A two-year hospital based study of Lung Cancer with reference to Histological subtypes, Demograhpics, risk factors and presentng stage

Lung cancer is one of the most common cause of mortality, highly attributed to an increase in tobacco use/ cigarette smoking. It ranks amongst the top 3 causes of cancer in Trinidad and Tobagonian men. The objective of this study is to the investigate the prevalence of Lung cancer in Trinidad and Tobago, its histological subtypes, demographics, predisposing risk factors and presenting stage. Additionally, comparison is made between current Lung cancer trends and those identified from previous studies. Our current findings is a more accurate representation of local trends, which can now provide foundational data that can be used to implement better approaches in the improvement of Lung cancer care in Trinidad and Tobago.

Community Priority setting for Fetal Alcohol Spectrum Disorder Research in Australia.

INTRODUCTION: Fetal Alcohol Spectrum Disorder (FASD) is a neurodevelopmental disorder caused by prenatal alcohol exposure (PAE). FASD research is a rapidly growing field that crosses multiple disciplines. To ensure research is relevant and meaningful for people living with FASD, their families, and the broader public there is a need to engage community members in setting priorities for research. OBJECTIVES: Our primary objective was to formally identify the views of people living with FASD, their parents/caregivers, service providers, and the general community on the research priorities for FASD and alcohol use in pregnancy in Australia. Our secondary objective was to provide an overview of current research in the highest priority areas identified. METHODS: The approach for this study involved two community surveys and a consensus workshop, followed by a rapid literature review. Survey responses (n = 146) were collected and grouped using qualitative thematic analysis. The themes identified were then ranked in a second survey (n = 45). The 22 highest ranked themes were considered in a workshop with 21 community members, and consensus on the top ten priority areas was sought. The priority areas were grouped into conceptually similar topics and rapid literature reviews were undertaken on each. RESULTS: A diverse range of priorities was identified within key areas of prevention, diagnosis, and therapy. On request from participants, separate priority lists were developed by Aboriginal and non-Aboriginal participants. CONCLUSION: There is need for a national network of researchers to take forward the research commenced by the Centre of Research Excellence, FASD Research Australia, in addressing community priorities. KEY WORDS: Community, priorities, FASD, rapid review, Australia.

A six-year observational study of 31 children with early-onset scoliosis treated using magnetically controlled growing rods with a minimum follow-up of two years.

Aims: Magnetically controlled growing rod (MCGR) systems use non-invasive spinal lengthening for the surgical treatment of early-onset scoliosis (EOS). The primary aim of this study was to evaluate the performance of these devices in the prevention of progression of the deformity. A secondary aim was to record the rate of complications. Patients and Methods: An observational study of 31 consecutive children with EOS, of whom 15 were male, who were treated between December 2011 and October 2017 was undertaken. Their mean age was 7.7 years (2 to 14). The mean follow-up was 47 months (24 to 69). Distractions were completed using the tailgating technique. The primary outcome measure was correction of the radiographic deformity. Secondary outcomes were growth, functional outcomes and complication rates. Results: The mean Cobb angle was 54° (14° to 91°) preoperatively and 37° (11° to 69°) at the latest follow-up (p < 0.001). The mean thoracic kyphosis (TK) was 45° (10° to 89°) preoperatively and 42° (9° to 84°) at the latest follow-up. The mean T1-S1 height increased from 287 mm (209 to 378) to 338 mm (240 to 427) (p < 0.001) and the mean sagittal balance reduced from 68 mm (-76 to 1470) preoperatively to 18 mm (-32 to 166) at the latest follow-up. The mean coronal balance was 3 mm (-336 to 64) preoperatively and 8 mm (-144 to 64) at the latest follow-up. The mean increase in weight and sitting and standing height at the latest follow-up was 45%, 10% and 15%, respectively. The mean Activity Scale for Kids (ASKp) scores increased in all domains, with only personal care and standing skills being significant at the latest follow-up (p = 0.02, p = 0.03). The improvements in Cobb angle, TK and T1-S1 heights were not related to gender, the aetiology of the EOS, or whether the procedure was primary or conversion from a conventional growing rod system. A total of 21 children developed 23 complications at a rate of 0.23 per patient per year. Seven developed MCGR-specific complications. Complications developed at a mean of 38 months (3 to 67) after the initial surgery and required 22 further procedures. Children who developed a complication were more likely to be younger, have syndromic EOS, and have a single-rod construct (6.9 versus 9.3 years, p = 0.034). Conclusion: The progression of EOS can be controlled using MCGRs allowing growth and improved function. Younger and syndromic children are more likely to develop complications following surgery. Cite this article: Bone Joint J 2018;100-B:1187-1200.

An NIHR-approved two-year observational study on magnetically controlled growth rods in the treatment of early onset scoliosis.

Aims: The primary aim of this study was to evaluate the performance and safety of magnetically controlled growth rods in the treatment of early onset scoliosis. Secondary aims were to evaluate the clinical outcome, the rate of further surgery, the rate of complications, and the durability of correction. Patients and Methods: We undertook an observational prospective cohort study of children with early onset scoliosis, who were recruited over a one-year period and followed up for a minimum of two years. Magnetically controlled rods were introduced in a standardized manner with distractions performed three-monthly thereafter. Adverse events which were both related and unrelated to the device were recorded. Ten children, for whom relevant key data points (such as demographic information, growth parameters, Cobb angles, and functional outcomes) were available, were recruited and followed up over the period of the study. There were five boys and five girls. Their mean age was 6.2 years (2.5 to 10). Results: The mean coronal Cobb angle improved from 57.6° (40° to 81°) preoperatively, 32.8° (28° to 46°) postoperatively, and 41° (19° to 57°) at two years. Five children had an adverse event, with four requiring return to theatre, but none were related to the device. There were no neurological complications or infections. No devices failed. One child developed a proximal junctional kyphosis. The mean gain in spinal column height from T1 to S1 was 45.4 mm (24 to 81) over the period of the study. Conclusion: Magnetically controlled growth rods provide an alternative solution to traditional growing rods in the surgical management of children with early onset scoliosis, supporting growth of the spine while controlling curve progression. Their use has clear psychosocial and economic benefits, with the reduction of the need for repeat surgery as required with traditional growing rods. Cite this article: Bone Joint J 2018;100-B:507-15.

First-in-human study of the pharmacokinetics and antiviral activity of IDX375, a novel nonnucleoside hepatitis C virus polymerase inhibitor.

IDX375 is a potent and selective palm-binding nonnucleoside inhibitor of the hepatitis C virus (HCV) genotype 1 polymerase. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics of IDX375 in healthy volunteers, as well as its antiviral activity in HCV-infected patients. IDX375, as a choline salt, was administered for 1 day to 40 healthy male volunteers (25- to 200-mg IDX375-equivalent single ascending doses and a 200-mg twice-daily [BID] dose) and three patients chronically infected with HCV genotype 1 (200 mg BID only). IDX375 was well absorbed and well tolerated by all of the study participants. A single-day 200-mg BID dose resulted in exposure-related anti-HCV activity with maximal 0.5 to 1.1 log(10) reductions in plasma HCV RNA. These observations support further clinical investigations of IDX375.

Antiviral activity of low-dose alovudine in antiretroviral-experienced patients: results from a 4-week randomized, double-blind, placebo-controlled dose-ranging trial.

BACKGROUND: Alovudine inhibits replication of highly nucleoside reverse transcriptase inhibitor (NRTI)-resistant HIV strains in vitro. However, dose-dependent safety concerns resulted in its initial development being halted. Recently, a 4-week course of alovudine 7.5 mg/day added to a stavudine-free failing regimen yielded a significant decrease in viral load by -1.88 log(10) HIV-1 RNA copies/mL. The magnitude of the reduction in viral load suggested that lower doses might still be effective while offering adequate safety during long-term use. OBJECTIVE: To determine whether lower dosages of alovudine still provide significant antiviral activity in patients with broad NRTI resistance. METHODS: A randomized, double-blind, placebo-controlled trial investigating three doses of alovudine (0.5, 1 and 2 mg) or placebo added for 4 weeks to a failing regimen in patients with evidence of NRTI-resistant HIV strains [>or=2 thymidine-associated mutations (TAMs)]. The primary endpoint was the mean viral load reduction between baseline and week 4. RESULTS: Seventy-two patients were enrolled in the study: 21, 13, 18 and 20 in the placebo and 0.5, 1 and 2 mg arms, respectively. Baseline median CD4 count and viral load were 298 cells/microL (range 44-692 cells/microL) and 3.9 log(10) copies/mL (range 2.5-5.2 log(10) copies/mL), respectively. Baseline viral isolates harboured a median of four TAMs. Alovudine was added to a median four-drug failing regimen. At week 4, compared with placebo, mean viral load changes were -0.42 log(10) [95% confidence interval (CI) -0.67 to -0.18] and -0.30 log(10) (-0.55 to -0.06) in the 2 and 1 mg arms, respectively. There was no significant change in CD4 cell count. Alovudine was well tolerated. CONCLUSION: A 4-week course of alovudine 2 mg/day provided a modest but significant viral load reduction in patients harbouring viruses with a median of four TAMs.

Genetic diversity and response to IFN of the NS3 protease gene from clinical strains of the hepatitis C virus.

The N-terminal one-third of the hepatitis C virus nonstructural gene 3 (NS3) codes for a serine protease. To investigate natural genetic diversity of this enzyme a nested PCR reaction was developed to obtain NS3 protease sequence data directly from patient strains. This data was used to determine genetic diversity, phylogenetic and evolutionary rates, and selection of variants by interferon therapy. The potential effect of genetic diversity on enzyme structure using molecular modeling was also attempted. Results show significant variability in clinical HCV strains at both the nucleotide (30.2% for 1a and 25.8% for 1b) and amino acid sequences (11.0% for 1a and 9.9% for 1b). Phylogenic analysis shows two distinct clades with two HCV isolates grouping as a sister clade to 1b. Structural analysis reveals that most mutations lie in the N-terminus of the enzyme. When strains were sorted as to whether or not the patient had received antiviral therapy, no difference was found in the number or locations of mutations in 1a strains. However, 1b strains demonstrated an overall drop in the number of positions that were mutated. This study demonstrates significant differences among natural strains that may pose a problem for structure based drug development.

Genotypic drug resistance and cause of death in HIV-infected persons who died in 1999.

We analyzed the relationship between viral drug resistance and causes of death in 29 HIV-1-infected patients who had been followed in an HIV-outpatient clinic and died in 1999. Six patients (21%) died with plasma HIV-RNA levels <1000 copies/ml. Seven (24%) died with wild-type (WT) virus in plasma, 6 (21%) had reverse transcriptase (RT) mutations only, 10 (34%) had multidrug-resistant (MDR) virus. The causes of death were not differently distributed among these groups; however, 8 of 16 patients (50%) with resistant viruses died of end-organ failure versus 2 of 7 patients (29%) with WT virus. Seventeen of 32 patients (53%) were thought by their physicians to be noncompliant with prescribed therapy. Major resistance mutations to antiretroviral drugs were present in viruses from at least 55% of our HIV-1-infected patients who died in 1999. Nonetheless, deaths also occurred among patients with well-controlled HIV infection and among patients with WT virus in plasma. Infections related to incomplete immune restoration, inability to maintain suppressive antiretroviral drug levels, and end-organ failures all contribute to mortalities in the era of highly active antiretroviral therapy.

Selective increases in HIV-specific neutralizing antibody and partial reconstitution of cellular immune responses during prolonged, successful drug therapy of HIV infection.

Because the immune response to HIV depends on viral gene expression, we examined the HIV-specific immune responses in persons whose viral load after highly active antiretroviral therapy (HAART) was <400 on at least 3 occasions over a 12-month interval. Eleven patients were identified. While there was little change in mean HIV-binding antibody (Ab) titers in this group, two persons mounted increases in HIV envelope-specific binding antibody. Neutralizing antibody (NAb) titers against a panel of HIV-1 primary isolates (BZ167, US1, and CM237) increased post-HAART (80% neutralization titer against US1, p = 0.06; against CM237, p = 0.04). The two persons with large increases in binding antibody also had increases in primary isolate NAb. Roughly half of HAART recipients had significant increases in neutralizing antibody to the primary isolates US1 and CM237. Compared with CD4-matched, non-HAART controls, there were significant increases in NAb against the subtype B primary isolate US1 (p < 0.0009); no increases were seen against more easily neutralized primary isolate BZ167. There were no differences after HAART in antibody-directed cellular cytotoxicity (ADCC). HAART resulted in a partial restoration of lymphoproliferative responses to recall antigens (tetanus and diphtheria). New responses developed to HIV Gag p24. No patient responded to HIV Env gp160 or gp120 either before or after HAART. The data underscore the lack of functional reconstitution of HIV-specific, CD4-mediated responses despite durable suppression of viral replication. In the setting of stable anti-HIV Ab levels, the development of increased NAb in certain individuals suggests that control of the virus by HAART may assist in immune control of HIV.

Clinical prognosis of patients with early-stage human immunodeficiency virus (HIV) disease: contribution of HIV-1 RNA and T lymphocyte subset quantitation.

Systems for the staging of individuals with human immunodeficiency virus type 1 (HIV-1) infection were developed 15 years ago. Subsequently, assays for quantitating HIV-1 RNA and immunophenotyping of lymphocyte subsets have been developed and validated. The utility of these assays for improved staging in early disease was evaluated in 256 HIV-infected adults (52% minority) with CD4 counts > or = 400 cells/microL followed in U.S. military medical centers before the highly active anti-retroviral therapy era. HIV viral load (RNA) was quantitated; the frequencies of select CD4+ immunophenotypes were determined in 112 subjects. The results were analyzed in relation to three outcome measures: death, first acquired immunodeficiency syndrome-defining opportunistic infection, and CD4 count < or = 200 cells/microL. Serum RNA level and CD4 count were each found to be predictive of all three outcomes. In addition, increases in the T-cell subsets CD28-CD4+ and CD29+CD26-CD4+ were found to be independently predictive of more rapid progression. The classification of early-stage HIV patients is improved by the quantitation of both viral RNA and T-lymphocyte subsets.

Treatment of primary human immunodeficiency virus type 1 infection with potent antiretroviral therapy reduces frequency of rapid progression to AIDS.

Immunologic data supporting immediate antiretroviral therapy in primary human immunodeficiency virus type 1 (HIV-1) infection are emerging; however, clinical benefit has not been demonstrated. The clinical and virologic course of 47 patients who were enrolled from September 1993 through June 1996 and who were not initially treated with potent therapy was compared with the course of 20 patients who immediately began therapy with zidovudine, lamivudine, and indinavir. Demographic and baseline laboratory data were comparable. During 78 weeks of follow-up, the early-treatment cohort showed a reduced frequency of opportunistic infections (5% vs. 21.3%; relative risk, 0.11; P=.02), less frequent progression to AIDS (13% vs. 0%), and significantly less frequent nonopportunistic mucocutaneous disorders and respiratory infections (P<.01). Plasma HIV-1 RNA levels were <50 copies/mL in all patients who continued therapy; however, after 9--12 months, HIV-1 remained detectable in latently infected CD4(+) T cells and in lymph node mononuclear cells. Combination antiretroviral therapy during primary HIV-1 infection demonstrated a decreased frequency of minor opportunistic infections, mucocutaneous disorders, and respiratory infections and reduced progression to AIDS.

The rationale and design of the CPCRA (Terry Beirn Community Programs for Clinical Research on AIDS) 058 FIRST (Flexible Initial Retrovirus Suppressive Therapies) trial.

The CPCRA (Terry Beirn Community Programs for Clinical Research on AIDS) 058 FIRST (Flexible Initial Retrovirus Suppressive Therapies) trial is a large, long-term, randomized, prospective comparison of three different antiretroviral strategies in highly active antiretroviral therapy-naïve, HIV-1-infected persons. The trial was designed as a flexible framework upon which other studies could be added to answer more limited, but still important, questions. This article presents the study design, discusses the challenges we have faced in implementing the trial, and describes our preliminary experiences. Control Clin Trials 2001;22:176-190

In vitro evaluation of experimental agents for anti-HIV activity.

This unit presents an assay that has proven useful as an initial screening test is an HIV cytopathic effect (CPE) inhibition assay in which immortalized T cell lines (e.g., ATH8 or MT2) that are profoundly sensitive to the cytopathic effect of certain strains of HIV are utilized as target cells. Additional protocols assess the anti-HIV activity of certain candidate agents by measuring inhibition of syncytium formation or p24 gag protein production by ELISA. Calculation of the 50% inhibitory concentration (IC(50)) is also presented.

A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS.

OBJECTIVE: To determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors. DESIGN: Prospective randomized controlled trial. SETTING: Multicenter community-based clinical trials network. PATIENTS: One-hundred and fifty-three HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy. INTERVENTIONS: Randomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-GART group, where treatment choices were made without such input. MAIN OUTCOMES MEASURES: Plasma HIV-1 RNA levels and CD4 cell counts were measured at 4, 8, and 12 weeks following randomization. The primary endpoint was change in HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels. RESULTS: The average baseline CD4 cell count was 230 x 10(6) cells/l and the median HIV-1 RNA was 28,085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.19 log10 for the 78 GART patients and -0.61 log10 for the 75 no-GART patients (treatment difference: -0.53 log, 95% confidence interval, -0.77 to -0.29; P = 0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible. CONCLUSION: In patients failing triple drug therapy, GART with expert advice was superior to no-GART as measured by short-term viral load responses.

Frequency of antiretroviral drug resistance mutations in HIV-1 strains from patients failing triple drug regimens. The Terry Beirn Community Programs for Clinical Research on AIDS.

The frequency of protease and reverse transcriptase (RT) gene mutations was determined in HIV-1 strains from 153 patients entering the CPCRA 046 (GART) study who were failing triple-drug regimens consisting of one protease inhibitor (PI) and two RT inhibitors. Population-based sequence analyses showed that nearly all patients had similar RT gene mutations regardless of prior drug exposure, although the M184V mutation was significantly less prevalent in patients not recently treated with lamivudine. Whilst typical inhibitor-specific ('signature') protease gene mutations were found in patients failing their first PI, these mutations were significantly less likely to be found in patients exposed to two or more PIs. Protease gene mutations associated with multi-PI resistance were more likely to be observed in patients treated with more than one PI. These results suggest sequential treatment with PIs select for a relatively limited number of protease gene mutations that likely originated during early PI therapy. These protease gene mutations and a similarly limited set of RT gene mutations appear to be responsible for treatment failure in antiretroviral therapy.

Prevalence of HIV-1 resistant to antiretroviral drugs in 81 individuals newly infected by sexual contact or injecting drug use. Investigators of the Quebec Primary Infection Study.

OBJECTIVE: Prolonged treatment with antiretroviral drugs results in the selection of HIV-1 variants with mutations conferring resistance to nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTI and NNRTI) or to protease inhibitors (PI). There is serious concern about transmission of resistant viruses to newly infected persons. This study monitored the prevalence of resistant viruses in individuals undergoing primary HIV infection. DESIGN: Resistance testing was performed on 81 individuals infected between 1997 and 1999 by injecting drug use (n =21), sexual (n = 56), or unknown (n = 4) transmission. METHODS: Automated sequencing was used to genotype the reverse transcriptase (RT) and protease regions of virus isolated from patients' plasma. The phenotypic susceptibility of stimulated peripheral blood mononuclear cells to antiretroviral drugs was assayed. Line probe assays detected quasispecies variations in wild-type and mutated RT codons. RESULTS: A high prevalence of PI and RT genotypic variants, associated with high-level resistance to antiretroviral drugs, was observed in individuals newly infected by injecting drug use (PI = 24%, RT = 24%) or sexual transmission (PI = 12%, RT = 22%). The PI mutations, L101, V82A, and L90M, were found in 10.5, 3 and 4% of cases, respectively; whereas for RT, primary mutations at positions T215Y (zidovudine), M184V (lamivudine), T69D/A (zalcitabine), and K103N (multi-NNRTI) were present in 8, 5, 4, and 4% of subjects, respectively. Resistance to NRTI was demonstrated by phenotypic, genotypic, and line probe analyses. Transmission of multidrug (NRTI/NNRTI/PI) resistance in eight subjects (9.9%) was confirmed by showing that source partners possessed viruses of similar genotype. CONCLUSIONS: The transmission of drug-resistant HIV is a serious problem that merits further attention by public health officials as well as virologists and clinicians.

Exotic virus infections of military significance. Hemorrhagic fever viruses and pox virus infections.

Military personnel are frequently deployed to distant locations around the world under conditions of great stress, which involve potential exposure to hazardous viruses that are not commonly seen in the developed world. This article will provide an overview of two clinical presentations of viral infections of potential military significance: hemorrhagic fever and poxvirus infections. The three viral hemorrhagic fever viruses described--dengue, hemorrhagic fever with renal syndrome, and Congo-Crimean hemorrhagic fever--represent the diversity of potential hemorrhagic fever viruses that military forces may be exposed. Human poxvirus infections are currently uncommon but knowledge of these agents, will again become important should a terrorist threat of the use of smallpox become real and widespread use of vaccinia be considered to protect the military force.