Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less ...extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.
Display omitted
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Increased patellofemoral joint (PFJ) stress has been implicated in the development of PFJ pathologies. Previous studies have identified a relationship between reduced hamstring length and ...patellofemoral pain syndrome. Hamstring stretching is also recommended in the management thereof. However, the relationship between reduced hamstring length and PFJ stress has not been explored in vivo during activities that load the PFJ, such as squatting. The objective of this study was to determine if persons with reduced hamstring length demonstrate increased PFJ stress during squatting compared with individuals without reduced hamstring length. Eight participants with, and eight participants without, reduced hamstring length were assessed to determine their PFJ contact area using magnetic resonance imaging, and their PFJ reaction force during squatting using motion analysis. Data collected were entered into a biomechanical model to calculate medial, lateral and total PFJ stress. It was found that participants with reduced hamstring length had significantly greater total (393.39 Pa/kg vs. 213.01 Pa/kg) and lateral (311.23 Pa/kg vs. 142.55 Pa/kg) PFJ stress at 60° knee flexion during squat descent and ascent (427.75 Pa/kg vs. 255.64 Pa/kg and 337.75 Pa/kg vs. 170.63 Pa/kg, respectively). This was due to significantly increased PFJ reaction force at 60° knee flexion during squat descent (12.18 N/kg vs. 7.21 N/kg) and ascent (13.03 N/kg vs. 8.72 N/kg), and lower medial PFJ contact area at 60° knee flexion (88 mm2 vs. 160 mm2 ). The results of this study demonstrate a relationship between reduced hamstring length and increased PFJ stress during squatting due to increased PFJ reaction force and reduced medial PFJ contact area.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Consensus
Background
The management of primary rectal cancer beyond total mesorectal excision planes (PRC‐bTME) and recurrent rectal cancer (RRC) is challenging. There is global variation in ...standards and no guidelines exist. To achieve cure most patients require extended, multivisceral, exenterative surgery, beyond conventional total mesorectal excision planes. The aim of the Beyond TME Group was to achieve consensus on the definitions and principles of management, and to identify areas of research priority.
Methods
Delphi methodology was used to achieve consensus. The Group consisted of invited experts from surgery, radiology, oncology and pathology. The process included two international dedicated discussion conferences, formal feedback, three rounds of editing and two rounds of anonymized web‐based voting. Consensus was achieved with more than 80 per cent agreement; less than 80 per cent agreement indicated low consensus. During conferences held in September 2011 and March 2012, open discussion took place on areas in which there is a low level of consensus.
Results
The final consensus document included 51 voted statements, making recommendations on ten key areas of PRC‐bTME and RRC. Consensus agreement was achieved on the recommendations of 49 statements, with 34 achieving consensus in over 95 per cent. The lowest level of consensus obtained was 76 per cent. There was clear identification of the need for referral to a specialist multidisciplinary team for diagnosis, assessment and further management.
Conclusion
The consensus process has provided guidance for the management of patients with PRC‐bTME or RRC, taking into account global variations in surgical techniques and technology. It has further identified areas of research priority.
To assist decision‐making
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Consensus
Background
The management of primary rectal cancer beyond total mesorectal excision planes (PRC‐bTME) and recurrent rectal cancer (RRC) is challenging. There is global variation in ...standards and no guidelines exist. To achieve cure most patients require extended, multivisceral, exenterative surgery, beyond conventional total mesorectal excision planes. The aim of the Beyond TME Group was to achieve consensus on the definitions and principles of management, and to identify areas of research priority.
Methods
Delphi methodology was used to achieve consensus. The Group consisted of invited experts from surgery, radiology, oncology and pathology. The process included two international dedicated discussion conferences, formal feedback, three rounds of editing and two rounds of anonymized web‐based voting. Consensus was achieved with more than 80 per cent agreement; less than 80 per cent agreement indicated low consensus. During conferences held in September 2011 and March 2012, open discussion took place on areas in which there is a low level of consensus.
Results
The final consensus document included 51 voted statements, making recommendations on ten key areas of PRC‐bTME and RRC. Consensus agreement was achieved on the recommendations of 49 statements, with 34 achieving consensus in over 95 per cent. The lowest level of consensus obtained was 76 per cent. There was clear identification of the need for referral to a specialist multidisciplinary team for diagnosis, assessment and further management.
Conclusion
The consensus process has provided guidance for the management of patients with PRC‐bTME or RRC, taking into account global variations in surgical techniques and technology. It has further identified areas of research priority.
To assist decision‐making
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Neutrophil granule proteases are thought to function as anti-microbial effectors, cooperatively hydrolyzing microorganisms within phagosomes, or upon deployment into the extracellular space. However, ...evidence also suggests that neutrophil proteases play an important role in the coordination and escalation of inflammatory reactions, but how this is achieved has been obscure. IL-1 family cytokines are important initiators of inflammation and are typically released via necrosis but require proteolytic processing for activation. Here, we show that proteases liberated from activated neutrophils can positively or negatively regulate the activity of six IL-1 family cytokines (IL-1α, IL-1β, IL-33, IL-36α, IL-36β, and IL-36γ) with exquisite sensitivity. In contrast, extracellular neutrophil proteases displayed very poor bactericidal activity, exhibiting 100-fold greater potency toward cytokine processing than bacterial killing. Thus, in addition to their classical role as phagocytes, neutrophils play an important immunoregulatory role through deployment of their granule proteases into the extracellular space to process multiple IL-1 family cytokines.
Display omitted
•Activated neutrophils release multiple proteases into the extracellular space•Extracellular neutrophil proteases modulate the activity of IL-1 family cytokines•Neutrophil proteases process cytokines 100-fold better than they kill microbes•Neutrophils play an immunoregulatory role in addition to their role as phagocytes
Here, Clancy et al. show that proteases released by activated neutrophils into the extracellular space exhibited poor antimicrobial activity but were potent modulators of IL-1α, IL-1β, IL-33, IL-36α, IL-36β, and IL-36γ activation states. Thus, neutrophils play a key role in modulating inflammatory responses through processing of multiple IL-1 family cytokines.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nephrolithiasis, or renal stone disease, is common and the incidence is increasing globally. In the UK the lifetime risk is estimated to be 8-10%. On a population level, the increase in stone ...incidence, erosion of gender disparity, and younger age of onset is likely to reflect increasing prevalence of obesity and a Western diet with a high intake of animal protein and salt. Stones can be detected by a variety of imaging techniques. The gold standard is a non-contrast CT of kidneys, ureters and bladder (CT KUB) which can identify > 99% of stones. CT KUB should be the primary mode of imaging for all patients with colic unless contraindicated. In such instances, or if a CT KUB is not available, an ultrasound KUB is an alternative. This has advantages in terms of radiation exposure and cost, but is limited in sensitivity, particularly for ureteric stones. Once diagnosed, a plain film KUB can be used for follow-up of radiopaque stones. For most patients diclofenac is a reasonable first choice of analgesia, e.g. 50-100 mg rectally, or 75 mg IM. Opioid medication can worsen nausea and be less effective, but should be used if there is a contraindication to NSAIDs. A combination of diclofenac, paracetamol, and/or codeine regularly can provide adequate pain control in many cases. Failure of this analgesic combination should prompt consideration of secondary care support. If a ureteric stone < 5 mm in diameter is identified, the expectation is that this will pass without intervention. Initially medical management is still useful for stones between 5 and 10mm in diameter, but urology input is more likely to be necessary as up to 50% of these may require intervention. Stones that are >10 mm in diameter should be discussed with the urology service as they are unlikely to pass spontaneously.
Chronic spontaneous urticaria (CSU) is a common, debilitating skin disorder characterized by recurring episodes of raised, itchy and sometimes painful wheals lasting longer than 6 weeks. CSU is ...mediated by mast cells which are absent from peripheral blood. However, lineage
CD34
CD117
FcεRI
cells in blood have previously been shown to represent a mast cell precursor.
We enumerated FcεRI
, FcεRI
and FcεRI
lineage
CD34
CD117
cells using flow cytometry in blood of patients with CSU (n = 55), including 12 patients receiving omalizumab and 43 not receiving omalizumab (n = 43). Twenty-two control samples were studied. Disease control and patient response to omalizumab was evaluated using the urticaria control test. We performed single-cell RNA sequencing (scRNA-Seq) on lineage
CD34
CD117
blood cells from a subset of patients with CSU (n = 8) and healthy controls (n = 4).
CSU patients had more lineage
CD34
CD117
FcεRI
blood cells than controls. Lineage
CD34
CD117
FcεRI
cells were significantly higher in patients with CSU who had an objective clinical response to omalizumab when compared to patients who had poor disease control 90 days after initiation of omalizumab. scRNA-Seq revealed that lineage
CD34
CD117
FcεRI
cells contained both lymphoid and myeloid progenitor lineages, with omalizumab responsive patients having proportionally more myeloid progenitors. The myeloid progenitor lineage contained small numbers of true mast cell precursors along with more immature FcεRI
and FcεRI
myeloid progenitors.
Increased blood CD34
CD117
FcεRI
cells may reflect enhanced bone marrow egress in the setting of CSU. High expression of these cells strongly predicts better clinical responses to the anti-IgE therapy, omalizumab.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Up to 70% of patients with ANCA-associated vasculitis (AAV) develop GN, with 26% progressing to ESKD. Diagnostic-grade and noninvasive tools to detect active renal inflammation are needed. Urinary ...soluble CD163 (usCD163) is a promising biomarker of active renal vasculitis, but a diagnostic-grade assay, assessment of its utility in prospective diagnosis of renal vasculitis flares, and evaluation of its utility in proteinuric states are needed.
We assessed a diagnostic-grade usCD163 assay in (
) a real-world cohort of 405 patients with AAV and 121 healthy and 488 non-AAV disease controls; (
) a prospective multicenter study of 84 patients with potential renal vasculitis flare; (
) a longitudinal multicenter cohort of 65 patients with podocytopathy; and (
) a cohort of 29 patients with AAV (with or without proteinuria) and ten controls.
We established a diagnostic reference range, with a cutoff of 250 ng/mmol for active renal vasculitis (area under the curve AUC, 0.978). Using this cutoff, usCD163 was elevated in renal vasculitis flare (AUC, 0.95) but remained low in flare mimics, such as nonvasculitic AKI. usCD163's specificity declined in patients with AAV who had nephrotic-range proteinuria and in those with primary podocytopathy, with 62% of patients with nephrotic syndrome displaying a "positive" usCD163. In patients with AAV and significant proteinuria, usCD163 normalization to total urine protein rather than creatinine provided the greatest clinical utility for diagnosing active renal vasculitis.
usCD163 is elevated in renal vasculitis flare and remains low in flare mimics. Nonspecific protein leakage in nephrotic syndrome elevates usCD163 in the absence of glomerular macrophage infiltration, resulting in false-positive results; this can be corrected with urine protein normalization.
Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could ...reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision.
TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8–10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743.
Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months’ follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients.
Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules.
Cancer Research UK.