A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy.

In many cancers early intervention involves surgical resection of small localised tumour masses. Inadequate resection leads to recurrence whereas overzealous treatment can lead to organ damage. This work describes production of a HER2 targeting antibody Fab fragment dual conjugated to achieve both real time near-infrared fluorescent imaging and photodynamic therapy. The use of fluorescence emission from a NIR-dye could be used to guide resection of tumour bulk, for example during endoscopic diagnosis for oesophago-gastric adenocarcinoma, this would then be followed by activation of the photodynamic therapeutic agent to destroy untreated localised areas of cancer infiltration and tumour infiltrated lymph nodes. This theranostic agent was prepared from the Fab fragment of trastuzumab initially by functional disulfide re-bridging and site-specific click reaction of a NIR-dye. This was followed by further reaction with a novel pre-activated form of the photosensitiser chlorin e6 with the exposed fragments' lysine residues. Specific binding of the theranostic agent was observed in vitro with a HER2 positive cell line and cellular near-infrared fluorescence was observed with flow cytometry. Specific photo-activity of the conjugates when exposed to laser light was observed with HER2 positive but not HER2 negative cell lines in vitro, this selectivity was not seen with the unconjugated drug. This theranostic agent demonstrates that two different photo-active functions can be coupled to the same antibody fragment with little interference to their independent activities.

Development and validation of a symptom-based severity score for haemorrhoidal disease: the Sodergren score.

AIM: One major obstacle in assessing the efficacy of treatment of haemorrhoids and the comparison of trials has been the lack of a standardized, validated symptom severity score. This study aimed to develop an objective, validated symptom-based score of severity for haemorrhoids that can be used to compare treatments, monitor disease and assist in surgical decisions. METHOD: A symptom and quality-of-life questionnaire was developed from the literature in conjunction with expert surgical opinion. The questionnaire was circulated to patients with confirmed haemorrhoids. A statistical model was used to derive a weighted score of symptoms most affecting patients' quality of life. Patients who were offered operative treatment were independently judged by specialists to have more severe symptoms, with further validation of the scoring system against treatment. RESULTS: Forty-five patients were included in final validation analysis, of whom 44 (98%) reported multiple symptoms, the most common being rectal bleeding. Patient-reported effects on quality of life were 47.5 ± 36.3 (1-100 visual analogue scale). Calculated symptom severity scores were used to compare patients receiving operative or ambulatory care, with significant difference in the scores (7.7 ± 3.9 vs 2.8 ± 3.5, P = 0.002) and a receiver operating characteristic area under the curve of 0.842. CONCLUSION: A novel validated score for the assessment of haemorrhoidal disease adopting a standardized global score for symptom severity may have important implications in future for research, assessment and the management of this common pathology.

Meta-analysis of the effect of postoperative in-hospital morbidity on long-term patient survival.

BACKGROUND: Major surgery is associated with high rates of postoperative complications, many of which are deemed preventable. It has been suggested that these complications not only present a risk to patients in the short term, but may also reduce long-term survival. The aim of this review was to examine the effects of postoperative complications on long-term survival. METHODS: MEDLINE, Web of Science and reference lists of relevant articles were searched up to July 2013. Studies assessing only procedure-specific, or technical failure-related, complications were excluded, as were studies of poor methodological quality. Meta-analysis was performed using a random-effects model. Risk of bias was assessed using funnel plots. RESULTS: Eighteen eligible studies were included, comprising results for 134 785 patients with an overall complication rate of 22·6 (range 10·6-69) per cent. The studies included operations for both benign and malignant disease. Median follow-up was 43 (range 28-96) months. Meta-analysis demonstrated reduced overall survival after any postoperative complication for ten studies with eligible data (20 755 patients), with a hazard ratio (HR) of 1·28 (95 per cent confidence interval 1·21 to 1·34). Similar results were found for overall survival following infectious complications: HR 1·92 (1·50 to 2·35). In analyses of disease-free survival the HR was 1·26 (1·10 to 1·42) for all postoperative complications and 1·55 (1·12 to 1·99) for infectious complications. Inclusion of poor-quality studies in a sensitivity analysis had no effect on the results. CONCLUSION: Postoperative complications have a negative effect on long-term survival. This relationship appears to be stronger for infectious complications.

Randomized clinical trial of the impact of surgical ward-care checklists on postoperative care in a simulated environment.

BACKGROUND: Complications are a common and accepted risk of surgery. Failure to optimize the management of patients who suffer postoperative morbidity may result in poorer surgical outcomes. This study aimed to evaluate a checklist-based tool to improve and standardize care of postoperative complications. METHODS: Surgical trainees conducted baseline ward rounds of three patients with common postoperative complications in a high-fidelity simulated ward environment. Subjects were randomized to intervention or control groups, and final ward rounds were conducted with or without the aid of checklists for management of postoperative complications. Adherence to critical care processes was assessed, in addition to technical (Surgical Ward-care Assessment Tool, SWAT) and non-technical (Ward NOn-TECHnical Skills (W-NOTECHS) scale) performance. Subjects completed a feedback questionnaire regarding their perception of the checklists. RESULTS: Twenty trainees completed 120 patient assessments. All intervention group subjects opted to use the checklists, resulting in significantly fewer critical errors compared with controls (median (i.q.r.) 0 (0-0) versus 60 (40-73) per cent; P < 0·001). The intervention group demonstrated improved patient management (SWAT-M) (P < 0·001) and non-technical skills (P = 0·043) between baseline and final ward rounds, whereas controls did not (P = 0·571 and P = 0·809 respectively). A small learning effect was seen with improvement in patient assessment (SWAT-A) in both groups (P < 0·001). Intervention group subjects found checklists easy and effective to use, and would want them used for their own care if they were to experience postoperative complications. CONCLUSION: Checklist use resulted in significantly improved standardization, evidence-based management of postoperative complications, and quality of ward rounds. Simulation-based piloting aided appropriate use of checklists and staff engagement. Checklists represent a low-cost intervention to reduce rates of failure to rescue and to improve patient care.

Ventilation practices in the neonatal intensive care units in Saudi Arabia, survey of the utilization of volume-targeted ventilation among practicing neonatologists.

OBJECTIVE: To assess the current practice in using volume-targeted ventilation among neonatologists working at the Neonatal Intensive Care Units (NICU) of Saudi Arabia. METHODS: The questionnaire was provided electronically to 153 practicing Neonatologists working in 39 NICUs. The survey's results were received and statistically analyzed. RESULTS: One hundred nineteen (119) responses were received with, a 78% response rate. Volume Targeted Ventilation (VTV) was used routinely by 67.2%, whereas 21.8% still use only pressure control (PC)/pressure limited (PL) mode. During the acute phase of ventilation support, Assist Control was the most popular synchronized mode, whereas Synchronized Intermittent Mandatory Ventilation (SIMV) with pressure support (PS) or PSV were the two most common modes during the weaning phase, 31.8%, and 31% respectively. The majority of the neonatologists used a tidal volume of 4 ml/kg as the lowest and 6 ml/kg as the highest. The major reasons for not implementing VTV were the limited availability of ventilator devices that have an option of VTV, followed by lack of experience. CONCLUSION: VTV is the predominant ventilation practice approach among neonatologists working in the KSA. Limited availability and lack of experience in using are the main challenges. Efforts to equip NICUs with the most advanced ventilation technology, enhance practitioners' experience and sufficient training in its use are warranted.

Clinical characteristics and liver profiles of Dubin-Johnson syndrome in neonates: Multicenter retrospective study.

OBJECTIVES: Dubin-Johnson syndrome (DJS) is a rare benign autosomal recessive disorder characterized by cholestasis in neonates. The aim of the present study was to describe the clinical characteristics, hepatic profiles, histopathology, gene mutations, and treatment outcomes of neonatal DJS. MATERIAL AND METHODS: A multicenter retrospective study was undertaken with patients who had DJS. The authors identified DJS in neonates and reviewed medical records for details. The diagnosis of DJS was based on the presence of unexplained prolonged conjugated hyperbilirubinemia and presence of a mutation in the ATP Binding Cassette Subfamily C Member 2 (ABCC2) gene detected in genomic DNA extracted from circulating blood cells. RESULTS: Eleven children with DJS were identified in the study. The study population comprised eight males and three females. The median age at presentation was 21 days. Dysmorphic features were not recorded in any of the patients. Cholestasis, high serum bile acids, and normal transaminase levels were found in all patients (100%). Serum alkaline phosphatase and gamma glutamyl transferase were elevated in four patients (36%). Hypoalbuminemia and coagulopathy were not noted in these patients. Consanguinity was present in nine patients (82%). All patients had normal abdominal ultrasound findings. Genetic molecular testing showed that 82% of the patients reported a pathogenic variant of the ABCC2 gene defect with the same variant c.2273G>T (Gly 758 val) chromosome 10. All patients were alive without liver transplantation. CONCLUSIONS: This is the largest study worldwide describing that neonatal DJS is a benign cholestatic disease with favorable outcomes. Low-grade direct hyperbilirubinemia, normal transaminases, and elevated serum bile acids are the main characteristic findings of DJS.

Prenatal diagnosis of idiopathic infantile arterial calcification with hydrops fetalis.

Idiopathic infantile arterial calcification (IIAC) is a rare and nearly always fatal disorder. To date, prenatal diagnosis has been reported in fewer than 10 cases. We describe a series of three cases in which the diagnosis of IIAC was made at 23, 25 and 29 weeks' gestation. All three cases presented with a normal anatomy scan at 20 weeks' gestation with an echogenic intracardiac focus. Follow-up scans showed generalized hyperechogenicity and calcification of the walls of the large arteries, particularly the aorta and the iliac arteries. All cases developed hydrops fetalis with cardiomegaly and polyhydramnios later in gestation, resulting in intrauterine fetal death in two cases and neonatal death immediately following delivery in the third. This is the largest case series and the earliest gestational age of prenatal diagnosis of IIAC reported to date. When surveying for the disease, serial scans are important, perhaps from 20 weeks' gestation, with close examination of the iliac and aortic arteries. Detection of echogenic intracardiac focus could be an early marker in patients with a family history of the disease.

Utility of various clinical, noninvasive, and invasive procedures for determining the causes of recurrence of myocardial ischemia or infarction > or = 1 year after percutaneous transluminal coronary angioplasty.

In patients with recurrent symptoms > or = 1 year after successful percutaneous transluminal coronary angioplasty (PTCA), the decision of whether to proceed directly with coronary angiography or to evaluate the patient noninvasively can be difficult. To determine which demographic, historical, clinical, and laboratory factors are useful in helping to make this decision, 76 consecutive patients who presented > 1 year (768 +/- 309 days) after successful PTCA with resolution of symptoms were studied. The initial PTCA successfully treated all stenoses (except chronically occluded vessels) in all major vessels and segments. The patient group was predominantly men (68%), with a mean age of 64 +/- 10 years. A prior myocardial infarction was present in 39 patients (51%), and there was a mean of 2.8 risk factors per patient. In patients who presented with recurrent symptoms, the Canadian Cardiovascular Society functional class was 2.0 +/- 0.9; 2 patients presented with acute infarctions, 57 were admitted to the hospital with unstable angina, and 17 had stable angina. New electrocardiographic changes at rest were found in 19 of 74 patients (26%) with recurrent angina. A thallium stress test was performed in 40 patients (53%), with a sensitivity of 77% and a specificity of 36% for the presence of a significant stenosis. No nonangiographic variable was predictive of angiographic findings. At angiography, the number of coronary arteries with > or = 50% diameter narrowing was 1.4 +/- 1.0. Forty-two patients had stenosis at a new site, 7 had restenosis, and 27 had no new stenoses.(ABSTRACT TRUNCATED AT 250 WORDS)

Traumatic brain injury in a child psychiatry inpatient population: a controlled study.

OBJECTIVE: To extend our findings from child psychiatry outpatients to child psychiatry inpatients regarding the similarity of children with a history of traumatic brain injury (TBI), particularly mild TBI, to matched children without such a history. METHOD: This is a chart review of patients consecutively admitted to a child psychiatry inpatient unit over a 5-year period. Children with TBI were matched by age, sex, race, and social class to children with no history of TBI. Axis I and II diagnoses and diagnostic clusters and use of special education services and IQ scores were compared. RESULTS: Fifty-six (8.1%) of 694 consecutive patients admitted had a definite TBI. Not one of more than 50 variables compared between TBI and control subjects was significantly different. CONCLUSION: In a child psychiatry inpatient unit, patients with a history of TBI were virtually indistinguishable from matched children without TBI. Caution should be exercised before attributing the child's problems, especially long-term problems, to the TBI unless the injury was severe or the child is exhibiting related phobic or posttraumatic stress symptomatology.

Hyaluronate levels and markers of oxidative stress in the serum of Sudanese subjects at risk of infection with Schistosoma mansoni.

We showed previously that infection by Schistosoma mansoni not only triggers the production of reactive oxygen species in mouse liver but also leads to the alteration of antioxidant defences. To determine whether such events occur in humans, we measured the serum markers of oxidative stress, i.e., lipid peroxides and protein carbonyl, as well as hyaluronate levels in subjects in the Managil area of the Sudan. Grades of fibrosis were determined by ultrasonographic examination. Two groups were used as controls, one Sudanese and the other European. We found that Sudanese subjects in the endemic area differed from the control groups, both Sudanese and European, insofar as they had higher levels of the serum metabolites measured. The latter increased with the grade of fibrosis. Moreover, protein carbonyl and hyaluronic acid levels correlated positively with lipid peroxide levels. These findings indicate that oxidative stress might contribute to S. mansoni-associated pathology in man. The serum markers considered in our study, obtained by relatively simple techniques, may provide a useful biochemical index for the identification of almost asymptomatic patients who, however, are at risk of developing severe schistosomiasis.

Calcium channel blockers. Consensus amid controversy.

Although the calcium channel blockers have been used to treat hypertension for a number of years, they are now under close scrutiny because of disturbing findings regarding their safety. Drs Kochar and Qurashi sort out the controversies surrounding these widely used drugs and make recommendations based on current consensus.

Unusual cause of neonatal cyanosis.

We present a case of a full-term female neonate who presented at 6 h of age with severe cyanosis and was partially responsive to oxygen supplementation. An echocardiogram showed an isolated congenital severe tricuspid valve insufficiency due to rupture of the papillary muscle of the anterior tricuspid valve leaflet. Magnesium sulfate was infused to lower the pulmonary resistance and thus enhancing the antegrade pulmonary blood flow. Ductal patency was secured by prostaglandin infusion thus providing an additional pulmonary blood flow through the ductus arteriosus. The above measures were adequate to stabilize the patient with no further deterioration or the need for other supportive measures such as Nitric Oxide therapy or extracorporeal membrane oxygenation (ECMO). Therefore, early diagnosis and adequate measures to improve the pulmonary blood flow are mandatory, important pre-operative measures in the management of these patients.