Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme.

BACKGROUND: Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. METHODS: PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 µg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive. FINDINGS: Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4-7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80-1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86-1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001). INTERPRETATION: Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer. FUNDING: Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London.

Quality-of-life outcomes from the Prostate Adenocarcinoma: TransCutaneous Hormones (PATCH) trial evaluating luteinising hormone-releasing hormone agonists versus transdermal oestradiol for androgen suppression in advanced prostate cancer.

OBJECTIVES: To compare quality-of-life (QoL) outcomes at 6 months between men with advanced prostate cancer receiving either transdermal oestradiol (tE2) or luteinising hormone-releasing hormone agonists (LHRHa) for androgen-deprivation therapy (ADT). PATIENTS AND METHODS: Men with locally advanced or metastatic prostate cancer participating in an ongoing randomised, multicentre UK trial comparing tE2 versus LHRHa for ADT were enrolled into a QoL sub-study. tE2 was delivered via three or four transcutaneous patches containing oestradiol 100 µg/24 h. LHRHa was administered as per local practice. Patients completed questionnaires based on the European Organisation for Research and Treatment of Cancer quality of life questionnaire 30-item core (EORTC QLQ-C30) with prostate-specific module QLQ PR25. The primary outcome measure was global QoL score at 6 months, compared between randomised arms. RESULTS: In all, 727 men were enrolled between August 2007 and October 2015 (412 tE2, 315 LHRHa) with QoL questionnaires completed at both baseline and 6 months. Baseline clinical characteristics were similar between arms: median (interquartile range) age of 74 (68-79) years and PSA level of 44 (19-119) ng/mL, and 40% (294/727) had metastatic disease. At 6 months, patients on tE2 reported higher global QoL than those on LHRHa (mean difference +4.2, 95% confidence interval 1.2-7.1; P = 0.006), less fatigue, and improved physical function. Men in the tE2 arm were less likely to experience hot flushes (8% vs 46%), and report a lack of sexual interest (59% vs 74%) and sexual activity, but had higher rates of significant gynaecomastia (37% vs 5%). The higher incidence of hot flushes among LHRHa patients appear to account for both the reduced global QoL and increased fatigue in the LHRHa arm compared to the tE2 arm. CONCLUSION: Patients receiving tE2 for ADT had better 6-month self-reported QoL outcomes compared to those on LHRHa, but increased likelihood of gynaecomastia. The ongoing trial will evaluate clinical efficacy and longer term QoL. These findings are also potentially relevant for short-term neoadjuvant ADT.

Post-licensing safety of fosamprenavir in HIV-infected children in Europe.

PURPOSE: Fosamprenavir, combined with low-dose ritonavir (FPV/r), is indicated for treatment of HIV-infected children aged ≥ 6 years in Europe. Our purpose was to assess the safety of licensed use of FPV/r in HIV-infected children reported to six cohorts in the European Pregnancy and Paediatric HIV Cohort Collaboration. METHODS: Retrospective analysis of individual patient data for all children aged 6-18 years taking the licensed dose of FPV up to 31/12/10. Adverse events (clinical events and absolute neutrophil counts, total cholesterol and triglycerides, and alanine transaminase) were summarised and DAIDS gradings characterised severity. RESULTS: Ninety-two HIV-infected children aged 6-18 years took the licensed dose, comprising 3% of the total number of children in follow-up in participating cohorts. Median age at antiretroviral therapy initiation was 6 years (interquartile range 1-11 years), and median age at start of FPV/r was 15 years (12-17 years). Estimated median time on an FPV-containing regimen was 52 months, with a total of 266.9 patient years of exposure overall. Half (54%) were on an FPV-containing regimen at last follow-up. Rates of grade 3/4 events were generally low for all biochemical toxicity markers, and no serious adverse events considered to be causally related to FPV/r were reported. CONCLUSIONS: Results suggest that long-term licensed dose FPV-containing regimens appear to be generally well tolerated with few reported toxicities in HIV-infected children in Europe, although relatively infrequently prescribed. No serious events were reported

Health and illness beliefs in adults with tuberculosis infection during the COVID-19 pandemic in the UK.

Background: COVID-19 disrupted the TB prevention programme in the UK, especially for TB infection (TBI) care. We explore whether experience of the COVID-19 pandemic impacted on patients' perceptions of TBI and its treatment. Methods: Semi-structured interviews were conducted as part of the Research to Improve Detection and Treatment of TBI (RID-TB) programme, exploring perceptual and practical barriers to TBI treatment. Nineteen people diagnosed with TBI were interviewed between August 2020 and April 2021. Recordings were transcribed and analysed using a constant comparative approach, allowing for a dynamic and iterative exploration of themes. Themes are organised using the Perceptions and Practicalities Approach. Findings: Some participants perceived TBI as a risk factor for increased susceptibility to COVID-19, while some thought that treatment for TBI might protect against COVID-19 or mitigate its effects. Adaptations to TB services (e.g., remote follow-up) and integrated practices during the COVID-19 restrictions (e.g., medication being posted) addressed some practical barriers to TBI treatment. However, we identified beliefs about TBI and COVID-19 that are likely to act as barriers to engagement with TBI treatment, including: interpreting service delays as an indication of TBI not being serious enough for treatment and concerns about contracting COVID-19 in TB clinics. Interpretation: COVID-19 and TBI service delays influence people's perceptions and practical barriers to TBI treatment adherence. Failure to address these beliefs may lead to people's concerns about their treatment not being fully addressed. Utilised service adaptations like remote consultations to address practical barriers may be relevant beyond COVID-19. Funding: NIHR RID-TB Program (RP-PG-0217-20009).

Preparation of PCL Electrospun Fibers Loaded with Cisplatin and Their Potential Application for the Treatment of Prostate Cancer.

Prostate cancer is a global fatal type of cancer. It is a type of cancer that affect men. Signs and symptoms of the disease include blood in the urine, pain when one micturates, and difficulties in penis erection. Cisplatin chemotherapy is a principal treatment normally given to the prostate cancer patients. Nonetheless, on its own, cisplatin loses efficacy once administered due to liver pass effects and other biochemical attacks. In this paper, we looked at preparation of PCL nanoparticles loaded with cisplatin and their potential for the treatment of prostate cancer. PCL nanoparticles protect cisplatin from biochemical attack, thus increasing drug efficacy. Incorporation of P-glycoprotein inhibitors in PCL nanoparticles (NPs) loaded with cisplatin could improve prostate cancer treatment even more.

Biochemical Behaviours of Salmeterol/Fluticasone Propionate in Treating Asthma and Chronic Obstructive Pulmonary Diseases (COPD).

Chronic obstructive pulmonary diseases (COPD) and asthma are fatal. The respiratory tract may be blocked, robbed of the adequate amounts of oxygen; hence, death ensues if a quick medical attention is not provided. The treatment available for the duo are inhaled corticosteroids (ICS). The ICS can work synergically with LABAS (long-acting ß 2-antagonists) and so many other medicines like bronchodilators. The drugs used for the treatment of asthma and COPD are metabolised once in the body system and at the same time exerting the therapeutic effect provided the concentration of the drug is within the therapeutic window. The CYP3A isoforms metabolise the ICS, in this case, salmeterol and fluticasone propionate (FP). Methods of administration are not limited to inhalation. Specific doses are prescribed accurately paying attention to factors like age, gender, race, and genetic makeup since these affect drug metabolisms. Generally, the ICS work by translocating glucocorticoid receptors to the nucleus from the cytosol. The mechanism is potentiated by the ß-antagonists and this brings about an anti-inflammatory effect which is greater than either of the two drugs alone. Once this happens, it is not necessary to increase ICS dose. The ICS, in addition, cause more production of ß-receptors by activating the ß-receptor genes. This mode of action begets the LABAs' bronchodilator-effects. The challenge is that ICS are not limited only to "double" therapy. Analysing such therapies is daunting since coadministration interferes with pharmacology and pharmacokinetics of drugs. This work focuses on salmeterol/fluticasone propionate combination and aspects which has to do with administration, monitoring, metabolism, toxicity, and adverse effects.

Emergency Medicine with Advanced Surgery Protocols: A Review.

One of the most burning issues in health system is the concern of handling patients that requires emergency surgery. Emergency general surgery is done on both traumatic and nontraumatic acute disorders. Severe traumatic injury and bleeding is one of the causing agents for high mortality rate globally. Another group of patients that are in need of emergency surgery are those with heart failure, and in this particular paper, we analyzed emergency medicine with advanced surgery protocols focusing on gastric cancer, cardiac surgery, and bleeding as well as coagulopathy following traumatic injury.

Type 2 Diabetes Mellitus (T2DM) and Carbohydrate Metabolism in Relation to T2DM from Endocrinology, Neurophysiology, Molecular Biology, and Biochemistry Perspectives.

Type 2 diabetes mellitus (T2DM) is a severe disease caused by metabolic disorders, particularly carbohydrate metabolism disorders. The disease is a fatal global trouble characterised by high prevalence rates, causing death, blindness, kidney failure, myocardial infarction, amputation of lower limps, and stroke. Biochemical metabolic pathways like glycolysis, gluconeogenesis, glycogenesis, and glycogenolysis are critical pathways that regulate blood glucose levels with the glucokinase (GK) enzyme playing a central role in glucose homeostasis. Any factor that perturbs the aforementioned biochemical pathways is detrimental. Endocrinological, neurophysiological, and molecular biological pathways that are linked to carbohydrate metabolism should be studied, grasped, and manipulated in order to alleviate T2DM global chaos. The challenge, howbeit, is that, since the body is an integration of systems that complement one another, studying one "isolated" system is not very useful. This paper serves to discuss endocrinology, neurophysiology, and molecular biology pathways that are involved in carbohydrate metabolism in relation to T2DM.

A Critical Scrutiny on Liposomal Nanoparticles Drug Carriers as Modelled by Topotecan Encapsulation and Release in Treating Cancer.

The medical field is looking for drugs and/or ways of delivering drugs without harming patients. A number of severe drug side effects are reported, such as acute kidney injury (AKI), hepatotoxicity, skin rash, and so on. Nanomedicine has come to the rescue. Liposomal nanoparticles have shown great potential in loading drugs, and delivering drugs to specific targeted sites, hence achieving a needed bioavailability and steady state concentration, which is achieved by a controlled drug release ability by the nanoparticles. The liposomal nanoparticles can be conjugated to cancer receptor tags that give the anticancer-loaded nanoparticles specificity to deliver anticancer agents only at cancerous sites, hence circumventing destruction of normal cells. Also, the particles are biocompatible. The drugs are shielded by attack from the liver and other cytochrome P450 enzymes before reaching the desired sites. The challenge, however, is that the drug release is slow by these nanoparticles on their own. Scientists then came up with several ways to enhance drug release. Magnetic fields, UV light, infrared light, and so on are amongst the enhancers used by scientists to potentiate drug release from nanoparticles. In this paper, synthesis of liposomal nanoparticle formulations (liposomal-quantum dots (L-QDs), liposomal-quantum dots loaded with topotecan (L-QD-TPT)) and their analysis (cytotoxicity, drug internalization, loading efficiency, drug release rate, and the uptake of the drug and nanoparticles by the HeLa cells) are discussed.

The Use of Bacteria in Cancer Treatment: A Review from the Perspective of Cellular Microbiology.

Cellular microbiology, which is the interaction between harmful microbes and infected cells, is important in the determination of the bacterial infection processes and in the progression of data of different cellular mechanisms. The therapeutic role of bacteria has gained attention since the known methods such as radiation, chemotherapy, and immunotherapy have got drawbacks. Bacteria have demonstrated a favorable impact in treating cancer through eradication of tumors. Bacteria, in cancer treatment, have proven to be promising and have been shown in some of the previous work that it can successfully suppress the growth of tumors. In this paper, we analyzed the difficulties and settlement for using bacteria in cancer therapy as well the mechanisms in which bacteria works in order to achieve tumor eradication. Future works may focus on the use of bacteria along with other treatments in order to achieve effective tumor therapy.

Evaluating the effect of short-course rifapentine-based regimens with or without enhanced behaviour-targeted treatment support on adherence and completion of treatment for latent tuberculosis infection among adults in the UK (RID-TB: Treat): protocol for an open-label, multicentre, randomised controlled trial.

INTRODUCTION: The successful scale-up of a latent tuberculosis (TB) infection testing and treatment programme is essential to achieve TB elimination. However, poor adherence compromises its therapeutic effectiveness. Novel rifapentine-based regimens and treatment support based on behavioural science theory may improve treatment adherence and completion. METHODS AND ANALYSIS: A pragmatic multicentre, open-label, randomised controlled trial assessing the effect of novel short-course rifapentine-based regimens for TB prevention and additional theory-based treatment support on treatment adherence against standard-of-care. Participants aged between 16 and 65 who are eligible to start TB preventive therapy will be recruited in England. 920 participants will be randomised to one of six arms with allocation ratio of 5:5:6:6:6:6: daily isoniazid +rifampicin for 3 months (3HR), routine treatment support (control); 3HR, additional treatment support; weekly isoniazid +rifapentine for 3 months (3HP), routine treatment support; weekly 3HP, additional treatment support ; daily isoniazid +rifapentine for 1 month (1HP), routine treatment support; daily 1HP, additional treatment support. Additional treatment support comprises reminders using an electronic pillbox, a short animation, and leaflets based on the perceptions and practicalities approach. The primary outcome is adequate treatment adherence, defined as taking ≥90% of allocated doses within the pre-specified treatment period, measured by electronic pillboxes. Secondary outcomes include safety and TB incidence within 12 months. We will conduct process evaluation of the trial interventions and assess intervention acceptability and fidelity and mechanisms for effect and estimate the cost-effectiveness of novel regimens. The protocol was developed with patient and public involvement, which will continue throughout the trial. ETHICS AND DISSEMINATION: Ethics approval has been obtained from The National Health Service Health Research Authority (20/LO/1097). All participants will be required to provide written informed consent. We will share the results in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT 2020-004444-29.

Comparison of two active case-finding strategies for community-based diagnosis of symptomatic smear-positive tuberculosis and control of infectious tuberculosis in Harare, Zimbabwe (DETECTB): a cluster-randomised trial.

BACKGROUND: Control of tuberculosis in settings with high HIV prevalence is a pressing public health priority. We tested two active case-finding strategies to target long periods of infectiousness before diagnosis, which is typical of HIV-negative tuberculosis and is a key driver of transmission. METHODS: Clusters of neighbourhoods in the high-density residential suburbs of Harare, Zimbabwe, were randomised to receive six rounds of active case finding at 6-monthly intervals by either mobile van or door-to-door visits. Randomisation was done by selection of discs of two colours from an opaque bag, with one disc to represent every cluster, and one colour allocated to each intervention group before selection began. In both groups, adult (≥16 years) residents volunteering chronic cough (≥2 weeks) had two sputum specimens collected for fluorescence microscopy. Community health workers and cluster residents were not masked to intervention allocation, but investigators and laboratory staff were masked to allocation until final analysis. The primary outcome was the cumulative yield of smear-positive tuberculosis per 1000 adult residents, compared between intervention groups; analysis was by intention to treat. The secondary outcome was change in prevalence of culture-positive tuberculosis from before intervention to before round six of intervention in 12% of randomly selected households from the two intervention groups combined; analysis was based on participants who provided sputum in the two prevalence surveys. This trial is registered, number ISRCTN84352452. FINDINGS: 46 study clusters were identified and randomly allocated equally between intervention groups, with 55 741 adults in the mobile van group and 54,691 in the door-to-door group at baseline. HIV prevalence was 21% (1916/9060) and in the 6 months before intervention the smear-positive case notification rate was 2·8 per 1000 adults per year. The trial was completed as planned with no adverse events. The mobile van detected 255 smear-positive patients from 5466 participants submitting sputum compared with 137 of 4711 participants identified through door-to-door visits (adjusted risk ratio 1·48, 95% CI 1·11-1·96, p=0·0087). The overall prevalence of culture-positive tuberculosis declined from 6·5 per 1000 adults (95% CI 5·1-8·3) to 3·7 per 1000 adults (2·6-5·0; adjusted risk ratio 0·59, 95% CI 0·40-0·89, p=0·0112). INTERPRETATION: Wide implementation of active case finding, particularly with a mobile van approach, could have rapid effects on tuberculosis transmission and disease. FUNDING: Wellcome Trust.

Long-term survival of HIV-infected children receiving antiretroviral therapy in Thailand: a 5-year observational cohort study.

BACKGROUND: There are scarce data on the long-term survival of human immunodeficiency virus (HIV)-infected children receiving antiretroviral therapy (ART) in lower-middle income countries beyond 2 years of follow-up. METHODS: Previously untreated children who initiated ART on meeting immunological and/or clinical criteria were followed in a prospective cohort in Thailand. The probability of survival up to 5 years from initiation was estimated using Kaplan-Meier methods, and factors associated with mortality were assessed using Cox regression analyses. RESULTS: Five hundred seventy-eight children received ART; of these, 111 (19.2%) were followed since birth. At start of ART (baseline), the median age was 6.7 years, 128 children (22%) were aged <2 years, and the median CD4 cell percentage was 7%. Median duration of follow-up was 53 months; 42 children (7%) died, and 38 (7%) were lost to follow-up. Age <12 months, low CD4 cell percentage, and low weight-for-height z score at ART initiation were independently associated with mortality (P < .001). The probability of survival among infants aged <12 months at baseline was 84.3% at 1 year and 76.7% at 5 years of ART, compared with 95.7% and 94.8%, respectively, among children aged ≥1 year. Low CD4 cell percentage and wasting at baseline had a strong association with mortality among older children but weak or no association among infants. CONCLUSIONS: Children who initiated ART as infants after meeting immunological and/or clinical criteria had a high risk of mortality which persisted beyond the first year of therapy. Among older children, those with severe wasting or low CD4 cell percentage at treatment initiation were at high risk of mortality during the first 6 months of therapy. These findings support the scale-up of early HIV diagnosis and immediate treatment in infants, before advanced disease progression in older children.

Effect of praziquantel treatment of Schistosoma mansoni during pregnancy on intensity of infection and antibody responses to schistosome antigens: results of a randomised, placebo-controlled trial.

BACKGROUND: Praziquantel treatment of schistosomiasis during pregnancy was only recommended in 2002; hence the effects of treatment during pregnancy are not fully known. We have therefore evaluated the effects on infection intensity and the immunological effects of praziquantel treatment against Schistosoma mansoni during pregnancy, compared with treatment after delivery. METHODS: A nested cohort of 387 Schistosoma mansoni infected women was recruited within a larger trial of de-worming during pregnancy. Women were randomised to receive praziquantel or placebo during pregnancy. All women were treated after delivery. Infection intensity after treatment was assessed by a single Kato-Katz examination of stool samples with duplicate slides and categorised as undetected, light (1-99 eggs per gram (epg)), moderate (100-399 epg) or heavy (>or=400 epg). Antibodies against S. mansoni worm and egg antigens were measured by ELISA. Results were compared between women first treated during pregnancy and women first treated after delivery. RESULTS: At enrollment, 252 (65.1%) of the women had light infection (median (IQR) epg: 35 (11, 59)), 75 (19.3%) moderate (median (IQR) epg: 179(131, 227)) and 60 (15.5%) had heavy infection (median (IQR) epg: 749 (521, 1169)) with S. mansoni. At six weeks after praziquantel treatment during pregnancy S. mansoni infection was not detectable in 81.9% of the women and prevalence and intensity had decreased to 11.8% light, 4.7% moderate and 1.6% heavy a similar reduction when compared with those first treated after delivery (undetected (88.5%), light (10.6%), moderate (0.9%) and heavy (0%), p = 0.16). Parasite specific antibody levels were lower during pregnancy than after delivery. Praziquantel treatment during pregnancy boosted anti-worm IgG isotypes and to a lesser extent IgE, but these boosts were less pronounced than in women whose treatment was delayed until after delivery. Praziquantel had limited effects on antibodies against egg antigens. CONCLUSION: S mansoni antigen-specific antibody levels and praziquantel-induced boosts in antibody levels were broadly suppressed during pregnancy, but this was not associated with major reduction in the efficacy of praziquantel. Long-term implications of these findings in relation to resistance to re-infection remain to be explored.

Modeling ENSO impact on rice production in the Mekong River Delta.

The Mekong River Delta is the rice production hub in South-east Asia and has a key role in determining rice prices in the world market. The increasing variability in the local climate due to global climate changes and the increasing severity of the ENSO phenomenon threatens rice production in the region, which has consequences for local and global food security. Though existing mapping efforts delineate the consequences of saline water intrusion during El Niño and flooding events during La Niña in the basin, research to predict future impacts in rice production is rather limited. The current work uses ORYZA, an ecophysiological model, combined with historical climate data, climate change scenarios RCP4.5 and 8.5 and climate-related risk maps to project the aggregate productivity and rice production impacts by the year 2050. Results show that in years of average salinity intrusion and flooding, the winter-spring rice crop in the MRD would experience an average annual decrease of 720,450 tons for 2020-2050 under the RCP4.5 scenario compared to the baseline of 2005-2016 average and another 1.17 million tons under the RCP8.5 scenario. The autumn-winter crop would decrease by 331,480 tons under RCP4.5 and 462,720 tons under RCP8.5. In years of severe salinity intrusion and flooding, the winter-spring rice crop would decrease by 2.13 million tons (10.29% lower than the projection for an average year) under RCP4.5 and 2.5 million tons (13.62%) under RCP8.5. Under severe conditions, the autumn-winter crop would have an average decrease of 1.3 million tons (7.36%) under RCP4.5 and 1.4 million tons (10.88%) for the RCP8.5 scenario. Given that most of the rice produced in this area is exported, a decline in rice supply at this scale would likely have implications on the global market price of rice affecting global food security. Such decline will also have implications for the rural economy and food security of Vietnam. Suggestions for corrective measures to reduce the impacts are briefly discussed.

HIV-1 drug resistance in HIV-1-infected children in the United Kingdom from 1998 to 2004.

We reviewed HIV-1 genotypes from 200 of 979 (20%) HIV-infected children in the U.K. Collaborative HIV in Pediatric Study (CHIPS) cohort (343 resistance tests). Three of 44 samples had major primary resistance mutations before antiretroviral therapy. Three-class resistance was noted in 42 samples (14.1%). Our study also highlighted underutilization of testing and the need for prompt genotyping after drug discontinuation which may have lead to an underestimation of HIV-1 resistance.

Morbidity, mortality, and response to treatment by children in the United Kingdom and Ireland with perinatally acquired HIV infection during 1996-2006: planning for teenage and adult care.

BACKGROUND: Recent evidence suggests that decreases in morbidity and mortality in cohorts of adults infected with human immunodeficiency virus (HIV) are showing signs of reversal. We describe changes over time in these characteristics and in the response to treatment among children in the United Kingdom and Ireland with perinatally acquired HIV infection, many of whom are now adolescents. METHODS: We analyzed prospective cohort data reported to the National Study of HIV in Pregnancy and Childhood (NSHPC) and the Collaborative HIV Paediatric Study. RESULTS: By mid 2006, 1441 HIV-infected children were reported to NSHPC; 40% were > or = 10 years old at their most recent follow-up visit, and 34% were receiving care outside London. The proportion of children born abroad increased from 24% during 1994-1996 to 64% during 2003-2006. The percentage of total child time during which children received highly active antiretroviral therapy (HAART) increased from 36% during 1997-1999 to 61% during 2000-2002 and 63% during 2003-2006. Of children who were naive to antiretroviral therapy at the start of HAART, the percentage with an HIV-1 RNA load of < 400 copies/mL after 12 months increased from 52% during 1997-1999 to 79% during 2003-2006. In multivariate analysis, only calendar time predicted virological response, whereas both younger age and lower CD4 cell percentage at HAART initiation predicted increases of > 10% in the CD4 cell percentage. A total of 31% of children aged 5-14 years and 38% aged > or = 15 years at their most recent follow-up visit had been exposed to drugs from each of the 3 main HAART classes. The rate of AIDS and mortality combined decreased from 13.3 cases per 100 person-years before 1997 to 3.1 and 2.5 cases per 100 person-years, respectively, during 2000-2002 and 2003-2006; rates of hospital admission also declined during this interval. Of 18 children known to have died since 2003, 9 died within 1 month after presentation. CONCLUSIONS: Morbidity and mortality rates among HIV-infected children continue to decrease over time. Because these children are increasingly dispersed outside London, specialist care is now provided in national clinical networks. Transition pathways to adolescent and adult services and long-term observation to monitor the effects of prolonged exposure to both HIV and HAART are required.

Transient viral load increases in HIV-infected children in the U.K. and Ireland: what do they mean?

OBJECTIVES: To investigate transient increases in viral load during sustained suppression in children in the UK and Ireland Collaborative HIV Paediatric Study (CHIPS). DESIGN: Cohort of HIV-infected children from 39 centres. METHODS: Transient viraemia was defined as > or =1 detectable viral loads (> or =50 copies/ml) between two undetectable values (<50 copies/ml) <280 days apart, during a period of sustained viral suppression (from a confirmed level of <50 copies/ml until the last undetectectable measurement before antiretroviral therapy change or until a confirmed level of >50 copies/ml). RESULTS: Of 595 children initiating HAART without previous treatment, 347 (58%) achieved sustained suppression. Of these, 78 (23%) experienced 109 episodes of transient viraemia (median 134 copies/ml); 92 (84%) had levels of <1000 copies/ml (maximum 39,839). Transient viraemia was more common during second-line therapy (25/100 child-years [CY]) and following a previous episode (19/100 CY) compared with first-line therapy without a previous episode (11/100 CY). Rates decreased with age at HAART initiation (incidence rate ratio [IRR] 0.95 per year older; P = 0.05), but were higher in those suppressed for longer (IRR 1.63 in those suppressed for 21 year versus <1 year; P = 0.03). CD4+ and CD8+ T-cell counts were similar before and after transient viraemia. Of detectable viral loads during periods of suppression 44% were transient increases rather than virological failure: experiencing transient viraemia did not increase subsequent virological failure (P = 0.20). CONCLUSIONS: Transient viraemia is relatively common among children on HAART, occurring more frequently in those starting HAART at younger ages, on second-line therapy and after longer suppression. It does not appear to affect CD4+ or CD8+ T-cell counts or the risk of subsequent virological failure. Natural variation, assay effects and adherence might all have a role.

Prognostic value of blood pressure measured during hospitalization after acute myocardial infarction: an insight from survival trials.

BACKGROUND: The prognostic value of blood pressure measured during hospitalization after acute myocardial infarction (MI) has not been investigated, particularly with regard to arrhythmic death. METHODS: A total of 3311 placebo patients (2612 men, median age 64 years; range 23-92) from the EMIAT, CAMIAT, SWORD, TRACE and DIAMOND-MI studies with left ventricular ejection fraction less than 40% or asymptomatic ventricular arrhythmia surviving more than 45 days after MI were pooled. Systolic and diastolic blood pressures and pulse pressures were measured soon after MI (median 6 days, range 0-53 days). Mortality up to 2 years was examined using Cox regression. RESULTS: At the 2-year follow-up, after adjustment for age, sex, smoking, previous MI, hypertension, heart rate, New York Heart Association functional class, baseline treatments, study effect and diastolic blood pressure, reduced systolic blood pressure measured during hospitalization after acute MI significantly increased the risk of all-cause mortality [hazard ratio (HR) for 10% increase in systolic blood pressure 0.80, 95% confidence interval (CI) 0.71-0.90; P < 0.001] and arrhythmic mortality (HR 0.73, 95% CI 0.61-0.86; P = 0.001). Reduced diastolic blood pressure significantly increased the risk of all-cause mortality (HR 0.87, 95% CI 0.77-0.98; P = 0.02) and arrhythmic mortality (HR 0.80, 95% CI 0.68-0.93; P = 0.005). CONCLUSION: In post-MI patients with left ventricular ejection fraction less than 40% or asymptomatic ventricular arrhythmia, reduced blood pressure measured during hospitalization after MI significantly predicts all-cause mortality and arrhythmic mortality, and can be reliably used to identify patients who are at risk of dying after MI.