Initial Suppression Research Articles

Long-term outcomes of early initiated antiretroviral therapy in sub-Saharan children: a Cameroonian cohort study (ANRS-12140 Pediacam study, 2008\u20132013, Cameroon)

BackgroundIn most studies, the virological response is assessed during the first two years of antiretroviral treatment initiated in HIV-infected infants. However, early initiation of antiretroviral therapy exposes infants to very long-lasting treatment. Moreover, maintaining viral suppression in children is difficult. We aimed to assess the virologic response and mortality in HIV-infected children after five years of early initiated antiretroviral treatment (ART) and identify factors associated with virologic success in Cameroon.MethodsIn the ANRS-12140 Pediacam cohort study, 2008–2013, Cameroon, we included all the 149 children who were still alive after two years of early ART. Virologic response was assessed after 5 years of treatment. The probability of maintaining virologic success between two and five years of ART was estimated using Kaplan-Meier curve. The immune status and mortality were also studied at five years after ART initiation. Factors associated with a viral load < 400 copies/mL in children still alive at five years of ART were studied using logistic regressions.ResultsThe viral load after five years of early ART was suppressed in 66.8% (60.1–73.5) of the 144 children still alive and in care. Among the children with viral suppression after two years of ART, the probability of maintaining viral suppression after five years of ART was 64.0% (54.0–74.0). The only factor associated with viral suppression after five years of ART was achievement of confirmed virological success within the first two years of ART (OR = 2.7 (1.1–6.8); p = 0.033).ConclusionsThe probability of maintaining viral suppression between two and five years of early initiated ART which was quite low highlights the difficulty of parents to administer drugs daily to their children in sub-Saharan Africa. It also stressed the importance of initial viral suppression for achieving and maintaining virologic success in the long-term. Further studies should focus on identifying strategies that would enhance better retention in care and improved adherence to treatment within the first two years of ART early initiated in Sub-Saharan HIV-infected children.

17. Should we screen for Müllerian anomalies following diagnosis of congenital renal anomaly?

<h3>Background</h3> Despite the well-established embryological relationship in the development of renal and Müllerian structures, no guidelines exist regarding screening for Müllerian anomalies (MA) in the setting of a renal anomaly (RA). Delayed diagnosis of MA can have significant reproductive consequences. The primary outcome of this study is to evaluate the prevalence and types of MA associated with various RA. <h3>Methods</h3> This is a retrospective cohort study of females age 12-35 years with a diagnosis of RA, identified by ICD-10 codes, who were followed for care between 2013-2020. Data were collected on demographics, medical history, imaging studies, and clinical presentation. MA were characterized using the American Society for Reproductive Medicine classification system. Descriptive statistics were used to summarize the data. This study was IRB approved. <h3>Results</h3> Of 490 patients identified, 365 met inclusion criteria and 264 had pelvic imaging performed. In patients with ARM, 77% had MA. Excluding patients with ARM, MA were found in 67% of patients with unilateral renal agenesis, 25% with horseshoe or fused kidneys, 25% with pelvic or ectopic kidneys, and 23% with renal hypoplasia or dysplasia. Overall 129/264 (49%) were diagnosed with MA, including 18% Müllerian agenesis, 18% unicornuate uterus, 47% uterine didelphys, 12% bicornuate uterus, and 6% septate uterus. Fifty-two patients had Müllerian obstruction at the time of diagnosis, including 36 with obstructed hemivagina and ipsilateral renal agenesis. Forty-eight underwent urgent surgery, including 2 with pyocolpos, and 4 were treated with initial hormonal suppression. The average age of RA diagnosis was 4 years, compared to 18 years for MA (range 0-36 years for both). In 3 patients, MA was diagnosed prior to RA, and in 21 cases, both anomaly diagnoses were made simultaneously. The most common imaging modality performed was pelvic ultrasound (58%), often followed by magnetic resonance imaging (32%). Imaging was most commonly performed for abdominal pain or dysmenorrhea. In 15% of cases, pelvic ultrasounds were performed for obstetric reasons. Only 5% of patients had routine screening to evaluate pelvic anatomy; a quarter of whom were pre-pubertal. <h3>Conclusions</h3> Almost half of patients with congenital RA are eventually diagnosed with MA, of whom 40% have an obstructive anomaly. Screening for MA in patients with RA near the time of menarche can prevent delays in diagnosis that could have significant implications on reproductive health and quality of life.

Brief induction of loneliness decreases vagal regulation during social information processing

Perceived social isolation, or loneliness, has been repeatedly linked to numerous adverse health outcomes. Much effort has been directed towards elucidating the mechanisms underlying its effects on the cardiovascular system, which may explain the deleterious effects on morbidity and mortality. It has been previously suggested that perceived social isolation can impair effective parasympathetic regulation and physiological adjustment to the demands of the social environment. Thus, the present study aimed at investigating the causal impact of an induction of loneliness on vagal activity during social stimuli processing. In the study, participants (N = 119) were led to anticipate either a future filled with satisfying relationships (Future Belong) or a lonely life (Future Alone). Then, they were asked to complete an implicit emotion regulation task while their cardiovascular activity was recorded.In the Future Belong group, a pattern of vagal suppression was observed between the resting period and task completion, which was followed by vagal recovery during the post-task resting period. However, in the Future Alone group, a change from the baseline HRV was observed only at the beginning of the task, but not during its consecutive stages. Moreover, in participants who believed in the given FA feedback, the initial vagal suppression was absent. These findings provide evidence that even a brief induction of loneliness can result in a blunted vagal suppression during social information processing. It can be hypothesized that the lack of the ability to regulate vagal activity while processing social cues may potentially underlie problems with social engagement and self-control.

Atazanavir/ritonavir vs Efavirenz como primeira linha de tratamento em adultos vivendo com HIV

Introdução: Novos regimes de terapia antirretroviral (TARV) para HIV podem melhorar os resultados clínicos para os pacientes e de alterar a história natural da infecção. Os guidelines nacionais e internacionais recomendam atualmente a iniciar o tratamento dos indivíduos infectados para prevenir a deterioração do sistema imunológico e controlar a replicação viral, e consequente prevenção da transmissão da infecção pelo HIV. Objetivo: Analisar o uso da terapia antirretroviral que incluem Atazanavir/ritonavir (ATV/r) ou Efavirenz (EFV) na primeira linha de tratamento de pacientes adultos vivendo com HIV. Material e Métodos: O presente trabalho consiste em um estudo coorte retrospectivo. A coleta de dados ocorreu no período de agosto de 2019 a julho de 2020 e se concentrou no Serviço de Imunologia Clínica/Hospital-Dia do Instituto de Medicina Integral Prof. Fernando Figueira - IMIP. Os dados foram retirados dos prontuários selecionados de maneira aleatória e registrados em questionários padronizados com posterior transcrição em planilhas computadorizadas. O projeto foi aprovado pelo Comitê de Ética em Pesquisa em Seres Humanos (CEP) do IMIP/PE. Os dados foram transcritos no programa Excel, analisados no Epi Info™. Resultados: 131 pacientes participaram do estudo utilizando EFV ou ATV/r como terceira droga do esquema antirretroviral, sendo 73,3% pacientes EFV e 26,7% usando ATV/r. A supressão viral inicial foi observada em 88% (p &gt; 0,05) dos pacientes, independentemente do esquema utilizado. Esquemas contendo ATV/r apresentaram uma prevalência de 47,1% de efeitos adversos e EFV 52,1% (p &lt; 0,001). Conclusão: Os achados do desse estudo sugerem que tanto ATV/r quanto o EFV apresentaram efetividade semelhante quando utilizados como primeira linha de tratamento.

Weight Calculation of Risk Factors of Aircraft Hangar Fire Suppression System using AHP

Aircraft hangars are used to store and maintain aircraft. Although the frequency of fires in such hangars is low, the physical damage caused by a fire can be extremely large, and thus it is important to verify the reliability of an automatic fire suppression system. For intensive fire management, it is necessary to identify the risk factors of an automatic fire suppression system and calculate the weights for each factor. In this study, through a hierarchical analysis, fire risk factors of an automatic fire suppression system used in aircraft hangars were identified and the weights for each risk factor were calculated. As the analysis results indicate, the risk of failing in the initial fire suppression factor of foamhead fire suppression system was the highest among the 26 items considered and the calculated weight can be used as basic data necessary for a future quantitative fire risk assessment of an aircraft hangar fire suppression system.

Origins and History of the Minimal Model of Glucose Regulation.

It has long been hoped that our understanding of the pathogenesis of diabetes would be helped by the use of mathematical modeling. In 1979 Richard Bergman and Claudio Cobelli worked together to find a “minimal model” based upon experimental data from Bergman’s laboratory. Model was chosen as the simplest representation based upon physiology known at the time. The model itself is two quasi-linear differential equations; one representing insulin kinetics in plasma, and a second representing the effects of insulin and glucose itself on restoration of the glucose after perturbation by intravenous injection. Model would only be sufficient if it included a delay in insulin action; that is, insulin had to enter a remote compartment, which was interstitial fluid (ISF). Insulin suppressed endogenous glucose output (by liver) slowly. Delay proved to be due to initial suppression of lipolysis; resultant lowering of free fatty acids reduced liver glucose output. Modeling also demanded that normalization of glucose after injection included an effect of glucose itself on glucose disposal and endogenous glucose production – these effects were termed “glucose effectiveness.” Insulin sensitivity was calculated from fitting the model to intravenous glucose tolerance test data; the resulting insulin sensitivity index, SI, was validated with the glucose clamp method in human subjects. Model allowed us to examine the relationship between insulin sensitivity and insulin secretion. Relationship was described by a rectangular hyperbola, such that Insulin Secretion x Insulin Sensitivity = Disposition Index (DI). Latter term represents ability of the pancreatic beta-cells to compensate for insulin resistance due to factors such as obesity, pregnancy, or puberty. DI has a genetic basis, and predicts the onset of Type 2 diabetes. An additional factor was clearance of insulin by the liver. Clearance varies significantly among animal or human populations; using the model, clearance was shown to be lower in African Americans than Whites (adults and children), and may be a factor accounting for greater diabetes prevalence in African Americans. The research outlined in the manuscript emphasizes the powerful approach by which hypothesis testing, experimental studies, and mathematical modeling can work together to explain the pathogenesis of metabolic disease.

Stacked Inverse Probability of Censoring Weighted Bagging: A Case Study In the InfCareHIV Register

Abstract We propose an inverse probability of censoring weighted (IPCW) bagging (bootstrap aggregation) pre-processing that enables the application of any machine learning procedure for classification to be used to predict the cause-specific cumulative incidence, properly accounting for right-censored observations and competing risks. We consider the IPCW area under the time-dependent ROC curve (IPCW-AUC) as a performance evaluation metric. We also suggest a procedure to optimally stack predictions from any set of IPCW bagged methods. We illustrate our proposed method in the Swedish InfCareHIV register by predicting individuals for whom treatment will not maintain an undetectable viral load for at least 2 years following initial suppression. The R package stackBagg that implements our proposed method is available on Github.

Development of Initial Payload-sway Suppression Control for Overhead Crane

Development of Initial Payload-sway Suppression Control for Overhead Crane

비밀폐계에서 CO2 소화에 영향을 미치는 인자에 관한 연구 : 선박화재 사례에서

In the ship fire, the initial fire extinguishing is very important because evacuation space is limited. Large ships are equipped with various extinguishing devices such as portable and fixed extinguishing equipment. The CO2 extinguishing equipment which lowers the oxygen density is one of the devices used in the ship fires. In actually, when a lot of fires occur in the engine room of a ship, a CO2 extinguishing system is often used to extinguish the fire. However, there is a space in the ship that can not be sealed in a large space such as a cargo storage compartment. The fire often occur in cargo compartments. In general, it is understood that CO2 extinguishing must be used in sealed spaces to be effective. Almost studies on the effectiveness of CO2 extinguishing systems for ship fires have been conducted only in a completely closed system such as an engine room. At present, studies on the effectiveness of CO2 extinguishing when there is no closed system has been insufficient. If the initial suppression of the fire is not successful, the combustion will increase, making it difficult to identify the exact cause of the fire. It is important to identify the cause of all fires, but especially for ship fires, it is very important to extinguish the fire early in order to identify the cause of fire. Therefore, in this paper, we analyzed the factors affecting CO2 extinguishing in an unsealed space based on the case of ship fire and investigated the effectiveness of CO2 extinguishing by approximating actual fire cases.

Social Vulnerability among Foreign-Born Pregnant Women and Maternal Virologic Control of HIV.

The aim of this study was to assess whether social vulnerability among foreign-born pregnant women living with HIV is associated with maternal viremia during pregnancy. This retrospective cohort study included all foreign-born pregnant women living with HIV who received prenatal care in a multidisciplinary prenatal clinic between 2009 and 2018. A licensed clinical social worker evaluated all women and kept detailed clinical records on immigration status and social support. Social vulnerability was defined as both living in the United States for less than 5 years and reporting no family or friends for support. The primary outcome was evidence of viral non-suppression after achievement of initial suppression. Secondary outcomes were the proportion of women who required > 12 weeks after starting antiretroviral therapy to achieve viral suppression, median time to first viral suppression (in weeks) after initiation of antiretroviral therapy, and the proportion who missed ≥ 5 doses of antiretroviral therapy. Bivariable analyses were performed. A total of 111 foreign-born women were eligible for analysis, of whom 25 (23%) were classified as socially vulnerable. Social and clinical characteristics of women diverged by social vulnerability categorization but no differences reached statistical significance. On bivariable analysis, socially-vulnerable women were at increased risk for needing > 12 weeks to achieve viral suppression (relative risk: 1.78, 95% confidence interval: 1.18-2.67), though there was no association with missing ≥ 5 doses of antiretroviral therapy or median time to viral suppression after initiation of antiretroviral therapy. Among foreign-born, pregnant women living with HIV, markers of virologic control during pregnancy were noted to be worse among socially-vulnerable women. Insofar as maternal viremia is the predominant driver of perinatal transmission, closer clinical surveillance and support may be indicated in this population. · 23% of foreign-born pregnant women living with HIV were identified as socially vulnerable.. · Socially-vulnerable women were at higher risk for re-emergent viremia (24 vs. 7%, RR 3.44).. · Socially-vulnerable women were at higher risk for needing >12 weeks to become aviremic (64 vs. 36%, RR: 1.7)..

Absence of superconducting dome at the charge-density-wave quantum phase transition in 2H−NbSe2

Superconductivity is often found in a dome around quantum critical points, i.e. 2nd-order quantum phase transitions. Here, we show that an enhancement of superconductivity is avoided at the critical pressure of the charge-density-wave (CDW) state in NbSe$_2$. We present comprehensive high-pressure Hall effect and magnetic susceptibility measurements of the CDW and superconducting state in NbSe$_2$. Initially, the 2nd-order CDW transition is suppressed smoothly but it drops to zero abruptly at PCDW = 4.4 GPa thus indicating a change to 1st order whilstthe superconducting transition temperature Tc rises continuously up to PCDW but is constant above. The putative 1st-order nature of the CDW transition is suggested as the cause for the absence of a superconducting dome at PCDW. Indeed, we show that the suppression of the superconducting state at low pressures is due to the loss of density of states inside the CDW phase whilst the initial suppression of the CDW state is accounted for by the stiffening of the underlying bare phonon mode.

Prognostic value of nadir GH levels for long-term biochemical remission or recurrence in surgically treated acromegaly.

Outcome of acromegaly surgery is assessed by IGF-1 and glucose-suppressed GH, but whether the latter provides additional clinically relevant information when IGF-1 is normal is unclear. The role of GH suppression testing after surgery requires clarification. We studied 97 acromegaly patients with normal IGF-1 after surgery by measuring GH after oral glucose longitudinally, initially at ≥ 3months after surgery and repeated one or more times ≥ 1year later. Nadir GH was categorized as normal or abnormal relative to the 97.5th percentile of nadir GH in 100 healthy subjects, which were ≤ 0.14µg/L (DSL IRMA) or ≤ 0.15µg/L(IDS iSYS). Signs and symptoms scores and insulin resistance were followed longitudinally. Of 68 patients with initial normal GH suppression 63 (93%) remained in remission and of 29 with initial abnormal GH suppression, 9 (31%) recurred. Recurrence was more common in patients with abnormal suppression (P < 0.001). A total of 14 patients recurred, including 5 with normal GH suppression progressing to abnormal and then recurrence. Overall, serial signs and symptoms and insulin resistance assessments did not identify patients with abnormal suppression or recurrence. Risk of recurrence after surgery is increased for patients with a normal IGF-1 level, but abnormal GH suppression. We newly find, using both our and others' cut-offs, that while normal suppression predicts long-term remission in most patients, some can progress from normal to abnormal suppression and then recurrence after many years of follow up. Nadir GH levels are of prognostic value in acromegaly patients with normal IGF-1 levels after surgery.

Analysis of the strategy of LT4 prescribing and TSH monitoring for thyroid carcinoma after lobectomy.

BackgroundThyrotropin (TSH) suppression is a critical step in the management of differentiated thyroid carcinoma (DTC). The objectives of this study were to evaluate changes in TSH levels and a strategy of initial levothyroxine (LT4) supplementation for TSH suppression in low-risk differentiated thyroid carcinoma (lr-DTC) patients after lobectomy.MethodsOne hundred and ten patients with lr-DTC who received lobectomy were enrolled. Each of the patients was given 50 µg LT4 immediately after lobectomy and were retrospectively analyzed to evaluate the initial dose of LT4 suppression during the first year of follow-up. Risk factors influencing the TSH trend were also evaluated.ResultsMedian TSH levels decreased significantly after lobectomy and the initiation of LT4 suppression and were stable from 3 to 12 months. Three months after lobectomy, 44.9% of patients fell into the newly recommended first TSH goal (0.35 to 2.0 mIU/L). Insufficient suppression (≥2.0 mIU/L) and oversuppression (<0.35 mIU/L) was observed in 9.4% and 45.8% of the patients, respectively. Preoperative TSH ≥2.0 mIU/L and the coexistence of Hashimoto thyroiditis (HT) were risk factors influencing the TSH trend.ConclusionsThe monitoring of TSH could start from 3 months after lobectomy. An initial dose (50 µg) of LT4 could be adequate for initial suppression therapy in most patients. However, individual adjustment of the first dose may be necessary based on preoperative TSH concentration and the presence of HT.

DDIT4 Licenses Only Healthy Cells to Proliferate During Injury-induced Metaplasia

In stomach, metaplasia can arise from differentiated chief cells that become mitotic via paligenosis, a stepwise program. In paligenosis, mitosis initiation requires reactivation of the cellular energy hub mTORC1 after initial mTORC1 suppression by DNA damage induced transcript 4 (DDIT4 aka REDD1). Here, we use DDIT4-deficient mice and human cells to study how metaplasia increases tumorigenesis risk. A tissue microarray of human gastric tissue specimens was analyzed by immunohistochemistry for DDIT4. C57BL/6 mice were administered combinations of intraperitoneal injections of high-dose tamoxifen (TAM) to induce spasmolytic polypeptide-expressing metaplasia (SPEM) and rapamycin to block mTORC1 activity, and N-methyl-N-nitrosourea (MNU) in drinking water to induce spontaneous gastric tumors. Stomachs were analyzed for proliferation, DNA damage, and tumor formation. CRISPR/Cas9-generated DDIT4-/- and control human gastric cells were analyzed for growth invitro and in xenografts with and without 5-fluorouracil (5-FU) treatment. DDIT4 was expressed in normal gastric chief cells in mice and humans and decreased as chief cells became metaplastic. Paligenotic Ddit4-/- chief cells maintained constitutively high mTORC1, causing increased mitosis of metaplastic cells despite DNA damage. Lower DDIT4 expression correlated with longer survival of patients with gastric cancer. 5-FU-treated DDIT4-/- human gastric epithelial cells had significantly increased cells entering mitosis despite DNA damage and increased proliferation invitro and in xenografts. MNU-treated Ddit4-/- mice had increased spontaneous tumorigenesis after multiple rounds of paligenosis induced by TAM. During injury-induced metaplastic proliferation, failure of licensing mTORC1 reactivation correlates with increased proliferation of cells harboring DNA damage, as well as increased tumor formation and growth in mice and humans.

Mass Events Trigger Malta's Second Peak After Initial Successful Pandemic Suppression.

The second COVID-19 wave is sweeping the globe as restrictions are lifted. Malta, the ‘poster child of Europe’s COVID-19 first wave success’ also fell victim shortly after it welcomed the first tourists on 1st of July 2020. Only four positive cases were reported over the successive 15 days. Stability was disrupted when two major mass events were organized despite various health professional warnings. In a matter of few just days, daily cases rose to two-digit figures, with high community transmission, a drastic rise in active cases, and a rate per hundred thousand in Europe second only to Spain. Frontliners were swamped with swabbing requests while trying to sustain robust case management, contact tracing and follow-up. Indeed, the number of hospitalizations and the need for intensive ventilation increased. Despite the initial cases were among young adults, within weeks a small spill off on the more elderly population was observed. Restrictions were re-introduced including mandatory mask wearing in specific locations and capping of the total number of people in a single gathering. Malta is an island and the potential for containment would have been relatively simple and effective and permitting mass gatherings was unwise. Protecting the health of the population should take centre stage while carrying out extensive testing, contact tracing and surveillance. Containment and mitigation along with public cooperation is the key to curbing resurgences especially with the influenza season around the corner.

The relative contributions of HIV drug resistance, nonadherence and low-level viremia to viremic episodes on antiretroviral therapy in sub-Saharan Africa.

To achieve viral suppression among more than 90% of people on antiretroviral therapy (ART), improved understanding is warranted of the modifiable causes of HIV viremic episodes. We assessed the relative contributions of drug-resistance, nonadherence and low-level viremia (LLV) (viral load 50-999 cps/ml) on viremic episodes in sub-Saharan Africa. In a multicountry adult cohort initiating nonnucleoside reverse transcriptase inhibitor-based first-line ART, viremic episodes (viral load ≥1000 cps/ml) were classified as first, viral nonsuppression at 12 months; second, virological rebound at 24 months (after initial viral suppression at 12 months); third, failure to achieve viral resuppression at 24 months (after viremic episode at 12 months). We used adjusted odds ratios from multivariable logistic regression to estimate attributable fractions for each risk factor. Of 2737 cohort participants, 1935 had data on pretreatment drug resistance (PDR) and at least 1 viral load outcome. Viral nonsuppression episodes [173/1935 (8.9%)] were attributable to nonadherence in 30% (35% in men vs. 24% in women) and to PDR to nonnucleoside reverse transcriptase inhibitors in 10% (15% in women vs. 6% in men). Notably, at contemporary PDR prevalences of 10-25%, PDR would explain 13-30% of viral nonsuppression. Virological rebound episodes [96/1515 (6.3%)] were mostly attributable to LLV (29%) and nonadherence (14%), and only rarely to PDR (1.1%). Failures to achieve viral resuppression [66/81 (81.5%)] were mostly attributable to the presence of acquired drug resistance (34%) and only rarely to nonadherence (2.4%). Effective adherence interventions could substantially reduce viral nonsuppression (especially in men) and virological rebound (especially during LLV), but would have limited effect on improving viral resuppression. Alternative ART regimens could circumvent PDR and acquired resistance.

Pharmacodynamic evaluation of intermittent versus extended and continuous infusions of piperacillin/tazobactam in a hollow-fibre infection model against Klebsiella pneumoniae.

To compare bacterial killing and the emergence of resistance to piperacillin/tazobactam, administered by intermittent versus prolonged infusion (i.e. extended or continuous), for ceftriaxone-resistant Klebsiella pneumoniae clinical isolates in an in vitro dynamic hollow-fibre infection model (HFIM). K. pneumoniae 68 (Kp68; MIC = 8 mg/L, producing SHV-106 and DHA-1) and K. pneumoniae 69 (Kp69; MIC = 1 mg/L, producing CTX-M-14) were studied in the HFIM over 7 days (initial inoculum ~107 cfu/mL). Six piperacillin/tazobactam dosing regimens for Kp68 (4/0.5 g 8 hourly as 0.5 and 4 h infusions, 12/1.5 g/24 h continuous infusion, 4/0.5 g 6 hourly as 0.5 and 3 h infusions and 16/2 g/24 h continuous infusion) and three piperacillin/tazobactam dosing regimens for Kp69 (4/0.5 g 8 hourly as 0.5 and 4 h infusions and 12/1.5 g/24 h continuous infusion) were simulated (piperacillin clearance = 14 L/h, creatinine clearance = 100 mL/min). Total and resistant populations and MICs were quantified/determined. For Kp68, all simulated dosing regimens exhibited approximately 4 log10 of bacterial killing at 8 h followed by regrowth to approximately 1011 cfu/mL within 24 h. The MICs for resistant subpopulations exceeded 256 mg/L at 72 h. Similarly, for Kp69, all simulated dosing regimens exhibited approximately 4 log10 of bacterial killing over 8 h; however, only the continuous infusion prevented bacterial regrowth. Compared with intermittent infusion, prolonged infusion did not increase initial bacterial killing and suppression of regrowth of plasmid-mediated AmpC- and ESBL-producing K. pneumoniae. However, continuous infusion may suppress regrowth of some ESBL-producing susceptible K. pneumoniae, although more data are warranted to confirm this observation.

P1115Cardiac SABR for ventricular tachycardia - initial UK experience

Abstract OnBehalf United Kingdom Cardiac SABR consortium Background Stereotactic Ablative Body Radiotherapy (SABR) is a novel non-invasive treatment for Ventricular Tachycardia (VT) refractory to standard catheter ablation. 3 UK hospitals have started compassionate use cardiac SABR programmes, and are working in close collaboration. Purpose To report initial UK experience for treatment of refractory VT with cardiac SABR. Methods All patients had undergone prior unsuccessful invasive ablation with VT recurrence despite anti-arrhythmic drug (AAD) use. High-resolution CT imaging with 3D reconstruction was combined with 12 lead ECGs of VT and prior invasive +/- non-invasive electrophysiology mapping data to define a cardiac target. Treatment margins were modified to account for cardiac/respiratory motion and to minimise off target treatment to other organs as per clinical SABR practice. Single fraction high dose treatment (20-25 Gy) was delivered by CT guided Linear Accelerator. Patients were assessed regularly with clinical review and remote device monitoring. Results 3 patients have been treated so far with aetiologies of prior myocarditis, non-ischaemic dilated cardiomyopathy and ischaemic cardiomyopathy. All patients successfully received planned SABR treatment in &amp;lt;1 hour with no peri-procedural complications. Current follow up is to 4 months. Clinical course was variable – patient 1 had a flare of VT post-SABR requiring temporary escalation of AADs before VT was suppressed, patient 2 had initial suppression of VT but died from decompensated heart failure with further VT after 4 weeks, patient 3 had further VT with a different exit site and underwent repeat invasive ablation and escalated AAD use to achieve VT suppression. Conclusions Cardiac SABR shows promise for VT control, but further experience and trials are needed. Integration of imaging and electrophysiology data to generate accurate targets appears critical. The effect of SABR seems to develop over several weeks after therapy. Patient selection and timing of SABR delivery is important with acknowledgement that competing causes of death exist in patients with refractory VT entering a compassionate use program. Abstract Figure. Example SBRT plan

Diminished hepatic IFN response following HCV clearance triggers HBV reactivation in coinfection.

In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we studied the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon (IFN) signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV superinfection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic IFN response. Using blood samples of coinfected patients, IFN-stimulated gene products including C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic IFN response following HCV clearance and identify serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV-coinfected persons.

Soil Microbes Trade-Off Biogeochemical Cycling for Stress Tolerance Traits in Response to Year-Round Climate Change.

Winter air temperatures are rising faster than summer air temperatures in high-latitude forests, increasing the frequency of soil freeze/thaw events in winter. To determine how climate warming and soil freeze/thaw cycles affect soil microbial communities and the ecosystem processes they drive, we leveraged the Climate Change across Seasons Experiment (CCASE) at the Hubbard Brook Experimental Forest in the northeastern United States, where replicate field plots receive one of three climate treatments: warming (+5°C above ambient in the growing season), warming in the growing season + winter freeze/thaw cycles (+5°C above ambient +4 freeze/thaw cycles during winter), and no treatment. Soil samples were taken from plots at six time points throughout the growing season and subjected to amplicon (rDNA) and metagenome sequencing. We found that soil fungal and bacterial community composition were affected by changes in soil temperature, where the taxonomic composition of microbial communities shifted more with the combination of growing-season warming and increased frequency of soil freeze/thaw cycles in winter than with warming alone. Warming increased the relative abundance of brown rot fungi and plant pathogens but decreased that of arbuscular mycorrhizal fungi, all of which recovered under combined growing-season warming and soil freeze/thaw cycles in winter. The abundance of animal parasites increased significantly under combined warming and freeze/thaw cycles. We also found that warming and soil freeze/thaw cycles suppressed bacterial taxa with the genetic potential for carbon (i.e., cellulose) decomposition and soil nitrogen cycling, such as N fixation and the final steps of denitrification. These new soil communities had higher genetic capacity for stress tolerance and lower genetic capacity to grow or reproduce, relative to the communities exposed to warming in the growing season alone. Our observations suggest that initial suppression of biogeochemical cycling with year-round climate change may be linked to the emergence of taxa that trade-off growth for stress tolerance traits.