Germline V repertoires: Origin, maintenance, diversification.

In our view, Melvin Cohn (Scand J Immunol. 2018;87:e12640) has set out the logical guidelines towards a resolution of the very real enigma of the selectability of vertebrate germline Ig V repertoires under the current evolutionary paradigm…" A somatically derived repertoire scrambles this (germline VL + VH) substrate so that its specificities are lost, making it un-selectable in the germline. Consequently, evolution faced an incompatibility." It is argued here in Reply that a reverse transcriptase-based soma-to-germline process (S->G) targeting germline V segment arrays goes some considerable way to resolving fundamental contradictions on the origin, maintenance and then real-time adaptive diversification of these limited sets of V segments encoded within various V repertoire arrays.

Management of hip fractures in older people in Beijing: a retrospective audit and comparison with evidence-based guidelines and practice in the UK.

UNLABELLED: Despite the high burden of hip fracture in China, there is limited information on its management. This study investigated the management of hip fractures in a Beijing tertiary hospital and compared practice with that in 180 hospitals in the UK. The findings show a significant gap exists between the countries. INTRODUCTION: The purpose of this study was to determine if the management of older people with hip fractures in a Beijing tertiary hospital is comparable with the UK best practice guidelines for hip fracture management and the UK National Hip Fracture Database 2012, obtained from 180 hospitals. METHODS: A retrospective audit was undertaken in a large tertiary care hospital in Beijing. Data were compared with the National Hip Fracture Database 2012 collected in 180 hospitals in the UK on the proportion of patients managed according to the UK Blue Book standards. RESULTS: Sixty-six percent of patients were admitted to an orthopaedic ward within 24 h of fracture, while 100 % of patients in the UK were admitted to an orthopaedic ward within 24 h of arrival to an accident and emergency department. Only 8 % of patients received surgery within 48 h of admission compared with 83 % in the UK; 10 % received no surgery compared with 2.5 % in the UK; and 27 % received orthogeriatrician assessment compared with 70 % in the UK. New pressure ulcers developed in 2 % of patients compared with 3.7 % of those in the UK; whereas, 0.3 % of patients were assessed for osteoporosis treatment and 3.8 % received falls assessment, and comparable figures for the UK were 94 and 92 %, respectively. CONCLUSIONS: Significant gaps exist in hip fracture management in the Beijing hospital compared with the best practice achieved in 180 UK hospitals, highlighting the need to implement and evaluate proactive strategies to increase the uptake of best practice hip fracture care in China.

Ordinal Outcome State-Space Models for Intensive Longitudinal Data.

Intensive longitudinal (IL) data are increasingly prevalent in psychological science, coinciding with technological advancements that make it simple to deploy study designs such as daily diary and ecological momentary assessments. IL data are characterized by a rapid rate of data collection (1+ collections per day), over a period of time, allowing for the capture of the dynamics that underlie psychological and behavioral processes. One powerful framework for analyzing IL data is state-space modeling, where observed variables are considered measurements for underlying states (i.e., latent variables) that change together over time. However, state-space modeling has typically relied on continuous measurements, whereas psychological data often come in the form of ordinal measurements such as Likert scale items. In this manuscript, we develop a general estimation approach for state-space models with ordinal measurements, specifically focusing on a graded response model for Likert scale items. We evaluate the performance of our model and estimator against that of the commonly used "linear approximation" model, which treats ordinal measurements as though they are continuous. We find that our model resulted in unbiased estimates of the state dynamics, while the linear approximation resulted in strongly biased estimates of the state dynamics. Finally, we develop an approximate standard error, termed slice standard errors and show that these approximate standard errors are more liberal than true standard errors (i.e., smaller) at a consistent bias.

Stroke management: updated recommendations for treatment along the care continuum.

The Australian Clinical Guidelines for Stroke Management 2010 represents an update of the Clinical Guidelines for Stroke Rehabilitation and Recovery (2005) and the Clinical Guidelines for Acute Stroke Management (2007). For the first time, they cover the whole spectrum of stroke, from public awareness and prehospital response to stroke unit and stroke management strategies, acute treatment, secondary prevention, rehabilitation and community care. The guidelines also include recommendations on transient ischaemic attack. The most significant changes to previous guideline recommendations include the extension of the stroke thrombolysis window from 3 to 4.5 h and the change from positive to negative recommendations for the use of thigh-length antithrombotic stockings for deep venous thrombosis prevention and the routine use of prolonged positioning for contracture management.

An evaluation of an Internet-based approach to weight loss with low glycaemic load principles.

BACKGROUND: The prevalence of overweight and obesity is increasing worldwide at an alarming rate. An Internet-based weight-loss programme has the potential to reach larger numbers of people than traditional face-to-face programmes. A growing body of evidence supports the use of low glycaemic load (GL) diets for weight loss. The present study aimed to investigate the efficacy of an Internet-based weight-loss programme that included foods with a low GL. METHODS: One hundred and three volunteers, with a body mass index (BMI) ≥28 kg m(-2) , enrolled into an Internet weight-loss programme. A dietitian counselled participants over the Internet via weekly interactive chat rooms and monthly e-mails. Participants self-recorded body weight and food intake directly on to the Internet site. Weight, BMI and waist circumference were measured, and dietary data collected, at baseline and 6 months. RESULTS: Seventy participants completed the 6-month weight-loss programme. Among these, mean weight, BMI and waist circumference significantly decreased by 3.5 kg (95% CI = 2.3-4.7), 1.2 kg m(-2) (95% CI = 0.8-1.7) and 4.8 cm (95% CI = 2.8-6.8), of baseline values respectively (P < 0.001). Twenty-five (36%) of the 70 participants lost a clinically significant amount of weight (>5% of initial body weight). CONCLUSIONS: This descriptive study has shown that an Internet-based weight-loss programme with low GL principles can promote weight loss. This type of intervention and approach could be used to enhance other weight-loss strategies.

Surveillance for outbreaks of influenza-like illness in the institutionalized elderly.

Respiratory outbreaks are common in aged-care facilities (ACFs), are both underreported and frequently identified late, and are often associated with considerable burden of illness and death. There is emerging evidence that active surveillance coupled with early and systematic intervention can reduce this burden. Active surveillance for influenza-like illness and rapid diagnosis of influenza were established in 16 ACFs in Sydney, Australia, prior to the winter of 2006. A point-of-care influenza test and laboratory direct immunofluorescence tests for common respiratory viruses were used for diagnosis. We achieved early identification of seven respiratory disease outbreaks, two of which were caused by influenza. For the influenza outbreaks, antiviral treatment and prophylaxis were initiated 4-6 days from symptom onset in the primary case. A simple active surveillance system for influenza was successfully implemented and resulted in early detection of influenza and other respiratory disease outbreaks. This enabled earlier implementation of prevention and control measures and increased the potential effectiveness of anti-influenza chemoprophylaxis.

A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population. The PRIME trial.

OBJECTIVES: To assess whether omission of postoperative radiotherapy in women with 'low-risk' axillary node negative breast cancer (T0-2) treated by breast-conserving surgery and endocrine therapy improves quality of life and is more cost-effective. DESIGN: A randomised controlled clinical trial, using a method of minimisation balanced by centre, grade of cancer, age, lymphatic/vascular invasion and preoperative endocrine therapy, was performed. A non-randomised cohort was also recruited, in order to complete a comprehensive cohort study. SETTING: The setting was breast cancer clinics in cancer centres in the UK. PARTICIPANTS: Patients aged 65 years or more were eligible provided that their cancers were considered to be at low risk of local recurrence, were suitable for breast-conservation surgery, were receiving endocrine therapy and were able and willing to give informed consent. INTERVENTIONS: The standard treatment of postoperative breast irradiation or the omission of radiotherapy. MAIN OUTCOME MEASURES: Quality of life was the primary outcome measure, together with anxiety and depression and cost-effectiveness. Secondary outcome measures were recurrence rates, functional status, treatment-related morbidity and cosmesis. The principal method of data collection was by questionnaire, completed at home with a research nurse at four times over 15 months. RESULTS: The hypothesised improvement in overall quality of life with the omission of radiotherapy was not seen in the EuroQol assessment or in the functionality and symptoms summary domains of the European Organisation for Research in the Treatment of Cancer (EORTC) scales. Some differences were apparent within subscales of the EORTC questionnaires, and insights into the impact of treatment were also provided by the qualitative data obtained by open-ended questions. Differences were most apparent shortly after the time of completion of radiotherapy. Radiotherapy was then associated with increased breast symptoms and with greater fatigue but with less insomnia and endocrine side-effects. Patients had significant concerns about the delivery of radiotherapy services, such as transport, accommodation and travel costs associated with receiving radiotherapy. By the end of follow-up, patients receiving radiotherapy were expressing less anxiety about recurrence than those who had not received radiotherapy. Functionality was not greatly affected by treatment. Within the randomised controlled trial, the Barthel Index demonstrated a small but significant fall in functionality with radiotherapy compared with the no radiotherapy arm of the trial. Results from the non-randomised patients did not confirm this effect, however. Cosmetic results were better in those not receiving radiotherapy but this did not appear to be an important issue to the patients. The use of home-based assessments by a research nurse proved to be an effective way of obtaining high-quality data. Costs to the NHS associated with postoperative radiotherapy were calculated to be of the order of 2000 pounds per patient. In the follow-up in this study, there were no recurrences, and the quality of life utilities from EuroQol were almost identical. CONCLUSIONS: Although there are no differences in overall quality of life scores between the patients treated with and without radiotherapy, there are several dimensions that exhibit significant advantage to the omission of irradiation. Over the first 15 months, radiotherapy for this population is not a cost-effective treatment. However, the early postoperative outcome does not give a complete answer and the eventual cost-effectiveness will only become clear after long-term follow-up. Extrapolations from these data suggest that radiotherapy may not be a cost-effective treatment unless it results in a recurrence rate that is at least 5% lower in absolute terms than those treated without radiotherapy. Further research is needed into a number of areas including the long-term aspects of quality of life, clinical outcomes, costs and consequences of omitting radiotherapy.

Visceral leishmaniasis (kala azar) in a patient with AIDS.

A patient with HIV infection presented with multiple cutaneous Kaposi's sarcomata. Biopsy of one of these showed the presence of amastigotes within an otherwise typical Kaposi's sarcoma. Further investigations proved the patient to have visceral leishmaniasis (kala azar). Visceral leishmaniasis has been reported in HIV infection but it is rare and this presentation is unique. The patient made a good response to a prolonged course of treatment with sodium stibogluconate and allopurinol.

Iron overload in multiply transfused patients who are HIV seropositive.

AIMS: To assess histologically the amount of iron deposited in liver biopsy specimens from HIV positive patients; and to perform estimations of liver iron on tissue from patients with an increase in parenchymal stainable iron. To correlate the amount of blood transfused and the degree of iron overload. METHODS: Liver biopsy specimens (n = 120) from 109 HIV positive patients, 74 of whom had AIDS, were examined retrospectively and the amount of iron, as visualised with Perls's stain, was graded. Fibrosis was assessed using connective tissue stains. Estimations of liver iron were performed on tissue retrieved from paraffin wax blocks in cases with histological grade 3 or 4 iron overload. The amount of blood transfused before liver biopsy was determined from the notes for each patient. RESULTS: Fifteen of the 120 liver biopsy specimens had significantly increased amounts of iron in their hepatocytes, as assessed histologically, and this was confirmed in seven cases by measurement of liver iron. There was a close correlation between the amount of blood transfused and the degree of iron overload. In the initial biopsy specimens only one case showed portal tract expansion. Three of the five patients who had repeat biopsies, however, showed progressive fibrosis. CONCLUSION: Multiply transfused HIV positive patients may develop clinically important iron overload and are at risk of developing progressive fibrosis. Superimposed liver disease, especially viral hepatitis, in these high risk patients may exacerbate the effects of the iron overload.

Histologic features predictive of an increased risk of early local recurrence after treatment of breast cancer by local tumor excision and radical radiotherapy.

A histopathologic review was undertaken of 293 patients with breast cancer treated by local tumor excision and radical radiotherapy. In a 6-year period, there were 37 local treatment failures with 16 deaths, and an additional 20 patients died without local recurrence. Pathologic data were available for 272 patients. Multivariate analysis indicated that the pathologic features in an invasive tumor most predictive for local recurrence were the combination of a high proportion of intraduct carcinoma with extensive necrosis (comedocarcinoma). Of 18 patients with these features, nine have had early local recurrence (a risk of 50% with these features vs 10% in those without), and four have died (a risk of 22% against 12%). Despite the short follow-up, the results already appear significant, and the study is ongoing. The importance of comedonecrosis in the intraduct component as a prognostic indicator in invasive carcinoma of the breast is not widely recognized and might constitute a relative contraindication to conservative treatment of the breast.

Drug therapy for acute ischaemic stroke: risks versus benefits.

Stroke is a very common medical emergency that, until recently, had no specific treatment. Following the results of several major trials (including 2 'mega-trials'), aspirin (acetylsalicylic acid) can be recommended for the majority of patients with acute ischaemic stroke. While the benefit of aspirin is only modest, i.e. an increase of 11 per 1000 long term independent survivors, the public health benefit in the world will be substantial as this treatment could be given to millions of patients with acute ischaemic stroke each year. Heparin is associated with a reduction in early recurrent ischaemic stroke, but there is no net benefit because of a similar sized excess of recurrent haemorrhagic stroke (even for those in atrial fibrillation). Thrombolytic therapy has not been so widely tested and the results of the small trials to date have yielded conflicting results. The only positive publication to date (comprised of 2 related trials) evaluated the recombinant tissue plasminogen activator alteplase, but such treatment is probably only indicated for highly selected patients. Further trials are almost certainly required and it would be unwise to change clinical practice based on the current evidence. No other stroke treatments have been shown to be beneficial, and much larger trials will be required to confirm or refute possible moderate benefits of treatment. A well organised stroke service and participation in clinical trials will improve the future care of patients with acute ischaemic stroke.

The validity of a simple clinical classification of acute ischaemic stroke.

The aim of the study reported here was to test the validity of a simple clinical classification of acute ischaemic stroke (Oxfordshire Community Stroke Project, OCSP) in predicting the site and size of cerebral infarction on computed tomography (CT). Consecutive patients admitted to hospital with acute ischaemic stroke were prospectively identified and classified into one of four clinical syndromes according to the OCSP classification, blind to the result of CT. The CT brain scans were classified blind to the clinical features into those demonstrating: small, medium or large cortical infarcts; small or large subcortical infarcts in the anterior circulation territory; and posterior cerebral circulation territory infarcts. A total of 108 patients were included. A recent infarct was seen on the CT scan in 91 patients (84%), and the clinical classification correctly predicted the site and size of the cerebral infarct in 80 of these (88%; 95% confidence interval 77-92%). The positive predictive value was best for large cortical infarcts (0.94) and worst for small subcortical infarcts (0.63). The OCSP clinical classification is a reasonably valid way of predicting the site and size of cerebral infarction on CT and can, therefore, be used very early after stroke onset before the infarct appears on the scan.

Long-term outcome in bladder detrusorectomy augmentation.

BACKGROUND AND OBJECTIVES: Bladder augmentation in children can have significant benefits in terms of continence and social function. In an attempt to overcome the problems associated with using foreign mucosa in the urinary tract, techniques to increase to bladder volume and improve compliance by resecting the detrusor muscle alone have been described. Here we describe our experience using an omental-backed detrusorectomy augmentation and examine possible reasons for a poor outcome observed in some patients in the longer term. METHODS: This was a retrospective review covering an eight-year period with a minimum follow-up of 2 years. Pre- and post-operative urodynamics were performed in every case. RESULTS: 11 patients were included in the study. There were 7 male and 4 female patients with a median age of 10 years (range 4 - 16). The underlying pathology in 6 patients was myelodysplasia and in the remaining cases there was one each of ano-rectal malformation with neuropathic bladder, Guillain-Barré syndrome, a myopathy of unknown cause, transverse myelitis and one case of a non-neuropathic neuropathic bladder. Detrusorectomy provided a modest increase in bladder capacity (median 26 %) and decrease in maximum bladder pressure (median 12 %). Long-term follow-up has revealed treatment failure in 6 patients, resulting in revision augmentation surgery in 3 (with surgery planned in a further 2), and one patient developing end-stage renal failure. Notable complications were bladder stone formation in 4 patients and troublesome lower abdominal pain related to bladder drainage in 2. There appeared to be no correlation between initial diagnosis, age at operation, pre-operative urodynamics, peri- or post-operative factors, and long-term outcome. CONCLUSIONS: In our series, omental-backed detrusorectomy for a neuropathic bladder in children resulted in a poor outcome in 55 % of cases. We were unable to identify factors that would allow this result to be predicted pre-operatively.

Pathological features of invasive breast cancer associated with a high risk of local recurrence after tumour excision and radical radiotherapy.

The histological slides of 273 breast cancer patients, treated by local excision and radiotherapy and followed up for 2-6 years, were reviewed in search of factors predictive of local recurrence. Local recurrence was found to be most closely related to the combination of a high proportion of intraduct carcinoma and extensive necrosis (comedocarcinoma). This latter group of 18 patients had a local recurrence rate of 50%. These patients are of particular interest since they form a small group with readily identifiable histological features.

Oral metastasis in malignant pleural mesothelioma.

A case is reported of a 48-year-old man with malignant sarcomatous pleural mesothelioma, who presented with a secondary deposit in the mandibular alveolus. We believe that this is the first reported case of this nature.

Synchronous laparoscopic-assisted percutaneous endoscopic gastrostomy and peritoneal dialysis catheter placement is a valid alternative to open surgery.

OBJECTIVE: Gastrostomy feeding is frequently necessary in children receiving chronic peritoneal dialysis (PD). Synchronous laparoscopic-assisted placement of percutaneous endoscopic gastrostomy (PEG) and PD catheter has many potential advantages. This study investigates whether this technique is comparable to open placement. METHODS: The notes of all patients over a 16-year time period were reviewed retrospectively. Peritonitis was defined as the presence of a white blood cell count > 100/mm(3) with at least 50% being polymorphonuclear leukocytes, and infection was defined as the presence of positive peritoneal cultures with peritonitis. RESULTS: Ten patients received primary laparoscopic-assisted PEG and PD catheter insertion (LAP) and 23 patients open gastrostomy and PD catheter (OPEN). PD catheter survival was median 12 months in the LAP group and 17 months in the OPEN group. Peritonitis and infection rates per catheter-year were 0.89 and 0.7 LAP and 0.59 and 0.5 OPEN. The risk of peritonitis and infection was not related to method of placement. CONCLUSIONS: There were no statistically significant differences in outcomes between the two groups. We conclude that laparoscopic-assisted synchronous PD and PEG catheter insertion is safe and effective.

The relationship between aortic stiffness and changes in retinal microvessels among Asian ischemic stroke patients.

Large-artery stiffness is a risk factor for stroke, including cerebral small-vessel disease. Retinal microvascular changes are thought to mirror those in cerebral microvessels. We investigated the relationship between aortic stiffness and retinal microvascular changes in Asian ischemic stroke patients. We studied 145 acute ischemic stroke patients in Singapore who had aortic stiffness measurements using carotid-femoral pulse wave velocity (cPWV). Retinal photographs were assessed for retinal microvessel caliber and qualitative signs of focal arteriolar narrowing, arteriovenous nicking and enhanced arteriolar light reflex. Aortic stiffening was associated with retinal arteriolar changes. Retinal arteriolar caliber decreased with increasing cPWV (r=-0.207, P=0.014). After adjusting for age, gender, hypertension, diabetes, mean arterial pressure and small-vessel stroke subtype, patients within the highest cPWV quartile were more likely to have generalized retinal arteriolar narrowing defined as lowest caliber tertile (odds ratio (OR) 6.84, 95% confidence interval (CI) 1.45-32.30), focal arteriolar narrowing (OR 13.85, CI 1.82-105.67), arteriovenous nicking (OR 5.08, CI 1.12-23.00) and enhanced arteriolar light reflex (OR 3.83, CI 0.89-16.48), compared with those within the lowest quartile. In ischemic stroke patients, aortic stiffening is associated with retinal arteriolar luminal narrowing as well as features of retinal arteriolosclerosis.

Retinal microvascular changes and subsequent vascular events after ischemic stroke.

OBJECTIVES: Retinal microvasculature changes are associated with vascular events including stroke in healthy populations. It is not known whether retinal microvascular changes predict recurrent vascular events after ischemic stroke. We examined the relationship between retinal microvascular signs and subsequent vascular events in a prospective cohort of 652 acute ischemic stroke patients admitted to a tertiary hospital in Singapore from 2005 to 2007. METHODS: Retinal photographs taken within 1 week of stroke onset were assessed in a masked manner for quantitative and qualitative measures. Follow-up data over 2-4 years were obtained by standardized telephone interview and then were verified from medical records. Predictors of recurrent vascular events (cerebrovascular, coronary, vascular death, and composite vascular events) were determined using Cox regression models. RESULTS: Follow-up data over a median of 29 months were obtained for 89% (652 patients) of the cohort. After adjustment for covariates including traditional risk factors and index stroke etiology, patients with severe arteriovenous nicking (AVN) were more likely to have a recurrent cerebrovascular event (hazard ratio [HR] 2.28, 95% confidence interval [CI] 1.20-4.33) compared with those without AVN. Patients with severe focal arteriolar narrowing (FAN) were more likely to have a recurrent cerebrovascular event (HR 2.75, 95% CI 1.14-6.63) or subsequent composite vascular event (HR 2.77, 95% CI 1.31-5.86) compared to those without FAN. CONCLUSIONS: Retinal microvascular changes predicted subsequent vascular events after ischemic stroke, independent of traditional risk factors and stroke subtype. Thus, retinal imaging has a potential role in predicting the risk of recurrent vascular events after ischemic stroke and in understanding novel vascular risk factors.

Difficulties in recruiting older people in clinical trials: an examination of barriers and solutions.

Limited information exists regarding optimal methods for the recruitment and retention of older people in clinical trials. The aim of this review is to identify common barriers to the recruitment of older people in clinical trials and to propose solutions to overcome these barriers. A review of literature was performed to identify common difficulties in recruiting older people. This in combination with our experience during recruitment for a randomized control trial, have highlighted numerous barriers. Population-specific recruitment strategies, simple informed-consent processes, and effective communication between the researcher and subject are effective strategies to overcome these barriers.

Lack of pneumococcal carriage in the hospitalised elderly.

UNLABELLED: There have been few surveys of Streptococcus pneumoniae and Neisseria meningitidis carriage in sick or frail elderly people who, with the very young, comprise the group who are at highest risk for pneumococcal disease. We studied pneumococcal carriage among participants in a pneumococcal immunisation study in the frail elderly. METHODS: Subjects aged >or=60 years were recruited from a large tertiary referral hospital in Sydney, Australia. Nose and throat swabs were collected at the time of enrolment and 12 months after immunisation. RESULTS: Before immunisation, only 1 of 315 participants was identified as a nasal carrier of S. pneumoniae; another was identified as throat carrier of N. meningitidis. None of the participants examined after immunisation was carrying either S. pneumoniae or N. meningitidis. CONCLUSION: The low rate of pneumococcal carriage in this population of hospitalised elderly patients was unexpected. The most likely reason is that long-term carriage is rare in this population and suggests that pneumococcal disease primarily follows recent acquisition of S. pneumoniae types not associated with carriage.