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We present an endoscopic probe that combines three distinct optical fibre technologies including: A high-resolution imaging fibre for optical endomicroscopy, a multimode fibre for time-resolved fluorescence spectroscopy, and a hollow-core fibre with multimode signal collection cores for Raman spectroscopy. The three fibres are all enclosed within a 1.2 mm diameter clinical grade catheter with a 1.4 mm end cap. To demonstrate the probe’s flexibility we provide data acquired with it in loops of radii down to 2 cm. We then use the probe in an anatomically accurate model of adult human airways, showing that it can be navigated to any part of the distal lung using a commercial bronchoscope. Finally, we present data acquired from fresh ex vivo human lung tissue. Our experiments show that this minimally invasive probe can deliver real-time optical biopsies from within the distal lung - simultaneously acquiring co-located high resolution endomicroscopy and biochemical spectra. This article is protected by copyright. All rights reserved.

Purpose The relentless rise in antimicrobial resistance is a major societal challenge and requires, as part of its solution, a better understanding of bacterial colonization and infection. To facilitate this, we developed a highly efficient no-wash red optical molecular imaging agent that enables the rapid, selective, and specific visualization of Gram-positive bacteria through a bespoke optical fiber–based delivery/imaging endoscopic device. Methods We rationally designed a no-wash, red, Gram-positive-specific molecular imaging agent (Merocy-Van) based on vancomycin and an environmental merocyanine dye. We demonstrated the specificity and utility of the imaging agent in escalating in vitro and ex vivo whole human lung models (n = 3), utilizing a bespoke fiber–based delivery and imaging device, coupled to a wide-field, two-color endomicroscopy system. Results The imaging agent (Merocy-Van) was specific to Gram-positive bacteria and enabled no-wash imaging of S. aureus within the alveolar space of whole ex vivo human lungs within 60 s of delivery into the field-of-view, using the novel imaging/delivery endomicroscopy device. Conclusion This platform enables the rapid and specific detection of Gram-positive bacteria in the human lung.

Worldwide there is a shortage of available organs for patients requiring transplants. However, some countries such as France, Italy and Spain have had greater success by allowing donations from patients with unexpected and unrecoverable circulatory arrest who arrive in the ED. Significant advances in the surgical approach to organ recovery from donation after circulatory death (DCD) led to the establishment of a pilot programme for uncontrolled DCD in the ED of the Royal Infirmary of Edinburgh. This paper describes the programme and discusses the lessons learnt.

Objective To study the effect of testicular vessel division on testicular volume during laparoscopic staged Fowler Stephens orchiopexy (LSFSO). Methods Testicular dimensions were prospectively measured intraoperatively at both first (S1) and second stages (S2) of LSFSO, and with scrotal ultrasound 3-12 months postoperatively. Testicular volumes were compared to reference ranges. Volume changes were tracked with a change of >20% considered clinically significant. Results A total of 52 nonpalpable testes treated with LSFSO between 2008 and 2018 were included in the study. After a median follow-up of 6.8 (3-91.3) months, 46 (88.5%) testes were palpable in a scrotal location without adjunctive procedures and 39 (75%) maintained vascular flow on duplex ultrasound. One testis retracted to an inguinal position and was successfully treated with inguinal orchiopexy for an overall success of 90.4% (47/52). Of 36 testes with intra- and postoperative testicular volume documentation, only 2 (5.6%) had significant volume loss after S1. Both testes had catch-up growth after S2. Eight (22.2%) testes had significant volume loss after S2. At follow-up, 24 (66.7%) testes were smaller than the mean for age, of which 20 (83.3%) were small at baseline. Only 41.7% of testes larger than mean for age at follow-up, were small at baseline (P = .02). Conclusion Significant testicular volume loss does not occur after testicular vessel division at S1, but expected in approximately 1 quarter of testes after S2. We propose that testicular atrophy after LSFSO is primarily due to defective testicular development and rarely due to vascular compromise during S2.

The success of immune checkpoint therapy shows tumour-reactive T cells can eliminate cancer cells but are restrained by immunosuppression within the tumour micro-environment (TME). Cancer Associated Fibroblasts (CAFs) are the dominant stromal cell in the TME and co-localise with T cells in non-small cell lung cancer. We demonstrate the bi-directional nature of CAF / T cell interactions; T cells promote expression of co-inhibitory ligands, MHC molecules and CD73 on CAFs, increasing their production of IL-6 and eliciting production of IL-27. In turn CAFs upregulate co-inhibitory receptors on T cells including the ectonucleotidase CD39 promoting development of an exhausted but highly cytotoxic phenotype. Our results highlight the bi-directional interaction between T cells and CAFs in promoting components of the immunosuppressive CD39, CD73 adenosine pathway and demonstrate IL-27 production can be induced in CAF by activated T cells.

Despite the success of vaccines and selected repurposed treatments, COVID-19 is likely to remain a global health problem and further chemotherapeutics are required. Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials without characterisation of Pharmacokinetics (PK)/Pharmacodynamics (PD) including safety in COVID-19. One such drug is Nafamostat Mesylate (Nafamostat), a synthetic serine protease inhibitor with anticoagulant and anti-inflammatory properties. Preclinical data has demonstrated that it is has potent antiviral activity against SARS-CoV-2 by directly inhibiting the transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell entry.MethodsWe present the findings of a phase Ib/II open label, platform randomised controlled trial (RCT), exploring the safety of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative therapy. Secondary endpoints included clinical endpoints such as number of oxygen free days and clinical improvement/ deterioration, PK/PD, thromboelastometry, D Dimers, cytokines, immune cell flow cytometry and viral load.ResultsData is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more adverse events and a lower number of oxygen free days. There were no other statistically significant differences in the primary or secondary endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no differences in cytokine profile and immune cell phenotype and viral loads between the groups.ConclusionIn hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat delivered via a different route may be warranted. This trial demonstrates the importance of experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.

Using the shifted-excitation Raman difference spectroscopy technique and an optical fibre featuring a negative curvature excitation core and a coaxial ring of high numerical aperture collection cores, we have developed a portable, background and fluorescence free, endoscopic Raman probe. The probe consists of a single fibre with a diameter of less than 0.25 mm packaged in a sub-millimetre tubing, making it compatible with standard bronchoscopes. The Raman excitation light in the fibre is guided in air and therefore interacts little with silica, enabling an almost background free transmission of the excitation light. In addition, we used the shifted-excitation Raman difference spectroscopy technique and a tunable 785 nm laser to separate the fluorescence and the Raman spectrum from highly fluorescent samples, demonstrating the suitability of the probe for biomedical applications. Using this probe we also acquired fluorescence free human lung tissue data.

Introduction: PR has been shown to improve patients with COPD and reduces admissions but many patients decline PR as they feel too unwell. Repeating offers of PR at all contacts may mean more enrol and increase completion. Advertising PR to primary and secondary care needs repeating to increase referrals. Methods: We provide PR for a population of 500,000 for COPD, MRC3-4 from primary and secondary care and the community respiratory nursing team. We studied referral rates and outcome for PR in 2017&2018 and tracked 364 patients referred in 6/12 in 2018 v 122 who agreed to do PR in 2017. Results: PR referrals are increasing; April-Dec 2017 425, 2018, 656; 46% team, 22% primary care, 32% secondary care. We have identified more patients for PR at respiratory team initial triage 51% 2016, 65% 2017, 75% 2018. From 1.1.-1.7.18 there were 329 identified hospital discharges for COPD exacerbations, 74 referrals for PR, 47 direct, 27 from the team after contact(22.4%) 32 declined PR, 3 too well, 1 moved away, 2 agreed later, 26 too ill of whom 50% died within 6.12. 19/74 did 9/12 sessions. Of the total 364 referred 37% declined PR.229 booked for assessment, 140 (61%) completed 9/12 sessions v 61% in 2017. Outcomes: 47% >40 metres longer 6 min walk v 54% 2017, CAT Conclusion: We need to offer PR at every opportunity and encourage referrals ; more do PR. Post discharge many decline PR as too ill but some do it later, of those who agree to be assessed 61% complete 9/12 sessions ( v UK national Audit 2016=45%). Still too few do PR after exacerbation and few use other options. Always consider PR to offer:advertise to all.

Introduction: Testotoxicosis is a rare gonadotropin-independent form of precocious puberty. Herein we discuss a uniquely severe case of severe testotoxicosis in infant male with a c.1732G>C (p.ASP578His) LHCGR gene mutation requiring surgical intervention. Case Description: This 9-month-old male initially presented with extremely elevated levels of testosterone (1383 ng/dl) and undetectable ultrasensitive LH and FSH titers. On physical exam he was Tanner stage 3. Scrotal ultrasound showed multiple bilateral nodular hypoechoic lesions. A genomic DNA 1732G->C mutation within the LHCGR gene leading to a p.Asp578His amino acid change was confirmed on genetic testing. Combination medical therapy with an androgen receptor blocker and aromatase inhibitor was initiated for testotoxicosis; however, his condition worsened on medical therapy with a further rise in testosterone levels (2177 ng/dl). He subsequently underwent 2 sequential orchiectomies for his condition with both pathologies demonstrating diffuse nodular Leydig cell hyperplasia. Conclusions Herein we report the youngest case of medically refractory testotoxicosis associated with progressive bilateral diffuse nodular Leydig cell hyperplasia requiring aggressive surgical intervention. The germline c.1732G>C (p.ASP578His) mutation found in this case was previously described as somatic mutations in 3 boys with benign nodular adenoma of the testes.

Summary Introduction Antenatal hydronephrosis is a steady source of urology referrals since the era of routine fetal ultrasonography. Although most resolve, there are no guidelines for follow-up. Objective Our goal is to define safe parameters with which patients can be discharged early and avoid unnecessary follow-up. Methods We retrospectively reviewed all patients referred to a single children's referral hospital center for isolated antenetal hydronephrosis between 2010 and 2012. We looked at patients and renal units separately and divided the cohort into two groups for comparison. Our analysis endpoint is progression. That is, if the initial postnatal anterior-posterior diameter (APD) is less than 10 mm, progression occurs if the APD increases to 10 mm or above upon follow-up. Conversely, if the initial APD is 10 mm or more in at least one renal unit, progression occurs if the APD remains at 10 mm or above upon follow-up. Results There majority of the 186 patients and 308 renal units included in the analysis, were classified in the APD less than 10 mm group. Most renal units in the APD of less than 10 mm group were of SFU grades 0–2 (92.1%) and most of the renal units in the APD of 10 mm or greater group were of SFU grades 3–4 (60%) ( Table ). Only 19 renal units (6.2%) underwent pyeloplasty, and they were all from the APD of 10 mm or greater group and classified as SFU grade 3–4. No renal unit with an APD of less than 10 mm, nor any with an APD of 10 mm or greater and a SFU grade 0–2 underwent pyeloplasty. More than half of the renal units' hydronephrosis resolved in the APD of 10 mm or greater group, in comparison with 96.1% of the APD of less than 10 mm group. On multivariate analysis, patients with an APD of 10 mm or greater were 7.76 times more likely to show progression (p = 0.0006). Conclusion An initial postnatal APD of 10 mm or greater, with a SFU grade 3–4, merits follow-up. However, all patients with an APD of less than 10 mm, especially when with a SFU grade 1–2, can be safely discharged as they are unlikely to experience complications. Table Characteristics and progression status according to group. . Renal units APD APD>10 mm (n = 80) p-value Pyeloplasty 0 19 (23.8) Status Non-progression 219 (96.1) 50 (62.5) Progression 9 (3.9) 30 (37.5) SFU grade Grades 0–2 210 (92.1) 32 (40.0) Grades 3–4 18 (7.9) 48 (60.0)

We serve 450,000 people in Essex, UK, with close integration between community and hospital based respiratory teams, referral to community team as part of the discharge process bundle, pulmonary rehabilitation, oxygen services, and regular review of COPD patients in the community. Community based nurses visit the hospital for in-reach to facilitate early discharge. Patients with severe disease are discussed at a multi-disciplinary MDT. Methods: We carried out a series of nested audits to examine the clinical characteristics of our patients, the effect of nurse in-reach and the effect of an integrated approach on admissions and length of stay. Results: In 2016 there were 1234 referrals to the community team. 95% with COPD. There were 459 oxygen and 586 direct pulmonary rehabilitation referrals. In 2015-6 compared to 2014-5 the activities of the integrated team lead to a reduction in admissions from 841-774 (8.4%) This has continued into 2016-7 with April to October admissions for 2014 of 367, 2015, 320, and 2016, 329. This is a 10.4% drop between 2014-6. Length of stay 2014 was 7.4 days; 2015: 6.1 days. In 2016 nurse in-reach saw 323 patients, 285 in AE 109 patients were discharged that day. Referral to the community team as part of the discharge bundle occurred in 87.4% of patients discharged alive from our area. Conclusion: Integration of community and hospital respiratory teams with use of a robust discharge process and access to community PR and oxygen services leads to reduction in admissions and appropriate care for patients with COPD.

We examined the utility for phylogenetic reconstruction of the second internal transcribed spacer (ITS2), lying between the nuclear 5.8S gene and the gene for large subunit ribosomal RNA, using sequences of Ceratitis, Bactrocera, Musca, and Drosophila. We aligned and analyzed 13 sequences from GenBank and 11 new sequences from diverse species of Drosophila. Derivation of the secondary structure of the ITS2, the RNA transcript folding pattern required for transcript processing into functional RNA units, revealed the facets of sequence conservation common to all the sequences, that then allowed alignment of all the genera. The resultant tree, though including only a sparse representation of the enormous Drosophila diversity, conforms generally with the consensus of all prior phylogenetic reconstructions, using eight other nuclear and mitochondrial gene regions; where species representation is greater, as in the melanogaster subgroup of the Sophophora subgenus representatives, it conforms exactly. The paradigm ITS2 secondary structure presented can now be used to assess the genus more thoroughly, since its base pairing pattern makes alignment of sequences obvious. In addition, it shows that these insects share the ITS2 secondary structure characteristics of the other major animal groups as well as the green line of eukaryote evolution. The relatively short (