Experiences of workers with long-term disabilities on employer support throughout the RTW process in The Netherlands: a qualitative study.

PURPOSE: The aim of this qualitative study was to explore ways that employer support influenced successful return to work (RTW) in workers with disabilities. METHODS: We conducted a semi-structured interview study among 27 workers with disabilities in the Netherlands who received a partial disability benefit two years after sick leave and who continued working in paid (part-time) employment after a period of long-term sickness absence (> 2 years). We analyzed data by means of thematic analysis. RESULTS: We identified four types of employer support that were experienced as factors of successful RTW: 1. Supervisor accessibility; 2. Supervisor engagement; 3. Supervisor strategies; and 4. Supervisor-initiated work accommodations. More specifically, during the preparations for RTW phase, the supervisor's active role involved having a positive and open attitude toward facilitating RTW; during the initial RTW phase, the supervisor's role involved being creative in finding solutions for work accommodations; and during the sustained RTW phase, the supervisor's role included helping workers who still needed changes in their work situations. CONCLUSION: The elements of successful employer support reveals that the pressure on the shoulders of the supervisor is high. Future research should further investigate whether supervisors need more phase-specific training from their organization.

The support of the employer is found to be crucial to help workers on long-term sick leave to return- to and remain at work.Supervisors may need more training in skills relevant for RTW, not often having faced cases of long-term sick leave.An important precondition for supervisors to apply these skills is the provision of resources for work accommodations, which should be provided by the employer.

A blended module (STAIRS) to promote functional and personal recovery in patients with a major depressive disorder in remission: study protocol of a concurrent mixed methods randomized controlled trial.

BACKGROUND: Despite the availability of a wide variety of evidence-based treatments for major depressive disorder (MDD), many patients still experience impairments in their lives after remission. Programs are needed that effectively support patients in coping with these impairments. The program Storytelling and Training to Advance Individual Recovery Skills (STAIRS) was developed to address this need and combines the use of peer contact, expert-by-experience guidance, family support and professional blended care. The aim of the planned study is (1) to assess the efficacy of the STAIRS program in patients with remitted MDD, (2) to investigate patients' subjective experiences with STAIRS, and (3) to evaluate the program's cost-effectiveness. METHODS: A concurrent mixed-methods randomized controlled trial design will be used. Patients aged between 18 and 65 years with remitted MDD (N = 140) will be randomized to either a group receiving care as usual (CAU) + the STAIRS-program or a control group receiving CAU + some basic psychoeducation. Quantitative efficacy data on functional and personal recovery and associated aspects will be collected using self-report questionnaires at the start of the intervention, immediately following the intervention, and at the six-month follow-up. Insights into patients' experiences on perceived effects and the way in which different program elements contribute to this effect, as well as the usability and acceptability of the program, will be gained by conducting qualitative interviews with patients from the experimental group, who are selected using maximum variation sampling. Finally, data on healthcare resource use, productivity loss and quality of life will be collected and analysed to assess the cost-effectiveness and cost-utility of the STAIRS-program. DISCUSSION: Well-designed recovery-oriented programs for patients suffering from MDD are scarce. If efficacy and cost-effectiveness are demonstrated with this study and patients experience the STAIRS program as usable and acceptable, this program can be a valuable addition to CAU. The qualitative interviews may give insights into what works for whom, which can be used to promote implementation. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov on 1 July 2021, registration number NCT05440812.

Values and practice of collaboration in a mental health care system in the Netherlands: a qualitative study.

BACKGROUND: To offer optimal care, the mental health system needs new routes for collaboration, involving both interprofessional and interorganizational aspects. The transition from intramural to extramural mental health care has given rise to new dynamics between public and mental health care, introducing a challenge for interprofessional and interorganizational collaboration. This study aims to determine values and expectations of collaboration and to understand how collaboration in mental health care organizations takes shape in daily practice. METHODS: We conducted a qualitative study using semi-structured interviews and a focus group, in the setting of the Program for Mentally Vulnerable Persons (PMV). Data were analysed following thematic analysis. RESULTS: We found three aspect that were considered important in collaboration: commonality, relationships, and psychological ownership. However, our findings indicate a discrepancy between what is considered essential in collaboration and how this materializes in day-to-day practice: collaboration appears to be less manageable than anticipated by interviewees. Our data suggest psychological ownership should be added as value to the interorganizational collaboration theory. CONCLUSION: Our study offers a new definition of collaboration and adding "psychological ownership" to the existing literature on collaboration theory. Furthermore, we gained insight into how collaboration between different organizations works in practice. Our research points to a discrepancy between what all the partners find important in collaboration, and what they actually do in practice. Finally, we expressed ways to improve the collaboration, such as choosing between a chain or a network approach and acting on it and re-highlighting the goal of the Program Mentally Vulnerable persons.

Sustained employment, work disability and work functioning in CKD patients: a cross-sectional survey study.

INTRODUCTION: Kidney failure negatively affects opportunities for work participation. Little is known about work functioning of employed CKD patients. This study investigates work-related outcomes, and examines associations between patient characteristics and employment status. METHODS: We performed a cross-sectional survey study in nine nephrology outpatient clinics in the Netherlands among working age (18-67 years) CKD Stage G3b-G5, dialysis and transplant patients (n = 634; mean age 53.4 years (SD 10); 53% male; 47% Stage G3b-G5, 9% dialysis, 44% transplantation). We assessed employment status, work disability, work-related characteristics (i.e., work situation, working hours, job demands), work functioning (i.e., perceived ability to work, productivity loss, limitations in work), work environment (i.e., work accommodations, psychosocial work environment), as well as health status and fatigue. RESULTS: Sixty-five percent were employed reporting moderate work ability. Of those, 21% received supplementary work disability benefits, 37% were severely fatigued, 7% expected to drop out of the workforce, and 49% experienced CKD-related work limitations. Work accommodations included reduced working hours, working at a slower pace, adjustment of work tasks or work schedule, and working from home. Multivariable analysis of sustained employment showed associations with younger age, male gender, higher level of education, better general and physical health and pre-emptive transplantation. Transplant patients had the highest work ability and highest expectation to maintain work. Dialysis patients had the highest productivity loss and perceived the most limitations regarding functioning in work. Stage G3b-G5 patients reported the lowest social support from colleagues and highest conflict in work and private life. CONCLUSIONS: Employed CKD patients experience difficulties regarding functioning in work requiring adjustment of work or partial work disability. In addition to dialysis patients, stage G3b-G5 patients are vulnerable concerning sustained employment and work functioning.

Storytelling and training to advance individual recovery skills (STAIRS). A feasibility study of a blended program to support personal recovery among patients with a major depressive disorder in remission.

Because major depressive disorder (MDD) has a strong negative impact on patients' lives, well-designed treatment programs are needed that address the lasting effects of MDD. Previous work has shown that such programs should not only focus on symptomatic recovery, but also on the subsequent personal recovery process. Currently, few programs with this specific focus exist. Therefore, this study aimed to assess the feasibility of a newly developed blended program to support the personal recovery process of MDD patients: Storytelling and Training to Advance Individual Recovery Skills (STAIRS). STAIRS is a program using peer support and guidance by experts by experience and clinicians, which can be added to regular depression treatment when symptomatic recovery is almost reached. Topics addressed in this program are: (1) effects of depression and treatment; (2) structure; (3) (self) stigma; (4) self-image; (5) meaning of life; (6) connection to others; (7) physical health; (8) relaxation; and (9) preventing relapse. Experiences with the STAIRS program were collected from five participating patients with questionnaires and a focus-group interview, as well as from four trainers using semi-structured interviews. Participants valued the topics addressed in STAIRS, the used working methods, the presence of an expert by experience and the ability to share experiences with peers. The use of an online platform and the involvement of others is seen as potentially supportive but turned out to be more challenging. Perceived effects of STAIRS include positive changes in participants' daily lives and their contacts with others. Overall, the results indicate that when implemented accessibly, STAIRS is a promising and feasible program to foster personal recovery among patients recovering from MDD.

What hides beneath the scar: sexuality and breast cancer what women don't say: A single-center study.

Background: Breast is a symbol of femininity, motherhood and sexuality. Breast cancer (BC) is the leading cause of cancer death in women worldwide and most frequent cancer in Italy: in 2019, 53.500 new cases were diagnosed. BC and its treatment, the disturbances of body image, and mental health problems such as anxiety and depression could influence sexuality. Very often the aspect of sexuality in BC is likely not to be fully investigated: cultural barriers may also contribute to lack of attention to these issues. In Italy, there are very few Breast Units that provide the figure of the sexologist and psycho-oncologist. Methods: We enlisted 141 BC patients (pts), mean age was 54 years afferent to Breast Unit S. Maria Goretti Hospital, Latina, from March 2019 to March 2020. All pts had undergone surgical intervention. Participants were invited to complete a structured questionnaire, which included four close-up questions regarding self-image, sexual activity, sexual satisfaction, analyzing these aspects before and after BC and its treatments. Finally the participants were asked if they needed the sexologist and psycho-oncologist. Results: Only 2/141 pts (1.41%) refused to participate in our study. Of 139 participants, 68 (48.92%) had disturbances of body image, 26 (18.7%) had sexuality greatly negatively affected, and 103 (74.1%) every kind of sexual dissatisfaction after BC. 38 pts (27.3%) would require the help of the sexologist. 135 ( 97%) would require the help of the psycho-oncologist. Despite the negative influence in their body-image and sexuality, few pts require the help of the sexologist, but nearly all pts require the help of the psycho-oncologist. Conclusion: In our study nearly all pts require the help of the psycho-oncologist, but few pts of the sexologist. Further studies will be needed to understand the reasons for this disparity: at the moment we are carrying out another project following this illustration, with the aim of understanding why this disparity.

Detecting sleep apnea in adults with Down syndrome using WatchPAT: A feasibility study.

BACKGROUND: In daily practice, sleep apnea is underdiagnosed in people with Down syndrome. The WatchPAT can detect sleep apnea in a less invasive way. AIM: This study aimed to evaluate the feasibility of the WatchPAT to detect sleep apnea in individuals with Down syndrome. METHODS AND PROCEDURES: Thirty-one participants with Down syndrome (aged 18+) were included. Sleep apnea was detected with the WatchPAT and compared to results of the STOP-Bang Questionnaire (current practice). Experiences of participants, caregivers and clinicians were studied using a combination of quantitative and qualitative methods. OUTCOMES AND RESULTS: Among the 68% of participants who accepted the WatchPAT, sleep apnea was detected in 95% of participants. Younger participants and participants with mild/moderate intellectual disabilities were more likely to accept the device. STOP-Bang did not detect most cases of sleep apnea. For the degree of sleep apnea, interrater reliability was substantial (k = 0.71) to almost perfect (k = 0.91). Considering experiences, caregivers and clinicians were predominantly positive about the WatchPAT. CONCLUSIONS: Our study showed that the WatchPAT is a promising device to detect sleep apnea in people with Down syndrome. Compared to polysomnography, detection with this device is less invasive and less burdensome for people with Down syndrome. Furthermore, the WatchPAT is a relatively accessible solution to implement in care institutions.

Employment and ability to work after kidney transplantation in the Netherlands: The impact of preemptive versus non-preemptive kidney transplantation.

BACKGROUND: Work can have a major positive impact on health and wellbeing. Employment of kidney transplant recipients (KTR) of working age is much lower than in the general population. The first aim of this study was to examine the impact of a preemptive kidney transplantation (PKT) on employment, in addition to other possible influencing factors. The second aim was to explore differences in work ability, absenteeism and work performance among employed KTR with different types of transplantations. METHODS: A cross-sectional survey study was conducted between 2018 and 2019 in nine Dutch hospitals. PKT as potential predictor of employment was examined. Furthermore, work ability, absenteeism and loss of work performance were compared between employed preemptive recipients with a living donor (L-PKT) and non-preemptive recipients with a living donor (L-nPKT) and with a deceased donor (D-nPKT). RESULTS: Two hundred and twenty four KTR participated; 71% reported having paid work. Paid work was more common among PKT recipients (82% vs. 65% in L-nPKT and 55% in D-nPKT) and recipients who were younger (OR .950, 95%CI .913-.989), had no comorbidities (1 comorbidity: OR .397, 95%CI .167-.942; 2 comorbidities: OR .347, 95%CI .142-.844), had less fatigue (OR .974, 95%CI .962-.987) and had mentally demanding work tasks (only in comparison with physically demanding tasks, OR .342, 95%CI .145-.806). If recipients were employed, D-nPKT recipients worked fewer hours (mean 24.6±11.3 vs. PKT 31.1±9.6, L-nPKT 30.1±9.5) and D-nPKT and L-nPKT recipients received more often supplemental disability benefits (32 and 33.3%, respectively) compared to PKT recipients (9.9%). No differences were found for self-reported ability to work, sick leave (absenteeism) and loss of work performance with the exception of limitations in functioning at work. CONCLUSIONS: Preemptive kidney transplantation recipients with a kidney from a living donor are employed more often, work more hours per week (only in comparison with D-nPKT) and have a partial disability benefit less often than nPKT recipients. More knowledge regarding treatments supporting sustainable participation in the labor force is needed as work has a positive impact on recipients' health and wellbeing and is also beneficial for society as a whole.

[Experience of first COVID-19 patients in Northern part of the Netherlands: Information provision, source investigation, contact tracing and home isolation]. / Eerste covid-19-patiënten in Noord-Nederland.

OBJECTIVE: The aim of this study was to investigate how patients experience the information, the source investigation and contact tracing and the measures in isolation at the start of a pandemic. DESIGN: Secondary analysis of semi-structured interviews was conducted as part of a larger exploratory mixed-methods study on COVID-19 patient experiences. METHODS: Semi-structured interviews were conducted with 29 people from Friesland and Groningen who tested positive for SARS-CoV-2 between 9 March and 3 April 2020, recruited via maximum variation sampling. Thematic analysis was used. RESULTS: The following themes emerged from the analysis: 1) Information: Conflicting information by different advisors led to a lack of clarity. Patients admitted to hospital usually felt uninformed about the rules of home isolation after discharge. 2) Investigation into the source of infection: For most it was unclear whether and how this investigation took place. Some expected feedback on their suggestions. 3) Informing contacts: Not everyone felt able to inform the right contacts. Some felt stigmatized. 4) Living with the measures in home isolation: The recommended living rules were often not fully applied. Some patients felt insufficiently supported. CONCLUSION: Our study shows that not all COVID-19 patients felt well cared for at the start of the outbreak. Scaling down monitoring by the public health service can mean that questions about source and contact investigation and isolation remain unanswered or are answered by others. This leads to conflicting information and non-compliance with measures. The supervision of patients in isolation should be better guarded.

What affects the implementation of lifestyle interventions in patients with osteoarthritis? A multidisciplinary focus group study among healthcare professionals.

PURPOSE: To identify factors affecting the implementation of lifestyle interventions (LIs) in patients with hip and/or knee osteoarthritis (OA) from the perspective of primary and secondary healthcare professionals (HCPs) in the Dutch healthcare system. METHODS: Multidisciplinary focus groups were composed. Data analysis was performed following thematic analysis. The Tailored Implementation for Chronic Diseases checklist was used to guide data analysis. RESULTS: Four focus groups meetings were conducted with 38 participating HCPs (general practitioners (or in-training), orthopedic surgeons (or in-training), physiotherapists, dieticians, a general practice assistant, lifestyle counselors, and nurse practitioners). Influencing factors were grouped into nine themes: (1) intervention factors; (2) individual HCP factors; (3) patient factors; (4) professional interactions; (5) incentives and resources; (6) capacity for organizational change; (7) social, political and legal factors; (8) patient and HCP interactions; and (9) disease factors. CONCLUSIONS: A wide variety of factors affecting the implementation of LIs was identified in this study, where the importance of effective interdisciplinary collaboration was emphasized by the multidisciplinary group of participants. This thorough analysis of influencing factors is an important first step toward improved implementation of LIs within OA care. Further research is required to identify the most significant targets for change in daily practice.Implications for RehabilitationThe implementation of lifestyle interventions (LIs) by healthcare professionals (HCPs) in patients with hip and/or knee osteoarthritis (OA) is affected by both individual and environmental factors.The influencing factors identified in this study can support the development of interventions aimed at improving the implementation of LIs in OA care.A multilevel approach is required when developing interventions to improve the implementation of LIs in OA care.Continued efforts of both primary and secondary HCPs and policymakers are needed in order to promote the use of LIs within OA care.

Patients' experience of an ecological momentary intervention involving self-monitoring and personalized feedback for depression.

Experts in clinical mental health research count on personalized approaches based on self-monitoring and self-management to improve treatment efficacy in psychiatry. Among other things, researchers expect that Ecological Momentary Interventions (EMI) based on self-monitoring and personalized feedback will reduce depressive symptoms. Clinical trial findings have, however, been conflicting. A recent trial (ZELF-i) investigated whether depression treatment might be enhanced by an add-on EMI with self-monitoring items and feedback focused on positive affect and activities (Do-module) or on negative affect and thinking patterns (Think-module). There was no statistical evidence that this EMI impacted clinical or functional outcomes beyond the effects of regular care, regardless of module content. In apparent contrast, 86% of the participants who completed the intervention indicated they would recommend it to others. In the present study, we used in-depth interviews (n = 20) to better understand the EMI's personal and clinical benefits and downsides. A thematic analysis of the interviews generated six areas of impact with various subthemes. In line with the trial results, few participants reported behavioral changes or symptom improvement over time; the self-assessments mainly amplified momentary mood, in either direction. The most often mentioned benefits were an increase in self-awareness, insight, and self-management (e.g., a stronger sense of control over complaints). Consistently, these domains received the highest ratings in our evaluation questionnaire (n = 89). Furthermore, the EMI instilled a routine into the days of individuals without regular jobs or other activities. Participants reported few downsides. The experiences were rather similar between the two modules. This study suggests that EMI might contribute to health by helping individuals deal with their symptoms, rather than reducing them. Measures on self-awareness, insight, and self-management should be more emphatically involved in future EMI research.

Barriers to and Facilitators of Sustained Employment: A Qualitative Study of Experiences in Dutch Patients With CKD.

RATIONALE & OBJECTIVE: Although patients with chronic kidney disease (CKD) are at risk for work disability and loss of employment, not all experience work disruption. We aimed to describe the barriers to and facilitators of sustained employment experienced by Dutch patients with CKD. STUDY DESIGN: Qualitative study using semistructured interviews. SETTING & PARTICIPANTS: 27 patients with CKD glomerular filtration rate categories 3b-5 (G3b-G5) from 4 nephrology outpatient clinics in The Netherlands. ANALYTICAL APPROACH: Content analyses with constant comparison of interview data based on the International Classification of Functioning, Disability and Health framework. RESULTS: Participants were 6 patients with CKD G3b-G4, 8 patients receiving maintenance dialysis, and 13 patients with functioning kidney transplants. We identified health-related barriers (symptoms, physical toll of dialysis/transplantation, limited work capacity) and facilitators (few physical symptoms, successful posttransplantation recovery, absence of comorbidities, good physical condition), personal barriers (psychological impact, limited work experience) and facilitators (positive disposition, job satisfaction, work attitude, person-job fit), and environmental barriers and facilitators. Environmental barriers were related to nephrology care (waiting time, use of a hemodialysis catheter) and work context (reorganization, temporary contract, working hours, physical demands); environmental facilitators were related to nephrology care (personalized dialysis, preemptive transplant), work context (large employer, social climate, job requiring mental rather than physical labor, flexible working hours, adjustment of work tasks, reduced hours, remote working, support at work, peritoneal dialysis exchange facility), and support at home. Occupational health services and social security could be barriers or facilitators. LIMITATIONS: The study sample of Dutch patients may limit the transferability of these findings to other countries. CONCLUSIONS: The wide range of barriers and facilitators in all International Classification of Functioning, Disability and Health components suggests great diversity among patients and their circumstances. These findings underline the importance of personalized nephrology and occupational health care as well as the importance of individually tailored workplace accommodations to promote sustained employment for patients with CKD.

Patients' and clinicians' perspectives on relevant treatment outcomes in depression: qualitative study.

BACKGROUND: Although symptomatic remission is considered the optimal outcome in depression, this is not always achieved. Furthermore, symptom indicators do not fully capture patients' and clinicians' perspectives on remission. Broader indicators of (partial) remission from depression should be considered. AIMS: To investigate relevant outcomes of depression treatment in specialist care from patients' and clinicians' perspectives and to investigate whether these perspectives differ from each other. METHOD: Three focus groups with 11 patients with depression and seven semi-structured interviews with clinicians were conducted exploring their perspectives on remission. All interviews were audio-recorded and transcribed verbatim. We analysed the transcripts thematically using the phenomenologist approach. RESULTS: Independently, both patients and clinicians perceived the following outcomes relevant: restoring social functioning and interpersonal relations, regaining quality of life and achieving personal goals. All clinicians emphasised symptom reduction and satisfaction with treatment as relevant outcomes, whereas the former was not an obvious theme in patients. Unlike clinicians, patients made a clear distinction between treatment outcomes in first versus recurrent/chronic depression. CONCLUSIONS: Classically defined study outcomes based on symptom resolution only partly reflect issues considered important by patients and clinicians in specialist depression treatment. Incorporating patients' and clinicians' perspectives in the development of measurable end-points makes them more suitable for use in trials and subsequent translation to clinical practice. Furthermore, evaluating patients' perspectives on treatment outcomes helps in the development of tailored interventions according to patients' needs.

First urinary tract infections in children: the role of the risk factors proposed by the Italian recommendations.

AIM: In 2009, the Italian society for paediatric nephrology suggested the need for cystography, following a first febrile urinary tract infection (UTI), only in children at high risk for dilating vesicoureteral reflux or in the event of a second infection. The aim of this study was to evaluate the adequacy of the risk factors proposed by the Italian guidelines. METHODS: Children aged 2-36 months, managed by 10 Italian hospitals between 2009 and 2013, with a first febrile UTI were retrospectively evaluated. RESULTS: Four hundred and fourteen children were included: 51% female, mean age eight months. Escherichia coli was responsible of 84% UTIs. 269 children (65%) presented at least one risk factor, thus were further investigated: 44% had a reflux. The presence of a pathogen other than E. coli significantly predicted high-grade reflux, both in the univariate (Odd Ratio 2.52, 95% Confidence Interval 1.32-4.81, p < 0.005) and multivariate analysis (OR 2.74, 95% CI: 1.39-5.41, p: 0.003). 26/145 children (18%) with no risk factors experienced a second UTI, which prompted the execution of cystography, showing a dilating reflux in 11. CONCLUSION: Among the risk factors proposed by the Italian guidelines, only the presence of a pathogen other than E. coli significantly predicted reflux. Cystography can be postponed in children with no risk factors.

'Frequently recurring' nocturnal polyuria is predictive of response to desmopressin in monosymptomatic nocturnal enuresis in childhood.

INTRODUCTION: The nocturnal polyuria is considered a significant predictive value for response to desmopressin. The cutoff value useful to define nocturnal polyuria is still a matter of debate. Moreover, it is current notion that maximal voided volume (MVV) could be used as a predictor for desmopressin response. OBJECTIVE: The objective of this study was to assess the impact of different definitions of nocturnal polyuria (and of its frequency) and MVV in predicting the response to desmopressin. STUDY DESIGN: A total of 103 patients with frequent monosymptomatic nocturnal enuresis (≥4 wet nights/week) were enrolled. A bladder diary over a 4-day period was collected. The MVV was defined as the highest micturition volume detected at bladder diary. Nocturnal diuresis was measured in 5 wet nights. Then, patients were administered with 120 mcg of sublingual desmopressin. After 2 months, if there was no complete response, the dose was increased to 240 mcg. Nocturnal polyuria was defined as follows: 1.Definition 1: nocturnal urine production >130% of the expected bladder capacity (EBC). 2. Definition 2: >100% EBC. 3. Definition 3: > 20×(age + 9) mL. The primary outcome was 'response to desmopressin' after 3 months of treatment. RESULTS: Fifty-three patients responded to desmopressin. Comparing the responses to desmopressin on the basis of the three definitions of nocturnal polyuria, no significant difference was found. There was no cutoff value of nocturnal polyuria expressed as %EBC useful in providing a significant receiver-operating characteristic (ROC) curve. The area under the ROC curve for MVV expressed as %EBC was 0.67 (95% confidence interval [CI], 0.54-0.80; p = 0.01). A MVV >103.1% of EBC had 78.8% (95% CI, 61.1-91.0) sensitivity and 47.5% (95% CI, 31.5-63.9) specificity for predicting response to desmopressin. Among the patients with nocturnal polyuria according to definition 1, a higher percentage of subjects with nocturnal polyuria in 4 out of 5 or 5 out of 5 nights responded to desmopressin, compared with other patients. Patients presenting with nocturnal polyuria according to definition 3 in 5 out of 5 nights showed a 100% of response to desmopressin. At multivariate analysis, the only significant odds ratio (OR) to respond to desmopressin was that of patients with nocturnal polyuria according to definition 1 in >3 nights (OR = 7.1, 95% CI, 1.3-40.3). DISCUSSION AND CONCLUSIONS: The presence or absence of nocturnal polyuria-according to all three definitions-in at least one night was not effective in predicting the response to desmopressin. Predictors of desmopressin response were nocturnal polyuria in >3 out of 5 wet nights according to definition 1 and in 5 out of 5 wet nights according to definition 3.

Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment.

Although ibrutinib is highly effective in Waldenstrom macroglobulinemia (WM), no complete remissions in WM patients treated with ibrutinib have been reported to date. Moreover, ibrutinib-resistant disease is being steadily reported and is associated with dismal clinical outcome (overall survival of 2.9-3.1 months). To understand mechanisms of ibrutinib resistance in WM, we established ibrutinib-resistant in vitro models using validated WM cell lines. Characterization of these models revealed the absence of BTKC481S and CXCR4WHIM-like mutations. BTK-mediated signaling was found to be highly attenuated accompanied by a shift in PI3K/AKT and apoptosis regulation-associated genes/proteins. Cytotoxicity studies using the AKT inhibitor, MK2206±ibrutinib, and the Bcl-2-specific inhibitor, venetoclax±ibrutinib, demonstrated synergistic loss of cell viability when either MK22016 or venetoclax were used in combination with ibrutinib. Our findings demonstrate that induction of ibrutinib resistance in WM cells can arise independent of BTKC481S and CXCR4WHIM-like mutations and sustained pressure from ibrutinib appears to activate compensatory AKT signaling as well as reshuffling of Bcl-2 family proteins for maintenance of cell survival. Combination treatment demonstrated greater (and synergistic) antitumor effect and provides rationale for development of therapeutic strategies encompassing venetoclax+ibrutinib or PI3K/AKT inhibitors+ibrutinib in ibrutinib-resistant WM.

Alport syndrome: impact of digenic inheritance in patients management.

Alport syndrome (ATS) is a genetically heterogeneous nephropathy with considerable phenotypic variability and different transmission patterns, including monogenic (X-linked/autosomal) and digenic inheritance (DI). Here we present a new series of families with DI and we discuss the consequences for genetic counseling and risk assessment. Out of five families harboring variants in more than one COL4 gene detected by next generation sequencing (NGS), minigene-splicing assay allowed us to identify four as true digenic. Two families showed COL4A3/A4 mutations in cis, mimicking an autosomal dominant inheritance with a more severe phenotype and one showed COL4A3/A4 mutations in trans, mimicking an autosomal recessive inheritance with a less severe phenotype. In a fourth family, a de novo mutation (COL4A5) combined with an inherited mutation (COL4A3) triggered a more severe phenotype. A fifth family, predicted digenic on the basis of silico tools, rather showed monogenic X-linked inheritance due to a hypomorphic mutation, in accordance with a milder phenotype. In conclusion, this study highlights the impact of DI in ATS and explains the associated atypical presentations. More complex inheritance should be therefore considered when reviewing prognosis and recurrence risks. On the other side, these findings emphasize the importance to accompany NGS with splicing assays in order to avoid erroneous identification of at risk members.

Non-migratory tumorigenic intrinsic cancer stem cells ensure breast cancer metastasis by generation of CXCR4(+) migrating cancer stem cells.

Although the role of metastatic cancer stem cells (mCSCs) in tumor progression has been well documented, our study reveals a hitherto unidentified role of tumorigenic intrinsic CSCs (iCSCs) in breast cancer metastasis. We show that unlike highly migratory mCSCs residing in the breast tumor disseminating/peripheral regions, iCSCs populate the inner mass of the tumor and are non-migratory. However iCSCs, via paracrine signaling, induce conversion of non-stem cancer cells to CSCs that (i) are identical to the previously reported mCSCs, and (ii) in contrast to iCSCs, express chemokine receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), which is crucial for their metastatic potential. These mCSCs also demonstrate high in vivo tumorigenicity. Physical non-participation of iCSCs in metastasis is further validated in vivo, where only mCSCs are found to exist in the metastatic sites, lymph nodes and bone marrow, whereas the primary tumor retains both iCSCs and mCSCs. However, iCSCs ensure metastasis since their presence is crucial for deliverance of highly metastatic CXCR4(+) mCSCs to the migrating fraction of cells. Cumulatively, these results unveil a novel role of iCSCs in breast cancer metastasis as parental regulators of CXCR4(+) mCSCs, and highlight the therapeutic requisite of targeting iCSCs, but not CXCR4(+) mCSCs, to restrain breast cancer metastasis from the root by inhibiting the generation of mCSCs from iCSCs. Considering the pivotal role of iCSCs in tumor metastasis, the possibility of metastasis to be a 'stem cell phenomena' is suggested.