Survival update of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma in the OpACIN and OpACIN-neo trials.

BACKGROUND: Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking. PATIENTS AND METHODS: In OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2× ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n = 30), arm B (2× ipilimumab 1 mg/kg plus nivolumab 3 mg/kg q3w; n = 30), or arm C (2× ipilimumab 3 mg/kg q3w plus 2× nivolumab 3 mg/kg q2w; n = 26) followed by surgery. RESULTS: The median recurrence-free survival (RFS) and overall survival (OS) were not reached in either trial. After a median follow-up of 69 months for OpACIN, 1/7 patients with a pathologic response to neoadjuvant therapy had disease recurrence. The estimated 5-year RFS and OS rates for the neoadjuvant arm were 70% and 90% versus 60% and 70% for the adjuvant arm. After a median follow-up of 47 months for OpACIN-neo, the estimated 3-year RFS and OS rates were 82% and 92%, respectively. The estimated 3-year RFS rate for OpACIN-neo was 95% for patients with a pathologic response versus 37% for patients without a pathologic response (P < 0.001). In multiple regression analyses, pathologic response was the strongest predictor of disease recurrence. Of the 12 patients with distant disease recurrence after neoadjuvant therapy, 5 responded to subsequent anti-PD-1 and 8 to targeted therapy, although 7 patients showed progression after the initial response. CONCLUSIONS: Updated data confirm the high survival rates after neoadjuvant combination checkpoint inhibition in macroscopic stage III melanoma, especially for patients with a pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome.

The Observable Movement Quality scale for patients with low back pain (OMQ-LBP): validity and reliability in a primary care setting of physical therapy.

BACKGROUND: The Observable Movement Quality scale for patients with low back pain (OMQ-LBP) is a newly developed measurement instrument for use in primary care settings of physical and exercise therapists to assess movement quality (MQ) of patients with low back pain (LBP). OBJECTIVE: This study aims to determine validity, reliability and feasibility of the OMQ-LBP. The OMQ-LBP consists of a standardized movement circuit (performed twice) consisting of five daily activities problematic for LBP patients, which are scored with an 11-item observation list. METHODS: Construct validity was determined by testing seven hypotheses on associations between constructs (n = 85 patients with LBP) and four hypotheses on known group differences (n = 85 patients with LBP and n = 63 healthy controls; n = 35 matched participant-patients having VAS-pain ≥ 20 mm during and/or after both circuits and healthy controls). Internal consistency was analyzed with Cronbach's alpha (n = 85 patients with LBP). For inter- and intra-rater reliability Intraclass Correlation Coefficient (ICC) values were examined (n = 14 therapists: seven primary care physical therapists and seven exercise therapists). Additionally, content validity and feasibility were determined using thematic analysis of a brief interview with participants, patients (n = 38) and therapists (n = 14). RESULTS: After Bonferroni correction 2/7 associations between constructs and 2/4 significant group differences were confirmed. Cronbach's alpha was 0,79. The ICC-values of interrater reliability of the OMQ-LBP total score and the duration score were 0.56 and 0.99 and intra-rater reliability 0.82 and 0,93, respectively. Thematic analysis revealed five themes. Three themes elucidate that both patients and therapists perceived the content of the OMQ-LBP as valid. The fourth theme exhibits that OMQ-LBP provides a clear and unambiguous language for MQ in patients with LBP. Theme 5 depicts that the OMQ-LBP seems feasible, but video recording is time-consuming. CONCLUSIONS: The OMQ-LBP is a promising standardized observational assessment of MQ during the five most problematic daily activities in patients with LBP. It is expected that uniform and objective description and evaluation of MQ add value to clinical reasoning and facilitate uniform communication with patients and colleagues.

[A PhD completed. Positive effects for multidisciplinary orofacial treatment on tinnitus complaints]. / Serie: Hora est. Positieve effecten van multidisciplinaire orofaciale therapie op tinnitusklachten.

Tinnitus can be influenced by somatosensory input from the temporomandibular area and is then called somatic tinnitus. However, not much research has been conducted on whether orofacial treatment can decrease tinnitus severity in patients with somatic tinnitus. Therefore, the purpose of this thesis was 1) to evaluate the effect of orofacial treatment on tinnitus complaints, 2) to investigate potential prognostic indicators for a positive treatment outcome after orofacial therapy, and 3) to explore to what extent a decrease in temporomandibular disorder contributes to a reduction in tinnitus severity. In this thesis, it was found that orofacial therapy can reduce tinnitus severity in 61% of the patients with temporomandibular-related somatic tinnitus. Specifically, young female patients with a shorter duration of their tinnitus have the best prognosis. The analysis showed that 35% of the decrease of the tinnitus severity can be explained by the reduction in temporomandibular disorder.

Correction to: Cardiovascular causes of sudden unexpected death in children and adolescents (0-17 years) : A nationwide autopsy study in the Netherlands.

Correction to:Neth Heart J 2018 https://doi.org/10.1007/s12471-018-1152-y In the version of the article originally published online, there was an error in the 'Methods and results' section of the Abstract. It is stated that 'In the 10-14 year group, hypertrophic cardiomyopathy (n = 1) and ruptured ….

Cardiovascular causes of sudden unexpected death in children and adolescents (0-17 years) : A nationwide autopsy study in the Netherlands.

BACKGROUND: Little is known about the causes of unexpected death in minors (0-17 years). In young adults an important cause is cardiovascular disease, with primary arrhythmogenic disorders, atherosclerotic events, cardiomyopathies and myocarditis as main contributors. The aim of this autopsy study was to determine the contribution of cardiovascular disease to unexpected death in minors. METHODS AND RESULTS: In the Netherlands, systematic investigation of all cases of unexplained death in minors was compulsory in a nationwide governmental project during a 15-month period. Autopsies were performed according to a standardised protocol (autopsy rate 85%). A cardiovascular cause of death was found in 13/56 cases (23%). In the group <1 year, the main cardiovascular causes were various congenital defects (n = 3) and myocarditis (n = 2). In the 1-9 year group, no cardiovascular causes were found. In the 10-14 year group, coronary anomalies (n = 2) and arrhythmogenic cardiomyopathy (n = 1) were observed. In the 15­17 year group, hypertrophic cardiomyopathy (n = 1) and ruptured ascending aortic aneurysm (n = 1) were among the observed cardiovascular causes [corrected]. In 14/56 (25%) cases autopsy revealed no structural abnormalities that could explain the sudden death, mostly in the group <1 year. CONCLUSION: This national cohort with a high autopsy rate reveals a high incidence (23%) of cardiovascular diseases as the pathological substrate of sudden unexpected death in children. Another high percentage of minors (25%) showed no structural abnormalities, with the possibility of a genetic arrhythmia. These findings underline the importance of systematic autopsy in sudden death in minors, with implications for cardiogenetic screening of relatives.

One-stop-shop with confocal microscopy imaging vs. standard care for surgical treatment of basal cell carcinoma: an open-label, noninferiority, randomized controlled multicentre trial.

BACKGROUND: Routine punch biopsies are considered to be standard care for diagnosing and subtyping basal cell carcinoma (BCC) when clinically suspected. OBJECTIVES: We assessed the efficacy of a one-stop-shop concept using in vivo reflectance confocal microscopy (RCM) imaging as a diagnostic tool vs. standard care for surgical treatment in patients with clinically suspected BCC. METHODS: In this open-label, parallel-group, noninferiority, randomized controlled multicentre trial we enrolled patients with clinically suspected BCC at two tertiary referral centres in Amsterdam, the Netherlands. Patients were randomly assigned to the RCM one-stop-shop (diagnosing and subtyping using RCM followed by direct surgical excision) or standard care (planned excision based on the histological diagnosis and subtype of a punch biopsy). The primary outcome was the proportion of patients with tumour-free margins after surgical excision of BCC. RESULTS: Of the 95 patients included, 73 (77%) had a BCC histologically confirmed using a surgical excision specimen. All patients (40 of 40, 100%) in the one-stop-shop group had tumour-free margins. In the standard-care group tumour-free margins were found in all but two patients (31 of 33, 94%). The difference in the proportion of patients with tumour-free margins after BCC excision between the one-stop-shop group and the standard-care group was -0·06 (90% confidence interval -0·17-0·01), establishing noninferiority. CONCLUSIONS: The proposed new treatment strategy seems suitable in facilitating early diagnosis and direct treatment for patients with BCC, depending on factors such as availability of RCM, size and site of the lesion, patient preference and whether direct surgical excision is feasible.

Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma.

BACKGROUND: In vivo reflectance confocal microscopy (RCM) is a promising non-invasive skin imaging technique that could facilitate early diagnosis of basal cell carcinoma (BCC) instead of routine punch biopsies. However, the clinical value and utility of RCM vs. a punch biopsy in diagnosing and subtyping BCC is unknown. OBJECTIVE: To assess diagnostic accuracy of RCM vs. punch biopsy for diagnosing and subtyping clinically suspected primary BCC. METHODS: A prospective, consecutive cohort of 100 patients with clinically suspected BCC were included at two tertiary hospitals in Amsterdam, the Netherlands, between 3 February 2015 and 2 October 2015. Patients were randomized between two test-treatment pathways: diagnosing and subtyping using RCM imaging followed by direct surgical excision (RCM one-stop-shop) or planned excision based upon the histological diagnosis and subtype of punch biopsy (standard care). The primary outcome was the agreement between the index tests (RCM vs. punch biopsy) and reference standard (excision specimen) in correctly diagnosing BCC. The secondary outcome was the agreement between the index tests and reference standard in correctly identifying the most aggressive BCC subtypes. RESULTS: Sensitivity to detect BCC was similar for RCM and punch biopsy (100% vs. 93.94%), but a punch biopsy was more specific than RCM (79% vs. 38%). RCM expert evaluation for diagnosing BCC had a sensitivity of 100% and a specificity of 75%. The agreement between RCM and excision specimen in identifying the most aggressive BCC subtype ranged from 50% to 85% vs. 77% by a punch biopsy. CONCLUSION: Reflectance confocal microscopy and punch biopsy have comparable diagnostic accuracy to diagnose and subtype BCC depending on RCM experience. Although experienced RCM users could accurately diagnose BCC at a distance, we found an important difference in subtyping BCC. Future RCM studies need to focus on diagnostic accuracy, reliability and specific criteria to improve BCC subtype differentiation.

Neglected role of fungal community composition in explaining variation in wood decay rates.

Decomposition of wood is an important component of global carbon cycling. Most wood decomposition models are based on tree characteristics and environmental conditions; however, they do not include community dynamics of fungi that are the major wood decomposers. We examined the factors explaining variation in sapwood decay in oak tree stumps two and five years after cutting. Wood moisture content was significantly correlated with sapwood decay in younger stumps, whereas ITS-based composition and species richness of the fungal community were the best predictors for mass loss in the older stumps. Co-occurrence analysis showed that, in freshly cut trees and in younger stumps, fungal communities were nonrandomly structured, whereas fungal communities in old stumps could not be separated from a randomly assembled community. These results indicate that the most important factors explaining variation in wood decay rates can change over time and that the strength of competitive interactions between fungi in decaying tree stumps may level off with increased wood decay. Our field analysis further suggests that ascomycetes may have a prominent role in wood decay, but their wood-degrading abilities need to be further tested under controlled conditions. The next challenging step will be to integrate fungal community assembly processes in wood decay models to improve carbon sequestration estimates of forests.

Diagnosis of early pancreas graft failure via antibody-mediated rejection: single-center experience with 256 pancreas transplantations.

Early pancreas graft loss is usually attributed to technical failure while the possibility of antibody-mediated rejection (AMR) is generally overlooked. To investigate the role of AMR in early pancreas graft loss, we retrospectively assessed 256 patients with simultaneous pancreas-kidney transplantation (SPK) between 1985 and 2010 at our institute. We included 33 SPK patients who lost their pancreas graft <1 year after transplantation. AMR was diagnosed based on donor-specific antibodies, C4d and histology in 7 cases, 8 cases were suspicious for AMR and 18 pancreas graft losses were not due to AMR. Acute AMR occurred >1 month after transplantation in 6/7 cases, whereas all other causes typically led to loss <1 month after transplantation. Thrombotic lesions occurred equally among the 33 cases. In 12/18 concurrent kidney specimens, the diagnostic results paralleled those of the pancreas graft. All patients with acute AMR of the pancreas graft lost their renal grafts <1 year after transplantation. In the setting of a thrombotic event, histopathological analysis of early pancreas graft loss is advisable to rule out the possibility of AMR, particularly because a diagnosis of acute AMR has important consequences for renal graft outcomes.

Intraplaque hemorrhage in cardiac allograft vasculopathy.

Plaque hemorrhage, inflammation and microvessel density are key determinants of plaque vulnerability in native coronary atherosclerosis (ATS). This study investigates the role of intraplaque hemorrhage (IPH) and its relation with inflammation and microvessels in cardiac allograft vasculopathy (CAV) in posttransplanted patients. Seventy coronary plaques were obtained from 12 patients who died because of CAV. For each patient we collected both native heart and the allograft, at the time of transplantation and autopsy, respectively. Intralesion inflammation, microvessels and IPH were assessed semi-quantitatively. IPH was observed in 21/35 (60%) CAV lesions and in 8/35 (22.9%) native ATS plaques, with a strong association between fibrocellular lesions and IPH (p = 0.0142). Microvessels were detected in 26/35 (74.3%) of CAV lesions with perivascular leakage as sign of endothelial damage in 18/26 (69.2%). IPH was strongly associated with microvessels (p < 0.0001). Inflammation was present in 31/35 (88.6%) of CAV lesions. CAV IPH+ lesions were characterized by presence of both fresh and old hemorrhage in 12/21 (57.1%). IPH, associated with microvessel damage and inflammation, is an important feature of CAV. Fresh and old intralesion hemorrhage suggests ongoing remodeling processes promoting the lesion progression and vulnerability.

Advanced drinking water production by 1 kDa hollow fiber nanofiltration - Biological activated carbon filtration (HFNF - BACF) enhances biological stability and reduces micropollutant levels compared with conventional surface water treatment.

This study comprehensively investigates the quality of drinking water produced by novel advanced treatment encompassing 1 kDa hollow fiber nanofiltration (HFNF) - Biological Activated Carbon Filtration (BACF) from (reservoir) surface water, and compares this with drinking water after conventional 'CSF' pretreatment (coagulation - flocculation - sedimentation - media filtration - UV-disinfection) - BACF. The objective of HFNF - BACF treatment is to enhance the drinking water's quality in increased biological stability, reduced concentrations of organic micropollutants (OMP), and improvement in other chemical-physical parameters, whilst maintaining sufficient hardness to avoid subsequent remineralization. For this study a large suite of quality parameters was extensively monitored in pilot plants during nearly two years, enabling the incorporation of seasonal effects. HFNF - BACF treatment accomplished a similarly high level of biological stability as regrowth-free drinking waters (total organic carbon (DOC) 0.6 mg/L, assimilable organic carbon (AOC) 4 µg/L Ac-C and <1 µg/L biopolymer-C, total microbial growth potential (MGP) as BPC14 50 ng d/L and as BGP 170 × 103 cells/mL), unlike the conventional treatment (1.9 mg/L, 10 µg/L, 9 µg/L, 130 ng d/L and 170 × 103 cells/mL, respectively) where regrowth occurred in its distribution network. Average OMP removal, including perfluoro-alkyl substances (PFAS), by HFNF - BACF (54%) was higher than conventional treatment (37%). This improvement was mainly attributable to rejection in the HFNF membrane step, indicating that the DOC concentration after HFNF pretreatment was not yet sufficiently low to eliminate competitive adsorption and/or preloading in the BACF (confirmed by laboratory experiments). The advanced treatment also performed better in turbidity, particulates and most trace metals. Importantly, hardness retention by HFNF was only moderate, rendering remineralization unnecessary. Overall, this study demonstrates the superior performance in water quality of advanced HFNF - BACF treatment compared to conventional treatment.

Relative expression of hormone receptors by endothelial and smooth muscle cells in proliferative and non-proliferative areas of congenital arteriovenous malformations.

BACKGROUND: Episodic growth due to microvascular proliferations (MVP) has been reported in congenital arteriovenous malformations (AVM), which are normally quiescent lesions composed of mature malformed vessels. Since AVM also may worsen under conditions of hormonal dysregulation, we hypothesized that hormonal influences may stimulate this process of vasoproliferative growth through potential interactions with hormone receptors (HR). METHODS: 13 Cases of AVM tissue with histologically documented vasoproliferative growth were analyzed quantitatively for the presence and tissue localization of estrogen receptor (ER), progesterone receptor (PGR), growth hormone receptor (GHR) and follicle-stimulating hormone receptor (FSHR) in relation to resident cells of interest (endothelial cells (EC), smooth muscle cells (SMC) and mast cells (MC)) by applying multiplex immunohistochemistry (IHC) staining. Expression patterns in lesions with MVP and mature vessels were quantified and compared. Available fresh frozen tissues of 3 AVM samples were used to confirm the presence of HR using Reverse-Transcriptase quantitative Polymerase Chain Reaction (RT-qPCR). RESULTS: All four HR studied were expressed in all cases within EC and SMC in areas of MVP and mature vessels, but not in normal skin tissue. ER, GHR, and FSHR showed more expression in EC of MVP and in SMC of mature vessels. RT-qPCR confirmed presence of all 4 HR in both areas. CONCLUSION: Expression of ER, PGR, GHR, and FSHR in vasoproliferative areas of congenital AVM could explain onset of sudden symptomatic growth, as has observed in a subpopulation of patients. These findings may have implications for eventual anti-hormonal targeted therapy in the lesions involved.

Comparison of preserved vascular allografts using glycerol and University of Wisconsin solution in a goat carotid artery transplantation model.

BACKGROUND: Prosthetic grafts have poor patency rates in peripheral arterial reconstructions. Glycerol (GL)-preserved grafts are an alternative. The aim of this study was to examine patency, graft morphology and function of GL-preserved allografts in a goat carotid artery animal model. METHODS: The first group (n = 7) underwent bilateral replacement of the carotid artery by a carotid allograft that was preserved in GL for 1 week. In the second group (n = 5), a carotid artery allograft that was preserved in University of Wisconsin solution (UW) for 48 h was used. In the third group (n = 5), the jugular vein (autologous vein, AU) was used. The follow-up was 3 months. RESULTS: One UW graft and 1 GL graft occluded in the first 24 h postoperatively. Three-month primary patency rates for GL, UW and AU grafts were 93, 100 and 80%, respectively (p = 0.39). Graft diameter was increased in UW allografts (p < 0.005), whereas GL allografts remained unchanged. After explantation, GL allografts demonstrated contraction and relaxation capacity and lower intimal thickness (p < 0.001). CONCLUSION: GL preservation has proven to be a feasible method for arterial allograft transplantation in a large animal model with decreased intimal hyperplasia and renewed functional capability.

The iatrogenic pathology of percutaneous interventions in coronary arteries.

Acute coronary syndromes (ACS) represent the clinical manifestations of sudden flow limiting coronary artery disease leading to acute myocardial ischemia or necrosis. Treatment of progressive coronary stenosis or acute thrombotic occlusion by means of percutaneous coronary intervention (PCI) with balloon dilatation and stent placement aims to reduce the risk of myocardial ischemia or necrosis by restoring coronary flow. But, being an invasive technique, it is associated with a periprocedural and also eventually long-term risk of complications. Pathological examination of atherosclerotic coronary arteries after PCI treatment has been shown to be very helpful in providing insights in this iatrogenic pathology. Importantly, the pathological substrate of the treated coronary artery segment in patients with ACS differs significantly from coronary artery segments in patients with stable coronary artery disease. Such studies have shown that besides the physical trauma induced by a balloon or a stent also the specific histomorphological and biological properties of the treated coronary plaques play an important role in the risk of PCI related vascular complications. Major complications, which are thrombosis and restenosis, have reduced significantly over the past years. Still, late stent thrombosis remains a small but clinically important problem after placement of drug eluting stents DES, mainly related to delayed in stent wound healing and early withdrawal of antiplatelet therapy. Moreover, restenosis remains a problem in the still large group of patients treated with bare metal stents (BMS) worldwide. Both in case of BMS and DES emerging evidence from recent histopathological studies on coronary resected stents shows that the outcome of PCI can be influenced by the occurrence of in stent neo- atherosclerosis, in DES more frequent than in BMS, which in turn may stimulate both thrombosis and restenosis on the very long term.

Inflation and deflation timing of the AutoCAT 2 WAVE intra-aortic balloon pump using the autoPilot mode in a clinical setting.

The primary goal of this observational clinical study was to register the occurrence of incorrect inflation and deflation timing of an intra-aortic balloon pump in autoPilot mode. The secondary goal was to identify possible causes of incorrect timing. During IABP assistance of 60 patients, every four hours a strip was printed with the IABP frequency set to 1:2. Strips were examined for timing discrepancies beyond 40 ms from the dicrotic notch (inflation) and the end of the diastolic phase (deflation). In this way, 320 printed strips were examined. A total of 52 strips (16%) showed incorrect timing. On 24 of these strips, the incorrect timing was called incidental, as it showed on only one or a few beats. The other 28 cases of erroneous timing were called consistent, as more than 50% of the beats on the strip showed incorrect timing. We observed arrhythmia in 69% of all cases of incorrect timing. When timing was correct, arrhythmia was found on 13 (5%) of 268 strips. A poor quality electrocardiograph (ECG) signal showed on 37% of all strips with incorrect timing and 11% of all strips with proper timing. We conclude that inflation and deflation timing of the IABP is not always correct when using the autoPilot mode. The quality of the ECG input signal and the occurrence of arrhythmia appear to be related to erroneous timing. Switching from autoPilot mode to operator mode may not always prevent incorrect timing.

Modeling micropollutant removal by nanofiltration and reverse osmosis membranes: considerations and challenges.

Organic micropollutants (OMPs) in drinking water constitute a potential risk to human health; therefore, effective removal of these pollutants is required. Nanofiltration (NF) and reverse osmosis (RO) are promising membrane-based technologies to remove OMPs. In NF and RO, the rejection of OMPs depends on the properties and characteristics of the membrane, the solute, and the solution. In this review, we discuss how these properties can be included in models to study and predict the rejection of OMPs. Initially, an OMP classification is proposed to capture the relevant properties of 58 OMPs. Following the methodology described in this study, more and new OMPs can be easily included in this classification. The classification aims to increase the comprehension and mechanistic understanding of OMP removal. Based on the physicochemical principles used to classify the 58 OMPs, it is expected that other OMPs in the same groups will be similarly rejected. From this classification, we present an overview of the rejection mechanisms involved in the removal of specific OMP groups. For instance, we discuss the removal of OMPs classified as perfluoroalkyl substances (e.g., perfluorooctanoic acid, PFOA). These substances are highly relevant due to their human toxicity at extremely low concentration as well as their persistence and omnipresence in the environment. Finally, we discuss how the rejection of OMPs can be predicted by describing both the membrane-solution interface and calculating the transport of solutes inside the membrane. We illustrate the importance and impact of different rejection mechanisms and interfacial phenomena on OMP removal and propose an extended Nernst-Plank equation to calculate the transport of solutes across the membrane due to convection, diffusion, and electromigration. Finally, we show how the theory discussed in this review leads to improved predictions of OMP rejection by the membranes.

Therapeutic potential of vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: optimal timing and dosing of the drug.

BACKGROUND: The renoprotective effect of vasopressin V2 receptor antagonist (V2RA) is currently being tested in a clinical trial in early autosomal dominant polycystic kidney disease (ADPKD). If efficacious, this warrants life-long treatment with V2RA, however, with associated side effects as polydipsia and polyuria. We questioned whether we could reduce the side effects without influencing the renoprotective effect by starting the treatment later in the disease or by lowering drug dosage. METHODS: To investigate this, we administered V2RA OPC-31260 at a high (0.1%) and low (0.05%) dose to a tamoxifen-inducible kidney epithelium-specific Pkd1-deletion mouse model starting treatment at Day 21 (early) or 42 (advanced). After 3 and 6 weeks of treatment, we monitored physiologic and potential renoprotective effects. RESULTS: Initiation of V2RA treatment at advanced stage of the disease lacked renoprotective effects and had less pronounced physiologic effects than early initiation. After 3 weeks on a high dose, cyst ratio and kidney weight were reduced versus untreated controls (18 versus 25%, P = 0.05, and 0.33 versus 0.45 g, P = 0.03, respectively). After 6 weeks of treatment, however, this did not reach significance anymore, even at a high dose (cyst ratio 24 versus 27%, P = 0.12, and kidney weight 0.55 versus 0.66 g, P = 0.38). CONCLUSIONS: Our results suggest that intervention with V2RA should be instituted early in ADPKD and that it might be necessary to further increase the dosage of this drug later in the disease to decrease cyst growth.

The significance of the biomass subfraction of high-MW organic carbon for the microbial growth and maintenance potential of disinfectant-free drinking water produced from surface water.

Drinking water must be sufficiently biostable to avoid excessive microbial and invertebrate growth in disinfectant-free distribution systems. The production of biologically stable drinking water is challenging for conventional surface water treatment plants using reservoirs as feed water due to the presence of slowly biodegradable particulate and high-molecular weight biopolymeric organic carbon (high-MW OC) which increases the Microbial Growth Potential (MGP) in the feed water and produced drinking water. The study presented here provides new insights in the relationship between high-MW OC and MGP for a full-scale surface water treatment plant. Controlled-conditions addition series experiments showed that MGP increases linearly with the high-MW OC concentration with a seasonally variable ratio. Laboratory filtration indicated that MGP is mainly attributable to the high-MW OC subfraction of >  0.12 µm particle size coinciding with microbial biomass. Intensive field monitoring revealed clear seasonal patterns in the plant's feed water and treated water levels of high-MW OC, biomass and MGP. These parameters reach maximum levels in the periods of high water temperature with the notable exception of the treated water's high-MW OC concentration which exhibits an opposite seasonal pattern (reflecting seasonally variable removal in the treatment). Moreover, the field monitoring showed that MGP correlates well with the concentrations of biodegradable biopolymeric OC and with microbial biomass measured as ATP (adenosine triphosphate) and cell counts, but not with the total high-MW OC concentration in the treated water. Theoretical estimations showed that the OC quantities present in and consumed by the microbial biomass are in the same order of magnitude as slowly biodegradable biopolymers. From these results it is concluded that specifically the microbial biomass-associated and biodegradable biopolymeric OC subfraction of the totally present high-MW OC is important for MGP. Finally, the MGP-assay results and theoretical calculations showed for the high-MW OC matrix that the microbial biomass' OC consumption for maintenance is significant vis-á-vis that for growth, and that stable and high levels of biomass are sustained in the treated water which may adversely affect biological stability in the distribution network.