, p = 0.40) was comparable. The rate of successful implantation was equally high (97.4% vs 97.8%, p = 0.77). In the three-month echo follow-up, LA thrombi (2.1% vs 7.3%, p = 0.12) and peridevice leak > 5 mm (0.0% vs 7.1%, p = 0.53) were numerically higher in the NPAF group. Overall, in-hospital complications occurred in 15.0% of the PAF cohort and 10.7% of the NPAF cohort (p = 0.12). In the one-year follow-up, unadjusted mortality (8.4% vs 14.0%, p = 0.039) and combined outcome of death, stroke and systemic embolism (8.8% vs 15.1%, p = 0.022) were significantly higher in the NPAF cohort. After adjusting for CHA2DS2-VASc and previous bleeding, NPAF was associated with increased death/stroke/systemic embolism (HR 1.67, 95% CI 1.02–2.72, p = 0.041). Conclusion Atrial fibrillation type did not impair periprocedural safety or in-hospital MACE patients undergoing LAAC. However, after one year, NPAF was associated with higher mortality. Graphic abstract

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Eculizumab discontinuation in atypical hemolytic uremic syndrome: TMA recurrence risk and renal outcomes

Clinical Kidney Journal ◽

10.1093/ckj/sfab005 ◽

2021 ◽

Author(s):

Gema Ariceta ◽

Fadi Fakhouri ◽

Lisa Sartz ◽

Benjamin Miller ◽

Vasilis Nikolaou ◽

...

Keyword(s):

Family History ◽

Hemolytic Uremic Syndrome ◽

Univariate Analysis ◽

Atypical Hemolytic Uremic Syndrome ◽

Renal Response ◽

Pathogenic Variants ◽

Increased Risk ◽

History Of ◽

Uremic Syndrome

ABSTRACT Background Eculizumab modifies the course of disease in patients with atypical hemolytic uremic syndrome (aHUS), but data evaluating whether eculizumab discontinuation is safe are limited. Methods Patients enrolled in the Global aHUS Registry who received ≥1 month of eculizumab before discontinuing, demonstrated hematologic or renal response prior to discontinuation and had ≥6 months of follow-up were analyzed. The primary endpoint was the proportion of patients suffering thrombotic microangiopathy (TMA) recurrence after eculizumab discontinuation. Additional endpoints included: eGFR changes following eculizumab discontinuation to last available follow-up; number of TMA recurrences; time to TMA recurrence; proportion of patients restarting eculizumab; and changes in renal function. Results We analyzed 151 patients with clinically diagnosed aHUS who had evidence of hematologic or renal response to eculizumab, before discontinuing. Thirty-three (22%) experienced a TMA recurrence. Univariate analysis revealed that patients with an increased risk of TMA recurrence after discontinuing eculizumab were those with a history of extrarenal manifestations prior to initiating eculizumab, pathogenic variants, or a family history of aHUS. Multivariate analysis showed an increased risk of TMA recurrence in patients with pathogenic variants and a family history of aHUS. Twelve (8%) patients progressed to end-stage renal disease after eculizumab discontinuation; 7 (5%) patients eventually received a kidney transplant. Forty (27%) patients experienced an extrarenal manifestation of aHUS after eculizumab discontinuation. Conclusions Eculizumab discontinuation in patients with aHUS is not without risk, potentially leading to TMA recurrence and renal failure. A thorough assessment of risk factors prior to the decision to discontinue eculizumab is essential.

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