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Introduction Juul is the most popular electronic cigarette on the market. Amid concerns around uptake of e-cigarettes by never smokers, can we detect whether someone uses Juul based on their social media activities? This is the central premise of the effort reported in this paper. Several recent social media-related studies on Juul use tend to focus on the characterization of Juul-related messages on social media. In this study, we assess the potential in using machine learning methods to automatically identify Juul users (past 30-day usage) based on their Twitter data. Methods We obtained a collection of 588 instances, for training and testing, of Juul use patterns (along with associated Twitter handles) via survey responses of college students. With this data, we built and tested supervised machine learning models based on linear and deep learning algorithms with textual, social network (friends and followers), and other hand-crafted features. Results The linear model with textual and follower network features performed best with a precision-recall trade-off such that precision (PPV) is 57 % at 24 % recall (sensitivity). Hence, at least every other college-attending Twitter user flagged by our model is expected to be a Juul user. Additionally, our results indicate that social network features tend to have a large impact (positive) on classification performance. Conclusion There are enough latent signals from social feeds for supervised modeling of Juul use, even with limited training data, implying that such models are highly beneficial to very focused intervention campaigns. This initial success indicates potential for more involved automated surveillance of Juul use based on social media data, including Juul usage patterns, nicotine dependence, and risk awareness.

The capping of vials plays a critical role in drug product manufacturing process due to its complex interplay of several adjustable process steps. Seal quality, integrity and assurance of containment is essential for parenteral pharmaceuticals as the vial’s content may be contaminated, or in case of highly potent drugs (e.g. antibody drug conjugates) may bear a risk of contamination. The residual seal force (RSF) method can enable further insight in capping equipment settings independently of the container closure system (CCS) and their resulting seal quality. The present study investigates the accuracy of the RSF method focusing on different force settings, RSF development over time, distance between capping plates and vial neck (roller-axis), time point of flip-off button removal and internal and external vial pressure differences (flight simulation and vials closed under vacuum). Results show that the forces used on a RSF tester should be kept low to minimize deformation of the CCS and a period of stable RSF values after the initial decrease should be implemented between capping and RSF measurement to increase accuracy. Variations in the distance between the capping plates and vial neck (roller-axis) can result in incomplete crimps, or visual defects of the seals. Additionally, the time point of removal of the flip-off button as part of the sample preparation had no significant impact on RSF measurements. Finally, pressure differences between the vial interior and exterior had no significant impact on the RSF data.

In silico screening of toxin payloads typically employed in ADCs revealed a wide range of hydrophobicities and sizes as measured by log P and topological polar surface area (tPSA) values. These descriptors were used to identify three nontoxic surrogate payloads that encompass the range of hydrophobicity defined by the ADC toxin training set. The uniform drug to antibody ratio (DAR) ADCs were prepared for each surrogate payload by conjugation to the interchain cysteine residues of a model IgG1 subtype mAb. Linkage of these surrogate payloads to a common mAb with a matched DAR value allowed for preliminary analytical interrogation of the influence of payload hydrophobicity on global structure, self-association, and aggregation properties. The results of differential scanning fluorimetry and dynamic light scattering experiments clearly revealed a direct correlation between the destabilization of the native mAb structure and the increasing payload hydrophobicity. Also, self-association/aggregation propensity examined by self-interaction biolayer interferometry or size exclusion HPLC was consistent with increased conversion of the monomeric mAb to higher order aggregated species, with the degree of conversion directly proportional to the payload hydrophobicity. In summary, these findings prove that the payload-dependent structure destabilization and enhanced propensity to self-associate/aggregate driven by the increasing payload hydrophobicity contribute to reduced ADC stability and more complex behavior when assessing exposure and safety/efficacy relationships.

Background Stoma reversal is often considered a straightforward procedure with low short-term complication rates. The aim of this study was to determine the rate of incisional hernia following stoma reversal and identify risk factors for its development. Methods This was an observational study of consecutive patients who underwent stoma reversal between 2009 and 2015 at a teaching hospital. Patients followed for at least 12 months were eligible. The primary outcome was the development of incisional hernia at the previous stoma site. Independent risk factors were assessed using multivariable logistic regression analysis. Results After a median follow-up of 24 (range 12-89) months, 110 of 318 included patients (34·6 per cent) developed an incisional hernia at the previous stoma site. In 85 (77·3 per cent) the hernia was symptomatic, and 72 patients (65·5 per cent) underwent surgical correction. Higher BMI (odds ratio (OR) 1·12, 95 per cent c.i. 1·04 to 1·21), stoma prolapse (OR 3·27, 1·04 to 10·27), parastomal hernia (OR 5·08, 1·30 to 19·85) and hypertension (OR 2·52, 1·14 to 5·54) were identified as independent risk factors for the development of incisional hernia at the previous stoma site. In addition, the risk of incisional hernia was greater in patients with underlying malignant disease who had undergone a colostomy than in those who had had an ileostomy (OR 5·05, 2·28 to 11·23). Conclusion Incisional hernia of the previous stoma site was common and frequently required surgical correction. Higher BMI, reversal of colostomy in patients with an underlying malignancy, stoma prolapse, parastomal hernia and hypertension were identified as independent risk factors.

PURPOSE: There has been an increased utilization of the posterior retroperitoneal approach (PRA) for adrenalectomy alongside the "classic" laparoscopic transabdominal technique (LTA). The aim of this study was to compare both procedures based on outcome variables at various ranges of tumor size.METHODS: A retrospective analysis was performed on 204 laparoscopic transabdominal (UMC Groningen) and 57 retroperitoneal (UMC Utrecht) adrenalectomies between 1998 and 2013. We applied a univariate and multivariate regression analysis. Mann-Whitney and chi-squared tests were used to compare outcome variables between both approaches.RESULTS: Both mean operation time and median blood loss were significantly lower in the PRA group with 102.1 (SD 33.5) vs. 173.3 (SD 59.1) minutes (p < 0.001) and 0 (0-200) vs. 50 (0-1000) milliliters (p < 0.001), respectively. The shorter operation time in PRA was independent of tumor size. Complication rates were higher in the LTA (19.1%) compared to PRA (8.8%). There was no significant difference in recovery time between both approaches.CONCLUSIONS: Application of the PRA decreases operation time, blood loss, and complication rates compared to LTA. This might encourage institutions that use the LTA to start using PRA in patients with adrenal tumors, independent of tumor size.

Implementation of population screening for colorectal cancer by direct colonoscopy or follow-up colonoscopy after a positive fecal blood test has challenged the overall capacity of bowel examinations. Certain countries are facing serious colonoscopy capacity constraints, which have led to waiting lists and long-time latency of follow-up examinations. Various options for improvement are considered, including increased cut-off values of the fecal blood tests. Results from major clinical studies of blood-based, cancer-associated biomarkers have led to focus, however, on a triage concept for improved selection to colonoscopy. The triage test may include subject age, concentration of hemoglobin in a feces test and a combination of certain blood-based cancer associated biomarkers. Recent results have indicated that triage may reduce the requirements for colonoscopy by around 30%. Such results may be advantageous for the capacity, the heath budgets and in particular, the subjects, who do not need an unnecessary, unpleasant and risk-associated bowel examination.

IntroductionCan we predict whether someone uses Juul based on their social media activities? This is the central premise of the effort reported in this paper. Several recent social media-related studies on Juul use tend to focus on the characterization of Juul-related messages on social media. In this study, we assess the potential in using machine learning methods to automatically identify whether an individual uses Juul (past 30-day usage) based on their Twitter data.MethodsWe obtained a collection of 588 instances, for training and testing, of Juul use patterns (along with associated Twitter handles) via survey responses of college students. With this data, we built and tested supervised machine learning models based on linear and deep learning algorithms with textual, social network (friends and followers), and other hand-crafted features.ResultsThe linear model with textual and follower network features performed best with a precision-recall trade-off such that precision (PPV) is 57% at 24% recall (sensitivity). Hence, at least every other college-attending Twitter user flagged by our model is expected to be a Juul user. Additionally, our results indicate that social network features tend to have a large impact (positive) on predictive performance.ConclusionThere are enough predictive signals from social feeds for supervised modeling of Juul use, even with limited training data, implying that such models are highly beneficial to very focused intervention campaigns. Moreover, this initial success indicates potential for more involved automated surveillance of Juul use based on social media data, including Juul usage patterns, nicotine dependency, and risk awareness.

BACKGROUND: Recombinant human thyroid stimulating hormone (RhTSH) aided radioiodine ablative therapy (RIT) is current-day practice in the treatment of differentiated thyroid cancer (DTC). It is often planned 4 to 6 weeks after surgery or sometimes even longer (standard protocol). The RhTSH-aided RIT, however, has the advantage that it can be planned shortly after thyroidectomy. The FASTHYNA trial was designed to test the hypothesis that RIT 1 week after thyroidectomy (fast-track protocol) results in a significant reduction of sick leave with lower societal costs and with a better quality of life (QOL) compared with the current standard treatment.METHODS: In a randomized, multicenter trial, we included patients with differentiated thyroid cancer, stage T1-3 N0-1 M0-x, who were treated with a total or completion thyroidectomy, with a paid job of at least 12 hours per week. The primary study end point was days of sick leave reported from time of surgery. Secondary end points were QOL and societal costs associated with absence from work.RESULTS: Twenty patients were eligible for inclusion between November 2013 and May 2016. Significant decreases in mean duration of sick leave in the fast-track group versus the standard care group (115 and 280 hours, respectively, P = 0.02) and in costs associated with productivity losses (&OV0556;4070.77 vs &OV0556;9202.90, P = 0.02) were found. There were no significant differences in QOL between both groups.CONCLUSIONS: The trial showed a significant reduction in sick leave and in societal costs in the fast-track group without a deterioration of QOL. Therefore, fast-track ablation is desirable.TRIAL REGISTRATION: Netherlands trial register: NTR 3933.

Objective: Examine Juul use patterns, sociodemographic and personal factors associated with Juul use, and reasons for Juul initiation and current use, among college students. Participants: Convenience sample of 371 undergraduates at a large university in the southeast; recruited April 2018. Methods: Cross-sectional design using an online survey. Logistic regression identified the personal risk factors for current use. Results: Over 80% of participants recognized Juul; 36% reported ever use and 21% past 30-day use. Significant risk factors for current Juul use were: male, White/non-Hispanic, lower undergraduate, and current cigarette smoker. Current Juul users chose ease of use and lack of a bad smell as reasons for use. Ever Juul users most commonly endorsed curiosity and use by friends as reasons for trying Juul. Conclusions: Given the propensity for nicotine addiction among youth and young adults, rates of Juul use are alarming and warrant immediate intervention.

The time between the moment of referral for the diagnostic workup for thyroid nodules and the outcome can be worrisome for patients. In general, patients experience high levels of anxiety during the evaluation of a lesion suspicious for cancer. Therefore, the implementation of same-day fine-needle aspiration cytology (FNAC) diagnosis is becoming standard-of-care for many solid tumors. Our aim was to assess the feasibility of same-day FNAC diagnosis for thyroid nodules and to assess patient anxiety during the diagnostic process.For feasibility of same-day FNAC diagnosis, we assessed the proportion of patients receiving a diagnosis at the end of the visit. Accuracy was measured by comparing histology with the FNAC result. Patient anxiety was measured by the State Trait Anxiety Inventory at 6 moments during the diagnostic workup.Of the 131 included patients, 112 (86%) were female, and the mean age was 53 years. All patients, except those with a nondiagnostic FNAC result (n = 26; 20%), had a diagnosis at the end of the day. There were only two discordant results. Anxiety levels at the beginning of the day were high throughout the group, State Trait Anxiety Inventory (STAI) score 43.1 (SD 2.0) and decreased significantly more in patients with a benign FNAC result (STAI score 30.2), compared to patients with a malignant or indeterminate result (STAI score 39.6).Distress of patients with a thyroid nodule undergoing same-day FNAC diagnostics was high. Same-day FNAC diagnosis is feasible and accurate for the evaluation of thyroid nodules. Therefore, same-day FNAC diagnosis seems a safer, more patient-friendly approach to diagnose thyroid nodules.

UNLABELLED: Patients with suspected recurrence from differentiated thyroid carcinoma, based on an increased thyroglobulin (Tg) level and negative neck ultrasound (US), pose a clinical dilemma. Because standard imaging has a low yield identifying potential recurrence, blind (131)I treatment is often applied. However, a tumor-negative (131)I whole-body scintigraphy (WBS) prevails in 38%-50% of patients. We performed a prospective multicenter observational cohort study to test the hypothesis that (124)I PET/CT can identify the patients with a tumor-negative posttherapy (131)I WBS.METHODS: Our study was designed to include 100 patients with detectable Tg and a negative neck US, who were planned for blind (131)I therapy. All patients underwent (124)I PET/CT after administration of recombinant human thyroid-stimulating hormone. Subsequently, after 4-6 wk of thyroid hormone withdrawal patients were treated with 5.5-7.4 GBq of (131)I, followed by WBS a week later. The primary endpoint was the number of (131)I therapies that could have been omitted using the predicted outcome of the (124)I PET/CT, operationalized as the concordance of tumor detection by (124)I PET/CT, using post-(131)I therapy WBS as the reference test. The study would be terminated if 3 patients had a negative (124)I PET/CT and a positive posttherapy (131)I scan.RESULTS: After inclusion of 17 patients, we terminated the study preliminarily because the stopping rule had been met. Median Tg level at (131)I therapy was 28 μg/L (interquartile range, 129). Eight posttherapy WBS were negative (47%), all of which were correctly predicted by negative (124)I PET/CT. Nine posttherapy WBS showed iodine-avid tumor, of which 4 also had positive (124)I PET/CT findings. Sensitivity, specificity, negative predictive value, and positive predictive value of (124)I PET/CT were 44% (confidence interval [CI], 14%-79%), 100% (CI, 63%-100%), 62% (CI, 32%-86%), and 100% (CI, 40%-100%), respectively. Implementation of (124)I PET in this setting would have led to 47% (8/17) less futile (131)I treatments, but 29% of patients (5/17) would have been denied potentially effective therapy.CONCLUSION: In patients with biochemical evidence of recurrent differentiated thyroid carcinoma and a tumor-negative neck US, the high false-negative rate of (124)I PET/CT after recombinant human thyroid-stimulating hormone (124)I PET/CT as implemented in this study precludes its use as a scouting procedure to prevent futile blind (131)I therapy.

Background Dual-energy CT iodine maps are used to detect pulmonary embolism (PE) with CT angiography but require dedicated hardware. Subtraction CT, a software-only solution, results in iodine maps with high contrast-to-noise ratios. Purpose To compare the use of subtraction CT versus dual-energy CT iodine maps to CT angiography for PE detection. Materials and Methods In this prospective study ( https://clinicaltrials.gov , NCT02890706), 274 participants suspected of having PE underwent precontrast CT followed by contrast material-enhanced dual-energy CT angiography between July 2016 and April 2017. Iodine maps from dual-energy CT were derived. Subtraction maps (contrast-enhanced CT minus precontrast CT) were calculated after motion correction. Truth was established by expert consensus. A total of 75 randomly selected participants with and without PE (1:1 ratio) were evaluated by three radiologists and six radiology residents (blinded to final diagnosis) for the presence of PE using three types of CT: CT angiography alone, dual-energy CT, and subtraction CT. The partial area under the receiver operating characteristic curve (AUC) for the clinically relevant specificity region (maximum partial AUC, 0.11) was compared by using multireader multicase variance. A P value less than or equal to .025 was considered indicative of a significant difference due to multiple comparisons. Results There were 35 men and 40 women in the reader study (mean age, 63 years ± 12 [standard deviation]). The pooled sensitivities were not different (P ≥ .31 among techniques) (95% confidence intervals [CIs]: 67%, 89% for CT angiography; 72%, 91% for dual-energy CT; 70%, 91% for subtraction CT). However, pooled specificity was higher for subtraction CT (95% CI: 100%, 100%) than for CT angiography (95% CI: 89%, 97%) or dual-energy CT (95% CI: 89%, 98%) (P < .001). Partial AUCs for the average observer improved equally when adding iodine maps (subtraction CT [0.093] vs CT angiography [0.088], P = .03; dual-energy CT [0.094] vs CT angiography, P = .01; dual-energy CT vs subtraction CT, P = .68). Average reading times were equivalent (range, 97-101 seconds; P ≥ .41) among techniques. Conclusion Subtraction CT iodine maps had greater specificity than CT angiography alone in pulmonary embolism detection. Subtraction CT had comparable diagnostic performance to that of dual-energy CT, without the need for dedicated hardware. © RSNA, 2019 Online supplemental material is available for this article.

Oxidation of biopharmaceutics represents a major degradation pathway, which may impact bioactivity, serum half-life, and colloidal stability. This study focused on the quantification of oxidation and its effects on structure and colloidal stability for a model antibody and its lysine (ADC-L) and cysteine (ADC-C) conjugates. The effects of oxidation were evaluated by a forced degradation study using H2O2 and a shelf-life simulation, which used degrading polysorbate 80 as source for reactive oxygen species. Differential scanning fluorimetry revealed decreasing transition temperatures of the CH2 domain with rising oxidation, resulting in a loss of colloidal stability as assessed by size-exclusion high pressure liquid chromatography. The conjugation technique influences structural changes of the monoclonal antibody (mAb) and subsequently alters the impact of oxidation. ADC-C was most effected by oxidation as the CH2 domain showed the biggest destabilization on conjugation compared to the mAb and ADC-L. Quantification of Fc methionine oxidation by analytical protein A chromatography revealed 4-fold higher oxidation after 8 weeks for the ADC-C compared to the mAb. Payload degradation was observed independently of the conjugation technique used or if free in solution by ultraviolet-visible. In addition, adding antioxidants can be a suitable approach to prevent oxidation and achieve baseline stabilization of the proteins.

PURPOSE: Differentiated thyroid cancer is the most common endocrine malignancy. Recurrences (5-20%) are the main reason for follow-up. Thyroglobulin (Tg) has proven to be an excellent disease marker, but thyroglobulin-antibodies (Tg-Ab) may interfere with Tg measurement, leading to over or underestimation. It is proposed that the Tg-Ab trend can be used as a marker for disease recurrence, yet few studies define trend and have a long-term follow-up. The objective of our study was to investigate the value of a well-defined Tg-Ab trend as a surrogate marker for disease recurrence during long-term follow-up.METHODS: We retrospectively studied patients treated at the Nuclear Department of the University Medical Center Utrecht from 1998 to 2010 and the Netherlands Cancer Institute from 2000 to 2009. All patients with Tg-Ab 12 months after treatment were included. The definition of a rise was >50% increase of the Tg-Ab value in a 2 year time period. A decline as >50% decrease of the Tg-Ab value.RESULTS: Twenty-five patients were included. None of the patients with declining or stable Tg-Ab without a concomitant rise in Tg developed a recurrence. Four patients did suffer a recurrence. Three of these patients had a rising Tg-Ab trend, in two of these patients Tg was undetectable.CONCLUSIONS: Tg-Ab trend can be used as a crude surrogate marker for long-term follow-up of Tg-Ab patients. A rising trend in Tg-Ab warrants further investigation to detect recurrent disease. Stable or declining Tg-Ab levels do not seem to reflect a risk for recurrence.

Objectives Oxidation of protein therapeutics is a major chemical degradation pathway which may impact bioactivity, serum half-life and stability. Therefore, oxidation is a relevant parameter which has to be monitored throughout formulation development. Methods such as HIC, RPLC and LC/MS achieve a separation of oxidized and non-oxidized species by differences in hydrophobicity. Antibody–drug conjugates (ADC) although are highly more complex due to the heterogeneity in linker, drug, drug-to-antibody ratio (DAR) and conjugation site. The analytical protein A chromatography can provide a simple and fast alternative to these common methods. Methods A miniature analytical protein A chromatography method in combination with an IdeS digest was developed to analyse ADCs. The IdeS digest efficiency of an IgG1 was monitored using SEC-HPLC and non-reducing SDS-PAGE. An antibody-fluorescent dye conjugate was conjugated at different dye-to-antibody ratios as model construct to mimic an ADC. Key findings With IdeS, an almost complete digest of a model IgG1 can be achieved (digested protein amount >98%). This enables subsequent analytical protein A chromatography, which consequently eliminates any interference of payload with the stationary phase. Conclusion A novel high-throughput method for an interchain cysteine-linked ADC oxidation screens during formulation development was developed.

Contains fulltext : 172109.pdf (Publisher’s version ) (Open Access) PURPOSE: Traditionally, total thyroidectomy has been advocated for patients with tumors larger than 1 cm. However, according to the ATA and NCCN guidelines (2015, USA), patients with tumors up to 4 cm are now eligible for lobectomy. A rationale for adhering to total thyroidectomy might be the presence of contralateral carcinomas. The purpose of this study was to describe the characteristics of contralateral carcinomas in patients with differentiated thyroid cancer (DTC) larger than 1 cm. METHODS: A retrospective study was performed including patients from 17 centers in 5 countries. Adults diagnosed with DTC stage T1b-T3 N0-1a M0 who all underwent a total thyroidectomy were included. The primary endpoint was the presence of a contralateral carcinoma. RESULTS: A total of 1313 patients were included, of whom 426 (32 %) had a contralateral carcinoma. The contralateral carcinomas consisted of 288 (67 %) papillary thyroid carcinomas (PTC), 124 (30 %) follicular variant of a papillary thyroid carcinoma (FvPTC), 5 (1 %) follicular thyroid carcinomas (FTC), and 3 (1 %) Hurthle cell carcinomas (HTC). Ipsilateral multifocality was strongly associated with the presence of contralateral carcinomas (OR 2.62). Of all contralateral carcinomas, 82 % were

Humans routinely solve problems of immense computational complexity by intuitively forming simple, low-dimensional heuristic strategies. Citizen science exploits this ability by presenting scientific research problems to non-experts. Gamification is an effective tool for attracting citizen scientists to provide solutions to research problems. While citizen science games Foldit, EteRNA and EyeWire have been used successfully to study protein and RNA folding and neuron mapping, so far gamification has not been applied to problems in quantum physics. Does the fact that everyday experiences are based on classical physics hinder the use of non-expert citizen scientists in the realm of quantum mechanics? Here we report on Quantum Moves, an online platform gamifying optimization problems in quantum physics. We show that human players are able to find solutions to difficult problems associated with the task of quantum computing. Players succeed where purely numerical optimization fails, and analyses of their solutions provide insights into the problem of optimization of a more profound and general nature. Based on player strategies, we have thus developed a new, few-parameter heuristic optimization method which efficiently outperforms the most prominent established numerical methods. The numerical complexity associated with time-optimal solutions increases for shorter process durations. To better understand this, we have made a low-dimensional rendering of the optimization landscape. These studies show why traditional optimization methods fail near the quantum speed limit, and they bring promise that combined analyses of optimization landscapes and heuristic solution strategies may benefit wider classes of optimization problems in quantum physics and beyond., 19 pages, 7 figures, supplementary materials are included

REPLY: Thank you for the opportunity to respond to the letter to the editor by Pattison et al. regarding our article presenting the results of the THYROPET study ([1][1]). That study showed that after preparation with recombinant human thyroid-stimulating hormone (rh-TSH), 124I PET/CT could not

UNLABELLED: Radioiodine therapy with (131)I is used for treatment of suspected recurrence of differentiated thyroid carcinoma. Pretherapeutic (124)I PET/CT with a low activity (∼1% of (131)I activity) can be performed to determine whether uptake of (131)I, and thereby the desired therapeutic effect, may be expected. However, false-negative (124)I PET/CT results as compared with posttherapeutic (131)I SPECT/CT have been reported by several groups. The purpose of this study was to investigate whether the reported discrepancies may be ascribed to a difference in lesion detectability between (124)I PET/CT and (131)I SPECT/CT and, hence, whether the administered (124)I activity is sufficient to achieve equal detectability. METHODS: Phantom measurements were performed using the National Electrical Manufacturers Association 2007 image-quality phantom. As a measure of detectability, the contrast-to-noise ratio was calculated. The (124)I activity was expressed as the percentage of (131)I activity required to achieve the same contrast-to-noise ratio. This metric was defined as the detectability equivalence percentage (DEP). RESULTS: Because lower DEPs were obtained for smaller spheres, a relatively low (124)I activity was sufficient to achieve similar lesion detectability between (124)I PET/CT and (131)I SPECT/CT. DEP was 1.5%, 1.9%, 1.9%, 4.4%, 9.0%, and 16.2% for spheres with diameters of 10, 13, 17, 18, 25, and 37 mm, respectively, for attenuation- and scatter-corrected SPECT versus point-spread function (PSF) model-based and time-of-flight (TOF) PET. For no-PSF no-TOF PET, DEP was 3.6%, 2.1%, 3.5%, 7.8%, 15.1%, and 23.3%, respectively. CONCLUSION: A relatively low (124)I activity of 74 MBq (∼1% of (131)I activity) is sufficient to achieve similar lesion detectability between (124)I PSF TOF PET/CT and (131)I SPECT/CT for small spheres (≤10 mm), since the reported DEPs are close to 1%. False-negative (124)I PET/CT results as compared with posttherapeutic (131)I SPECT/CT may be ascribed to differences in detectability for large lesions (>10 mm) and for no-PSF no-TOF PET, since DEPs are greater than 1%. On the basis of DEPs of 3.5% for lesion diameters of up to 17 mm on no-PSF no-TOF PET, (124)I activities as high as 170 MBq may be warranted to obtain equal detectability.

Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with ≥3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR ≤ 60 ml/min/1.73 m2. Poisson regression was used to develop a risk score, externally validated on two independent cohorts. In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7–6.7; median follow-up 6.1 y, range 0.3–9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was −2 (interquartile range –4 to 2). There was a 1:393 chance of developing CKD in the next 5 y in the low risk group (risk score < 0, 33 events), rising to 1:47 and 1:6 in the medium (risk score 0–4, 103 events) and high risk groups (risk score ≥ 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166–3,367); NNTH was 202 (95% CI 159–278) and 21 (95% CI 19–23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506–1462), 88 (95% CI 69–121), and 9 (95% CI 8–10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3–12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6–8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD., Editors’ Summary Background About 35 million people are currently infected with HIV, the virus that causes AIDS. HIV destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other infections. HIV infection can be controlled, but not cured, using combination antiretroviral therapy (cART), and, nowadays, the life expectancy of many HIV-positive individuals is similar to that of HIV-negative people. HIV-positive individuals nevertheless experience some illnesses more frequently than HIV-negative people do. For example, up to a third of HIV-positive individuals develop chronic kidney disease (CKD), which is associated with an increased risk of cardiovascular disease and death. Persons with CKD may have an impaired effect of the filtration units in the kidneys that remove waste products and excess water from the blood to make urine, thereby leading to a reduced blood filtration rate (the estimated glomerular filtration rate [eGFR]) and waste product accumulation in the blood. Symptoms of CKD, which rarely occur until the disease is advanced, include tiredness, swollen feet, and frequent urination. Advanced stages of CKD cannot be cured, but its progression can be slowed by, for example, controlling hypertension (high blood pressure) and diabetes (two CDK risk factors) and by adopting a healthy lifestyle. Why Was This Study Done? The burden of CKD may increase among HIV-positive individuals as they age, and clinicians need to know which individuals are at high risk of developing CKD when choosing cART regimens for their patients. In addition, clinicians need to be able to identify those HIV-positive individuals at greatest risk of CKD so that they can monitor them for early signs of kidney disease. Some antiretroviral drugs—for example, tenofovir and atazanavir/ritonavir (a boosted protease inhibitor)—are associated with kidney damage. Clinicians may need to weigh the benefits and risks of giving such potentially nephrotoxic drugs to individuals who already have a high CKD risk. Here, the researchers develop and validate a simple, widely applicable risk score (a risk prediction model) for CKD among HIV-positive individuals and investigate the relationship between CKD and potentially nephrotoxic antiretroviral drugs among individuals with different CKD risk score profiles. What Did the Researchers Do and Find? To develop their CKD risk score, the researchers used clinical and demographic data collected from 17,954 HIV-positive individuals enrolled in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study who had an eGFR > 60 ml/min/1.73 m2 and were not taking a potentially nephrotoxic antiretroviral at baseline. During 103,185 person-years of follow-up, 641 individuals developed CKD. Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease predicted CKD. The researchers included these nine factors in their risk score model (which is available online) and defined three risk groups: low (risk score < 0), medium (risk score 0–4), and high (risk score ≥ 5) risk of CKD development in the next five years. Specifically, there was a 1 in 393, 1 in 47, and 1 in 6 chance of developing CKD in the next five years in the low, medium, and high risk groups, respectively. Because some patients started to use potentially nephrotoxic antiretroviral drugs during follow-up, the researchers were able to use their risk score model to calculate how many patients would have to be treated with one of these drugs for an additional patient to develop CKD over five years in each risk group. This “number needed to harm” (NNTH) for patients starting treatment with tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor was 739, 88, and 9 in the low, medium, and high risk groups, respectively. Finally, the researchers validated the accuracy of their risk score in two independent HIV study groups. What Do These Findings Mean? These findings provide a simple, validated risk score for CKD and indicate that the NNTH when starting potentially nephrotoxic antiretrovirals was low among HIV-positive individuals at the highest risk of CKD (i.e., treating just nine individuals with nephrotoxic antiretroviral drugs will likely lead to an additional case of CKD in five years). Although various aspects of the study, including the lack of data on race, limit the accuracy of these findings, these findings highlight the need for monitoring, screening, and chronic disease prevention to minimize the risk of HIV-positive individuals developing diabetes, hypertension, or cardiovascular disease, or becoming coinfected with hepatitis C, all of which contribute to the CKD risk score. Moreover, the development of a tool for estimating an individual’s five-year risk of developing CKD with or without the addition of potentially nephrotoxic antiretroviral drugs will enable clinicians and patients to weigh the benefits of certain antiretroviral drugs against the risk of CKD and make informed decisions about treatment options. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001809. Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and personal stories about living with AIDS/HIV Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including personal stories about living with HIV/AIDS The World Health Organization provides information on all aspects of HIV/AIDS (in several languages), including its guidelines on the use of ART for treating and preventing HIV infection The UNAIDS World AIDS Day Report 2014 provides up-to-date information about the AIDS epidemic and efforts to halt it The UK National Health Service Choices website provides information for patients on chronic kidney disease, including some personal stories The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease (in English and Spanish) A tool for calculating the CDK risk score developed in this study is available Additional information about the D:A:D study is available, Amanda Mocroft and colleagues develop and validate a model for determining risk of developing chronic kidney disease for individuals with HIV if treated with different antiretroviral therapies.

AIM To investigate the microRNA expression profile in esophageal neosquamous epithelium from patients who had undergone ablation of Barrett’s esophagus. METHODS High throughput screening using TaqMan® Array Human MicroRNA quantitative PCR was used to determine expression levels of 754 microRNAs in distal esophageal mucosa (1 cm above the gastro-esophageal junction) from 16 patients who had undergone ablation of non-dysplastic Barrett’s esophagus using argon plasma coagulation vs pretreatment mucosa, post-treatment proximal normal non-treated esophageal mucosa, and esophageal mucosal biopsies from 10 controls without Barrett’s esophagus. Biopsies of squamous mucosa were also taken from 5 cm above the pre-ablation squamo-columnar junction. Predicted mRNA target pathway analysis was used to investigate the functional involvement of differentially expressed microRNAs. RESULTS Forty-four microRNAs were differentially expressed between control squamous mucosa vs post-ablation neosquamous mucosa. Nineteen microRNAs were differentially expressed between post-ablation neosquamous and post-ablation squamous mucosa obtained from the more proximal non-treated esophageal segment. Twelve microRNAs were differentially expressed in both neosquamous vs matched proximal squamous mucosa and neosquamous vs squamous mucosa from healthy patients. Nine microRNAs (miR-424-5p, miR-127-3p, miR-98-5p, miR-187-3p, miR-495-3p, miR-34c-5p, miR-223-5p, miR-539-5p, miR-376a-3p, miR-409-3p) were expressed at higher levels in post-ablation neosquamous mucosa than in matched proximal squamous and healthy squamous mucosa. These microRNAs were also more highly expressed in Barrett’s esophagus mucosa than matched proximal squamous and squamous mucosa from controls. Target prediction and pathway analysis suggests that these microRNAs may be involved in the regulation of cell survival signalling pathways. Three microRNAs (miR-187-3p, miR-135b-5p and miR-31-5p) were expressed at higher levels in post-ablation neosquamous mucosa than in matched proximal squamous and healthy squamous mucosa. These miRNAs were expressed at similar levels in pre-ablation Barrett’s esophagus mucosa, matched proximal squamous and squamous mucosa from controls. Target prediction and pathway analysis suggests that these microRNAs may be involved in regulating the expression of proteins that contribute to barrier function. CONCLUSION Neosquamous mucosa arising after ablation of Barrett’s esophagus expresses microRNAs that may contribute to decreased barrier function and microRNAs that may be involved in the regulation of survival signaling pathways.

Use of histochemical techniques for the detection of carbohydrates showed variable quantities of glycoproteins in deposits of amyloid, fibrinoid, and hyaline in vessel walls. Staining with alcian blue demonstrated acid mucopolysaccharides in vascular deposits of amyloid. After proteolysis acid mucopolysaccharides were also found in vascular hyaline. Fibrinoid, however, did not tend to bind alcian blue.

Background The production of new neurons during adulthood and their subsequent integration into a mature central nervous system have been shown to occur in all vertebrate species examined to date. However, the situation in insects is less clear and, in particular, it has been reported that there is no proliferation in the Drosophila adult brain. Results We report here, using clonal analysis and 5'-bromo-2'-deoxyuridine (BrdU) labelling, that cell proliferation does occur in the Drosophila adult brain. The majority of clones cluster on the ventrolateral side of the antennal lobes, as do the BrdU-positive cells. Of the BrdU-labelled cells, 86% express the glial gene reversed polarity (repo), and 14% are repo negative. Conclusion We have observed cell proliferation in the Drosophila adult brain. The dividing cells may be adult stem cells, generating glial and/or non-glial cell types.