Culturally adapted psychosocial interventions (CaPSI) for early psychosis in a low-resource setting: study protocol for a large multi-center RCT.

BACKGROUND: Psychosis treatment guidelines recommend cognitive behaviour therapy (CBT) and family intervention (FI), for all patients with first episode psychosis (FEP), though guidance borrows heavily from literature in adults from high income countries. To our knowledge, there are few randomized controlled trials (RCTs) examining the comparative effect of these commonly endorsed psychosocial interventions in individuals with early psychosis from high-income countries and no such trials from low and middle-income countries (LMICs). The present study aims to confirm the clinical-efficacy and cost-effectiveness of delivering culturally adapted CBT (CaCBT) and culturally adapted FI (CulFI) to individuals with FEP in Pakistan. METHOD: A multi-centre, three-arm RCT of CaCBT, CulFI, and treatment as usual (TAU) for individuals with FEP (n = 390), recruited from major centres across Pakistan. Reducing overall symptoms of FEP will be the primary outcome. Additional aims will include improving patient and carer outcomes and estimating the economic impact of delivering culturally appropriate psychosocial interventions in low-resource settings. This trial will assess the clinical-efficacy and cost-effectiveness of CaCBT and CulFI compared with TAU in improving patient (positive and negative symptoms of psychosis, general psychopathology, depressive symptoms, quality of life, cognition, general functioning, and insight) and carer related outcomes (carer experience, wellbeing, illness attitudes and symptoms of depression and anxiety). CONCLUSIONS: A successful trial may inform the rapid scale up of these interventions not only in Pakistan but other low-resource settings, to improve clinical outcomes, social and occupational functioning, and quality of life in South Asian and other minority groups with FEP. TRIAL REGISTRATION: NCT05814913.

Highly efficient CRISPR-Cas9-mediated editing identifies novel mechanosensitive microRNA-140 targets in primary human articular chondrocytes.

OBJECTIVE: MicroRNA 140 (miR-140) is a chondrocyte-specific endogenous gene regulator implicated in osteoarthritis (OA). As mechanical injury is a primary aetiological factor in OA, we investigated miR-140-dependent mechanosensitive gene regulation using a novel CRISPR-Cas9 methodology in primary human chondrocytes. METHOD: Primary (passage 1/2) human OA chondrocytes were isolated from arthroplasty samples (six donors) and transfected with ribonuclear protein complexes or plasmids using single guide RNAs (sgRNAs) targeting miR-140, in combination with Cas9 endonuclease. Combinations of sgRNAs and single/double transfections were tested. Gene editing was measured by T7 endonuclease 1 (T7E1) assay. miRNA levels were confirmed by qPCR in chondrocytes and in wild type murine femoral head cartilage after acute injury. Predicted close match off-targets were examined. Mechanosensitive miR-140 target validation was assessed in 42 injury-associated genes using TaqMan Microfluidic cards in targeted and donor-matched control chondrocytes. Identified targets were examined in RNAseq data from costal chondrocytes from miR-140-/- mice. RESULTS: High efficiency gene editing of miR-140 (90-98%) was obtained when two sgRNAs were combined with double RNP-mediated CRISPR-Cas9 transfection. miR-140 levels fell rapidly after femoral cartilage injury. Of the top eight miR-140 gene targets identified (P < 0.01), we validated three previously identified ones (septin 2, bone morphogenetic protein 2 and fibroblast growth factor 2). Novel targets included Agrin, a newly recognised pro-regenerative cartilage agent, and proteins associated with retinoic acid signalling and the primary cilium. CONCLUSION: We describe a highly efficient CRISPR-Cas9-mediated strategy for gene editing in primary human chondrocytes and identify several novel mechanosensitive miR-140 targets of disease relevance.

Enhanced trabeculectomy in a UK district general hospital setting: is selective use of 5-fluorouracil all that is required?

To determine whether primary trabeculectomies performed in a UK district general hospital, specifically without making use of mitomycin-C augmentation but with selective use of the low potency anti-metabolite 5-fluorouracil, produce an acceptable long-term intraocular pressure (IOP)-lowering effect for an unselected patient group. Retrospective analysis of the outcomes of all the trabeculectomies (53 eyes) performed by a single surgeon in a UK district hospital with or without 5-fluorouracil enhancement. The mean follow-up period was 5.04 years. Mean IOP preoperatively was 26.4 mm Hg while postoperatively the mean was ≤14.9 at all the time periods examined. Intraoperative complications occurred in two eyes (3.8 %) including one suprachoroidal haemorrhage and one hyphema. Postoperative complications that occurred during the follow-up period included choroidal effusions in seven patients (13 %), early postoperative bleb leak in four patients (8 %) and immediate postoperative hypotony not requiring intervention in 18 patients (34 %). Five patients (9 %) developed postoperative hyphema (all <30 % anterior chamber height) and one patient (1.9 %) developed blebitis and endophthalmitis. None of our patients developed hypotony maculopathy. When trabeculectomy is performed on unselected patients attending a UK district general hospital, selective 5-fluorouracil augmentation is probably all that is required to obtain acceptable surgical outcomes.

A prospective study of social difficulties, acculturation and persistent depression in Pakistani women living in the UK.

BACKGROUND: The reasons for the high prevalence of depressive disorders in women of Pakistani origin living in the UK are not clear. The aim of this study was to determine the relative importance of life events, chronic social difficulties and acculturation in a population-based sample of British Pakistani women. METHOD: A cross-sectional and prospective cohort study of 18- to 65-year-old Pakistani women in UK was carried out. The Schedule for Clinical Assessment in Neuropsychiatry for diagnosis, the Life Events and Difficulties Schedule for social stress and an acculturation questionnaire were used. RESULTS: Depressive disorder at baseline was associated with older age, social isolation and marked difficulties involving health and close relationships. Depressive disorder at follow-up was associated with severity of depression at baseline, difficulties in close relationships and two aspects of acculturation, especially less acculturation in relation to use of the English language. CONCLUSIONS: Lack of acculturation, especially less familiarity with the English language, is an independent predictor of persistence of depression in Pakistani women in UK. This needs to be taken into consideration when planning treatment, which also needs to address the personal difficulties associated with persistent depression. The implication of this work is that women of Pakistani origin with depression should be encouraged to receive help in the use of English as one part of treatment that may prevent relapse.

Smoking behavior among 14-17 year old students: a comparison between Pakistan and the UK.

Smoking is a major public problem concern the world over. It is one of the major preventable causes of premature death and disease in the world. Fourteen to seventeen year olds are among a vulnerable group of individuals in society and susceptible to cigarette smoking. Older students act as role models to younger pupils and could influence smoking behavior. In a cross-sectional study we compared the differences in smoking between high school students in Pakistan and the United Kingdom. A self-administered anonymous questionnaire, adapted from a WHO questionnaire about tobacco smoking, was distributed to the students. In the UK, 235 participants were recruited; 16% (n = 38) were regular smokers. In Pakistan, 350 participants were recruited; 17% (n = 58) were regular smokers. In both countries males were significantly more likely to smoke. Reasons for smoking varied between the UK and Pakistan. In the UK, the majority smoked for recreational or social purposes and in Pakistan peer pressure played the major role. Beliefs regarding smoking were similar between the two countries. The lifetime prevalence of smoking was higher in the UK, but more students in Pakistan smoked daily. There were important differences in the smoking patterns between the two countries, which have potential public health implications.

Appropriate length of epidural catheter in the epidural space for postoperative analgesia: evaluation by epidurography.

In current practice, the length of epidural catheter that should be left in the epidural space is not standardised for effective postoperative analgesia. This prospective, randomised, double-blinded study aimed to determine the most appropriate length of epidural catheter that should be inserted into the epidural space for postoperative analgesia. We recruited 102 women and assigned them into three study groups (3, 5 and 7 cm insertion). An epidural catheter was inserted and epidurography was performed. Postoperatively, mean pain scores, motor and sensory levels, and any complications associated with the epidural catheter were recorded. No statistically significant difference for mean postoperative pain score was found at all study timings. Motor and sensory blockade was also statistically insignificant. Unilateral sensory analgesia developed in one patient in the 7 cm group and epidural catheter dislodgement was observed in four patients in the 3 cm group. In order to minimise catheter-related complications for postoperative analgesia, the most appropriate length that an epidural catheter should be left in the epidural space is 5 cm. You can respond to this article at http://www.anaesthesiacorrespondence.com.

Demographic and psychosocial characteristics of self-harm: The Pakistan perspective.

Self-harm is a major public health issue in Pakistan, yet the characteristics of those who self-harm are under-explored. This is a secondary analysis from a large randomized control trial on the prevention of self-harm, exploring demographic, clinical and psychological characteristics of people who self-harm in Pakistan. A total of 221 participants with a history of self-harm were recruited from medical wards of three major hospitals in Karachi. The Beck Scale for Suicidal Ideation (BSI), Beck Depression Inventory (BDI), Beck Hopelessness Scale (BHS), and Suicide Attempt Self Injury Interview (SASII) assessment scales were completed. The sample consisted predominantly of females (68.8%) in their 20's. Interpersonal difficulties were most commonly reported as the main antecedent to the self-harm, followed by financial difficulties. Participants had high severity scores on BSI, BDI and BHS. Pesticide and insecticide use were (n = 167, 75.6%) the most common methods of self-harm. The findings indicate that some characteristics of those who self-harm in Pakistan are comparable to other populations. This may raise the possibility of common causal mechanisms and processes. Future research needs to examine the efficacy of interventions targeting these risk factors in reducing rates of self-harm and thus suicide.

Detection of DNA by scraping the formalin-fixed paraffin-embedded tissue.

BACKGROUND: Pakistan is a developing country and most of the research laboratories have limited required infrastructures for the diagnosis of cancer at molecular level. The polymerase chain reaction (PCR) on formalin-fixed paraffin-embedded tissues is becoming a popular procedure in the research centres. The study was conducted to introduce two new methods of DNA extraction for the PCR from formalin-fixed paraffin-embedded sections of surgical pathology specimens. MATERIALS AND METHODS: Two methods of DNA detection were used. In method A the formalin-fixed tissues were grossed, proper sections were taken, processed in an automatic tissue processor, embedded in paraffin blocks, and microtomic sections were made. In method B, the procedure was the same until embedding in the paraffin blocks, after which the selected paraffin blocks were set on a black card paper (4 cm x 4 cm) and 1 mg of pure scraped tissue was obtained using a scalpel, manually without using microtone. RESULTS: DNA was successfully extracted but point mutation of p53 gene was not seen in SCP while it was determined in 96 and 93.75 per cent cases of SCC by method A and method B respectively. There was no statistical difference in the results by both methods (P = 0.359). CONCLUSION: Scraping of the tissue for DNA detection was a simple method and may be performed in any laboratory. The reliability, reproducibility, and quality assurance of the present results are consistent with the already established techniques of DNA extraction for PCR.

N-hexane neuropathy in screen printers.

BACKGROUND: To study the clinical and electrophysiological profile of n-hexane neuropathy in a tertiary care center of India. METHODS: Twenty five screen printers from five different factories, with peripheral neuropathy were included in the study. A detailed general physical, systemic and neurological examination was conducted Visual acuity, color vision and field charting was done in all the subjects. All patients were subjected to Folstein mini mental scale examination. Electrophysiological evaluation included motor and sensory conduction studies of the conventionally studied nerves of upper and lower limbs, Needle EMG of various distal and proximal muscles and patterned visual evoked responses. The electrophysiological profile was repeated every three months till one year. Sural nerve biopsy was studied in six patients. The patients were followed for a maximum of 4 years. RESULTS: Twenty three [92%] patients had sensory- motor neuropathy, while pure sensory neuropathy was seen in two. The sensory conductions were affected almost equally in upper as well as the lower limbs, while the motor conductions were affected more in the lower limbs than the upper limbs. The sensory conductions were not recordable in both the upper and the lower limbs in 18 [72%] patients. Motor conduction studies revealed an asymmetric and patchy involvement. Proximal conduction block was seen in 3 patients [12%]. On needle EMG features of denervation were seen in all patients. P100 latency was normal in all. Sural nerve biopsy showed a selective decrease in large myelinated axons with demyelination. Axonal swelling with focal areas of demyelination was observed in two patients. CONCLUSIONS: The electrophysiological patterns as well as the histopathology reflect the pathophysiology of n-hexane neuropathy.

Down beat nystagmus in vitamin B 12 deficiency syndrome.

A 34 years old male, presenting with progressive proximal weakness, with a neurogenic pattern on needle EMG, and a family history suggestive of an autosomal recessive disorder, was found to have additional features of myeloneuropathy and a down beat nystagmus. A low serum vitamin B12 level was found, and on vitamin B12 supplementation there was a partial clinical as well as electrophysiological recovery.

Mutation of p53 in skin papilloma and tubular breast adenoma of albino mice.

OBJECTIVE: To determine the mutation of p53 in chemically induced carcinogenesis on albino mice in skin papilloma and tubular adenoma breast by immunohistochemistry. DESIGN: An experimental study. PLACE AND DURATION OF STUDY: The animal house of Postgraduate Medical Institute and Pathology Department of King Edward Medical College University, Lahore, for the duration of 20 weeks, from 15 February, 2004 to 15 July, 2004. SUBJECTS AND METHODS: Twenty five albino mice (male and female) were selected for a study on chemical carcinogenesis. These animals were divided into five groups (A-E), five animals in each. DMBA (Dimethylebenz[a] Anthracene) and TPA (Tetradecanoyl-phorbal-13-Acetic Acid) [chemical carcinogens] were given to produce the tumors and mutation of p53 expression was evaluated on the tumors appearing during this period of carcinogenesis. Squamous cell papillomas and tubular adenoma breast were selected for this study. RESULTS: All the papillomas showed faint reactivity for immunomarker p53, while tubular adenomas were nonreactive. CONCLUSION: The results of this study show that p-53 is a marker for premalignant lesions and helps in selecting patients for constant monitoring, upon the clinical verification of these results.

Vitamin B12 deficiency: a clinical and electrophysiological profile.

OBJECTIVE: The present study was conducted to evaluate the clinical and electrophysiological profile of vitamin B12 deficiency syndrome and whether a correlation exists between the disease process and the various electrophysiological parameters. METHODS: 40 patients with vitamin B12 deficiency neurological syndromes with low serum vitamin B12 and high homocysteine levels were subjected to a detailed motor and sensory nerve conduction studies and pattern reversal VER (P100), SSEP (P37) after stimulation of the posterior tibial nerve and median nerve (N 20) were obtained bilaterally. MR cervical spine was done in all the patients and MR brain in those who presented with neuro-psychiatric symptoms. The patients were followed up at three months, six months and one year after treatment. RESULTS: On the basis of clinico-electrophysiological profile, 31 patients had myeloneuropathy, 5 isolated myelopathy, 4 isolated neuropathy. Four of the patients with myeloneuropathy, had concomitant dementia. MR imaging revealed abnormality in 12.5% of cases. Prolongation of P37 latency was observed in 39 (97.5%) patients, N 20 latency in 22 (55%), and P100 latency in 19 (47.5%) patients. Peripheral neuropathy was seen in 18 patients; optic neuropathy in 8; and combination of peripheral and optic neuropathy in 9 patients. The peripheral neuropathy was axonal in 19, and demyelinating in 6 patients. There was a significant correlation of the duration of the disease with N 20 latency (P < 0.04). Serum vitamin B12 level correlated well with the latencies of P37 (P < 0.005) and sural SNAP (P < 0.006). On treatment, normalization of P100, MRI signal, N 20 and partial recovery of P37 latencies was seen at 6 months, 9 months and one year respectively. CONCLUSION: Differential recovery of central and peripheral syndromes was seen. This correlated with the underlying demyelinating and axonal processes, which was well reflected by the electrophysiological studies, and has an important bearing on the outcome.

Oxytocin augmentation of labor and perinatal outcome in nulliparas.

Recent pharmacologic observations in vivo suggest the use of a lower starting dose (0.5-0.1 mU/minute) of oxytocin and a longer interval between dose augmentations (30-60 minutes) than previously advocated. In this study, a high-dose oxytocin protocol was used to augment nonprogressive labor in normal nulliparous women. The rate of oxytocin infusion started at 6 mU/minute and was increased by 6 mU/minute every 15 minutes to a maximum dose of 40 mU/minute. Charts were reviewed of 1080 nulliparous women for whom the principles of active management of labor were followed and delivery occurred between March 1, 1986 and December 31, 1988. Four hundred fifty-six who required oxytocin augmentation in labor were compared with 624 who did not receive oxytocin. There were no statistically significant differences in birth asphyxia or perinatal morbidity.

Idiopathic giant retinal tears in identical twins.

PURPOSE: To report idiopathic unilateral giant retinal tears with retinal detachment in identical twins that occurred 2 weeks apart. METHODS: Case reports. RESULTS: In both patients, giant retinal tear and retinal detachment was treated with pars plana vitrectomy, placement of encircling scleral buckle, fluid-perfluorocarbon exchange, endolaser treatment, perfluorocarbon-air exchange, and 16% perfluoropropane injection. One year after retinal detachment surgery, cataract developed in both postoperative eyes. Phacoemulsification with posterior chamber intraocular lens implantation was performed on both eyes. Three and a half years after retinal surgery, corrected visual acuity in both treated eyes was 20/20, and retinal reattachment was successful. CONCLUSIONS: To our knowledge, this is the first report of idiopathic giant retinal tears in identical twins and raises the issue of genetic influences in the pathogenesis of this disease.

Intravitreal antiviral injections as adjunctive therapy in the management of immunocompetent patients with necrotizing herpetic retinopathy.

PURPOSE: To report the use of intravitreal antiviral injections as adjunctive therapy in the management of three immunocompetent patients with necrotizing herpetic retinopathy. METHOD: Case series. RESULTS: Three patients with necrotizing herpetic retinopathy received intravitreal antiviral injections for treatment of progressive retinitis, despite standard intravenous acyclovir therapy. The retinitis resolved and visual acuity improved after a minimum of 6 months of follow-up in each case. CONCLUSION: Intravitreal antiviral injections may be a safe and efficacious adjunctive therapy in the management of patients with necrotizing herpetic retinopathy.

Pars plana vitrectomy during cataract surgery for prevention of aqueous misdirection in high-risk fellow eyes.

PURPOSE: To report the use of pars plana vitrectomy as a prophylactic measure during cataract surgery for prevention of aqueous misdirection in high-risk fellow eyes. METHODS: Chart review of two patients with severe aqueous misdirection in their first eye at the time of cataract surgery that only responded to pars plana vitrectomy. RESULTS: In both patients, cataract extraction with posterior chamber intraocular lens implantation was initially performed after pars plana vitrectomy, with the creation of hyaloido-capsulo-iridotomy to establish a communication between the vitreous cavity and the anterior chamber. CONCLUSION: Pars plana vitrectomy as a prophylactic measure during cataract surgery may have a beneficial role in fellow eyes at high risk for developing aqueous misdirection.

Emerging ciprofloxacin-resistant Pseudomonas aeruginosa.

PURPOSE: To report a clinical series of ciprofloxacin-resistant ocular isolates of Pseudomonas aeruginosa from a tertiary care ophthalmic center. METHODS: Review of in vitro sensitivities of all ocular isolates of P. aeruginosa be tween July 1991 and September 1998. In vitro resistance was defined as a minimum inhibitory concentration of 4 or more microg per ml. RESULTS: Nine of 423 ocular isolates of P. aeruginosa showed in vitro resistance to ciprofloxacin. From 1991 to 1994, 0.44% (1/227) of ocular isolates were resistant to ciprofloxacin, whereas from 1995 to 1998, 4.1% (8/ 196) of ocular isolates showed in vitro resistance (P = .014). CONCLUSIONS: Ciprofloxacin-resistant P. aeruginosa has been identified in recent clinical ocular specimens. Ciprofloxacin resistance among ocular isolates of P. aeruginosa is a local and worldwide concern.

Effect of potent antiretroviral therapy on recurrent cytomegalovirus retinitis treated with the ganciclovir implant.

PURPOSE: To determine the effect of highly active antiretroviral therapy on cytomegalovirus (CMV) retinitis treated with ganciclovir implants. METHODS: A retrospective cohort study was performed of 15 patients with recurrent CMV retinitis treated with the ganciclovir implant and highly active antiretroviral therapy (cases) and 38 patients with recurrent retinitis treated with ganciclovir implants before availability of improved antiretroviral therapy (controls). Progression was defined as occurrence of new lesions in the treated eye or advancement of the retinitis border by more than 750 microm. RESULTS: Cases and controls were statistically similar in age, ethnicity, and duration of acquired immunodeficiency syndrome (AIDS). Controls had received intravenous ganciclovir for 9.5 +/- 9.5 months vs 3.5 +/- 4.6 months in cases (P = .003). The mean (+/- SE) time to progression of retinitis after implantation of the device was 26.7 +/- 2.4 months (95% confidence interval, 22.1 to 31.3) in the cases receiving highly active antiretroviral therapy vs 6.2 +/- 0.9 months (95% confidence interval, 4.5 to 7.9) in the controls (P = .001). Multivariate analysis, adjusted for preoperative variables, confirmed a significantly prolonged time to progression in patients receiving highly active antiretroviral therapy (P = .0003). The odds ratio for progression in the cases vs controls was 0.034 (95% confidence interval, 0.003 to 0.350). Cases had higher CD4+ T-lymphocyte counts (P = .004) and longer survival (P < .001) than controls. CONCLUSION: Highly active antiretroviral therapy is associated with improved outcomes in patients with AIDS and recurrent CMV retinitis treated with the ganciclovir implant.

Purtscher-like retinopathy associated with pancreatic adenocarcinoma.

PURPOSE: To investigate a case of Purtscher-like retinopathy that occurred in association with pancreatic adenocarcinoma. METHOD: Case report. RESULTS: A 63-year-old woman presented with multiple gray patches in the central vision of both eyes. Visual acuity was 20/20 in both eyes. Funduscopy showed large peripapillary yellow-white patches within the superficial retina and small superficial retinal hemorrhages in both eyes. The patient subsequently had abdominal pain. Computed tomography of the abdomen demonstrated a large pancreatic mass with extension into the liver. Histologic examination of a percutaneous needle biopsy specimen showed mucinous pancreatic adenocarcinoma. CONCLUSION: Pancreatic adenocarcinoma should be added to the list of systemic diseases that can be associated with Purtscher-like retinopathy.