Shigella sonnei utilises colicins during inter-bacterial competition.

The mammalian colon is one of the most densely populated habitats currently recognised, with 1011-1013 commensal bacteria per gram of colonic contents. Enteric pathogens must compete with the resident intestinal microbiota to cause infection. Among these enteric pathogens are Shigella species which cause approximately 125 million infections annually, of which over 90 % are caused by Shigella flexneri and Shigella sonnei. Shigella sonnei was previously reported to use a Type VI Secretion System (T6SS) to outcompete E. coli and S. flexneri in in vitro and in vivo experiments. S. sonnei strains have also been reported to harbour colicinogenic plasmids, which are an alternative anti-bacterial mechanism that could provide a competitive advantage against the intestinal microbiota. We sought to determine the contribution of both T6SS and colicins to the anti-bacterial killing activity of S. sonnei. We reveal that whilst the T6SS operon is present in S. sonnei, there is evidence of functional degradation of the system through SNPs, indels and IS within key components of the system. We created strains with synthetically inducible T6SS operons but were still unable to demonstrate anti-bacterial activity of the T6SS. We demonstrate that the anti-bacterial activity observed in our in vitro assays was due to colicin activity. We show that S. sonnei no longer displayed anti-bacterial activity against bacteria that were resistant to colicins, and removal of the colicin plasmid from S. sonnei abrogated anti-bacterial activity of S. sonnei. We propose that the anti-bacterial activity demonstrated by colicins may be sufficient for niche competition by S. sonnei within the gastrointestinal environment.

'When the bedbugs come, that's another problem': exploring the lived experiences of bedbug infestations among low-income older adults and service providers who support them.

AIMS: Older adults in low-income housing communities are more vulnerable to bedbug infestations. Prior research, however, has predominately focused on the effectiveness of integrated pest-management strategies, with little attention given to the lived experiences of tenants struggling with infestations. We used a qualitative approach to explore what it is like to live with and treat bedbug infestations from the perspectives of low-income older adults and service providers. METHODS: Participants included low-income older adults (n = 58) and service providers (n = 58) who offer supports directly in the buildings. Semi-structured qualitative interviews and focus groups were used to explore the challenges of preparing and treating units for bedbugs, and examine how bedbugs impact access to support services. RESULTS: Bedbugs were a widespread issue, and underlying physical, mental, social, and financial challenges made it difficult for older tenants to prepare their units and access treatment. Tenants also faced bedbug stigma from community services, as many were unwilling to provide services in infested units. Although some service providers utilized strategies to minimize exposure, many were concerned these strategies created additional stigma. CONCLUSION: Our findings highlight an urgent need to increase public health funding to support older adults with the costs of bedbug elimination and to enhance pest-management strategies through partnerships with health and social service agencies to improve outcomes for older adults.

Dicer promotes genome stability via the bromodomain transcriptional co-activator BRD4.

RNA interference is required for post-transcriptional silencing, but also has additional roles in transcriptional silencing of centromeres and genome stability. However, these roles have been controversial in mammals. Strikingly, we found that Dicer-deficient embryonic stem cells have strong proliferation and chromosome segregation defects as well as increased transcription of centromeric satellite repeats, which triggers the interferon response. We conducted a CRISPR-Cas9 genetic screen to restore viability and identified transcriptional activators, histone H3K9 methyltransferases, and chromosome segregation factors as suppressors, resembling Dicer suppressors identified in independent screens in fission yeast. The strongest suppressors were mutations in the transcriptional co-activator Brd4, which reversed the strand-specific transcription of major satellite repeats suppressing the interferon response, and in the histone acetyltransferase Elp3. We show that identical mutations in the second bromodomain of Brd4 rescue Dicer-dependent silencing and chromosome segregation defects in both mammalian cells and fission yeast. This remarkable conservation demonstrates that RNA interference has an ancient role in transcriptional silencing and in particular of satellite repeats, which is essential for cell cycle progression and proper chromosome segregation. Our results have pharmacological implications for cancer and autoimmune diseases characterized by unregulated transcription of satellite repeats.

Obstructed defaecation syndrome: European consensus guidelines on the surgical management.

Clinical decision-making in the treatment of patients with obstructed defaecation remains controversial and no international guidelines have been provided so far. This study reports a consensus among European opinion leaders on the management of obstructed defaecation in different possible clinical scenarios.

Levator ani and puborectalis muscle rupture: diagnosis and repair for perineal instability.

BACKGROUND: Puborectalis muscle rupture usually arises from peri-partum perineal trauma and may result in anterior, middle compartment prolapses, posterior compartment prolapse which includes rectocele and rectal prolapse, with or without associated anal sphincter damage. Patients with puborectalis muscle and levator ani rupture may present some form of incontinence or evacuation disorder, sexual dysfunction or pelvic organ descent. However, the literature on this subject is scarce. The aim of our study was to evaluate management and treatment of functional disorders associated with puborectalis and/or pubococcygei rupture at the level of the insertion in the pubis in a cohort of patients referred to a tertiary care coloproctology center. METHODS: We conducted a prospective cohort study of patients with levator ani and puborectalis muscle avulsion in the Proctology and Pelvic Floor Unit, Division of Digestive Surgery of the University Hospitals of Geneva from January 2001 to November 2018. Clinical examination, anoscopy and ultrasound were performed on a routine basis. Rupture of the levator ani muscle was diagnosed by clinical examination and ultrasound. A Wexner incontinence score was completed before and 6 months after surgery. Levator ani muscle repair was performed using a transvaginal approach. RESULTS: Fifty-two female patients (median age 56 ± 11.69 SD years, range 38-86 years) were included in the study. Thirty-one patients (59.6%) had anal incontinence, 25 (48.1%) urinary incontinence, 28 (53.9%) dyschezia (obstructive defecation or excessive straining to defecate), 20 (38.5%) dyspareunia, 17 (32.7%) colpophony, and 13 (25.0%) impaired sensation during sexual intercourse. Deviation of the anus on the side opposite the lesion was observed in 50 patients (96.2%), confirmed with clinical examination and both endoanal and perineal ultrasound. Out of these 52 patients, levator ani rupture (including puborectalis rupture) were categorized into right sided, 43 (82.69%), left sided, 7 (13.46%) and bilateral, 2 (3.85%). Levator ani muscle repair was performed in all patients, associated with posterior repair and levatorplasty in 26 patients (50%) and with sphincteroplasty in 34 patients (63.4%). Four patients (7.7%) experienced postoperative complications: significant postoperative pain (n = 3; 5.77%), urinary retention (n = 2; 3.85%), hematoma (n = 1; 1.92%), and perineal abscess (n = 1; 1.92%). Forty-one patients (78.8%) had full restoration of normal puborectalis muscle function (Wexner score: 0/20) after surgery, and overall, all patients had an improvement in the Wexner score and in sexual function. Dyschezia was reported by 28 patients (53.9%) preoperatively, resolved in 18 (64.3%) and improved by 50% or more in 10 (35.71%). CONCLUSIONS: Diagnosis of levator ani and puborectalis muscle rupture requires careful history taking, clinical examination, endoanal and perineal ultrasound. Surgical repair improved anal continence as well as sexual function in all patients. Transvaginal levator ani repair seems to be well tolerated with good short-term results.

Development and internal validation of a diagnostic score for gastric linitis plastica.

BACKGROUND: There is no consensual definition for gastric linitis plastica (GLP). We aim to construct a diagnostic score to distinguish this rare tumor from usual gastric adenocarcinomas. METHODS: In this retrospective study, all patients who had gastrectomy for cancer between 2007 and 2017 in French tertiary centers were included. The outcome was a diagnosis of GLP based on pathological review of the surgical specimen. The diagnostic score was created by using variables that were most frequently associated with GLP using penalized logistic regression on multiply imputed datasets. We used discrimination measures to assess the performances of the score. Internal validation was performed using bootstrapping methods to correct for over-optimism. RESULTS: 220 patients including 71 linitis plastica (female 49%, median age 57 years) were analyzed. The six parameters retained in the diagnosis score were the presence of large folds and/or parietal thickening on at least one segment, pangastric infiltration and presence of gastric stenosis on the upper endoscopy, circumferential thickening on at least one segment and thickening of the third hyperechogenic layer on endoscopic ultrasound and the presence of signet ring cells on endoscopic biopsies. The area under the ROC curve (AUC) was 0.967 with a sensitivity of 94% [89.9-97.3] and a specificity of 88.7% [81.7-95.8] for a threshold of 2.75. After internal validation, the corrected AUC was 0.959. CONCLUSION: It is the first study validating a pre-therapeutic diagnostic score (Saint Louis linitis score) with an excellent ability to discriminate GLP from non-GLP adenocarcinomas. An external validation is necessary to confirm our data.

Rectal advancement flap plus adipose lipofilling (RAFAL) for the treatment of rectourethral fistulas after radical prostatectomy.

BACKGROUND: Rectourethral fistula (RUF) is a rare but significant complication after radical prostatectomy. Many different approaches have been used, but none of them has become the standard of care. METHODS: We present our series of seven patients treated with a transanal rectal advancement flap plus the injection of mesenchymal stem cells, to facilitate the healing of the fistula. Mesenchymal cells were obtained by a new mechanical device known as LIPOGEMS®. We called this technique RAFAL (rectal advancement flap plus adipose lipofilling). In all patients the RUF was a complication of laparoscopic radical prostatectomy. Fistula size ranged from 0.3 to 0.5 cm (median 0.4 cm). RESULTS: After a median follow-up of 53 months (range 6-163 months), 2 out of 7 patients experienced RUF recurrence. In both cases recurrence was successfully treated by the York-Mason technique in one case and by redo RAFAL in the other. Success rate of RAFAL was 71% (5 of 7). The total success rate of primary RAFAL and redo- RAFAL was 85.7% (6 of 7). No short- or long-term complications were seen. CONCLUSIONS: In our patient population this new procedure was safe and effective.

[Pharmacist's interview with type 2 diabetes: Development of a follow-up form]. / L'entretien pharmaceutique pour le patient diabétique de type 2 : élaboration d'une fiche de suivi.

OBJECTIVES: Type 2 diabetes is a major public health concern because of its prevalence, the severity of complications and the financial implications. Compliance and patient's autonomy in medications intake play key roles in the success of treatment. Pharmacists' interviews ensure an optimized and individual follow-up. Type 2 diabetes is not one of the targeted diseases to perform pharmacists' interviews on under Health Insurance. We thus judged useful to contribute to their development. METHODS: We applied a cross-disciplinary methodological process in order to define the specifications of the follow-up form useful to conduct the pharmacist's interview 1 by focusing on the identification of a non-compliance and its origins. A feasibility study was carried out in order to check its workability to the pharmacy practice. RESULTS: The follow-up form, associated with a pharmacist practical guide, includes 3 parts: (1) General informations, (2) Survey establishing patient's knowledge, (3) Summary including a level of knowledge assessment grid. Outcomes provide a long but appropriate-felt duration, few difficulties to conduct the interview and a proven usefulness in 90% of all cases that make the follow-up form suitable to the pharmacy practice. CONCLUSIONS: This tool could serve as a model for the pharmacist to conduct his future interviews for the type 2 diabetes patients, thus improving patient care, together with other health professionals.

Disease ecology, health and the environment: a framework to account for ecological and socio-economic drivers in the control of neglected tropical diseases.

Reducing the burden of neglected tropical diseases (NTDs) is one of the key strategic targets advanced by the Sustainable Development Goals. Despite the unprecedented effort deployed for NTD elimination in the past decade, their control, mainly through drug administration, remains particularly challenging: persistent poverty and repeated exposure to pathogens embedded in the environment limit the efficacy of strategies focused exclusively on human treatment or medical care. Here, we present a simple modelling framework to illustrate the relative role of ecological and socio-economic drivers of environmentally transmitted parasites and pathogens. Through the analysis of system dynamics, we show that periodic drug treatments that lead to the elimination of directly transmitted diseases may fail to do so in the case of human pathogens with an environmental reservoir. Control of environmentally transmitted diseases can be more effective when human treatment is complemented with interventions targeting the environmental reservoir of the pathogen. We present mechanisms through which the environment can influence the dynamics of poverty via disease feedbacks. For illustration, we present the case studies of Buruli ulcer and schistosomiasis, two devastating waterborne NTDs for which control is particularly challenging.This article is part of the themed issue 'Conservation, biodiversity and infectious disease: scientific evidence and policy implications'.

RNA interference is essential for cellular quiescence.

Quiescent cells play a predominant role in most organisms. Here we identify RNA interference (RNAi) as a major requirement for quiescence (G0 phase of the cell cycle) in Schizosaccharomyces pombe RNAi mutants lose viability at G0 entry and are unable to maintain long-term quiescence. We identified suppressors of G0 defects in cells lacking Dicer (dcr1Δ), which mapped to genes involved in chromosome segregation, RNA polymerase-associated factors, and heterochromatin formation. We propose a model in which RNAi promotes the release of RNA polymerase in cycling and quiescent cells: (i) RNA polymerase II release mediates heterochromatin formation at centromeres, allowing proper chromosome segregation during mitotic growth and G0 entry, and (ii) RNA polymerase I release prevents heterochromatin formation at ribosomal DNA during quiescence maintenance. Our model may account for the codependency of RNAi and histone H3 lysine 9 methylation throughout eukaryotic evolution.

Tailored therapy for different presentations of chronic pain after stapled hemorrhoidopexy.

BACKGROUND: As stapled hemorrhoidopexy (SH) becomes more widely used, we see more patients with chronic postoperative anal pain after this surgery. Its presentation is variable and difficult to treat. The aim of our study was to investigate the impact of chronic anal pain after SH and whether tailored therapy was likely to achieve a favorable outcome. METHODS: We retrospectively analyzed 31 consecutive patients with chronic anal pain who had undergone SH in other hospitals and were referred to our institutions. Depending on the type of pain, unrelated (at rest) or related to defecation, two groups of patients were identified. Moreover, the mean distance of the staple line from the anal verge was calculated in both groups. Treatments included: topical nifedipine, local anesthetic and steroid infiltration, removal of retained staples, anal dilation, and scar excision with mucosal suturing. A visual analog scale (VAS) was used to compare pain at baseline, postoperatively, and in the follow-up. This mean difference of the VAS score between stages was always used as the main outcome measure, depending on the type of presentation, type of pain, and type of treatment. Treatment response was defined as a 50 % decrease of VAS from baseline. RESULTS: There were 22 males and 9 females. The overall median age was 43 years (range 21-62 years). On digital examination and proctoscopy, 15 (48 %) patients had inflammatory changes, 19 (61 %) patients had staple retention, 8 (26 %) patients had anorectal stenosis, and 30 (97 %) patients had scar tissue. All patients had one or more of the following treatments listed from the least to most invasive: topical nifedipine in 12 (39 %) patients, anal dilation in 6 (19 %) patients, anesthetic and steroid infiltration in 18 (58 %) patients, removal of staples in 10 (32 %) patients, and scar excision in 18 (58 %) patients. The mean VAS score at baseline was 6.100, ± 1.953 SD, which dropped significantly after treatment to 1.733, ± 1.658 SD (p < 0.001) and remained low at follow-up (1.741 ± SD 1.251; p < 0.743). In patients with pain at rest (n = 20, 65 %), the symptoms improved in 19 (95 %) patients, while the VAS score decreased from 5.552 ± 2.115 SD to 1.457 ± 1.440 SD (95 % CI 3.217-4.964; p < 0.001). In patients with post-evacuation pain (n = 11, 35 %), the symptoms improved in 11 (100 %) patients, while the VAS score decreased from 6.429 ± 1.835 SD to 1.891 ± 1.792 SD (95 % CI 3.784-5.269; p < 0.001). Rating of response based on presentation was 90.0 % (0.9/10) after treatment of staple retention, which led to a significant decrease in the mean VAS score from 6.304 ± 1.845 SD to 1.782 ± 1.731 SD (95 % CI 3.859-5.185; p < 0.001). Anal stenosis was successfully treated in 100.0 % (n = 8/8) of cases with the mean VAS score dropping from 6.500 ± 1.309 SD to 2.125 ± 1.808 SD (95 % CI 2.831-5.919; p < 0.001). Anal inflammation improved in 60.0 % (n = 9/15) of patients and the mean VAS score dropped from 6.006 ± 2.138 SD to 1.542 ± 1.457 SD (95 % CI 3.217-4.964; p < 0.001). The response after scar tissue treatment was 94 % (n = 17/18) of patients with a mean VAS decreasing from 6.117 ± 2.006 SD to 1.712 ± 1.697 SD (95 % CI 3.812-4.974; p < 0.001). Success for topical nifedipine was between 13 and 25 % of patients depending on the clinical presentation. Anal dilation was successful in 75 % of patients, while Anesthetic and steroid infiltration in 23-54 % of patients depending on the clinical presentation. Staple removal was successful in 77 % of patients, and scar excision with mucosal suturing in 94 % of patients. CONCLUSIONS: Our retrospective study suggests that most patients with chronic anal pain after SH may be cured with treatment by applying a stepwise approach from the least to the most invasive treatment.

A multicenter experience with peri-rectal tumors: The risk of local recurrence.

BACKGROUND: Peri-rectal tumors are rare and their management is challenging, especially when presenting with local recurrence. The aim of the current study was to report a multicenter series of peri-rectal tumors, focusing on the risk of recurrence. MATERIAL AND METHODS: From 1994 to 2014, patients with peri-rectal tumors from three different centers were retrospectively analyzed. Sixty-two patients were identified and divided into two groups; Group 1: patients who presented with local recurrence at follow-up (n = 9, recurrence rate: 14.5%), and Group 2: patients without recurrence (n = 53). RESULTS: In Group 1, there were initially more patients with symptoms of a perineal mass (44.4% vs. 12.2%; p = 0.04), more malignant tumors (55.6% vs. 15.1%; p = 0.02), and larger lesions (+2.6 cm; p = 0.004). Incomplete resection was also more frequent in Group 1 (44.4% vs. 3.8%; p = 0.003). Eight patients with recurrence had further surgery, whilst one patient had radiological recurrence and was treated medically. Among the eight re-resections, five patients remain disease-free; two have had further recurrences and have had palliative treatment, whilst another has had a further resection and remains disease-free. CONCLUSIONS: Peri-rectal tumors are uncommon and there is no consensus on best management. Based on this large multicenter series, several risk factors seem to be associated with local recurrence, namely patient- (discovery of a perineal mass), tumor- (malignant and large lesion), and surgery-related (incomplete resection). Clinical follow-up should be adapted according to these factors.

Incidence of Severe Infections and Infection-Related Mortality During the Course of Giant Cell Arteritis: A Multicenter, Prospective, Double-Cohort Study.

OBJECTIVE: To assess the incidence of infections leading to hospitalization, the mortality rate related to infections, and the determinants of these factors in patients with giant cell arteritis (GCA). METHODS: In total, 486 patients with GCA (75% women) were enrolled at the time of diagnosis. All patients fulfilled the American College of Rheumatology criteria for GCA. As controls, age- and sex-matched subjects were randomly selected from the general population and matched to patients at the time of diagnosis of GCA. Both groups were prospectively followed up over a 5-year period. RESULTS: Severe infections were more frequent among patients with GCA during the first year after diagnosis, compared to general population controls (incidence rate ratio 2.1, 95% confidence interval [95% CI] 1.2-3.4; incidence rate 11.1/100 patient-years [95% CI 8.3-14.6] in patients with GCA versus 5.9/100 patient-years [95% CI 4-8.4] in controls). Specifically, septic shock and infectious colitis were more frequent among the patients with GCA. Mortality caused by infections was higher in patients with GCA compared to controls (P < 0.0001 by log rank test). In analyses adjusted for age, among patients with GCA, a diagnosis of diabetes (hazard ratio [HR] 3.3, 95% CI 1.4-7.7) and a corticosteroid dosage that was >10 mg/day after 12 months of treatment (HR 4.61, 95% CI 1.38-15.36) were associated with death attributed to severe infection. The observed overall incidence of mortality was increased in patients with GCA during the early period of enrollment in the study (before 1997) (P = 0.0001 by log rank test), but thereafter was the same as that in the general population controls. CONCLUSION: Frequencies of severe infections and rates of infection-related mortality are increased during the first year after the diagnosis of GCA. The risk of infection increases in GCA patients with older age or in the presence of diabetes, or is greater when the dosage of corticosteroids has been increased to >10 mg/day after 12 months of treatment.

The treatment of pilonidal disease: guidelines of the Italian Society of Colorectal Surgery (SICCR).

The Italian Society of Colorectal Surgery (SICCR.) has prepared clinical practice guidelines to help its members to optimize the treatment of pilonidal disease, a very common condition, especially among young people, and therefore of great importance on a socioeconomic level. The SICCR committee of experts on pilonidal disease analyzed the international literature and evaluated current evidence. Nonoperative management includes gluteal cleft shaving, laser epilation as well as fibrin glue and phenol injection: reported healing rates and recurrence incidence are satisfactory but the majority of studies are small series with low-quality evidence. Surgical therapy which can be divided into two categories: excision of diseased tissue with primary closure using different techniques or excision with healing by secondary intention. On the whole, no clear benefit is demonstrated for one technique over the other.

Does the weather play a role in the spread of pandemic influenza? A study of H1N1pdm09 infections in France during 2009-2010.

Understanding patterns of influenza spread and persistence is crucial for pandemic preparedness. The H1N1pdm09 virus caused the first influenza pandemic of the 21st century which resulted in at least 18500 deaths. Based on laboratory-confirmed primary-care case reports we investigated the role of weather conditions and socio-demographic variables in its initial spread and subsequent presence in France. Our findings suggest that low relative humidity and high population density were determinants in shaping the early spread of the virus at the national level. Those conditions also favoured the persistence of viral presence throughout the first 33 weeks of the pandemic. Additionally this persistence was significantly favoured by low insolation. These results confirm the increasingly recognized role of humidity in influenza dynamics and underlie the concomitant effect of insolation. Therefore climatic factors should be taken into account when designing influenza control and prevention measures.

Harvesting dissipated energy with a mesoscopic ratchet.

The search for new efficient thermoelectric devices converting waste heat into electrical energy is of major importance. The physics of mesoscopic electronic transport offers the possibility to develop a new generation of nanoengines with high efficiency. Here we describe an all-electrical heat engine harvesting and converting dissipated power into an electrical current. Two capacitively coupled mesoscopic conductors realized in a two-dimensional conductor form the hot source and the cold converter of our device. In the former, controlled Joule heating generated by a voltage-biased quantum point contact results in thermal voltage fluctuations. By capacitive coupling the latter creates electric potential fluctuations in a cold chaotic cavity connected to external leads by two quantum point contacts. For unequal quantum point contact transmissions, a net electrical current is observed proportional to the heat produced.