Hepatitis C and cigarette smoking behavior: Themes from focus groups.

INTRODUCTION: People with chronic hepatitis C virus (HCV; PWHC) use cigarettes at a much higher prevalence than other individuals, and smoking can exacerbate the harms specifically related to HCV (e.g., hepatocellular carcinoma). Little is known about factors related to cigarette use among PWHC. This study examined focus group data to explore beliefs and behaviors related to cigarette use among PWHC. METHODS: Qualitative data from two focus groups of PWHC reporting current cigarette smoking (n=15, 60% male) were collected using a semi-structured interview guide. Participants were asked about reasons for smoking, barriers to quitting smoking, and the relationship of HCV to smoking. Focus groups were transcribed verbatim and coded in NVivo 12. Four coders examined themes that arose in the focus groups. Common themes are described and supported with quotes. RESULTS: Reasons for smoking included addiction to cigarettes, stress, substituting cigarettes for other drugs, and social norms, while reasons for quitting included health and being free from the use of all drugs. Barriers to quitting included concerns about coping with stress, weight gain, and having a lack of support for and education about quitting. Many participants believed there was a link between smoking and HCV and discussed smoking in relation to the stress of an HCV diagnosis. CONCLUSIONS: Participants identified both HCV-related and non-HCV-related aspects of cigarette smoking and cessation-related behaviors that could be targeted in cessation treatment. More research is needed to identify the best treatment approaches that reduce the significant medical consequences of cigarette use among PWHC. IMPLICATIONS: People with chronic hepatitis C virus (HCV; PWHC) smoke cigarettes at a high prevalence, yet little is known about their smoking behaviors. Moreover, there are no cessation treatments targeting PWHC. This is the first study to collect focus group data from PWHC who smoke in order to identify reasons for cigarette use (HCV-related and non-HCV-related), and motivators and barriers to quitting cigarettes. PWHC report using cigarettes to cope with the stress of an HCV diagnosis and to celebrate HCV cure. These findings suggest there are specific times during the HCV care continuum where providers can aid with cessation efforts.

Second-Phase Hepatitis C Plasma Viral Kinetics Directly Reflects Reduced Intrahepatic Burden of Hepatitis C Virus.

BACKGROUND: Mathematical models explain how antivirals control viral infections. Hepatitis C virus (HCV) treatment results in at least 2 phases of decline in viremia. The first phase reflects clearance of rapidly produced virions. The second phase is hypothesized to derive from loss of infected cells but has been challenging to prove. METHODS: Using single-cell methods, we quantified the number of hepatitis C virus (HCV)-infected hepatocytes in liver biopsies taken before and within 7 days of initiating direct-acting antivirals (DAAs) in a double-blinded randomized controlled trial testing 2 (sofosbuvir-velpatasvir) versus 3 (sofosbuvir-velpatasvir-voxilaprevir) DAAs. RESULTS: We employed thousands of intrahepatic measurements in 10 persons with chronic genotype 1a HCV infection: median proportion of infected hepatocytes declined from 11.3% (range, 1.3%-59%) to 0.6% (range, <0.3%-5.8%), a loss of 75%-95% infected hepatocytes. Plasma viremia correlated with numbers of HCV-infected hepatocytes (r = 0.77; P < .0001). Second-phase plasma dynamics and changes in infected hepatocytes were indistinct (P = .16), demonstrating that second-phase viral dynamics derive from loss of infected cells. DAAs led to a decline in intracellular HCV RNA and interferon-stimulated gene expression (P < .05 for both). CONCLUSIONS: We proved that second-phase viral dynamics reflect decay of intrahepatic burden of HCV, partly due to clearance of HCV RNA from hepatocytes. CLINICAL TRIALS REGISTRATION: NCT02938013.

Nonadherence to Ledipasvir/Sofosbuvir Did Not Predict Sustained Virologic Response in a Randomized Controlled Trial of Human Immunodeficiency Virus/Hepatitis C Virus Coinfected Persons Who Use Drugs.

BACKGROUND: Eliminating hepatitis C virus (HCV) will require effective treatment delivery to persons with substance use disorders (SUDs). We evaluated the relationship between ledipasvir/sofosbuvir treatment persistence (receiving 84 tablets), adherence, and sustained virologic response (SVR) in persons with human immunodeficiency virus (HIV)/HCV coinfection. METHODS: Of the 144 participants with HIV/HCV and SUDs, 110 initiated a 12-week treatment course under 1 of 3 conditions (usual care, peer mentors, and cash incentives). We used self-report, pharmacy pill counts, and expected date of refill to examine adherence. Persistent participants were categorized as high adherence (taking ≥90% of doses) or low adherence (taking <90% of doses). RESULTS: Most participants persisted on treatment after initiation (n = 105), with 95% (n = 100) achieving SVR. One third (34%) of participants had moderate/heavy alcohol use by the biomarker phosphatidylethanol ([Peth] ≥50 ng/mL), and 44% had urine toxicology positive for cocaine or heroin at enrollment. The proportion of persons with high adherence was 72% (n = 76), and the proportion of persons with low adherence was 28%. Although low adherence was associated with moderate/heavy alcohol use by PEth (relative risk = 2.77; 95% confidence interval, 1.50-5.12), SVR did not vary according to adherence (P = .702), and most participants (97%) with low adherence achieved SVR. CONCLUSIONS: Treatment persistence led to high SVR rates among persons with HIV/HCV, despite imperfect adherence and SUDs.

Breast MRI during Neoadjuvant Chemotherapy: Lack of Background Parenchymal Enhancement Suppression and Inferior Treatment Response.

Background Suppression of background parenchymal enhancement (BPE) is commonly observed after neoadjuvant chemotherapy (NAC) at contrast-enhanced breast MRI. It was hypothesized that nonsuppressed BPE may be associated with inferior response to NAC. Purpose To investigate the relationship between lack of BPE suppression and pathologic response. Materials and Methods A retrospective review was performed for women with menopausal status data who were treated for breast cancer by one of 10 drug arms (standard NAC with or without experimental agents) between May 2010 and November 2016 in the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2, or I-SPY 2 TRIAL (NCT01042379). Patients underwent MRI at four points: before treatment (T0), early treatment (T1), interregimen (T2), and before surgery (T3). BPE was quantitatively measured by using automated fibroglandular tissue segmentation. To test the hypothesis effectively, a subset of examinations with BPE with high-quality segmentation was selected. BPE change from T0 was defined as suppressed or nonsuppressed for each point. The Fisher exact test and the Z tests of proportions with Yates continuity correction were used to examine the relationship between BPE suppression and pathologic complete response (pCR) in hormone receptor (HR)-positive and HR-negative cohorts. Results A total of 3528 MRI scans from 882 patients (mean age, 48 years ± 10 [standard deviation]) were reviewed and the subset of patients with high-quality BPE segmentation was determined (T1, 433 patients; T2, 396 patients; T3, 380 patients). In the HR-positive cohort, an association between lack of BPE suppression and lower pCR rate was detected at T2 (nonsuppressed vs suppressed, 11.8% [six of 51] vs 28.9% [50 of 173]; difference, 17.1% [95% CI: 4.7, 29.5]; P = .02) and T3 (nonsuppressed vs suppressed, 5.3% [two of 38] vs 27.4% [48 of 175]; difference, 22.2% [95% CI: 10.9, 33.5]; P = .003). In the HR-negative cohort, patients with nonsuppressed BPE had lower estimated pCR rate at all points, but the P values for the association were all greater than .05. Conclusions In hormone receptor-positive breast cancer, lack of background parenchymal enhancement suppression may indicate inferior treatment response. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Philpotts in this issue.

Prevalence and Correlates of Syringe Disposal Box Use in a Philadelphia Neighborhood with High Levels of Public Drug Injection.

Background: Philadelphia (Pennsylvania, USA) is facing an unprecedented public health crisis due to fentanyl use. To combat drug-related litter, the Philadelphia Department of Public Health installed 7 public syringe disposal boxes (SDB) in Kensington, the neighborhood most impacted by the opioid crisis and home to a syringe exchange. Methods: We used street- and business-intercepts to recruit residents (N=358) and business owners/staff (N=78) who completed a brief survey with two binary items measuring observing and using SDB. Multivariable logistic regression was used to assess factors independently associated with SDB observance and use. Results: 78% (340/436) observed SDB and 34.1% (116/340) had ever used SDB among those who had seen them. Unstably housed persons had 4.3 times greater odds of observing SDB (Adjusted odds ratio [aOR= 4.29; 95% confidence interval [CI]: 1.56, 11.82) and had 2.5 times greater odds of using SDB (aOR = 2.51; 95% CI: 1.33, 4.74) as did people who use opioids (aOR = 2.61; 95% CI: 1.45, 4.72). Among individuals reporting opioid use who also saw SDB (n=123), those who were unstably housed were more likely to use SDB than those with stable housing (67.8% vs 45.3%, p=.012). Conclusion: These results suggest Kensington residents, especially those who are unstably housed, use SDB once they see them in the neighborhood.

Network-based recruitment of people who inject drugs for hepatitis C testing and linkage to care.

Although oral direct-acting agent (DAA) therapies have the potential to reduce the burden of hepatitis C virus (HCV) infection, treatment uptake remains low, particularly among people who inject drugs (PWID). This study examined the feasibility of an innovative peer-based recruitment strategy to engage PWID in HCV testing and treatment. We interviewed an initial set of HCV antibody-positive PWID as 'primary indexes' to gather demographic, drug use, health information and drug network characteristics. Primary indexes were then briefly educated on HCV and its treatment and encouraged to recruit their injection drug 'network members' for HCV testing and linkage to care. Eligible network members were enrolled as 'secondary indexes' and completed the same index study procedures. In sum, 17 of 36 primary indexes initiated the recruitment of 64 network members who were HCV antibody positive and eligible to become indexes. In multivariable analysis, successful recruitment of at least one network member was positively associated with prior HCV treatment (OR 2.80; CI [1.01, 7.72]), daily or more injection drug use (OR 2.38; CI [1.04, 5.47]), and a higher number of injection drug network members (OR 1.20; CI [1.01, 1.42]). Among the 69 participants with chronic HCV not previously linked to HCV care at enrolment, 91% (n = 63) completed a linkage to HCV care appointment, 45% (n = 31) scheduled an appointment with an HCV provider, and 20% (n = 14) initiated HCV therapy. These findings suggest a potential benefit for peer-driven, network-based interventions focused on HCV treatment-experienced PWID as a mechanism to increase HCV linkage to care.

Unreported alcohol use was common but did not impact hepatitis C cure in HIV-infected persons who use drugs.

We investigated the prevalence and impact of heavy alcohol use on the hepatitis C virus (HCV) care continuum amongst HIV/HCV co-infected persons who use drugs. In the CHAMPS study, 144 HIV/HCV co-infected persons were randomized to contingent cash incentives, peer mentors and usual care to evaluate the impact on HCV care. Alcohol use was ascertained using the 10-item AUDIT (hazardous: male ≥8, female ≥4) and phosphatidylethanol (PEth) (heavy: ≥50 ng/mL), an alcohol biomarker. Log binomial regression was used to evaluate the association between heavy alcohol use and failure to initiate treatment and to achieve sustained virologic response (SVR). Of the 135 participants with PEth data, median age was 55 years, 59% were male, 92% were Black, 91% reported a history of drug use, and 97% were on antiretroviral therapy. Hazardous drinking was reported on AUDIT by 28% of participants, and 35% had heavy alcohol use by PEth. Of the 47 individuals with a PEth ≥50 ng/mL, 23 (49%) reported no or minimal alcohol use by AUDIT. HCV treatment was initiated in 103 of 135 participants, and SVR was achieved in 92%. PEth ≥50 ng/mL (Relative Risk [RR] 0.72, 95% CI 0.35-1.48) was not significantly associated with failure to initiate HCV treatment or failure to achieve SVR (RR 0.85, 95% CI 0.46-1.57).In conclusion, alcohol use was common and frequently not detected by self-report. However, heavy alcohol use, even when measured objectively, was not associated with failure to initiate HCV treatment or to achieve cure.

Can Slot-Machine Reward Schedules Induce Gambling Addiction in Rats?

Similar to drugs of abuse, random-ratio reward schedules are highly motivating and, in humans, are thought to foster gambling addiction. Animal gambling models, however, have not yet demonstrated the compulsivity so characteristic of drug addiction. Three criteria have been used to evaluate addiction-like behavior in drug models: (1) response inhibition when reward is not available, (2) persistence under a progressive ratio schedule, in which the response-to-reward ratio is stretched, and (3) persistence in spite of punishment. We tested whether prolonged exposure (6 weeks) to a gambling-like reward schedule would induce addiction-like symptoms in rats. In two studies, separate groups were trained to respond to either random- or fixed-ratio schedules for food reward. We found that rats trained on random-ratio schedules showed higher response rates and dramatically shorter pauses after rewards. Tests of addiction-like behavior, however, were largely negative. Response rates were not different during cued no-reward periods nor when reward was coupled with punishment. We also found no group differences when food was devalued nor in reinstatement of reward-seeking after a 1-week delay. The sole exception to this pattern was that rats in the second experiment showed greater persistence on a progressive ratio test. After experiment two, subjects were also orally administered pramipexole, which caused increased perseveration during progressive ratio testing, especially in the random ratio group. While, it is possible that longer training or more appetitive rewards might have led to addiction-like behavior, our results, on the surface, suggest that random-ratio schedules are motivating but not addictive.

Biopsy versus conservative management of sonographically benign-appearing solid breast masses in adolescents.

OBJECTIVES: To determine whether the size of palpable solid breast masses in adolescents at initial sonography and their growth at follow-up sonography could be used to decide between conservative management and tissue biopsy. METHODS: This retrospective study included 37 adolescent female patients with 45 palpable benign-appearing solid breast masses on initial sonography. They were grouped as follows: group I, masses undergoing follow-up sonography with subsequent biopsy (n = 9); group II, masses undergoing biopsy without follow-up sonography (n = 13); and group III, masses undergoing follow-up sonography without biopsy (n = 23). The largest dimension, volume, volume change per month, and change in the sonographic appearance were analyzed to predict the need for biopsy. A combination of a largest dimension greater than 3 cm and volume change per month greater than 16% was used to assess the need for biopsy. Sonograms of 22 masses were correlated with histopathologic diagnoses. RESULTS: None of the masses that underwent follow-up sonography showed changes in their sonographic appearance. All masses that underwent biopsy were benign on histopathologic analysis. There was no significant difference in the largest dimension among the groups at initial sonography or between groups I and III at follow-up sonography. The volume change was smaller for fibroadenomas (n = 7; mean, 22.67%) than benign phyllodes tumors (n = 2; mean, 45.30%) in group I, but the difference was not significant (P = .384). However, the volume change for groups I and III showed a significant difference (P = .026). Neither size greater than 3 cm nor volume change greater than 16% predicted pathologic outcomes. CONCLUSIONS: If the combined criteria for assessing benignity of palpable breast masses had been used, biopsy could have been reduced by 89% in group I and deemed not necessary in 96% of group III breast masses.

Changes in Inflammatory Cytokines After Chronic Hepatitis C Treatment Among People Living With HIV.

We aimed to evaluate the effect of hepatitis C virus cure on serum inflammatory markers among people with HIV. Among 127 people with HIV, serum alanine aminotransferase, soluble tumor necrosis factor receptor 1, and inflammatory index score were significantly lower at the 24-week time point in patients who achieved sustained virologic response as compared with those who did not.

Loneliness and fearfulness are associated with non-fatal drug overdose among people who inject drugs.

BACKGROUND: People who inject drugs (PWID) experience high rates of drug overdose death with the risk of mortality increasing after each non-fatal event. Racial differences exist in drug overdose rates, with higher rates among Black people who use drugs. Psychological factors may predict drug overdose. METHODS: Cross-sectional data from a survey administered to PWID in Baltimore, MD enrolled in a social network-based intervention were analyzed. Linear regression methods with generalized estimating equations were used to analyze data from indexes and network members to assess for psychological factors significantly associated with self-reported number of lifetime drug overdoses. Factors associated with number of overdoses were assessed separately by race. RESULTS: Among 111 PWID enrolled between January 2018 and January 2019, 25.2% were female, 65.7% were Black, 98.2% reported use of substances in addition to opioids, and the mean age was 49.0 ± 8.3 years. Seventy-five individuals (67.6%) had a history of any overdose with a mean of 5.0 ± 9.7 lifetime overdoses reported. Reports of feeling fearful (ß = 9.74, P = 0.001) or feeling lonely all of the time (ß = 5.62, P = 0.033) were independently associated with number of drug overdoses. In analyses disaggregated by race, only the most severe degree of fearfulness or loneliness was associated with overdose among Black participants, whereas among White participants, any degree of fearfulness or loneliness was associated with overdose. CONCLUSIONS: In this study of PWID loneliness and fearfulness were significantly related to the number of reported overdose events. These factors could be targeted in future interventions.

Impact of reduced restrictions on buprenorphine prescribing during COVID-19 among patients in a community-based treatment program.

Background: Medications such as buprenorphine are considered the gold standard for the treatment of opioid use disorders. This study aimed to determine whether less restrictive buprenorphine prescribing practices during the COVID-19 pandemic impacted retention in and adherence to buprenorphine among patients accessing treatment from 2018-2020 at a community-based syringe services program. Methods: In this retrospective cohort study, we compared retention in treatment before and during the COVID-19 pandemic. Then, with relaxed restrictions acting as the intervention in a natural experiment, we conducted a sub-analysis of "continuity participants" who accessed treatment services both before and during the COVID-19 period. Records of 418 historical control patients treated with buprenorphine before COVID-19 were compared to 88 patients enrolled during COVID-19 (n=43 remote telemedicine and n=45 remote provider with patient on-site). Cox proportional hazards regressions were used to assess risk factors for treatment discontinuation. The sub-analysis used proportion of days covered (PDC) differences before and during COVID-19 (n=164) for a paired analysis in a nonparametric bootstrap test. Results: The risk of discontinuation was 71% lower in those accessing remote telemedicine during COVID-19 (HR=0.29; CI: 0.18, 0.47) and 51% lower in those accessing their remote provider onsite during COVID-19 (HR=0.49; CI:0.31, 0.77), compared to the historical control group. The average PDC did not significantly differ before and during COVID-19 (difference=2.4%; CI:-0.6%, 5.3%). Conclusions: The risk of discontinuing treatment was lower in both COVID-19 treatment groups compared to historical controls. Less restrictive buprenorphine prescribing guidelines during COVID-19 led to improved retention in care over 6-months.

Validation of a tool to assess effectiveness of peer-recruitment for hepatitis C testing and linkage to care among people who inject drugs.

OBJECTIVE: People who inject drugs (PWID) have high hepatitis C virus (HCV) infection prevalence but low rates of HCV treatment uptake. To better harness the potential of peer-led social network-based interventions to increase HCV treatment uptake among PWID, simple tools that can help identify individuals with the potential to function effectively as peer-mentors who support network members to get HCV tested and linked to care are needed. METHODS: Data from a survey administered to index PWID enrolled in a social network-based intervention, in which they were invited to recruit drug use network members for HCV testing and linkage to care, was analyzed. Constructs derived from exploratory factor analysis were validated through confirmatory factor analysis (CFA). We used logistic regression analysis to assess the association between scores in identified constructs and subsequent effectiveness in the peer mentor role, defined as recruiting at least one network member for HCV testing and linkage to care in the 12 weeks following survey completion. RESULTS: Among 100 PWID with median age 53 years, 74% male, and 71% Black, CFA resulted in a multidimensional three-factor survey with 4 questions related to opinion leadership, 3 questions related to perceived HCV-related stigma, and 3 questions related to HCV communication comfort and care support willingness. Only self-designated opinion leadership was associated with effectiveness in the peer mentor role (adjusted odds ratio 3.76 (95% Confidence interval CI 1.01, 14.0)). CONCLUSION: We developed and validated a simple tool with potential to ease and improve the efficiency of peer-led social network interventions.

Meaningful learning actualized through a perinatal continuity of care experience.

Leaders in nursing education embrace innovative, real-world learning environments that transform today's generation of nursing students into critical thinkers. Scheduling exclusive child-bearing practicums are challenging due to staffing, time, and maternal client presentation. Utilizing transformative learning theory a perinatal continuum of care clinical learning experience evolved. This paper will discuss the qualitative, descriptive study of Bachelor of Science in Nursing students in rural, Midwestern United States who completed maternal/infant didactic, high-fidelity simulation, and real-world experiences relative to women during the perinatal period. Participants (n = 50) consisted of third-semester baccalaureate nursing students enrolled in the maternal/infant course. Data were collected from students' reflective journal blogs at the end of the semester. The aim of this study was to identify the outcomes of students learning through this perinatal experience. Three themes emerged from this study: self-analysis, critical thinking, and self-efficacy. Students' reflection indicated that through this comprehensive clinical experience, they developed a new self-awareness. Students noted that the experience was unique to any they had encountered. The perinatal assignment provided an opportunity for professional growth in this specialty area due to the interface of theory, simulation, and clinical applications expounded in the reflective clinical blog throughout the experience.

Perceptions of network based recruitment for hepatitis C testing and treatment among persons who inject drugs: a qualitative exploration.

BACKGROUND: Social network interventions that take advantage of existing individual and group relationships may help overcome the significant patient, provider, and system level barriers that contribute to low hepatitis C Virus (HCV) treatment uptake among people who inject drugs (PWID). METHODS: We conducted semi-structured interviews with 20 HCV antibody positive PWID (15 male, 5 female) in Baltimore, Maryland, USA. We utilized thematic analysis and employed both inductive and deductive coding techniques to assess perceptions of barriers and facilitators of social network interventions for HCV testing, linkage to care, and treatment among PWID. RESULTS: PWID perceived a high prevalence of HCV within their social networks, especially within injection drug use networks. Overwhelmingly, participants reported a willingness to discuss HCV and provide informational, instrumental, and emotional support to their network members. Support included sharing knowledge, such as where and how to access HCV care, as well as sharing lived experiences about HCV treatment that could help peers build trust within networks. Participants who were already linked into HCV care had an increased understanding of using social network interventions to provide peer navigation, by accompanying network members to HCV related appointments. Across interviews, drug use related stigma and feeling undeserving of HCV treatment due to previous negative experiences accessing the health care system emerged as a major barrier to linkage to HCV treatment and cure. Undeservingness was often internalized and projected onto network members. To overcome this, participants supported access to low-barrier HCV treatment in alternative locations such as community-based or mobile clinics and drug treatment centers. CONCLUSION: Social network based interventions have potential to increase HCV treatment uptake among PWID. To be successful, these interventions will need to train peers to share accurate information and personal experiences with HCV testing and treatment and enhance their ability to provide support to network members who face significant stigma related to both HCV and drug use.

Impact of Co-occurring Drug Use, Hazardous Alcohol Use, and Mental Health Disorders on Drug Use Patterns in People With HIV and Hepatitis C Virus Infection.

Drug use, hazardous alcohol use, and mental health disorders are prevalent among people with HIV and hepatitis C virus (HCV) infection. Co-occurrence of alcohol use and depression negatively impacts substance use patterns. Nevertheless, HCV treatment provides a promising opportunity to identify and address co-occurring drug use, hazardous alcohol use, and mental health disorders.

The real world impact of adalimumab on quality of life and the physical and psychological effects of moderate-to-severe psoriasis: a UK prospective, multicenter, observational study.

Psoriasis can adversely affect quality of life (QoL) and emotional well-being. In this UK prospective observational study we evaluated the 'real-world' impact of adalimumab on QoL and the physical/psychological effects of moderate-to-severe psoriasis. Hundred and forty-three biologic-naïve patients with moderate-to-severe psoriasis, receiving adalimumab in clinical practice, were included. Patients completed a series of questionnaires at baseline (adalimumab initiation), 4 and 16-weeks and 6-months post-adalimumab initiation during routine visits. The main outcome measure was the proportion of Dermatology Life Quality Index (DLQI) 'responders' at 16 weeks, defined as ≥5 point reduction from baseline or DLQI = 0.90% (95% CI = 80.8%-94.6%) of evaluable patients were DLQI responders at 16-weeks. There were significant improvements at 16 weeks in patient-reported measures of QoL, mental and physical well-being, cutaneous body image, anxiety, depression and psoriasis severity, which were maintained at 6-months. Adalimumab treatment was associated with improvements in patients' QoL and psychological functioning, which occurred contemporaneously with improvements in cutaneous disease.

Single hepatocytes show persistence and transcriptional inactivity of hepatitis B.

There is no cure for the more than 270 million people chronically infected with HBV. Nucleos(t)ide analogs (NUCs), the mainstay of anti-HBV treatment, block HBV reverse transcription. NUCs do not eliminate the intranuclear covalently closed circular DNA (cccDNA), from which viral RNAs, including pregenomic RNA (pgRNA), are transcribed. A key gap in designing a cure is understanding how NUCs affect HBV replication and transcription because serum markers yield an incomplete view of intrahepatic HBV. We applied single-cell laser capture microdissection and droplet digital PCR to paired liver biopsies collected from 5 HBV/HIV-coinfected persons who took NUCs over 2-4 years. From biopsy 1 to 2, proportions of HBV-infected hepatocytes declined with adherence to NUC treatment (P < 0.05); we extrapolated that eradication of HBV will take over 10 decades with NUCs in these participants. In individual hepatocytes, pgRNA levels diminished 28- to 73-fold during NUC treatment, corresponding with decreased tissue HBV core antigen staining (P < 0.01). In 4 out of 5 participants, hepatocytes with cccDNA but undetectable pgRNA (transcriptionally inactive) were present, and these were enriched in 3 participants during NUC treatment. Further work to unravel mechanisms of cccDNA transcriptional inactivation may lead to therapies that can achieve this in all hepatocytes, resulting in a functional cure.

Predicting breast cancer response to neoadjuvant treatment using multi-feature MRI: results from the I-SPY 2 TRIAL.

Dynamic contrast-enhanced (DCE) MRI provides both morphological and functional information regarding breast tumor response to neoadjuvant chemotherapy (NAC). The purpose of this retrospective study is to test if prediction models combining multiple MRI features outperform models with single features. Four features were quantitatively calculated in each MRI exam: functional tumor volume, longest diameter, sphericity, and contralateral background parenchymal enhancement. Logistic regression analysis was used to study the relationship between MRI variables and pathologic complete response (pCR). Predictive performance was estimated using the area under the receiver operating characteristic curve (AUC). The full cohort was stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status (positive or negative). A total of 384 patients (median age: 49 y/o) were included. Results showed analysis with combined features achieved higher AUCs than analysis with any feature alone. AUCs estimated for the combined versus highest AUCs among single features were 0.81 (95% confidence interval [CI]: 0.76, 0.86) versus 0.79 (95% CI: 0.73, 0.85) in the full cohort, 0.83 (95% CI: 0.77, 0.92) versus 0.73 (95% CI: 0.61, 0.84) in HR-positive/HER2-negative, 0.88 (95% CI: 0.79, 0.97) versus 0.78 (95% CI: 0.63, 0.89) in HR-positive/HER2-positive, 0.83 (95% CI not available) versus 0.75 (95% CI: 0.46, 0.81) in HR-negative/HER2-positive, and 0.82 (95% CI: 0.74, 0.91) versus 0.75 (95% CI: 0.64, 0.83) in triple negatives. Multi-feature MRI analysis improved pCR prediction over analysis of any individual feature that we examined. Additionally, the improvements in prediction were more notable when analysis was conducted according to cancer subtype.

Glucose deprivation increases nuclear DNA repair protein Ku and resistance to radiation induced oxidative stress in human cancer cells.

Recent studies have indicated that nutrient deprivation particularly glucose may play a major role in tumor cell tolerance to a generally oxidative stress environment in solid tumors. Here, we studied the impact of glucose deprivation on the response of human colon (HT29) and prostate (DU145) cancer cells to gamma radiation. A significant decrease in intracellular glucose level was observed in glucose deprived cells as measured by bioreductive assay. The survival of HT29 and DU145 were increased by 30 and 100% respectively when these cells were exposed to gamma radiation in the absence of glucose compared to that in the presence of glucose. In glucose depleted medium, glutathione (GSH), a free radical scavenger, content remained the same, and showed no correlation with the radiation resistance induced by glucose deprivation. Glucose regulated protein78 (GRP78), a stress response survival protein, was not significantly increased in cells deprived of glucose for 4 h compared to those cells in glucose. DNA repair protein Ku, which is known to play a major role in cellular resistance to radiation, was significantly increased in glucose deprived cancer cells that showed enhanced radiation resistance. These results have demonstrated, for the first time, that glucose deprivation mediated stress increased the expression of nuclear Ku and resistance to radiation induced oxidative stress in human cancer cells. The additional resistance caused by glucose deprivation in cancer cells has clinical significance since solid tumors are known to have low level of glucose due to diffusion limited blood supply and higher metabolic activity.