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The central circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus drives the 24-hr pattern in cortisol, which functions as the main central synchronizing signal that coordinates peripheral clocks in organs that control whole body metabolism. A superimposed pulsatile pattern of cortisol allows rapid responses that fine tune the body's reaction to changes in the environment. In addition to coordinating metabolic processes to predictable environmental events, cortisol is the main catabolic signal that acts with testosterone, the quintessential male anabolic hormone, to maintain catabolic–anabolic homeostasis in men. Sleep restriction, when sufficiently substantial, increases late afternoon/early evening cortisol levels, but does not alter 24-hr cortisol levels; whereas even maximal acute circadian misalignment only slightly delays the cortisol rhythm. Prolonged circadian misalignment decreases overall cortisol exposure. The implications of these regulatory changes on health and disease require further evaluation.

Purpose Lung transplant patients are at increased susceptibility to fungal infections. Isavuconazole, a triazole anti-fungal with broad-spectrum activity against medically important fungal pathogens, received a marketing authorisation in the U.K. in 2015. The use of isavuconazole has advantages over voriconazole and posaconazole as it presents a more favourable toxicity profile. There is some, but very limited data appraising its clinical effectiveness, but this is predominantly in the context of anti-fungal prophylaxis. This research looks to review the experience of a single centre by reviewing clinical outcome data in lung transplant patients who received isavuconazole as treatment for invasive fungal infections. Methods We performed a single-centre retrospective study to describe the clinical outcome data from patients commenced on treatment with Isavuconazole for invasive fungal infections between October 2016 and December 2019. We assessed outcomes at 3 months and 6 months post-commencement of treatment including patient reported improvement of presenting symptoms, stability or improvement in lung function (FEV1), radiological improvement or histocytoloical resolution on bronchoscopy (including galactomannan and persistent invasion of fungal hyphae/pseudohyphae or features in keeping with fungal infection). Results Fifty patients were treated with isavuconazole during the study period. Eleven patients were excluded from analysis (two due to transfer of care to a different centre and nine due to early treatment cessation). Of the thirty-nine patients, twenty-six were treated for possible and thirteen were treated for proven invasive fungal infection. A range of fungal isolates were encountered. Treatment success was observed in 60% (n=24). Isavuconazole was well tolerated by most patients (n = 37). Conclusion Isavuconazole is well tolerated and appears effective in the management of invasive fungal infection after lung transplantation. The limitations of this study are that it is a single centred, retrospective study, however, is the largest case series to date where clinical effectiveness of Isavuconazole has been appraised.

Purpose Lung transplant (LTx) patients have increased susceptibility to fungal infections. Isavuconazole received a marketing authorisation in the UK in 2015. The use of isavuconazole has advantages over voriconazole/posaconazole as it presents a more favourable pharmacokinetic and toxicity profile. This retrospective analysis reviews the experience of isavuconazole in LTx patients in a single centre. Methods Pharmacy records were used to identify LTx patients who had received ≥14 days isavuconazole therapy since 2016 and had ≥1 serum isavuconazole level taken. Immunosuppression (sirolimus or tacrolimus) and isavuconazole serum levels were collated to calculate a concentration/dose (C/D) ratio normalised for weight and percentage time in therapeutic range (%TTR, days). All patients received a loading dose of isavuconazole 200mg three times a day for 6 doses then 200mg once daily (OD). The serum isavuconazole levels were monitored, doses were adjusted to maintain therapeutic serum levels of 1-5ng/ml. Results Forty-two courses of isavuconazole were included, in thirty-eight patients (16 CF (Cystic Fibrosis), 22 non-CF). Isavuconazole doses were adjusted in 45% (n=19) of courses. All courses achieved serum isavuconazole levels ≥ 1ng/ml at day 28 with 20 at 200mg OD (18 200mg) and had 86.95±26.5 SD% days in therapeutic range of isavuconazole treatment days. The C/D ratio increased from 72 to 134 for sirolimus and 74.5 to 116.5 for tacrolimus. Conclusion Isavuconazole demonstrated favourable pharmacokinetics and was well tolerated in LTx patients. Immunosuppressant doses should be guided by close therapeutic drug monitoring on initiating and stopping isavuconazole; also, considering isavuconazole levels. The high TTR% showed that isavuconazole serum levels maintained in therapeutic range following day 28, suggesting routine monitoring of serum levels following this may not be imperative once target range is achieved.

Purpose Lung transplant (LTx) recipients require regular monitoring to ensure graft function, medicines optimisation and minimisation of side effects. Traditionally, clinics are time-limited and focus on medical aspects. The aim was to evaluate physical and psychological wellbeing of LTx recipients, identify unmet needs and develop personalised care pathways with the use of electronic Patient Reported Outcome Measures (PROMs). Methods A formal Multidisciplinary review Of Transplant (MOT) clinic was set up at 1-year post LTx. An electronic form was developed with validated questionnaires to assess quality of life, psychological wellbeing (post-traumatic stress, anxiety, depression), physical and socioeconomical wellbeing. Patients completed the form online ahead of their MOT to aid systematic assessment, monitoring comorbidities and complications. A process for receiving the responses, automatically calculating scores, and populating clinician-friendly templates with areas of concern for review was created. Personalised care pathways were established in clinic based on this. Results To date, six LTx patients have been reviewed in MOT clinic. All patients fully completed the form. No clinicians were required to process data, resulting in no increased clinician time/cost. All patients had routine investigations, medical and medication optimisation reviews. Identified unmet needs in their care included: investigation of reflux (2/6), psychological support (1/6), counselling on skin changes (3/6), skin cancer screening (6/6), lack of exercise (1/6), social support (1/6), infection prophylaxis (3/6), cholesterol treatment (1/6); each addressed accordingly. Analysis of patient experience is underway but initial response has been positive. Conclusion This pilot study was successful in providing detailed health and wellbeing information electronically allowing clinicians to identify patient unmet needs and create personalised care plans at MOT clinic. This had clinical impact as it helped provide a comprehensive and high standard of care with no administrative burden on clinicians. Future studies could assess using this technology to more frequently monitor PROMs to manage patients with less face-to-face contact given the risks associated with the ongoing risk of Covid-19 in this extremely clinically vulnerable population.

Extra-levator abdominal perineal excision of rectum (eLAPE) for low rectal tumours is associated with a lower incidence of circumferential resection involvement. However, there is no consensus on the ideal technique for perineal reconstruction following eLAPE. We thereby conducted a 5-year review of perineal closure outcomes following eLAPE. A systematic review of the literature was conducted between 2006 and July 2012. Perineal wound healing and complications in the post-operative period were examined. Original data following eLAPE were found in 27 studies involving 963 individuals to inform a qualitative synthesis. Pooled analysis revealed that investigators most commonly employed either biomesh closure (12 studies, n = 149), myocutaneous flap closure (9 studies, n = 201) and primary closure (4, n = 578). The incidence of minor and major wound complications and perineal hernias across the latter groups was (27.5, 13.4 and 2.7 %), (29.4, 19.4 and 0 %) and (17.1, 6.4 and 1.2 %), respectively. Two studies utilised synthetic mesh closure (n = 4) and omentoplasty (n = 31). Objective assessment of wound healing was strikingly deficient across most studies, largely due to low level retrospective evidence lacking randomised controls. Modest cohort sizes with short follow-up data were evident due to the relative novelty of eLAPE. The paucity of high quality data, suggests that a prospective, randomised trial is needed to determine the ideal technique for perineal reconstruction following eLAPE.

Donor human milk (DHM) is currently used in neonatal units (NNUs) for feeding preterm infants when own mother's milk is not available or insufficient. In 2014, the latest Cochrane review1 showed that in preterm and low birthweight infants, feeding with formula compared with DHM results in a higher risk of developing necrotising enterocolitis (NEC). As the incidence of NEC increases in relation to the other complications of preterm birth,2 there is growing interest in the use of DHM, as evidenced by an expansion in the number of milk banks worldwide (currently >500 in 44 countries).3 In the UK, it is estimated that 75% of neonatal intensive care units4 use DHM for the feeding of infants, most commonly for those at high risk of NEC. However, one part of the world where the use of DHM is not growing is in countries with predominantly Muslim population. Here, the introduction of anonymised DHM has been challenged by the Islamic concept of milk kinship. The sharing of human milk, historically in the form of a wet nurse, creates kinship ties and thus marriage prohibitions between the family of the donor and recipient.5 Surveys have shown that these beliefs may also affect the acceptability of DHM to Muslim parents …

Introduction Minimally invasive parathyroidectomy (MIP) is performed via a short incision (≤3cm). Previous studies have employed multiple imaging modalities including ultrasonography, sestamibi imaging and/or intraoperative parathyroid hormone assay. We present our eight-year experience of MIP using ultrasonography alone. Methods One hundred parathyroidectomies performed by a single surgeon between April 2004 and December 2012 were identified in a prospectively maintained database. All patients underwent ultrasonography including preoperative marking of the lesion by a single radiologist. No other localising diagnostic tests were performed. Results Of the 100 patients (69% female) who underwent parathyroidectomy, 93 had MIP. The median age of all cases was 58 years (range: 19–90 years). All patients exhibited an elevated parathyroid hormone level (median: 19pmol) in the presence of hypercalcaemia (median: 2.86mmol/l, range: 2.54–3.94mmol/l). Conventional surgery was indicated in seven patients owing to the need for concurrent thyroidectomy. The median operative time was 30 minutes (range: 10–130 minutes). Ultrasonography localised parathyroid tumour position correctly in 98% of patients who underwent MIP, and in 97% across both MIP and non-MIP groups. Postoperative complications requiring treatment included pancreatitis and symptomatic hypocalcaemia. Follow-up review at 6–8 weeks demonstrated that 86% of open cases (6/7) and 94% of MIP cases (87/93) were rendered normocalcaemic. Conclusions Our study is the first to demonstrate that the sole use of ultrasonography including preoperative marking can localise parathyroid tumours correctly in 98% of cases suitable for MIP.

Purpose: To measure blood flow velocity in the ophthalmic artery (OA) and central retinal artery (CRA) in patients with diabetic retinopathy. Subjects and Methods: 62 age-matched subjects divided into 3 groups: non-diabetic controls (n=17); diabetics with no clinical retinopathy or background changes (n=24); diabetics with either pre-proliferative or proliferative retinopathy (n=21). Colour Doppler imaging was performed on supine patients by one masked observer using the Acuson 128 machine. Results: There was a statistically significant (p

The purpose of this study was to compare the efficacy and tolerability of diclofenac-gentamicin combination eye drops with that of dexamethasoneneomycin-polymyxin B combination eye drops (Maxitrol®) in the postoperative management of patients undergoing extracapsular cataract surgery and lens implantation. This was a prospective, randomised, double-masked, parallel-group, 4-week, multicentre study with patient visits preoperatively, on the day of surgery and postoperatively on days 1, 5 to 8, 12 to 16, and 26 to 32. Of the 304 patients (diclofenac-gentamicin 152, Maxitrol® 152) enrolled in the study, 259 (diclofenac-gentamicin 131, Maxitrol® 128) were available for per-protocol analyses of efficacy. The two treatment groups were similar at baseline. There was no significant difference between the two treatment groups in the primary efficacy variable, the sum of grades of anterior chamber flare and cells, at any study visit (p = 0.91 on day 1, p = 0.12 on days 5 to 8, p = 0.28 on days 12 to 16 and p = 0.35 on days 26 to 32). Although possible drug-related adverse events were more frequent in the diclofenac-gentamicin group (14.9%) compared with Maxitrol® (7.5%), the difference was not statistically significant (p > 0.1), and all study patients normalised with appropriate therapy. In conclusion, diclofenac-gentamicin eye drops were as effective and well tolerated as Maxitrol® eye drops in the control of post-cataract surgery inflammation.

The purpose of this study was to compare the velocity of blood flow and vascular resistance measured by colour Doppler imaging in the ophthalmic and central retinal arteries in 34 eyes of 34 patients (mean age 68.1 years) with low tension glaucoma (LTG) and 17 eyes of 17 age-matched normal controls (mean age 65.2 years). The Acuson 128 machine (using a 7.5 MHz probe) was used to measure peak systolic velocity (PSV), end-diastolic velocity (EDV) and resistive index (RI). The EDV of the ophthalmic artery (OA) in the LTG was significantly (p = 0.04) less than in the normal control group. There was a significant (p = 0.02) increase in the vascular RI of both the OA and central retinal artery in the LTG group compared with the normal controls. The OA RI increased with age (r = 0.61, p = 0.0001), and the OA EDV decreased with age (r = -0.50, p = 0.003), in the LTG group but not in the normal control group. The results suggest an increased resistance to blood flow in the ophthalmic and central retinal arteries of LTG patients.

Altogether seven patients had pituitary ablation by yttrium90 performed by neurosurgeons in the 1960's-early 1970's for proliferative diabetic retinopathy with imminent danger of blindness. The authors present a long-term review (16 years-25 years) of the beneficial effects this operation has had on their retinopathy and to some extent, on nephropathy. Six of their patients still have documented evidence of inactive retinopathy. All except one are still alive and leading active lives.

The findings of two post-mortem examinations and one CT scan of patients with biopsy proved giant cell arteritis (GCA) are presented. The presence or absence of intracranial involvement in GCA is discussed.

The injection of local anaesthetic solutions is frequently a painful and unpleasant experience for patients. A double-masked randomised controlled trial was performed to study the potential benefit of warming lignocaine during local anaesthetic minor surgical procedures on the eyelids. The pain of subcutaneous injection of 1.5 ml of 2% lignocaine at room temperature (cold) and body temperature (warm) was compared in 60 patients during the surgical incision of solitary meibomian cysts of one eyelid. Patients were randomly allocated to receive either warm or cold lignocaine. Pain was assessed subjectively by the use of a linear analogue pain scale ranging from 0 to 100. The median pain score for the group receiving cold anaesthetic (19.5) was found to be greater than that for the warm group (10.0; p = 0.02). In conclusion, the simple process of warming lignocaine to 37 degrees C was found to reduce the pain associated with its injection significantly. It is recommended that this technique be more widely adopted in order to minimise patients' discomfort.

Purpose: To measure the pulsatile component of total ocular blood flow in patients with untreated diabetic retinopathy. Subjects and Methods: An adapted pneumotonometer attached to a slit-lamp biomicroscope. 82 age-matched subjects divided into 4 groups: non-diabetic controls (n = 22); diabetics with no clinical retinopathy (n = 20); background diabetic retinopathy (n = 20); pre-proliferative/proliferative diabetic retinopathy (n = 20). Results: The mean pulsatile ocular blood flow values were found to be increased in all grades of diabetic retinopathy (no retinopathy 818 μl/min, background 1015 μl/min, pre-proliferative/proliferative 1097 μl/min) compared to the control group (644 μl/min). These pulsatile ocular blood flow values were significantly higher (p

The authors studied the coagulation cascade and fibrinolysis pathway in patients with untreated glaucoma (P = 0.00001 and P = 0.0003, respectively) and patients with normal pressure glaucoma ([NPG] P = 0.00001 and P = 0.03, respectively).Forty-two untreated patients with NPG, 25 untreated patients with primary open-angle glaucoma (POAG), and 32 age-matched normal controls were recruited. Patients taking anticoagulant therapy beta blockers or calcium channel blockers were excluded. Venous blood was assessed for markers of the coagulation and fibrinolysis pathways using enzyme-linked immunosorbent assay techniques.Patients with POAG had elevated levels of prothrombin fragments 1 + 2 and D-dimer compared with both the NPG and controls (P = 0.00001 and P = 0.0003, respectively). Both glaucoma groups had more (P0.05) systemic vascular disease than the control group. The patients with POAG had higher (P0.05) systemic blood pressure (systolic and pulse pressure) than the control and NPG groups. Both glaucoma groups had greater levels of fibrinogen (which was of borderline statistical significance) than the control group.Elevated levels of prothrombin fragments 1 + 2 and D-dimer indicate activation of the coagulation cascade and fibrinolysis pathway, respectively, leading to a hypercoagulable state in untreated POAG. These findings may contribute to the reported increased prevalence of retinal venous thrombosis in glaucoma and also to the pathogenesis of optic nerve damage in glaucoma.

The ophthalmological manifestations of giant cell arteritis (GCA) present a difficult diagnostic and management problem to the ophthalmologist. The orbital circulation is frequently involved in the disease process. The effects of GCA on orbital blood flow assessed by colour Doppler imaging (CDI) were investigated in this study. Serial CDI examinations of the orbital blood vessels were performed (at presentation, 2 days, 1 week and at 1 month) on 7 patients with GCA. CDI examination at presentation was also performed on 4 patients with non-arteritic anterior ischaemic optic neuropathy (AION) for comparison. Blood flow could not be detected in up to three arteries in the affected (ipsilateral) orbit of 6 GCA patients at presentation. Five of these patients were also found to have undetectable blood flow in the posterior ciliary arteries of the contralateral orbit. Serial CDI examination revealed blood flow alterations in arteritic patients despite treatment. Return of blood flow to normal was slow, and related to the clinical features. By contrast, only 1 of the patients with non-arteritic AION showed undetectable blood flow in a posterior ciliary artery. GCA leads to widespread and prolonged alterations in orbital blood flow. CDI allows the detection and monitoring of such alterations in orbital blood flow, which correlate with the clinical features of GCA. Serial CDI examinations in GCA may be used to aid management decisions.

A case of central retinal artery occlusion in a patient with Marfan's syndrome secondary to possible thromboembolism from a prolapsed mitral valve is presented. Clinical investigations and treatment of this condition are discussed. The world literature on retinal occlusive events secondary to mitral valve prolapse is briefly summarised. To the best of our knowledge, this is the first case report in the literature of central retinal artery occlusion in a patient with Marfan's syndrome.

A 40-year-old man presented to casualty after losing control of a high-performance car and colliding with a tree. The driver was wearing a seat belt and was able to extricate …

SUMMARYPurposeLangham adapted the pneumotonometer to provide a waveform of the ocular pulse and using the heart rate derived values for pulsatile ocular blood flow. We have used a new pneumotonometer linked to an ocular blood flow system that has addressed several of the problems encountered with th

ObjectivesIn recent years ultrasound guided foam sclerotherapy (UGFS) has become an increasingly popular treatment for varicose veins. Although many published series detail the results of UGFS, little is known about the factors which are associated with outcomes and complications. The aim of this study was to identify these factors.DesignA review of a prospectively collected database of UGFS which commenced in July 2007.MethodsA successful outcome was defined as complete occlusion of the target vein on duplex scanning at follow-up. Eight factors were assessed to determine whether they were associated with outcomes and complications. These factors were age, gender, compliance with post-procedure compression hosiery, previous varicose vein surgery, single or multiple sites of injection, concentration of sclerosant, volume of sclerosant and pre-procedure severity score.ResultsBetween July 2007 and July 2009, a total of 126 patients (60 men, 66 women) attended follow-up visits and had a post-procedure duplex scan. Targets for UGFS included the great saphenous vein (n = 75), small saphenous vein (n = 13) and anterior accessory great saphenous vein (n = 8). The remainder of procedures involved other veins or more than a single target vein. The median timing of follow-up was 3 months (range 1.5–14 months) with duplex scans revealing complete occlusion of the target vein in 79% of patients. The only factor associated with a successful outcome was compliance with post-procedure compression hosiery (p