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Aim: In the last decade, the Netherlands has implemented various diagnostic and treatment strategies to enhance rectal cancer outcomes. This study, using data from the Prospective Dutch ColoRectal Cancer (PLCRC) cohort, investigates whether these multidisciplinary advancements have translated into improved health‐related quality of life (HRQoL) and functional outcomes for the general Dutch rectal cancer population. Methods: Patients with Stage I–III rectal cancer enrolled in the PLCRC cohort were included. HRQoL and functional outcomes were assessed 1 and 2 years after diagnosis using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ‐C30), EORTC QLQ Colorectal Cancer 29 and the Low Anterior Resection Syndrome score. HRQoL and functional outcomes were compared based on year of diagnosis (2014–2019). Results: A total of 1294 patients were included. Two years after diagnosis, patients diagnosed in 2019 (n = 392) had a clinically relevant higher score on physical (8.2, 95% CI 4.1–12.3), role (13.5, 95% CI 7.3–19.7) and social functioning (5.8, 95% CI 0.3–11.2) compared to those diagnosed in 2014 (n = 65). Additionally, patients diagnosed in 2019 experienced less fatigue 2 years after diagnosis compared to those diagnosed in 2014 (−8.6, 95% CI −14.1 to −3.0). The Low Anterior Resection Syndrome score showed no differences. Conclusion: The findings of this study suggest that over the past decade rectal cancer patients in the Netherlands have witnessed improvements in HRQoL across various domains. Most probably, the improvement is due to a combination of implementation of population screening, a more restrictive neoadjuvant radiotherapy policy and advances in minimally invasive surgery and organ preserving treatment options. [ABSTRACT FROM AUTHOR]

Fatigue is prevalent in colorectal cancer (CRC) survivors, impacting their health‐related quality of life (HRQoL). Inflammation‐induced activation of the kynurenine pathway may play a role in cancer‐related fatigue and HRQoL, but evidence is scarce. Therefore, we aimed to investigate longitudinal associations of plasma tryptophan, kynurenines, and ratios with fatigue and HRQoL in CRC survivors up to 12 months post‐treatment. Repeated measurements at 6 weeks, 6 months, and 12 months post‐treatment were performed in 249 stage I‐III CRC survivors. Plasma tryptophan and eight kynurenines were analyzed using liquid chromatography‐tandem mass spectrometry (LC/MS–MS). Fatigue and HRQoL outcomes were evaluated using validated questionnaires. Confounder‐adjusted linear mixed models were conducted to analyze longitudinal associations, with false discovery rate (FDR) correction. Higher tryptophan (Trp), kynurenic acid (KA), and xanthurenic acid (XA) concentrations, as well as a higher kynurenic acid‐to‐quinolinic acid ratio (KA/QA), were associated with less fatigue and better functioning, while a higher kynurenine‐to‐tryptophan ratio (KTR) and 3‐hydroxykynurenine ratio (HKr) were associated with more fatigue and worse functioning. Finally, higher KA and XA concentrations and a higher KA/QA ratio were associated with a higher overall HRQoL summary score, while a higher HKr was associated with a lower overall HRQoL summary score. In conclusion, we observed that tryptophan and several kynurenines were longitudinally associated with fatigue and HRQoL in CRC survivors up to 12 months post‐treatment. Future research is needed to validate our findings and explore the potential of the kynurenine pathway as intervention target for reducing fatigue and enhancing HRQoL after CRC treatment. [ABSTRACT FROM AUTHOR]

Aim: Faecal incontinence (FI) is a prevalent issue which can have a detrimental impact on the patient's quality of life. Current international guidelines lack strong treatment recommendations due to few studies in the field, in combination with the heterogeneity in outcome reporting. To address this, a core outcome set (COS) is proposed to standardize outcome reporting in FI studies, facilitating meta‐analyses and enhancing therapeutic recommendations. Through several steps outlined by COMET 'what' to measure will be determined prior to determining 'how' to measure these outcomes. This systematic review aims to identify 'what' outcomes have been used in FI intervention studies so far in adult patients as a starting phase for the development of a future COS for FI. Method: Medline, Embase and the Cochrane library were searched to identify all outcomes reported in comparative effectiveness trials assessing one or more treatment option in adult patients suffering from FI. The outcomes were categorized according to the Core Outcome Measurement in Effectiveness Trials (COMET) taxonomy to standardize outcome terminology, assess completeness, and inform subsequent steps in COS development. Results: A total of 109 studies were included, which revealed 51 unique outcomes classified into 38 domains within four core areas. On average four outcomes were reported per study (range 1–11). The most commonly reported outcomes were "severity of FI" (83%), "quality of life" (64%), "number of FI episodes" (40%), "anorectal motor function" (39%), and "frequency of bowel movements" (16%). Conclusion: This systematic review offers an overview of outcomes reported in FI studies, highlighting the heterogeneity between studies. This heterogeneity emphasizes the need for standardizing outcome reporting which can be established through the creation of a COS. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is identified as a lifestyle‐related type of cancer. There is an increasing emphasis on lifestyle interventions targeting pivotal lifestyle factors such as excess weight, cigarette smoking, alcohol consumption, poor diet and physical inactivity as primary and tertiary prevention. Furthermore, modifying these lifestyle factors has the potential to improve quality of life for cancer patients. We aim to identify, appraise and synthesise the available evidence regarding the effect of combined lifestyle interventions on quality of life in colorectal cancer survivors. Methods: Pubmed, Ovid Embase and the Cochrane Library were searched for studies reporting on quality of life in post‐treatment colorectal cancer patients. The systematic literature search was performed according to the Preferred Reporting Items for systematic reviews and meta‐analysis (PRISMA) guidelines. Results: Five articles reporting on 719 individual patients were included. Two studies reported significantly better results in (cancer‐specific) quality‐of‐life questionnaires for patients after combined lifestyle interventions. Conclusion: We conclude that there is some evidence that combined lifestyle interventions could have beneficial effects on the quality of life of colorectal cancer survivors. Future randomised controlled trials reporting on quality of life of combined lifestyle interventions in colorectal cancer survivors are warranted. [ABSTRACT FROM AUTHOR]

Aim: Sacral neuromodulation (SNM) is a minimally invasive treatment option for functional constipation. Evidence regarding its effectiveness is contradictory, driven by heterogeneous study populations and designs. The aim of this study was to assess the effectiveness, safety and cost‐effectiveness of SNM in children and adults with refractory idiopathic slow‐transit constipation (STC). Method: OVID Medline, OVID Embase, Cochrane Library, the KSR Evidence Database, the NHS Economic Evaluation Database and the International HTA Database were searched up to 25 May 2023. For effectiveness outcomes, randomized controlled trials (RCTs) were selected. For safety outcomes, all study designs were selected. For cost‐effectiveness outcomes, trial‐ and model‐based economic evaluations were selected for review. Study selection, risk of bias and quality assessment, and data extraction were independently performed by two reviewers. For the intervention 'sacral neuromodulation' effectiveness outcomes included defaecation frequency and constipation severity. Safety and cost‐effectiveness outcomes were, respectively, adverse events and incremental cost‐effectiveness ratios. Results: Of 1390 records reviewed, 67 studies were selected for full‐text screening. For effectiveness, one cross‐over and one parallel‐group RCT was included, showing contradictory results. Eleven studies on safety were included (four RCTs, three prospective cohort studies and four retrospective cohort studies). Overall infection rates varied between 0% and 22%, whereas reoperation rates varied between 0% and 29%. One trial‐based economic evaluation was included, which concluded that SNM was not cost‐effective compared with personalized conservative treatment at a time horizon of 6 months. The review findings are limited by the small number of available studies and the heterogeneity in terms of study populations, definitions of refractory idiopathic STC and study designs. Conclusion: Evidence for the (cost‐)effectiveness of SNM in children and adults with refractory idiopathic STC is inconclusive. Reoperation rates of up to 29% were reported. [ABSTRACT FROM AUTHOR]

Aim: The primary aim of the European Society of Coloproctology (ESCP) Guideline Development Group (GDG) was to produce high‐quality, evidence‐based guidelines for the management of cryptoglandular anal fistula with input from a multidisciplinary group and using transparent, reproducible methodology. Methods: Previously published methodology in guideline development by the ESCP has been replicated in this project. The guideline development process followed the requirements of the AGREE‐S tool kit. Six phases can be identified in the methodology. Phase one sets the scope of the guideline, which addresses the diagnostic and therapeutic management of perianal abscess and cryptoglandular anal fistula in adult patients presenting to secondary care. The target population for this guideline are healthcare practitioners in secondary care and patients interested in understanding the clinical evidence available for various surgical interventions for anal fistula. Phase two involved formulation of the GDG. The GDG consisted of 21 coloproctologists, three research fellows, a radiologist and a methodologist. Stakeholders were chosen for their clinical and academic involvement in the management of anal fistula as well as being representative of the geographical variation among the ESCP membership. Five patients were recruited from patient groups to review the draft guideline. These patients attended two virtual meetings to discuss the evidence and suggest amendments. In phase three, patient/population, intervention, comparison and outcomes questions were formulated by the GDG. The GDG ratified 250 questions and chose 45 for inclusion in the guideline. In phase four, critical and important outcomes were confirmed for inclusion. Important outcomes were pain and wound healing. Critical outcomes were fistula healing, fistula recurrence and incontinence. These outcomes formed part of the inclusion criteria for the literature search. In phase five, a literature search was performed of MEDLINE (Ovid), PubMed, Embase (Ovid) and the Cochrane Database of Systematic Reviews by eight teams of the GDG. Data were extracted and submitted for review by the GDG in a draft guideline. The most recent systematic reviews were prioritized for inclusion. Studies published since the most recent systematic review were included in our analysis by conducting a new meta‐analysis using Review manager. In phase six, recommendations were formulated, using grading of recommendations, assessment, development, and evaluations, in three virtual meetings of the GDG. Results: In seven sections covering the diagnostic and therapeutic management of perianal abscess and cryptoglandular anal fistula, there are 42 recommendations. Conclusion: This is an up‐to‐date international guideline on the management of cryptoglandular anal fistula using methodology prescribed by the AGREE enterprise. [ABSTRACT FROM AUTHOR]

Aim: In this study we aimed to assess the responsiveness of the symptom score of the recently developed Patient‐Reported Outcome Measure‐Haemorrhoidal Impact and Satisfaction Score (PROM‐HISS). Furthermore, the minimally relevant difference (MRD) was determined. Method: The responsiveness of PROM‐HISS was tested using a criterion‐based (i.e. anchor) and construct‐based (i.e. hypotheses testing) approach. Patients with haemorrhoidal disease (HD) completed the PROM‐HISS before and 1 week after treatment in hospital. A global self‐assessment of change question (SCQ) was administered 1‐week after treatment and functioned as the criterion. The following analyses were performed: (1) correlation between the PROM‐HISS symptom score and the criterion (SCQ) and (2) hypotheses testing. The MRD was determined as change in symptoms of the subgroup reporting 'somewhat fewer complaints' on the SCQ. Results: Between February and August 2022, 94 patients with grade II–IV HD from three hospitals were included. The correlation between the SCQ and a change on the PROM‐HISS symptom score was 0.595 indicating that an improvement on the SCQ corresponds to an improvement on the PROM‐HISS symptom score. As hypothesized, the mean change in PROM‐HISS scores was significantly different between subgroups of patients based on their SCQ responses. Patients reporting a small change in HD symptoms on the SCQ corresponded to a mean change of 0.3 on the PROM‐HISS symptom score. Conclusion: The PROM‐HISS symptom score is a responsive instrument as it identifies change in HD symptoms because of treatment. The estimated MRD of 0.3 can be used to inform clinical research and practice. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to translate the Dutch patient‐reported outcome measure‐haemorrhoidal impact and satisfaction score (PROM‐HISS) to English and perform a cross‐cultural validation. Method: The ISPOR good practice guidelines for the cross‐cultural validation of PROMs were followed and included two steps: (1) Two forward and two backward translations. The forward translation concerned the translation from the source language (Dutch) to the target language (English), performed by two independent English speakers, one medical doctor and one nonmedical. Subsequently, a discussion about discrepancies in the reconciled version was performed by a stakeholder group. (2) Cognitive interviews were held with patients with haemorrhoidal disease (HD), probing the comprehensibility and comprehensiveness of the PROM‐HISS. Results: Discrepancies in the reconciled forward translation concerned the terminology of HD symptoms. Furthermore, special attention was paid to the response options, ranging from "not at all", indicating minor symptoms, to "a lot", implying many symptoms. Consensus among the stakeholder group about the final version of the translated PROM‐HISS was reached. Interviews were conducted with 10 native English‐speaking HD patients (30% female), with a mean age of 44 years (24–83) and primarily diagnosed with grade II HD (80%). The mean time to complete the PROM‐HISS was 1 min 43 s. Patients showed a good understanding of the questions and response options, found all items relevant and did not miss important symptoms or topics. Conclusion: The translated English language PROM‐HISS is a valid tool to assess symptoms of HD, its impact on daily activities and patient satisfaction with HD treatment. [ABSTRACT FROM AUTHOR]

The underlying biological mechanisms causing persistent fatigue complaints after colorectal cancer treatment need further investigation. We investigated longitudinal associations of circulating concentrations of 138 metabolites with total fatigue and subdomains of fatigue between 6 weeks and 2 years after colorectal cancer treatment. Among stage I‐III colorectal cancer survivors (n = 252), blood samples were obtained at 6 weeks, and 6, 12 and 24 months posttreatment. Total fatigue and fatigue subdomains were measured using a validated questionnaire. Tandem mass spectrometry was applied to measure metabolite concentrations (BIOCRATES AbsoluteIDQp180 kit). Confounder‐adjusted longitudinal associations were analyzed using linear mixed models, with false discovery rate (FDR) correction. We assessed interindividual (between‐participant differences) and intraindividual longitudinal associations (within‐participant changes over time). In the overall longitudinal analysis, statistically significant associations were observed for 12, 32, 17 and three metabolites with total fatigue and the subscales "fatigue severity," "reduced motivation" and "reduced activity," respectively. Specifically, higher concentrations of several amino acids, lysophosphatidylcholines, diacylphosphatidylcholines, acyl‐alkylphosphatidylcholines and sphingomyelins were associated with less fatigue, while higher concentrations of acylcarnitines were associated with more fatigue. For "fatigue severity," associations appeared mainly driven by intraindividual associations, while for "reduced motivation" stronger interindividual associations were found. We observed longitudinal associations of several metabolites with total fatigue and fatigue subscales, and that intraindividual changes in metabolites over time were associated with fatigue severity. These findings point toward inflammation and an impaired energy metabolism due to mitochondrial dysfunction as underlying mechanisms. Mechanistic studies are necessary to determine whether these metabolites could be targets for intervention. [ABSTRACT FROM AUTHOR]

Aim: Due to the introduction of a new implantable pulse generator (IPG), the Interstim II, patients with either a dynamic graciloplasty or an abdominally placed IPG for sacral neuromodulation could not undergo surgery to replace their IPG in the case of end of battery life. For these patients, the Medtronic Replacement Adaptor 09106 was created. This retrospective case series aims to study safety and feasibility of the Medtronic Replacement Adaptor 09106 in patients with abdominally placed IPGs. Methods: Seventeen patients (11 women, six men) received a replacement adaptor with a follow‐up of 6 months. Outcome measures consisted of a bowel habit diary. Adverse events were classified using the Clavien–Dindo classification. Results: Outcome measures in the bowel habit diaries after replacement (feasibility) did not differ significantly from outcome measures before replacement. Adverse events occurred in four out of 17 patients (24%): two patients initially showed pocket site pain (Clavien–Dindo Grade I), which resolved without intervention. One patient suffered from poor wound closure (Clavien–Dindo Grade II) and one patient had persisting pocket pain (Clavien–Dindo Grade IIIa) for which a pocket revision was performed. Statistical analyses were performed making paired comparisons using a Wilcoxon signed rank test. Conclusion: The Medtronic Replacement Adaptor 09106 is a valuable option for patients with dynamic graciloplasty or sacral neuromodulation and abdominal IPG and has complication rates similar to replacement of the Interstim without Replacement Adaptor 09106. [ABSTRACT FROM AUTHOR]

Specific interactions with phospholipids are often critical for the function of proteins or drugs, but studying these interactions at high resolution remains difficult, especially in complex membranes that mimic biological conditions. In principle, molecular interactions with phospholipids could be directly probed by solid‐state NMR (ssNMR). However, due to the challenge to detect specific lipids in mixed liposomes and limited spectral sensitivity, ssNMR studies of specific lipids in complex membranes are scarce. Here, by using purified biological 13C,15N‐labeled phospholipids, we show that we can selectively detect traces of specific lipids in complex membranes. In combination with 1H‐detected ssNMR, we show that our approach provides unprecedented high‐resolution insights into the mechanisms of drugs that target specific lipids. This broadly applicable approach opens new opportunities for the molecular characterization of specific lipid interactions with proteins or drugs in complex fluid membranes. [ABSTRACT FROM AUTHOR]

Aim: Haemorrhoidal disease (HD) is a frequently occurring disorder with a significant negative impact on a patient's quality of life. Here, we describe the development and validation of the Dutch patient reported outcome measure‐haemorrhoidal impact and satisfaction score (PROM‐HISS). Methods: The development of the PROM‐HISS followed recommended guidelines. Face and content validity, structural properties, reliability and construct validity were evaluated in a HD population. Reliability was tested by assessing the test‐retest reliability, defined by the intraclass correlation coefficient (ICC), and internal consistency measured with Cronbach's alpha. Construct validity was evaluated using confirmatory factor analysis (CFA) and hypotheses testing. Results: The PROM‐HISS consists of three domains: (1) HD symptoms (blood loss; pain; prolapse; soiling; itching), (2) impact of symptoms on daily activities, and (3) satisfaction with treatment. The PROM‐HISS showed good face and content validity. The PROM‐HISS was completed by 102 patients (65% male), with a mean age of 58 years (23–81 years). The ICCs of the different items in the domain HD symptoms ranged between 0.56 and 0.79 and were interpreted as good. The Cronbach's alpha value was 0.80 and considered satisfactory. The CFA provided further evidence for construct validity with a good model fit. A high score on the symptoms of HD correlated with a high impact of HD on daily activities (Pearson's r = 0.632, p < 0.01) and a low degree of satisfaction (Pearson's r = 0.378, p < 0.01). Conclusion: The PROM‐HISS is a reliable and valid instrument to evaluate symptoms of HD, impact on daily activities and satisfaction with treatment. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to assess the clinical and oncological outcome of a selected group of stage IV rectal cancer patients managed by the watch‐and‐wait approach following a (near‐)complete response of the primary rectal tumour after radiotherapy. Method: Patients registered in the Dutch watch‐and‐wait registry since 2004 were selected when diagnosed with synchronous stage IV rectal cancer. Data on patient characteristics, treatment details, follow‐up and survival were collected. The 2‐year local regrowth rate, organ‐preservation rate, colostomy‐free rate, metastatic progression‐free rate and 2‐ and 5‐year overall survival were analysed. Results: After a median follow‐up period of 35 months, local regrowth was observed in 17 patients (40.5%). Nine patients underwent subsequent total mesorectal excision, resulting in a permanent colostomy in four patients. The 2‐year local regrowth rate was 39.9%, the 2‐year organ‐preservation rate was 77.1%, the 2‐year colostomy‐free rate was 88.1%, and the 2‐year metastatic progression‐free rate was 46.7%. The 2‐ and 5‐year overall survival rates were 92.0% and 67.5%. Conclusion: The watch‐and‐wait approach can be considered as an alternative to total mesorectal excision in a selected group of stage IV rectal cancer patients with a (near‐)complete response following pelvic radiotherapy. Despite a relatively high regrowth rate, total mesorectal excision and a permanent colostomy can be avoided in the majority of these patients. [ABSTRACT FROM AUTHOR]

Aim: Patient‐reported outcome measures (PROMs) are increasingly being used in routine cancer care to evaluate treatment and monitor symptoms, function and other aspects of quality of life (QoL). There is no suitable PROM for rectal cancer patients following a watch‐and‐wait (W&W) programme. Insight into patient experiences with this programme is an essential step in the development of a PROM. The aim of this qualitative study was to provide insights into the most important functional outcomes and QoL features experienced by patients during our W&W programme. Method: Patients with locally advanced rectal cancer who are enrolled in the W&W programme in the Netherlands were interviewed by telephone using a semistructured interview guide. All interviews were digitally audio‐recorded, transcribed verbatim and coded. A thematic approach was used to analyse the data and identify themes and subthemes of importance to patients. Results: Eighteen patients were interviewed (78% male, mean age 68 years, range 52–83 years). Physical complaints after treatment were present, most notably gastrointestinal problems, neuropathy and fatigue. Furthermore, patients were anxious about a possible recurrence, had a fear of surgery or a stoma, or were experiencing a general feeling of apprehension in daily life. Many patients had different coping mechanisms, such as acceptance, and there were few limitations in daily life. Conclusion: We identified important functional outcomes, such as gastrointestinal complaints, fatigue and neuropathy, in patients who were enrolled in this W&W programme. Furthermore, an emotional burden and unmet needs were reported by these patients. These findings can be used to improve clinical practice and inform the development of a PROM. [ABSTRACT FROM AUTHOR]

Purpose: To describe the treatment outcomes and recurrence risk of chronic central serous chorioretinopathy (cCSC) in patients who had complete resolution of subretinal fluid (SRF) after either primary half‐dose photodynamic therapy (PDT) or high‐density subthreshold micropulse laser (HSML) in the PLACE trial. Methods: This multicentre prospective follow‐up study evaluated cCSC patients at 1 year after completion of the PLACE trial. Outcomes included: complete resolution of SRF on OCT, best‐corrected visual acuity (BCVA) in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, retinal sensitivity on microperimetry and a visual function questionnaire (NEI‐VFQ25). Results: Twenty‐nine out of 37 patients who received half‐dose PDT and 15 out of 17 patients who received HSML could be evaluated at final visit. At final visit, 93% of the patients treated with half‐dose PDT had complete resolution of SRF, compared with 53% of HSML‐treated patients (p = 0.006). At final visit, the mean estimate increase in the PDT group compared with the HSML group was + 2.1 ETDRS letters, +0.15 dB for the retinal sensitivity and + 5.1 NEI‐VFQ25 points (p = 0.103, p = 0.784 and p = 0.071, respectively). The mean estimated central retinal thickness in the half‐dose PDT group was −7.0 µm compared with the HSML group (p = 0.566). The mean estimated subfoveal choroidal thickness in the half‐dose PDT group was −16.6 µm compared with the HSML group (p = 0.359). Conclusion: At 20 months after treatment, cCSC patients successfully treated with half‐dose PDT are less likely to have recurrences of SRF compared with those successfully treated with HSML. However, functional outcomes did not differ. [ABSTRACT FROM AUTHOR]

Aim: Many of the current follow‐up schedules in a watch‐and‐wait approach include very frequent MRI and endoscopy examinations to ensure early detection of local regrowth (LR). The aim of this study was to analyse the occurrence and detection of LR in a watch‐and‐wait cohort and to suggest a more efficient follow‐up schedule. Method: Rectal cancer patients with a clinical complete response after neoadjuvant therapy were prospectively and retrospectively included in a multicentre watch‐and‐wait registry between 2004 and 2018, with the current follow‐up schedule with 3‐monthly endoscopy and MRI in the first year and 6 monthly thereafter. A theoretical comparison was constructed for the detection of LR in the current follow‐up schedule against four other hypothetical schedules. Results: In all, 50/304 (16%) of patients developed a LR. The majority (98%) were detected at ≤2 years, located in the lumen (94%) and were visible on endoscopy (88%). The theoretical comparison of the different hypothetical schedules suggests that the optimal follow‐up schedule should focus on the first 2 years with 3‐monthly endoscopy and 3–6 monthly MRI. Longer intervals in the first 2 years will cause delays in diagnosis of LR ranging from 0 to 5 months. After 2 years, increasing the interval from 6 to 12 months did not cause important delays. Conclusion: The optimal follow‐up schedule for a watch‐and‐wait policy in patients with a clinical complete response after chemoradiation for rectal cancer should include frequent endoscopy and to a lesser degree MRI in the first 2 years. Longer intervals, up to 12 months, can be considered after 2 years. [ABSTRACT FROM AUTHOR]

Aim: There is an ongoing debate as to whether or not the efficacy of sacral neuromodulation (SNM) is optimized by maximizing the total number of active electrode poles (AEPs) during lead placement because there are more programming options. However, this is at the cost of increased operating time. The aims of this study were to establish if a higher number of AEPs improves SNM efficacy during the trial period and after permanent implantable pulse generator (IPG) placement and if there is there a correlation between number of AEPs and battery life of the first placed IPG. Method: This was a single centre retrospective cohort study of new patients with faecal incontinence who underwent SNM between 2000 and 2018. Exclusion criteria were sphincter defect > 30%, rectocele/enterocele Grade 3 or higher and incomplete records. Results: In all, 288/456 (63%) patients (women 91%; mean age 58.5 ± 11.7 years) were eligible for analysis. The number of AEPs during lead placement was two (n = 42, 14.5%), three (n = 82, 28.5%) and four (n = 164, 57%). There was no association between the number of AEPs during tined lead placement and long‐term efficacy. Neither the success rate of the trial phase nor the battery life after first placed IPG was influenced by the number of AEPs. Conclusion: In this study, the number of AEPs does not seem to influence long‐term efficacy of SNM success rate during the trial phase or the battery life of the first placed IPG. However, we also suggest that at the very least there should be two AEPs at lead placement. [ABSTRACT FROM AUTHOR]

Colorectal cancer is the second most common cause of cancer‐related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I–IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography‐mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I–IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (pFDR < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl‐alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (pFDR < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression. What's new? Metabolomics is a sophisticated method for investigating whether the metabolite profile of a patient's blood, etc., may reflect the pathophysiological state of cancers and other diseases. In the present study, the authors analyzed circulating metabolites, seeking biomarkers related to colorectal cancer progression. Their results at various stages of colorectal cancer suggest that metabolic pathways involving citrulline, histidine, and other molecules that have been previously implicated in colorectal cancer development may also be linked to progression. [ABSTRACT FROM AUTHOR]

Aim: The goal of this European Society of ColoProctology project was to establish a multidisciplinary, international guideline for haemorrhoidal disease (HD) and to provide guidance on the most effective (surgical) treatment for patients with HD. Methods: The development process consisted of six phases. In phase one we defined the scope of the guideline. The patient population included patients with all stages of haemorrhoids. The target group for the guideline was all practitioners treating patients with haemorrhoids and, in addition, healthcare workers and patients who desired information regarding the treatment management of HD. The guideline needed to address both the diagnosis of and the therapeutic modalities for HD. Phase two consisted of the compilation of the guideline development group (GDG). All clinical members needed to have affinity with the diagnosis and treatment of haemorrhoids. Further, attention was paid to the geographical distribution of the clinicians. Each GDG member identified at least one patient in their country who could read English to comment on the draft guideline. In phase three review questions were formulated, using a reversed process, starting with possible recommendations based on the GDG's knowledge. In phase four a literature search was performed in MEDLINE (Ovid), PubMed, Embase (Ovid) and the Cochrane Database of Systematic Reviews. The search was focused on existing systematic reviews addressing each review question, supplemented by other studies published after the time frame covered by the systematic reviews. In phase five data of the included papers were extracted by the surgical resident (RT) and checked by the methodologist (JK) and the GDG. If needed, meta‐analysis of the systematic reviews was updated by the surgical resident and the methodologist using Review Manager. During phase six the GDG members decided what recommendations could be made based on the evidence found in the literature using GRADE. Results: There were six sections: (i) symptoms, diagnosis and classification; (ii) basic treatment; (iii) outpatient procedures; (iv) surgical interventions; (v) special situations; (vi) other surgical techniques. Thirty‐four recommendations were formulated. Conclusion: This international, multidisciplinary guideline provides an up to date and evidence based summary of the current knowledge of the management of HD and may serve as a useful guide for patients and clinicians. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to determine predictive factors for the circumferential resection margin (CRM) within two northern European countries with supposed similarity in providing rectal cancer care. Method: Data for all patients undergoing rectal resection for clinical tumour node metastasis (TNM) stage I–III rectal cancer were extracted from the Swedish ColoRectal Cancer Registry and the Dutch ColoRectal Audit (2011–2015). Separate analyses were performed for cT1–3 and cT4 stage. Predictive factors for the CRM were determined using univariable and multivariable logistic regression analyses. Results: A total of 6444 Swedish and 12 089 Dutch patients were analysed. Over time the number of hospitals treating rectal cancer decreased from 52 to 42 in Sweden, and 82 to 79 in the Netherlands. In the Swedish population, proportions of cT4 stage (17% vs 8%), multivisceral resection (14% vs 7%) and abdominoperineal excision (APR) (37% vs 31%) were higher. The overall proportion of patients with a positive CRM (CRM+) was 7.8% in Sweden and 5.4% in the Netherlands. In both populations with cT1–3 stage disease, common independent risk factors for CRM+ were cT3, APR and multivisceral resection. No common risk factors for CRM+ in cT4 stage disease were found. An independent impact of hospital volume on CRM+ could be demonstrated for the cT1–3 Dutch population. Conclusion: Within two northern European countries with implemented clinical auditing, rectal cancer care might potentially be improved by further optimizing the treatment of distal and locally advanced rectal cancer. [ABSTRACT FROM AUTHOR]

The peptidoglycan (PG) sacculus provides bacteria with the mechanical strength to maintain cell shape and resist osmotic stress. Enlargement of the mesh‐like sacculus requires the combined activity of peptidoglycan synthases and hydrolases. In Escherichia coli, the activity of two PG synthases is driven by lipoproteins anchored in the outer membrane (OM). However, the regulation of PG hydrolases is less well understood, with only regulators for PG amidases having been described. Here, we identify the OM lipoprotein NlpI as a general adaptor protein for PG hydrolases. NlpI binds to different classes of hydrolases and can specifically form complexes with various PG endopeptidases. In addition, NlpI seems to contribute both to PG elongation and division biosynthetic complexes based on its localization and genetic interactions. Consistent with such a role, we reconstitute PG multi‐enzyme complexes containing NlpI, the PG synthesis regulator LpoA, its cognate bifunctional synthase, PBP1A, and different endopeptidases. Our results indicate that peptidoglycan regulators and adaptors are part of PG biosynthetic multi‐enzyme complexes, regulating and potentially coordinating the spatiotemporal action of PG synthases and hydrolases. Synopsis: In bacteria, enzyme activities regulating peptidoglycan biosynthesis and degradation have to be adjusted during cell wall growth. Here, the outer membrane‐anchored lipoprotein NlpI is shown to facilitate formation of peptidoglycan synthase and hydrolase multi‐enzyme complexes to coordinate correct enlargement of the cell wall peptidoglycan layer in E. coli. NlpI binds to different classes of peptidoglycan hydrolases.NlpI can specifically form multimeric complexes with various endopeptidases.NlpI contributes to peptidoglycan biosynthetic complexes active in cell elongation and cell division based on its cellular localization and genetic interactions.NlpI forms multi‐enzyme complexes containing peptidoglycan synthases and hydrolases in vitro. [ABSTRACT FROM AUTHOR]

Background and Aim: Standardizing evaluative outcomes and their assessment facilitates comparisons between clinical studies and provides a basis for comparing direct effects of different treatment options. The aim of this study was to systematically review types of outcomes and measurement instruments used in studies regarding treatment options for slow‐transit constipation (STC) in adults. Methods: In this systematic review of the literature, we searched MEDLINE, Embase, and PsycINFO from inception through February 2018, for papers assessing any STC treatment in adult patients. Outcomes were systematically extracted and categorized in domains using the conceptual framework of the Outcome Measures in Rheumatology filter 2.0. Outcome reporting was stratified by decade of publication, intervention, and study type. Results: Forty‐seven studies were included in this systematic review. Fifty‐nine different types of outcomes were identified. The outcomes were structured in three core areas and 18 domains. The most commonly reported domains were defecation functions (94%), gastrointestinal transit (53%), and health‐care service use (51%). The most frequently reported outcomes were defecation frequency (83%), health‐related quality of life (43%), and adverse events and complications (43%). In 62% of the studies, no primary outcome was defined, whereas in two studies, more than one primary outcomes were selected. A wide diversity of measurement instruments was used to assess the reported outcomes. Conclusion: Outcomes reported in studies on STC in adults are heterogeneous. A lack of standardization complicates comparisons between studies. Developing a core outcome set for STC in adults could contribute to standardization of outcome reporting in (future) studies. [ABSTRACT FROM AUTHOR]

Aim: There is considerable heterogeneity in outcomes in studies reporting on the treatment of haemorrhoidal disease (HD). The aim of this study was to develop a Core Outcome Set (COS) for HD in cooperation with the European Society of Coloproctology. Method: A Delphi study was performed according to the Outcome Measures in Rheumatology (OMERACT) methodology. In total 38 healthcare professionals and 30 patients were invited to the panel. Previously, 10 outcome domains and 59 outcomes were identified through a systematic literature review. In this study, these domains and outcomes were formed into one questionnaire for healthcare professionals and a separate questionnaire for patients. Sequential questionnaire rounds prioritizing the domains and outcomes were conducted. Panel members were asked to rate the appropriateness of each domain and outcome on a nine‐point Likert scale. During a face‐to‐face meeting, healthcare professionals agreed on the primary and secondary end‐points of the COS for HD. Finally, a short survey was sent to the healthcare professionals in order to reach consensus on how the chosen end‐points should be assessed and at which time points. Results: The response rate in questionnaire round 1 for healthcare professionals was 44.7% (n = 17). Sixteen out of 17 healthcare professionals also completed the questionnaire in round 2. The response rate for the patient questionnaire was 60% (n = 18). Seventeen healthcare professionals participated in the face‐to‐face meeting. The questionnaire rounds did not result in a clear‐cut selection of primary and secondary end‐points. Most domains and outcomes were considered important, and only three outcomes were excluded. During the face‐to‐face meeting, agreement was reached to select the domain 'symptoms' as primary end‐point, and 'complications', 'recurrence' and 'patient satisfaction' as secondary end‐points in the COS for HD. Furthermore, consensus was reached that the domain 'symptoms' should be a patient reported outcome measure and should include the outcomes 'pain' and 'prolapse', 'itching', 'soiling' and 'blood loss'. The domain 'complications' should include the outcomes 'incontinence', 'abscess', 'urinary retention', 'anal stenosis' and 'fistula'. Consensus was reached to use 'reappearance of initial symptoms' as reported by the patient to define recurrence. During an additional short survey, consensus was reached that 'incontinence' should be assessed by the Wexner Fecal Incontinence Score, 'abscess' by physical examination, 'urinary retention' by ultrasonography, 'anal stenosis' by physical examination, and 'fistula' by physical examination and MR imaging if inconclusive. During follow‐up, the outcome 'symptoms' should be assessed at baseline, 7 days, 6 weeks and 1 year post‐procedure. The outcomes 'abscess' and 'urinary retention' should be assessed 7 days post‐procedure and 'incontinence', 'anal stenosis' and 'fistula' 1 year post‐procedure. Conclusions: We developed the first European Society of Coloproctology COS for HD based on an international Delphi study among healthcare professionals. The next step is to incorporate the patients' perspective in the COS. Use of this COS may improve the quality and uniformity of future research and enhance the analysis of evidence. [ABSTRACT FROM AUTHOR]

Summary: Bacteria surround their cytoplasmic membrane with an essential, stress‐bearing peptidoglycan (PG) layer consisting of glycan chains linked by short peptides into a mesh‐like structure. Growing and dividing cells expand their PG layer using inner‐membrane anchored PG synthases, including Penicillin‐binding proteins (PBPs), which participate in dynamic protein complexes to facilitate cell wall growth. In Escherichia coli, and presumably other Gram‐negative bacteria, growth of the mainly single layered PG is regulated by outer membrane‐anchored lipoproteins. The lipoprotein LpoB is required to activate PBP1B, which is a major, bi‐functional PG synthase with glycan chain polymerising (glycosyltransferase) and peptide cross‐linking (transpeptidase) activities. In this work we show how the binding of LpoB to the regulatory UB2H domain of PBP1B activates both activities. Binding induces structural changes in the UB2H domain, which transduce to the two catalytic domains by distinct allosteric pathways. We also show how an additional regulator protein, CpoB, is able to selectively modulate the TPase activation by LpoB without interfering with GTase activation. The peptidoglycan cell wall synthesis activities of PBP1B are activated by binding of its regulator protein LpoB. This activation is achieved by binding‐induced conformational changes in PBP1B, which impact both of its catalytic domains. To ensure peptidoglycan synthesis is coordinated with outer membrane constriction during cell division, another regulatory protein CpoB binds to PBP1B and selectively modulates these conformational changes in response to Tol‐Pal function in the cell. [ABSTRACT FROM AUTHOR]

Abstract: Aim: The aim of this study was to validate the Dutch translation of the low anterior resection syndrome (LARS) score in a population of Dutch rectal cancer patients. Method: Patients who underwent surgery for rectal cancer received the LARS score questionnaire, a single quality of life (QoL) category question and the European Organization for Research and Treatment of Cancer (EORTC) QLQ‐C30 questionnaire. A subgroup of patients received the LARS score twice to assess the test–retest reliability. Results: A total of 165 patients were included in the analysis, identified in six Dutch centres. The response rate was 62.0%. The percentage of patients who reported ‘major LARS’ was 59.4%. There was a high proportion of patients with a perfect or moderate fit between the QoL category question and the LARS score, showing a good convergent validity. The LARS score was able to discriminate between patients with or without neoadjuvant radiotherapy (P = 0.003), between total and partial mesorectal excision (P = 0.008) and between age groups (P = 0.039). There was a statistically significant association between a higher LARS score and an impaired function on the global QoL subscale and the physical, role, emotional and social functioning subscales of the EORTC QLQ‐C30 questionnaire. The test–retest reliability of the LARS score was good, with an interclass correlation coefficient of 0.79. Conclusion: The good psychometric properties of the Dutch version of the LARS score are comparable overall to the earlier validations in other countries. Therefore, the Dutch translation can be considered to be a valid tool for assessing LARS in Dutch rectal cancer patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Fecal incontinence (FI) has a multifactorial pathophysiology with a severe social impact. The most common cause for FI is pudendal nerve damage, which mostly occurs in women during or after labor. A better understanding of the pathophysiology is required to optimize treatment of FI. In this study, we evaluate the use of a novel pelvic nerve damage rat model of FI. Methods: This new model simulates the forces on the pelvic floor during labor by prolonged transvaginal, retro‐uterine intrapelvic balloon distention in female rats. Number of fecal pellets produced per day and defecation pattern was compared between the experimental and control group for 2 weeks. The cages of the rats were divided in food, nesting and latrine areas to evaluate changes in defecation pattern. The FI Index (FII) was calculated to assess the ratio of fecal pellets between the non‐latrine areas and the total number of pellets. A higher score represents more random distribution of feces outside the latrine area. Results: Total number of fecal pellets was higher in the experimental group as compared with the controls. In both groups most fecal pellets were deposited in the nesting area, which is closest to the food area. The experimental group deposited more fecal pellets in the latrine area and had a lower FII indicating less random distribution of feces outside the latrine area. Conclusion: Transvaginal, retro‐uterine intrapelvic balloon distention is a safe and feasible animal model simulating the human physiologic impact of labor by downwards pressure on the pelvic floor. [ABSTRACT FROM AUTHOR]

Our aim is to establish a new patient-centred, international and multidisciplinary approach to support HD treatment decision-making. A patient enters your outpatient clinic with symptoms of blood loss and a prolapse that reduces spontaneously. With the introduction of this broader approach to HD treatment decision-making, we strive for more personalized HD management and better patient outcomes. [Extracted from the article]

Abstract: Aim: Sacral neuromodulation (SNM) is a minimally invasive therapy for functional constipation (FC) and is most often used to treat adults. Recent studies suggest that SNM may also beneficial in children. However, comparative data regarding preferred age of SNM for FC are lacking. Therefore, long‐term results of SNM for FC were compared between children and adults. Method: All patients treated with SNM for FC between 2004 and 2015 were evaluated. Outcomes of children (age 10–18 years) were compared with those for adults (≥ 18 years). The primary end‐point was a defaecation frequency of three or more times per week, which is consistent with the ROME‐III criteria. Secondary outcomes were quality of life (QoL; SF‐36) and the Cleveland Clinic Constipation Score. Results: One hundred and eighty patients (45 children, 135 adults) were eligible for SNM. The mean age was 15.8 (children) and 41.4 years (adults). One hundred and twenty‐six patients received permanent SNM (38 children, 88 adults). Mean follow‐up was 47 months in both groups. Defaecation frequency increased in both groups after SNM compared with baseline. Defaecation frequency in adults was higher than in children. The increased defaecation frequency was maintained during the entire follow‐up period in both groups. QoL of children was impaired compared with the Dutch population with regard to bodily pain, general health and vitality. Adults had worse QoL with regard to physical functioning, bodily pain, general health, vitality and social functioning compared with the Dutch population. QoL of children did not differ from adults. Conclusion: Sacral neuromodulation (SNM) should be considered in children (< 18 years) with FC. However, the indication of SNM for FC remains debatable considering the limited improvements and high costs. [ABSTRACT FROM AUTHOR]

Aim This study aimed to assess the cost-effectiveness of sacral neuromodulation ( SNM) compared with conservative treatment in children and adolescents with constipation refractory to conservative management. Method A Markov probabilistic model was used, comparing costs and effectiveness of SNM and conservative treatment in children and adolescents aged 10-18 years with constipation refractory to conservative management. Input for the model regarding transition probabilities, utilities and healthcare costs was based on data from a cohort of patients treated in our centre. This cohort consisted of 30 female patients (mean age 16 years) with functional constipation refractory to conservative management. The mean duration of laxative use in this group was 5.9 years. All patients had a test SNM, followed by a permanent SNM in 27/30. Median follow-up was 22.1 months (range 12.2-36.8). The model was run to simulate a follow-up period of 3 years. Results The mean cumulative costs for the SNM group and the conservative treatment group were €17 789 ( SD €2492) and €7574 ( SD €4332) per patient, respectively. The mean quality adjusted life years ( QALYs) in the SNM group was 1.74 ( SD 0.19), compared with 0.86 ( SD 0.14) in the conservatively managed group. The mean incremental cost-effectiveness ratio was €12 328 per QALY ( SD €4788). Sensitivity analysis showed that the outcomes were robust to a wide range of model assumptions. Conclusion Chronic constipation seriously affects the quality of life of children and adolescents. Preliminary evidence suggests that SNM can improve symptoms and quality of life at a reasonable cost. [ABSTRACT FROM AUTHOR]

Purpose To investigate whether patients who developed chronic central serous chorioretinopathy ( cCSC) in association with corticosteroid treatment respond differently to photodynamic therapy ( PDT) as compared to patients who have not used corticosteroids. Methods Clinical evaluation included visual acuity ( VA), fundoscopy, optical coherence tomography ( OCT), fluorescein and indocyanine green angiography. The main outcome measure was a complete resolution of subretinal fluid ( SRF) on OCT after PDT. Results One hundred and twenty-three eyes (117 patients), including 35 steroid-associated cases (29%), who received PDT treatment with reduced settings for active cCSC were included. Complete resolution of SRF on OCT was seen in 69% of the steroid-associated cases and in 50% of the controls after PDT treatment (p = 0.062). At the final follow-up moment, 74% of the cases had a complete resolution of SRF compared to 60% in the control group (p = 0.142). The VA at the first visit after therapy showed an increase in both groups (mean VA before treatment; cases: 69 ± 14 Early Treatment Diabetic Retinopathy Study ( ETDRS) letters, controls: 74 ± 13 ETDRS letters, mean VA first visit after treatment; cases: 76 ± 13 ETDRS letters, controls: 75 ± 13 ETDRS letters). No significant differences were seen in response to PDT between the patients who continued corticosteroid treatment and those who ceased the use of corticosteroids. Conclusions Photodynamic therapy appears to be equally effective in patients suffering from steroid-associated cCSC as compared to patients with cCSC who do not use corticosteroids. Continuation of corticosteroids at the time of PDT treatment does not seem to adversely affect PDT response. [ABSTRACT FROM AUTHOR]

Aims (i) To describe and analyse pelvic floor dysfunction symptoms in women referred to a Pelvic Care Centre (PCC). (ii) To describe the triage process of the same patients based on response to a first-contact interview. Methods Triage started with a telephone interview using previously constructed questions, asking for seven types of PF complaints during the preceding 6 months. If present, complaint severity was registered on a 0-10 scale. Next, these first-contact complaints were used to describe patient case mix profiles using cross-tabular analysis. Later on, at first PCC visit, an intake questionnaire containing questions on specific PF health problem(s) was filled out. This procedure contributed to a firm baseline characterization of the individual patient profile and a clinically valid allocation to structured, predefined assessment, and treatment. Results From 2005 to 2013, 4473 first-time patients (mean age 56.9 (SD 16.2) have been referred to the PCC. Most frequently mentioned complaints: voiding dysfunction (59.5%), urinary incontinence (46.6%), prolapse (41.1%), fecal incontinence (15.1%), constipation (12.6%), and sexual problems (4.6%). A first appointment to a single specialist was determined in 3.110 (69.5%) patients, in 1.192 (26.7%) consultation of >1 specialist. Data analysis revealed higher-order interactions between PF complaints, suggesting patient profile complexity and patient population heterogeneity. Conclusions More than one out of four PCC patients showed multifactorial problems, needing >1 specialist. PF complaints either turned out to stand alone or cluster with others, or even to strengthen, weaken, nullify, or inverse relationships. Neurourol. Urodynam. 35:503-508, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aims (i) To describe and analyse pelvic floor dysfunction symptoms in men referred to a Pelvic Care Centre (PCC). (ii) To describe the triage process of the same patients based on response to a first-contact interview. Methods Triage started with a telephone interview using previously constructed questions, asking for six types of PF complaints during the preceding 6 months. If present, complaint severity was registered on a 0-10 scale. Next, these first-contact complaints were used to describe patient case mix profiles using cross-tabular analysis. Later on, at first PCC visit, an intake questionnaire regarding specific PF health problem(s) was filled out. This procedure contributed to a firm baseline characterization of the individual patient profile and a clinically valid allocation to structured, predefined assessment and treatment. Results From 2005 to 2013 985 first-time patients (mean age 58.2 years (SD 15.3) have been referred to the PCC. Most frequently mentioned complaints: voiding dysfunctions (73.9%), urinary incontinence (29.5%), sexual problems (16.6%), faecal incontinence (13.9%), constipation (9.6%), and prolapse (0.3%). A first appointment to a single specialist was determined in 805 (81.7%) patients, in 137 (13.9%) consultation of >1 specialist. Data analysis revealed higher-order interactions between PF complaints, suggesting patient profile complexity and patient population heterogeneity. Conclusions One out of seven PCC patients showed multifactorial problems, needing >1 specialist. PF complaints either turned out to stand alone or cluster with others, or even to strengthen, weaken, nullify or inverse relationships. Neurourol. Urodynam. 35:487-491, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the outcome of a prospective protocol for the treatment of chronic central serous chorioretinopathy (CSC). Methods Interventional prospective case series in 59 eyes (59 patients) with active chronic CSC. All patients were first treated with indocyanine green angiography (ICGA)-guided half-dose photodynamic therapy (PDT). In case of persistent serous subretinal fluid (SRF) after a follow-up period of at least 6 weeks, ICGA-guided PDT was repeated. If the SRF persisted after two PDT treatments, additional ICGA-guided high-density subthreshold diode micropulse laser (HSML) therapy was performed. Clinical evaluation included best-corrected visual acuity (BCVA), fundoscopy, OCT, fundus autofluorescence, fluorescein angiography and ICGA. Results After a single PDT treatment, complete resolution of SRF was seen in 37 of 59 eyes. Of the 22 eyes with no complete resolution of SRF, 19 eyes received a second PDT treatment, after which seven eyes of the 19 eyes showed a complete resolution of SRF. Ten eyes underwent HSML, of which one eye had complete resolution of SRF within 7 weeks. At final follow-up a complete resolution of SRF was present in 80% of all eyes. The mean BCVA improved from 0.28 logMAR at baseline to 0.16 logMAR at final follow-up. Improvement of BCVA was highest after the first treatment (−0.12 logMAR, p < 0.001). Conclusions The proposed treatment strategy using half-dose PDT and HSML in active chronic CSC resulted in an anatomical success rate of 80%. The first half-dose PDT treatment has the highest likelihood of a favourable treatment response on OCT and BCVA increase. [ABSTRACT FROM AUTHOR]

The pneumococcus is an important Gram-positive pathogen, which shows increasing resistance to antibiotics, including β-lactams that target peptidoglycan assembly. Understanding cell-wall synthesis, at the molecular and cellular level, is essential for the prospect of combating drug resistance. As a first step towards reconstituting pneumococcal cell-wall assembly in vitro, we present the characterization of the glycosyltransferase activity of penicillin-binding protein (PBP)2a from Streptococcus pneumoniae. Recombinant full-length membrane-anchored PBP2a was purified by ion-exchange chromatography. The glycosyltransferase activity of this enzyme was found to differ from that of a truncated periplasmic form. The full-length protein with its cytoplasmic and transmembrane segment synthesizes longer glycan chains than the shorter form. The transpeptidase active site was functional, as shown by its reactivity towards bocillin and the catalysis of the hydrolysis of a thiol-ester substrate analogue. However, PBP2a did not cross-link the peptide stems of glycan chains in vitro. The absence of transpeptidase activity indicates that an essential component is missing from the in vitro system. Structured digital abstract and by () [ABSTRACT FROM AUTHOR]

Bacterial cell growth necessitates synthesis of peptidoglycan. Assembly of this major constituent of the bacterial cell wall is a multistep process starting in the cytoplasm and ending in the exterior cell surface. The intracellular part of the pathway results in the production of the membrane-anchored cell wall precursor, Lipid II. After synthesis this lipid intermediate is translocated across the cell membrane. The translocation (flipping) step of Lipid II was demonstrated to require a specific protein (flippase). Here, we show that the integral membrane protein FtsW, an essential protein of the bacterial division machinery, is a transporter of the lipid-linked peptidoglycan precursors across the cytoplasmic membrane. Using Escherichia coli membrane vesicles we found that transport of Lipid II requires the presence of FtsW, and purified FtsW induced the transbilayer movement of Lipid II in model membranes. This study provides the first biochemical evidence for the involvement of an essential protein in the transport of lipid-linked cell wall precursors across biogenic membranes. [ABSTRACT FROM AUTHOR]

Cell wall biosynthesis is a key target for antibacterial drugs. The major constituent of the bacterial wall, peptidoglycan, is a netlike polymer responsible for the size and shape of the cell and for resisting osmotic pressure. It consists of glycan chains of repeating disaccharide units cross-linked through short peptide chains. Peptidoglycan assembly is catalyzed by the periplasmic domain of bifunctional class A penicillin-binding proteins. Cross-linking of the peptide chains is catalyzed by their transpeptidase module, which can be inhibited by the most widely used antibiotics, the β-lactams. In contrast, no drug in clinical use inhibits the polymerization of the glycan chains, catalyzed by their glycosyltransferase module, although it is an obvious target. We report here the purification of the ectodomain of the class A penicillin-binding protein 1a from Thermotoga maritima (Tm-1a*), expressed recombinantly in Escherichia coli. A detergent screen showed that detergents with shorter aliphatic chains were better solubilizers. Cyclohexyl-hexyl-β-d-maltoside-purified Tm-1a* was found to be monomeric and to have improved thermal stability. A miniaturized, multiwell continuous fluorescence assay of the glycosyltransferase activity was used to screen for optimal reaction conditions. Tm-1a* was active as a glycosyltransferase, catalyzing the formation of glycan chains up to 16 disaccharide units long. Our results emphasize the importance of the detergent in preparing a stable monomeric ectodomain of a class A penicillin-binding protein. Our assay could be used to screen collections of compounds for inhibitors of peptidoglycan glycosyltransferases that could serve as the basis for the development of novel antibiotics. [ABSTRACT FROM AUTHOR]

Abstract: Defensins constitute a major class of cationic antimicrobial peptides in mammals and vertebrates, acting as effectors of innate immunity against infectious microorganisms. It is generally accepted that defensins are bactericidal by disrupting the anionic microbial membrane. Here, we provide evidence that membrane activity of human α-defensins does not correlate with antibacterial killing. We further show that the α-defensin human neutrophil peptide-1 (HNP1) binds to the cell wall precursor lipid II and that reduction of lipid II levels in the bacterial membrane significantly reduces bacterial killing. The interaction between defensins and lipid II suggests the inhibition of cell wall synthesis as a novel antibacterial mechanism of this important class of host defense peptides. [Copyright &y& Elsevier]

Translocation of the peptidoglycan precursor Lipid II across the cytoplasmic membrane is a key step in bacterial cell wall synthesis, but hardly understood. Using NBD-labelled Lipid II, we showed by fluorescence and TLC assays that Lipid II transport does not occur spontaneously and is not induced by the presence of single spanning helical transmembrane peptides that facilitate transbilayer movement of membrane phospholipids. MurG catalysed synthesis of Lipid II from Lipid I in lipid vesicles also did not result in membrane translocation of Lipid II. These findings demonstrate that a specialized protein machinery is needed for transmembrane movement of Lipid II. In line with this, we could demonstrate Lipid II translocation in isolated Escherichia coli inner membrane vesicles and this transport could be uncoupled from the synthesis of Lipid II at low temperatures. The transport process appeared to be independent from an energy source (ATP or proton motive force). Additionally, our studies indicate that translocation of Lipid II is coupled to transglycosylation activity on the periplasmic side of the inner membrane. [ABSTRACT FROM AUTHOR]

The spread of infectious diseases and the increase in antibiotic resistance represent a life-threatening global development that calls for new approaches to control microorganisms. Of all potential targets, the essential and unique pathway of bacterial cell wall synthesis, targeted by the first known antibiotic penicillin, remains a perfect candidate for the development of new antibiotics. Here we show that the lantibiotic nisin exercises its antibacterial action by targeting peptidoglycan intermediates' extracellular pyrophosphate, unique to bacterial cell wall precursors. We show that nisin sequesters cell wall precursors found in the outer leaflet of bacterial plasma membranes, Lipid II and undecaprenyl pyrophosphate, into stable complexes. We propose a model of antibacterial action for nisin in which the terminal amino group of Ile1 targets the pyrophosphate groups of the bacterial cell wall precursors, where it docks via a hydrogen bond. The pyrophosphate moiety, a highly conserved chemical group different from the L-Lys-D-Ala-D-Ala docking motif for vancomycin, has no biochemical analogs with comparable properties and is unlikely to be susceptible to bacterial adaptations akin to those responsible for resistance to penicillins and vancomycin.--Bonev, B. B., Breukink, E., Swiezewska, E., de Kruijff, B., Watts, A. Targeting extracellular pyrophosphates underpins the high selectivity of nisin. [ABSTRACT FROM AUTHOR]

Summary Motor unit action potential (MUP) analysis in human medicine is a valuable and important diagnostic technique enabling discrimination between myogenic and neurogenic problems. This study establishes normative data in subclavian, triceps and lateral vastus muscles for clinical application of MUP analysis in the Warmblood horse, and examines whether muscle differences are present. Electromyographic (EMG) needle examination and MUP analysis were performed of the triceps, lateral vastus and subclavian muscles in 7 awake, nonsedated, Warmblood horses age 4-10 years. The amplitude, duration, number of phases and turns were calculated from the recorded superimposed MUPs together with intramuscular and rectal temperatures. No significant differences were found in duration of insertional activity between the 3 muscles. The mean ± s.d. duration of the insertional activity was 526 ± 148.3 ms. The MUP amplitude of all 3 muscles differed significantly, with the highest amplitude (427 ± 3.20 μV) in the triceps and the lowest (220 ± 2.08 μV) in the subclavian muscle. The number of turns of the lateral vastus (3.0 ± 1.22) was significantly higher than that of the triceps muscle (2.7 ± 1.51). No differences were found in MUP duration (5.9-6.4 ms). [ABSTRACT FROM AUTHOR]