In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses ...in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolin-induced swelling and studied the correlation with in vivo effects. The in vitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-to-excellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an in vitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner.
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•Organoids of CF patients were used to quantitate individual drug response in vitro•Organoid responses correlate with two clinical response parameters ppFEV1 and SCC•In vivo (non)responders were identified with a PPV of 100% and a NPV of 80%•Organoids may be used for personalized medicine in cystic fibrosis
Berkers et al. demonstrate that stem cell cultures (organoids) can be a tool for personalized medicine. They show a high correlation between in vitro and in vivo effects of drugs and demonstrate good-to-excellent predictive values of the organoid test for preclinical identification of responders to CFTR modulators.
Physical and verbal violence toward staff or other detained individuals is a reoccurring problem within correctional facilities. Screening for violence risk within the prison setting could provide a ...valuable first step in the prevention of institutional violence. The brief and compact Risk Screener Violence (RS-V) has shown to be an efficient new method for assessing concerns regarding post-release violent offending for incarcerated persons. This study aimed to find out whether the RS-V is also able to predict future violent and aggressive incidents during imprisonment.
The predictive validity of the RS-V for future violent and aggressive incidents during a follow-up time of 4 months within prison was analyzed, using a file-based design. Violent incidents toward staff and other inmates (physical violence and violent threats), other aggressive incidents (aggression toward objects and verbal disruptive behavior), and both categories combined, were included as outcome measures based on disciplinary reports.
The RS-V showed medium to large predictive values for both violent and aggressive behavior during prison stay. In particular, good predictive values of the RS-V were found for violence toward prison staff.
This study shows that, besides post-release violent recidivism, the RS-V is able to accurately predict future violent and aggressive incidents during prison stay. By correctly differentiating between low concern and high concern individuals, the RS-V aims to contribute to more personalized interventions and risk management and, subsequently, to improved prison safety. Future studies using prospective prison practice data are needed to further support the validity of the RS-V regarding institutional violence.
Within the prison system, it is often not feasible to administer comprehensive risk assessment for all incarcerated persons because of limited time and resources. To enhance prison safety and ...facilitate the structured evaluation of concerns about violence risk for all individuals, the Risk Screener Violence (RS-V) was developed. The goal of this study was to evaluate whether the RS-V (N = 571) is able to retrospectively predict postrelease violent (re)offending for males (81%) and females (19%). The RS-V was scored with excellent interrater reliability and demonstrated medium to large predictive validity for all follow-up periods. Surprisingly, the predictive validity for females was even stronger than for males. This study demonstrates that the RS-V offers a promising new method for the efficient screening of concerns regarding violent behavior among incarcerated males and females. Further prospective studies in prison practice will have to consolidate these findings.
Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV
) <80% predicted and FEV
/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms ...and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities.
We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed.
22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (r
) between PRISm and spirometric COPD (r
=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (r
=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits.
This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals, rs7652391 (nearest gene
), rs9431040 (
), rs62018863 (
) and rs185937162 (
), have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extrapulmonary comorbidity.
Objectives
In addition to breathing problems, patients with Robin sequence (RS) often encounter feeding difficulties (FD). Data regarding the occurrence of FD and possible influencing factors are ...scarce. The study aim was to elucidate these factors to improve treatment strategies.
Material and methods
A retrospective comparative cohort study was conducted, consisting of 69 infants diagnosed with both RS and a cleft palate and 64 isolated cleft palate only (iCPO) infants. Data regarding FD, growth, and airway intervention were collected during the first 2 years of life. A systematic review of the literature was conducted to identify reported FD in RS patients.
Results
RS patients had more FD (91 %) than iCPO patients (72 %;
p
= 0.004). Also, nasogastric (NG)-tube feeding was necessary more frequently and for a longer period (both
p
< 0.001). Growth was lower in RS than iCPO infants (
p
= 0.008) and was not affected by the kind of airway management (conservative/surgical;
p
= 0.178), cleft palate grade (
p
= 0.308), or associated disorders (
p
= 0.785). By contrast, surgical intervention subtype did significantly affect growth. Mean reported FD for RS in the literature is 80 % (range = 47–100 %), and 55 % (range = 11–100 %) of infants need NG-tube feeding.
Conclusions
FD is present in a large proportion of infants with RS, which indicates the need for early recognition and proper treatment to ensure optimal growth. Growth during the first 2 years of life is significantly lower in RS patients than iCPO patients, which indicates the need for careful attention and long-term follow-up.
Clinical relevance
This study indicates the need for early recognition and proper treatment of FD in RS to ensure optimal growth. In addition, growth needs careful attention and long-term follow-up.
Acute liver failure may be caused by a variety of disorders including inborn errors of metabolism. In those cases, rapid metabolic investigations and adequate treatment may avoid the need for liver ...transplantation. We report two patients who presented with acute liver failure and were referred to our center for liver transplantation work-up. Urgent metabolic investigations revealed citrullinemia type I. Treatment for citrullinemia type I avoided the need for liver transplantation. Acute liver failure as a presentation of citrullinemia type I has not previously been reported in young children. Although acute liver failure has occasionally been described in other urea cycle disorders, these disorders may be underestimated as a cause. Timely diagnosis and treatment of these disorders may avoid liver transplantation and improve clinical outcome. Therefore, urea cycle disorders should be included in the differential diagnosis in young children presenting with acute liver failure.
Tumor-derived peptides are used frequently as antigen (Ag) source in dendritic cell (DC) therapy in cancer patients. An alternative is to load DC with tumor-associated Ag (TAA)-encoding RNA. ...RNA-loading obviates prior knowledge of CTL and Th epitopes in the Ag. Multiple epitopes for many HLA alleles (both MHC class I and class II) are encoded by the RNA and loading is independent of the patient's HLA make-up. Herein, we determined the optimal conditions for mRNA-electroporation of monocyte-derived DC for clinical application in relation to different maturation cocktails. The data demonstrate that TAA carcinoembryonic antigen, gp100 and tyrosinase are expressed already 30 min after electroporation with the encoding mRNA. Moreover, gp100-specific CTL are activated by gp100 mRNA-electroporated DC. Importantly, we show here that the presence of polyinosinic-polycytidylic acid poly(I:C) in the maturation cocktail prevents effective protein expression of the electroporated mRNA as well as subsequent CTL recognition. This effect of poly(I:C) correlates with the induction of IFN-induced genes and innate anti-viral effector molecules in DC. Together these data show that electroporation of mature DC with TAA-encoding mRNA is attractive for use in DC vaccination protocols in cancer patients, but protein expression should be tested for each maturation cocktail.
Sexual dysfunction is highly prevalent among patients with type 2 diabetes; however, little is known regarding these patients' needs and preferences for care for sexual problems. A cross-sectional ...survey and 25 semistructured interviews were therefore conducted among 40- to 75-year-old type 2 diabetes patients to explore this. We learned from the survey and interviews that most participants were unaware of the association between type 2 diabetes and sexual problems. Although certain barriers for discussing sexual problems with a care provider were identified (e.g., feelings of embarrassment), patients still reported a need for discussing their problems, because sex was viewed as an important part of their relationship. Some patients had sought help, but were dissatisfied with the offered care. Patients experienced a lack of attention and information from diabetes care providers. Improving this, together with a care provider-initiated conversation, was suggested to lower the threshold for discussion. Moreover, patients preferred a care provider with whom they have a close relationship, whereas age, gender, and medical specialty were regarded to be less important. An important recommendation was to make care for sexual problems an integral part of routine diabetes care. Future research should look into these recommendations.
Objective To investigate the current performance of urological residents regarding basic urological procedures in relation to patient safety issues and the identification of specific training needs. ...Design Observational data of 146 urethrocystoscopies (UCSs), 27 transrectal ultrasounds of the prostate (TRUSs), 38 transrectal ultrasound-guided prostatic biopsies (TRUSPs), and 30 transurethral resections of bladder tumor (TURBTs) were collected. Performance was evaluated using scoring lists including details on completeness of procedural steps, level of independence, time, and the incidence of unintended events. The causal factors contributing to the unintended events were identified by 2 expert urologists and classified according to the recognized PRISMA method. Setting This study was performed in 5 teaching hospitals in the Netherlands. Participants We included 11 junior residents and 5 senior residents in urology in the final study cohort. Results Senior residents showed a lower degree of completeness in material usage than junior residents did during UCS (p < 0.01) and in preparation, material usage, and procedure during TRUSP (all p < 0.05). In UCS and TURBT, senior residents received significantly less feedback than junior residents did (both p < 0.01). Incidence of unintended events for junior vs senior residents was 11% and 4% in UCS, 0% and 7% in transrectal ultrasound of the prostate, 36% and 62% in TRUSP, and 41% and 23% in TURBT, respectively. Overall, unintended events were mainly caused by human factors, in particular, verification and skills-based issues. Conclusion Present performance of basic urological procedures involves a high percentage of unintended events, especially in TRUSP and TURBT, which are mainly caused by human factors and are a potential threat for patient safety. Junior residents are less independent but more thorough in the performance of UCS and TRUSP than senior residents are. Targeted skills training including assessment should be implemented before privileges for independent practice are granted to reduce the incidence of unintended events and optimize patient safety.
Women with antibodies against the enzyme thyroid peroxidase TPO-Ab; formerly microsomal antibodies (MsAb) are at particular risk for developing postpartum thyroid dysfunction; the latter is ...significantly associated with postpartum depression. Although the negative effect of postpartum maternal depression on child development is well documented, the consequences of elevated titers of TPO-Ab during pregnancy and subsequent postpartum thyroid dysfunction on child development are not known. In a prospective study of a cohort of 293 pregnant women, the occurrence of TPO-Ab during gestation, thyroid dysfunction, and depression was investigated. Five years after delivery, child development was assessed in 230 children of the original cohort using the Dutch translation of the McCarthy Scales of Children's Abilities. Children of women with TPO-Ab during late gestation (n = 19, with normal thyroid function) had significantly lower scores (by t test) on the McCarthy Scales of Children's Abilities than antibody-negative women. The difference on the General Cognitive Scale, which reflects IQ scores, was substantial (10.5 points; t = 2.8; P = 0.005). After correction for possibly confounding variables, maternal TPO-Ab during gestation was found to be the most important factor related to the scores on the General Cognitive Scale (odds ratio = 10.5; 95% confidence interval = 3-34; P = 0.003). We conclude that children of pregnant women who had elevated titers of TPO-Ab but normal thyroid function are at risk for impaired development.
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