The structure of the PapD-PapGII pilin complex reveals an open and flexible P5 pocket

P pili are hairlike polymeric structures that mediate binding of uropathogenic Escherichia coli to the surface of the kidney via the PapG adhesin at their tips. PapG is composed of two domains: a lectin domain at the tip of the pilus followed by a pilin domain that comprises the initial polymerizing subunit of the 1,000-plus-subunit heteropolymeric pilus fiber. Prior to assembly, periplasmic pilin domains bind to a chaperone, PapD. PapD mediates donor strand complementation, in which a beta strand of PapD temporarily completes the pilin domain's fold, preventing premature, nonproductive interactions with other pilin subunits and facilitating subunit folding. Chaperone-subunit complexes are delivered to the outer membrane usher where donor strand exchange (DSE) replaces PapD's donated beta strand with an amino-terminal extension on the next incoming pilin subunit. This occurs via a zip-in-zip-out mechanism that initiates at a relatively accessible hydrophobic space termed the P5 pocket on the terminally incorporated pilus subunit. Here, we solve the structure of PapD in complex with the pilin domain of isoform II of PapG (PapGIIp). Our data revealed that PapGIIp adopts an immunoglobulin fold with a missing seventh strand, complemented in parallel by the G1 PapD strand, typical of pilin subunits. Comparisons with other chaperone-pilin complexes indicated that the interactive surfaces are highly conserved. Interestingly, the PapGIIp P5 pocket was in an open conformation, which, as molecular dynamics simulations revealed, switches between an open and a closed conformation due to the flexibility of the surrounding loops. Our study reveals the structural details of the DSE mechanism

The Impact of Nocturia on Mortality: A Systematic Review and Meta-Analysis

Purpose: Nocturia (waking from sleep at night to void) is a common cause of sleep disruption associated with increased comorbidity and impaired quality of life. However, its impact on mortality remains unclear. We performed a systematic review and meta-analysis to evaluate the association of nocturia with mortality as a prognostic factor and a causal risk factor. Materials and Methods: We searched PubMed (R), Scopus (R), CINAHL (R) (Cumulative Index of Nursing and Allied Health Literature) and major conference abstracts up to December 31, 2018. Random effects meta-analyses were done to address the adjusted RR of mortality in people with nocturia. Metaregression was performed to explore potential determinants of heterogeneity, including the risk of bias. We applied the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) framework to rate the quality of evidence for nocturia as a prognostic risk factor for mortality and separately as a cause of mortality. Results: Of the 5,230 identified reports 11 observational studies proved eligible for inclusion. To assess nocturia 10 studies used symptom questionnaires and 1 used frequency-volume charts. Nocturia was defined as 2 or more episodes per night in 6 studies (55%) and as 3 or more episodes per night in 5 (45%). Pooled estimates demonstrated a RR of 1.27 (95% CI 1.16-1.40, I-2=48%) with an absolute 1.6% and 4.0% 5-year mortality difference in individuals 60 and 75 years old, respectively. The pooled estimates of relative risk did not differ significantly across varying age, gender, followup, nocturia case definition, risk of bias or study region. We rated the quality of evidence for nocturia as a prognostic factor as moderate and as a cause of mortality as very low. Conclusions: Nocturia is probably associated with an approximately 1.3-fold increased risk of death.Peer reviewe

Therapeutic photography: enhancing patient communication.

Using photography with patients to help them express concerns, investigate coping strategies and learn from their peers is known as therapeutic photography. The practice has benefits to both professionals and participants, particularly with 'hard to reach' populations who may feel intimidated or disempowered. Neil Gibson explains how this intervention can be structured in the health setting

Immune modulation by group B Streptococcus influences host susceptibility to urinary tract infection by uropathogenic Escherichia coli

Urinary tract infection (UTI) is most often caused by uropathogenic Escherichia coli (UPEC). UPEC inoculation into the female urinary tract (UT) can occur through physical activities that expose the UT to an inherently polymicrobial periurethral, vaginal, or gastrointestinal flora. We report that a common urogenital inhabitant and opportunistic pathogen, group B Streptococcus (GBS), when present at the time of UPEC exposure, undergoes rapid UPEC-dependent exclusion from the murine urinary tract, yet it influences acute UPEC-host interactions and alters host susceptibility to persistent outcomes of bladder and kidney infection. GBS presence results in increased UPEC titers in the bladder lumen during acute infection and reduced inflammatory responses of murine macrophages to live UPEC or purified lipopolysaccharide (LPS), phenotypes that require GBS mimicry of host sialic acid residues. Taken together, these studies suggest that despite low titers, the presence of GBS at the time of polymicrobial UT exposure may be an overlooked risk factor for chronic pyelonephritis and recurrent UTI in susceptible groups, even if it is outcompeted and thus absent by the time of diagnosis

Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection

Chronic infections are an increasing problem due to the aging population and the increase in antibiotic resistant organisms. Therefore, understanding the host-pathogen interactions that result in chronic infection is of great importance. Here, we investigate the molecular basis of chronic bacterial cystitis. We establish that introduction of uropathogenic E. coli (UPEC) into the bladders of C3H mice results in two distinct disease outcomes: resolution of acute infection or development of chronic cystitis lasting months. The incidence of chronic cystitis is both host strain and infectious dose-dependent. Further, development of chronic cystitis is preceded by biomarkers of local and systemic acute inflammation at 24 hours post-infection, including severe pyuria and bladder inflammation with mucosal injury, and a distinct serum cytokine signature consisting of elevated IL-5, IL-6, G-CSF, and the IL-8 analog KC. Mice deficient in TLR4 signaling or lymphocytes lack these innate responses and are resistant, to varying degrees, to developing chronic cystitis. Treatment of C3H mice with the glucocorticoid anti-inflammatory drug dexamethasone prior to UPEC infection also suppresses the development of chronic cystitis. Finally, individuals with a history of chronic cystitis, lasting at least 14 days, are significantly more susceptible to redeveloping severe, chronic cystitis upon bacterial challenge. Thus, we have discovered that the development of chronic cystitis in C3H mice by UPEC is facilitated by severe acute inflammatory responses early in infection, which subsequently are predisposing to recurrent cystitis, an insidious problem in women. Overall, these results have significant implications for our understanding of how early host-pathogen interactions at the mucosal surface determines the fate of disease

Does clinical examination aid in the diagnosis of urinary tract infections in women? A systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Clinicians should be aware of the diagnostic values of various symptoms, signs and antecedents. This information is particularly important in primary care settings, where sophisticated diagnostic approaches are not always feasible. The aim of the study is to determine the probability that various symptoms, signs, antecedents and tests predict urinary tract infection (UTI) in women.</p> <p>Methods</p> <p>We conducted a systematic search of the MEDLINE and EMBASE databases to identify articles published in all languages through until December 2008. We particularly focused on studies that examined the diagnostic accuracy of at least one symptom, sign or patient antecedent related to the urinary tract. We included studies where urine culture, a gold standard, was preformed by primary care providers on female subjects aged at least 14 years. A meta-analysis of the likelihood ratio was performed to assess variables related to the urinary tract symptoms.</p> <p>Results</p> <p>Of the 1, 212 articles identified, 11 met the selection criteria. Dysuria, urgency, nocturia, sexual activity and urgency with dysuria were weak predictors of urinary tract infection, whereas increases in vaginal discharge and suprapubic pain were weak predictors of the absence of infection. Nitrites or leukocytes in the dipstick test are the only findings that clearly favored a diagnosis of UTI.</p> <p>Conclusions</p> <p>Clinical findings do not aid in the diagnosis of UTI among women who present with urinary symptoms. Vaginal discharge is a weak indicator of the absence of infection. The urine dipstick test was the most reliable tool for detecting UTI.</p

Yövirtsaamisen ennuste – meta-analyysista tukea päätöksentekoon

Incidence and remission of nocturia: a systematic review and meta-analysis Eur Urol, julkaistu verkossa 19.2.201

ELECtric Tibial nerve stimulation to Reduce Incontinence in Care homes: protocol for the ELECTRIC randomised trial

Background Urinary incontinence (UI) is highly prevalent in nursing and residential care homes (CH) and profoundly impacts on residents’ dignity and quality of life. Care homes predominantly use absorbent pads to contain UI rather than actively treat the condition. Transcutaneous posterior tibial nerve stimulation (TPTNS) is a non-invasive, safe, low-cost intervention with demonstrated effectiveness for reducing UI in adults. However, the effectiveness of TPTNS to treat UI in older adults living in care homes is not known. The ELECTRIC Trial aims to establish if a programme of TPTNS is a clinically effective treatment for UI in care home residents and investigate the associated costs and consequences. Methods This is a pragmatic, multicentre, placebo controlled randomised parallel group trial comparing effectiveness of TPTNS (target n=250) with sham stimulation (target n=250) in reducing volume of UI in CH residents. CH residents (men and women) with self- or staff- reported UI of more than once per week are eligible to take part, including those with cognitive impairment. Outcomes will be measured at 6, 12 and 18 weeks post randomisation using the following measures: 24-hour pad weight tests (PWT), post void residual urine (bladder scans), Patient Perception of Bladder Condition (PPBC), Minnesota Toileting Skills Questionnaire (MTSQ) and Dementia Quality of Life (DEMQOL). Economic evaluation based on a bespoke Resource Use Questionnaire will assess the costs of providing a programme of TPTNS. A concurrent process evaluation will investigate fidelity to the intervention and influencing factors and qualitative interviews will explore the experiences of TPTNS from the perspective of CH residents, family members, CH staff and managers. Discussion TPTNS is a non-invasive intervention that has demonstrated effectiveness in reducing UI in adults. The ELECTRIC Trial will involve CH staff delivering TPTNS to residents and establish whether TPTNS is more effective than sham stimulation for reducing the volume of UI in CH residents. Should TPTNS be shown to be an effective and acceptable treatment for UI in older adults in CHs, it will provide a safe, low-cost and dignified alternative to the current standard approach of containment and medication. Trial registration Clinical Trials.gov. NCT03248362. Registered on 14/08/2017. https://clinicaltrials.gov/ ISRCTN, ISRCTN 98415244. Registered on 25/04/2018. https://www.isrctn.com