Attrition during pre-ART and ART time periods among adolescents enrolled in Integrated HIV Care Programme in Myanmar, 2005-2017.

Retaining adolescents (aged 10-19 years), living with HIV (ALHIV) on antiretroviral therapy (ART) is challenging. In Myanmar, 1269 ALHIV were under an Integrated HIV Care (IHC) Programme by June 2017 and their attrition (death and lost to follow-up) rates were not assessed before. We undertook a cohort study using routinely collected data of ALHIV enrolled into HIV care from July 2005 to June 2017 and assessed their attrition rates in June 2018 by time-to-event analysis. Of 1269 enrolled, 197(16%) and of 1054 initiated ART, 224 (21%) had an attrition defining event. The pre-ART and ART attrition rates were 21.8 (95% CI 19.0-25.1) and 6.4 (95% CI 5.6-7.3) per 100 person-years follow-up, respectively. The factors 'at enrolment' that were associated with higher hazards of attrition were: (1) WHO stage 3 or 4; (2) haemoglobin <10 gm/dl; (3) no documented CD4 cell counts, hepatitis B and C test results; and (4) injection drug use. Baseline hazards were high during the initial 1-2 years and after 5-6 years. The pre-ART and ART attrition rates in ALHIV were lower than those in Africa but higher than the children under IHC. This warrants designing and implementing additional care tailored to the needs of ALHIV under IHC.

High prevalence and incidence of tuberculosis in people living with the HIV in Mandalay, Myanmar, 2011-2017.

SETTING: Two human immunodeficiency virus (HIV) clinics providing antiretroviral therapy (ART), Mandalay, Myanmar. OBJECTIVE: To assess prevalent TB at enrolment, incident TB during follow-up and associated risk factors in adult people living with HIV (PLHIV) between 2011 and 2017. DESIGN: Cohort study using secondary data. RESULTS: Of 11 777 PLHIV, 2911 (25%) had prevalent TB at or within 6 weeks of enrolment. Independent risk factors for prevalent TB were being male or single/widowed, daily alcohol consumption, CD4 count 200 cells/µl and anaemia. During 6 years follow-up in 8866 PLHIV with no prevalent TB, the rate of new TB was 2.9 per 100 person-years (95%CI 2.6-3.1). Cumulative TB incidence was 9.6%, with 370 (72%) of 517 new TB cases occurring in the first year. Independent risk factors for incident TB were being male and anaemia. Incident TB was highest in the first year of ART, in PLHIV with CD4 counts 200 cells/µl and those not receiving isoniazid preventive therapy (IPT). Incident TB declined with time on ART and rising CD4 counts. CONCLUSION: Prevalent and incident TB were high in PLHIV in the Mandalay clinics. Consideration should be given to earlier TB diagnosis using more sensitive diagnostic tools, effective ART and scaling up IPT.

IPT in people living with HIV in Myanmar: a five-fold decrease in incidence of TB disease and all-cause mortality.

SETTING: Myanmar, a country with a high human immunodeficiency virus-tuberculosis (HIV-TB) burden, where the tuberculin skin test or interferon-gamma release assays are not routinely available for the diagnosis of latent tuberculous infection. OBJECTIVE: To assess the effect of isoniazid (INH) preventive therapy (IPT) on the risk of TB disease and mortality among people living with HIV (PLHIV). DESIGN: A retrospective cohort study of routinely collected data on PLHIV enrolled into care between 2009 and 2014. RESULTS: Of 7177 patients (median age 36 years, interquartile range 31-42; 53% male) included in the study, 1278 (18%) patients received IPT. Among patients receiving IPT, 855 (67%) completed 6 or 9 months of INH. Patients who completed IPT had a significantly lower risk of incident TB than those who never received IPT (adjusted hazard ratio [aHR] 0.21, 95%CI 0.12-0.34) after controlling for potential confounders. PLHIV who received IPT had a significantly lower risk of death than those who never received IPT (PLHIV who completed IPT, aHR 0.25, 95%CI 0.16-0.37; those who received but did not complete IPT, aHR 0.55, 95%CI 0.37-0.82). CONCLUSION: Among PLHIV in Myanmar, completing a course of IPT significantly reduced the risk of TB disease, and receiving IPT significantly reduced the risk of death.

Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory.

Non-fibrillar soluble oligomeric forms of amyloid-ß peptide (oAß) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAß initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aß, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAß levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAß to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aß on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aß and tau pathology.

Neurovirulence detection of dengue virus using rhesus and cynomolgus monkeys.

The results of a comparative study of neurovirulence of dengue type 1 virus in two species of Old World monkeys, viz. rhesus monkeys (Macaca mulatta) and cynomolgus monkeys (Macaca fascicularis) are reported. In the present study, parental dengue type 1 (16007) and its vaccine viruses were tested by intrathalamic, intramuscular and intraspinal injections in these two species of monkey. Both species of monkeys inoculated with parental dengue type 1 virus developed neurovirulence-type lesions which were graded as minimal (V-1) and occasionally mild (V-2, in cynomolgus monkeys) in severity. The antibody response to either parental or vaccine virus was slightly less in rhesus monkeys than in cynomolgus inoculated with these strains. This comparative study possibly establishes the cynomolgus monkey as a suitable test model to replace the rhesus monkey for neurovirulence testing of dengue-1 vaccine intended for use in humans.

Dengue-4 vaccine: neurovirulence, viraemia and immune responses in rhesus and cynomolgus monkeys.

A dengue 4 (DEN-4, strain 1036-PDK 48) vaccine attenuated by passage in primary dog kidney cells was tested using rhesus (Macaca mulatta) and cynomolgus (M. fascicularis) monkeys to determine its safety, potency, and immunogenicity. 14 rhesus monkeys were divided into 3 groups: group 1, 2 animals given control culture fluid; group 2, 2 animals given DEN-4 parental virus; group 3, 10 animals given DEN-4 vaccine virus. 10 cynomolgus were similarly grouped, but group 3 contained 6 monkeys. No significant neurovirulence was observed with parental or with DEN-4 virus passaged in primary dog kidney (PDK) cells. Both cynomolgus monkeys inoculated with DEN-4 vaccine virus developed minimal (V-1) and mild (V-2) neurovirulence-type lesions in the central nervous system, which were nondestructive in both species. All parental and vaccine viruses produced moderate to high neutralizing antibody titres. Only parental virus produced viraemia, in 2 cynomolgus monkeys. Because of its safety and avirulence in monkeys, PDK 48 is recommended for human trial.

Leukemia induced in rats but not mice by dimethyl morpholinophosphoramidate, a simulant anticholinesterase agent.

Dimethyl morpholinophosphoramidate (DMMPA), an organophosphate, caused leukemia in male and female Fischer 344/N rats. DMMPA was administered in corn oil by oral intubation to groups of 50 male and 50 female rats at 0, 150, 300, or 600 mg/kg body weight, five times per week for 2 years. B6C3F1 mice were given 0, 150 (males only), 300, and 600 (females only) mg/kg body weight under the same schedule. DMMPA induced a dose-related enhancement in the incidence of mononuclear cell leukemia in rats--males: controls = 14/50, 150 mg group = 21/50; 300 mg group = 19/50; 600 mg group = 25/50; females: controls = 9/50, 150 mg group = 13/50; 300 mg group = 12/49; 600 mg group = 18/50. Survival-adjusted rates strengthen the DMMPA effect: males--31%, 50%, 47%, and 63%; females--20%, 32%, 30%, 50%. Latent periods for mononuclear cell leukemia development in exposed rats were not shortened compared to controls. No carcinogenic effects in mice were detected. DMMPA was not mutagenic in Salmonella, was mutagenic for mouse lymphoma cells, and induced both chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells.

The results of spinal arthrodesis for congenital spinal deformity in patients younger than five years old.

We reviewed the results of spinal arthrodesis for congenital spinal deformity in forty-nine patients who were younger than five years old. The minimum follow-up was five years, and eleven patients had completed their growth. Posterior arthrodesis alone was found to be effective in most scoliotic patients. There was minimum bending of the fusion mass in most patients, almost no creation of lordosis, and minimum effect on torso-lower limb relationships. For congenital kyphosis, posterior arthrodesis was highly effective, giving better eventual correction than when both anterior and posterior arthrodesis was done.

Posterior spinal arthrodesis for congenital scoliosis. An analysis of the cases of two hundred and ninety patients, five to nineteen years old.

We analyzed the results of posterior arthrodesis of the spine for congenital scoliosis, with or without Harrington instrumentation, in 290 of 323 patients who were operated on between the ages of five and nineteen years and were followed for two years or more. The length of follow-up averaged six years and ranged from two to twenty-eight years. The average curve before surgery was 55 degrees (range, 13 to 155 degrees), the average curve at correction was 38 degrees (range, 5 to 102 degrees), and the average curve at final follow-up was 44 degrees (range, 5 to 103 degrees). Bending of the fusion mass of more than 10 degrees was seen in forty patients; pseudarthrosis, in twenty; and adding-on of vertebrae with an increase in the curve of more than 10 degrees, in seven patients. There were four deaths, only one of them in the last twenty-five years. One was due to intraoperative cardiac arrest; one, to intraoperative overtransfusion; one, to postoperative overtransfusion; and one, to gastrointestinal bleeding eight months postoperatively while the patient was in a Risser jacket. Two patients became paraplegic due to excessive distraction with the Harrington rod, and two others had a partial cranial-nerve lesion due to halo traction. Based on these results, we concluded that posterior arthrodesis of the spine is satisfactory for most patients with congenital scoliosis. The most common problem was bending of the fusion mass in growing children, which occurred in 14 per cent of the patients. Use of Harrington instruments allowed slightly better correction (36 per cent compared with 28 per cent) but was associated with the only cases of paraplegia and infection in the series.

Excessive thoracic lordosis and loss of pulmonary function in patients with idiopathic scoliosis.

Idiopathic thoracic lordoscoliosis is more common and more productive of respiratory compromise than is kyphoscoliosis. In some patients with idiopathic scoliosis, thoracic lordosis is the predominant component of the disease. Five such patients, all of whom had idiopathic scoliosis with excessive thoracic lordosis, progressive deformity despite Milwaukee brace treatment, and significant compromise of pulmonary function, are presented. Harrington instrumentation (distraction rod only) and spine fusion improved the deformity and respiratory function. The recommended treatment for this type of idiopathic scoliosis is early recognition and prompt surgical correction. The Milwaukee brace should be avoided. Postoperative management must include early ambulation combined with vigorous breathing exercises.

Scoliosis in Marfan's syndrome. Its characteristics and results of treatment in thirty-five patients.

Of sixty-four patients with Marfan's syndrome, thirty-five had scoliosis, which in 44 per cent began in the infantile and juvenile age periods. The curve patterns were double major right thoracic-left lumbar in 48 per cent and single right thoracic in 33 per cent. At the start of treatment the curves were severe (average, 72 degrees) and quite structural (average bending correction, 36 per cent). Seventy-four per cent of the thirty-five patients had back pain. Inadequately treated and untreated curves usually progressed to severe and painful deformity. Milwaukee brace treatment was generally unsuccessful because of the severity and rigidity of the curves or the poor maintenance of correction obtained. Spine fusion combined with Harrington rod instrumentation (fourteen patients) gave an average correction of 41 per cent with an average loss of 7 degrees (average follow-up, 2.3 years). Operative treatment of scoliosis is indicated in most patients with Marfan's syndrome.

Management of severe spondylolisthesis in children and adolescents.

Forty-three patients with a fifth lumbar-first sacral spondylolisthesis of 50 per cent or greater were reviewed. Four had been treated non-operatively; eleven, by arthrodesis; eighteen, by decompression and arthrodesis; and ten, by reduction and arthrodesis. The angle of slipping (measurement of the kyphotic relationship of the fifth lumbar to the first sacral vertebra) was found to be as important a measurement as the percentage of slipping in measuring instability and progression of slipping. Hamstring tightness did not correlate with neural deficit. Arthrodesis alone, even in the presence of minor neural deficits, tight hamstrings, or both, gave relief of pain and resolution of neural deficits and tight hamstrings. Our experience with a limited number of patients suggests that management by postoperative extension casts may achieve a significant reduction in percentage of slipping and in angle of slipping. Progression of the spondylolisthesis may occur following a solid arthrodesis.

Long-term follow-up of scoliosis fusion.

One hundred and ten scoliotic patients underwent correction and spine fusion by one of us (J. H. M.) at Gillette Children's Hospital between 1947 and 1957. Sixty-one of these patients were evaluated in 1977 for this follow-up study. The evaluation consisted of physical and roentgenographic examination, photographs, and a detailed psychosocial analysis. The aims of the study were to evaluate: (1) the long-term stability of the fusion; (2) the incidence and severity of low-back pain; and (3) the degree of integration of the patient into society. The results showed that a solid fusion had no significant loss of correction with time. Eighty-four per cent of the patients lost only zero to 5 degrees of correction during an average follow-up of twenty-six years. Low-back pain was found to be no more frequent than in the normal population in this age group, and there was less low-back pain than in a comparable series of scoliotic patients without fusion. There was no correlation between the occurrence of low-back pain and the length or magnitude of the fused curve or the lowest extent of the fusion. An unexpected finding was the high incidence of neck pain, the cause of which is unknown. Psychosocial analysis revealed that the patients were productive, active, stable persons who were working and contributing members of society.

The lumbosacral curve in idiopathic scoliosis. Its significance and management.

In 850 consecutive patients with idiopathic scoliosis, no primary lumbosacral curve with only secondary curves above it was found. Forty-four patients with double structural thoracic and lumbar, single structural thoracic, and single structural lumbar curves showed progressive loss of flexibility in the lumbosacral area. Of these, five patients had correction and fusion of the lumbosacral curve and seventeen had correction and fusion of the major curve above the third or fourth lumbar segment without surgical treatment of the lumbosacral area. The results were better in the latter group. Correction and fusion in the lumbosacral area was difficult to achieve. No patient had a permanent list when only curves above the lumbosacral curve were corrected and fused. Lumbosacral fusion should be reserved for primary lumbosacral curves associated with congenital anomalies or spondylolisthesis.

Congenital thoracic lordosis.

The rare spinal deformity of congenital thoracic lordosis is illustrated in five patients. Often this deformity is progressive and may cause severe pulmonary deficits and death. In the two patients most recently treated, early spine fusion (one anterior and one posterior) showed promising results--halting of the progression of deformity and even some amelioration of the lordosis. In two patients in whom active attempts were made to correct the lordosis, the complications were severe--one patient died and quadriparesis developed in the other.

Scheuermann's kyphosis. Results of surgical treatment by posterior spine arthrodesis in twenty-two patients.

Twenty-two patients with Scheuermann's kyphosis were treated with correction, Harrington instrumentation (in twenty-one), and posterior spine fusion. This procedure relieved pain and corrected deformity in all patients but loss of correction of 5 degrees or more occurred in sixteen of the twenty-two patients, including all those whose initial kyphosis was greater than 70 degrees. The incidence of complications was so high that this procedure should ordinarily be performed only for disabling pain or spinal cord compression.

Treatment of idiopathic scoliosis in the Milwaukee brace.

The results of treatment of idiopathic scoliosis with a Milwaukee brace were studied in 133 patients (127 girls and six boys) whose ages ranged from eight years and five months to sixteen years and two months at the beginning of treatment. These 133 patients had 192 separate curves (119 right thoracic, thirty-nine high lumbar, twelve thoracolumbar, and twenty-two high left thoracic). Of these patients, seventy-four with 109 curves were followed for five years or more after the brace was discontinued (average, eight years; range, five to thirteen years); twenty-nine patients were treated surgically because of a poor response to the brace or progression of the curve; and thirty patients were lost to follow-up. More than 80 per cent of the seventy-four patients followed for five years or more showed some increase of their curves after the brace was discontinued. The average correction at follow-up compared with the original curve was 2 degrees for thoracic curves (range, -18 to 24 degrees) and 4 degrees for the thoracolumbar and lumbar curves (range, -11 to 17 degrees). The brace was more effective for curves of less than 40 degrees. More than one-third of the patients with curves of 40 degrees or more eventually required surgical treatment. Age, curve pattern, and status of the iliac and ring epiphyses did not correlate withe response to brace treatment. The best guideline for prediction of the results of brace treatment was the response of the curve to the brace, especially during the first year of treatment. If the curve is reduced in the brace to less than 50 per cent of its initial measurement, there is a good chance of obtaining significant permanent correction.

The surgical management of patients with Scheuermann's disease: a review of twenty-four cases managed by combined anterior and posterior spine fusion.

Twenty-four patients with Scheuermann's kyphosis underwent correction of the deformity through a combined anterior and posterior spine fusion. All patients had a solid arthrodesis and most were relieved of their preoperative pain. Deformity was improved in all patients. Significant loss of correction did not occur in the fusion area but it did occur below the posterior arthrodesis in five patients.

Congenital kyphosis due to defects of anterior segmentation.

Twenty-seven patients with Type-II congenital kyphosis (failure of anterior vertebral segmentation) all had progression of the kyphosis which varied in magnitude. The average rate of progression was 5 degrees per year. Pain due to compensatory lumbar hyperlordosis (eight patients) and objectionable deformity (fifteen patients) were the most frequent complaints. Unlike patients with Type-I kyphosis (failure of vertebral formation), paraplegia did not occur and associated congenital anomalies were infrequent (three of the twenty-seven patients). Spontaneous ossification of the anterior part of seemingly normal intervertebral discs leading to bar formation and progression of deformity occurred in five patients. A Milwaukee brace had little effect on this fixed kyphotic deformity in the six patients in whom the brace was used. Early recognition and spine fusion are the recommended treatment. Posterior fusion is sufficient in young children with progressive deformity, whereas combined two-stage anterior and posterior fusion with osteotomy of the anterior bar is recommended in children with severe deformity.

Surgical treatment of adult scoliosis. A review of two hundred and twenty-two cases.

We evaluated the cases of 222 patients older than twenty years in whom scoliosis was the primary diagnosis. No patient had had prior surgical treatment. The diagnoses were idiopathic scoliosis in 160 patients, paralytic scoliosis in forty-four, and congenital scoliosis in eleven, and there were miscellaneous diagnoses in seven patients. The average age of the patients when first seen was 30.7 years. The indications for operation were pain, progression of the curve, magnitude of the curve, and cardiopulmonary symptoms. Preoperative traction, including halo-femoral traction, did not result in increased correction when compared with the initial supine side-bending roentgenogram. A one-stage fusion was performed in 174 patients and multiple-stage procedures, in forty-eight patients. At an average follow-up of 3.6 years the average loss of correction was 6.2 degrees, 68 per cent of the patients were free of pain, and a solid fusion had been obtained in all but six patients. Complications developed in 53 per cent of the patients, the most common problems being pseudarthrosis, urinary tract infection, wound infection, instrumentation problems, a pulmonary disorder, and loss of lumbar lordosis. Paraplegia occurred in one patient. The over-all mortality rate was 1.4 per cent. Complications increased with age, and the highest mortality rate was in patients with congenital scoliosis who had cor pulmonale.