Monoclonal antibody and protein therapeutic formulations for subcutaneous delivery: high-concentration, low-volume vs. low-concentration, high-volume.

Biologic drugs are used to treat a variety of cancers and chronic diseases. While most of these treatments are administered intravenously by trained healthcare professionals, a noticeable trend has emerged favoring subcutaneous (SC) administration. SC administration of biologics poses several challenges. Biologic drugs often require higher doses for optimal efficacy, surpassing the low volume capacity of traditional SC delivery methods like autoinjectors. Consequently, high concentrations of active ingredients are needed, creating time-consuming formulation obstacles. Alternatives to traditional SC delivery systems are therefore needed to support higher-volume biologic formulations and to reduce development time and other risks associated with high-concentration biologic formulations. Here, we outline key considerations for SC biologic drug formulations and delivery and explore a paradigm shift: the flexibility afforded by low-to-moderate-concentration drugs in high-volume formulations as an alternative to the traditionally difficult approach of high-concentration, low-volume SC formulation delivery.

A rapid review of antenatal hepatitis C virus testing in the United Kingdom.

BACKGROUND: The United Kingdom (UK) has committed to the World Health Organization's viral hepatitis elimination targets. New case finding strategies, such as antenatal testing, may be needed to achieve these targets. We conducted a rapid review to understand hepatitis C-specific antibody (anti-HCV) and HCV RNA test positivity in antenatal settings in the United Kingdom to inform guidance. METHODS: Articles and conference abstracts published between January 2000 and June 2022 reporting anti-HCV testing in antenatal settings were identified through PubMed and Web of Science searches. Results were synthesised using a narrative approach. RESULTS: The search identified 2,011 publications; 10 studies were included in the final synthesis. Seven studies used anonymous testing methods and three studies used universal opt-out testing. Anti-HCV test positivity ranged from 0.1 to 0.99%, with a median value of 0.38%. Five studies reported HCV RNA positivity, which ranged from 0.1 to 0.57% of the testing population, with a median value of 0.22%. One study reported cost effectiveness of HCV and found it to be cost effective at £9,139 per quality adjusted life years. CONCLUSION: The relative contribution of universal opt-out antenatal testing for HCV should be reconsidered, as antenatal testing could play an important role in new case-finding and aid achieving elimination targets.

Adverse health outcomes among people who inject drugs who engaged in recent sex work: findings from a national survey.

OBJECTIVES: This study explores trends in sex work among people who inject drugs (PWID) by gender and the relationship between sex work and adverse health outcomes including overdose, injection-site, and blood-borne virus (BBV) infections. STUDY DESIGN: The Unlinked Anonymous Monitoring Survey of PWID is an annual cross-sectional survey that monitors BBV prevalence and behaviours, including transactional sex, among PWID recruited through specialist services in England, Wales, and Northern Ireland. METHODS: Trends in sex work among PWID (2011-2021) were described. Data were analysed to assess differences between PWID who engaged in sex work in the past year (sex workers [SWs]) and those who did not (non-SWs) by gender (Pearson Chi2 tests) (2018-2021). Associations between sex work in the past year and adverse health outcomes were investigated using logistic regression. RESULTS: Between 2011 and 2021, sex work among PWID remained stable, with 31% of women and 6.3% of men who inject, reporting having ever engaged in sex work, and 14% of women and 2.2% of men engaging in sex work in the past year. Between 2018 and 2021, SWs had greater odds of reporting symptoms of an injection-site infection (adjusted odds ratio (aOR): 1.68 [95% confidence interval {CI}: 1.31-2.16], P < 0.001) and reporting overdose (aOR: 2.21 [CI: 1.74-2.80], P < 0.001) than non-SWs had in the past year. Among men, SWs had 243% greater odds of having HIV than non-SWs (aOR: 3.43 [CI: 1.03-11.33], P = 0.043). CONCLUSIONS: Our findings highlight disproportionate vulnerability and intersection of overlapping risk factors experienced by PWID SWs and a need for tailored interventions which are inclusive and low-threshold.

Interchange reconnection as the source of the fast solar wind within coronal holes.

The fast solar wind that fills the heliosphere originates from deep within regions of open magnetic field on the Sun called 'coronal holes'. The energy source responsible for accelerating the plasma is widely debated; however, there is evidence that it is ultimately magnetic in nature, with candidate mechanisms including wave heating1,2 and interchange reconnection3-5. The coronal magnetic field near the solar surface is structured on scales associated with 'supergranulation' convection cells, whereby descending flows create intense fields. The energy density in these 'network' magnetic field bundles is a candidate energy source for the wind. Here we report measurements of fast solar wind streams from the Parker Solar Probe (PSP) spacecraft6 that provide strong evidence for the interchange reconnection mechanism. We show that the supergranulation structure at the coronal base remains imprinted in the near-Sun solar wind, resulting in asymmetric patches of magnetic 'switchbacks'7,8 and bursty wind streams with power-law-like energetic ion spectra to beyond 100 keV. Computer simulations of interchange reconnection support key features of the observations, including the ion spectra. Important characteristics of interchange reconnection in the low corona are inferred from the data, including that the reconnection is collisionless and that the energy release rate is sufficient to power the fast wind. In this scenario, magnetic reconnection is continuous and the wind is driven by both the resulting plasma pressure and the radial Alfvénic flow bursts.

Cutaneous lymphangitis carcinomatosa: a unique presentation of a rare disease.

A 75-year-old man with a three-year history of metastatic lung adenocarcinoma was diagnosed with cutaneous lymphangitic carcinomatosa of unique morphology. He was admitted to our hospital for right neck swelling, erythema, and failure to thrive. Skin examination demonstrated an indurated, thickened, firm, hyperpigmented plaque extending from the right neck and chest to the right ear, cheek, and eyelids. Skin biopsy demonstrated poorly differentiated adenocarcinoma, morphologically consistent with metastasis from the patient's known pulmonary adenocarcinoma and showed dermal invasion, perineural invasion, and involvement of dermal lymphatics. The diagnosis was an atypical presentation of cutaneous lymphangitis carcinomatosa from metastatic lung adenocarcinoma. This case presentation affirms that cutaneous lymphangitis carcinomatosa has a variety of atypical presentations, so physicians must maintain a high index of suspicion when evaluating cutaneous lesions in patients with known or suspected internal malignancy.

Parker Solar Probe Observations of Solar Wind Energetic Proton Beams Produced by Magnetic Reconnection in the Near-Sun Heliospheric Current Sheet.

We report observations of reconnection exhausts in the Heliospheric Current Sheet (HCS) during Parker Solar Probe Encounters 08 and 07, at 16 R s and 20 R s , respectively. Heliospheric current sheet (HCS) reconnection accelerated protons to almost twice the solar wind speed and increased the proton core energy by a factor of ∼3, due to the Alfvén speed being comparable to the solar wind flow speed at these near-Sun distances. Furthermore, protons were energized to super-thermal energies. During E08, energized protons were found to have leaked out of the exhaust along separatrix field lines, appearing as field-aligned energetic proton beams in a broad region outside the HCS. Concurrent dropouts of strahl electrons, indicating disconnection from the Sun, provide further evidence for the HCS being the source of the beams. Around the HCS in E07, there were also proton beams but without electron strahl dropouts, indicating that their origin was not the local HCS reconnection exhaust.

Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis.

Acute B-cell lymphoblastic leukemia (B-ALL) results from oligo-clonal evolution of B-cell progenitors endowed with initiating and propagating leukemia properties. The activation of both the Rac guanine nucleotide exchange factor (Rac GEF) Vav3 and Rac GTPases is required for leukemogenesis mediated by the oncogenic fusion protein BCR-ABL. Vav3 expression becomes predominantly nuclear upon expression of BCR-ABL signature. In the nucleus, Vav3 interacts with BCR-ABL, Rac, and the polycomb repression complex (PRC) proteins Bmi1, Ring1b and Ezh2. The GEF activity of Vav3 is required for the proliferation, Bmi1-dependent B-cell progenitor self-renewal, nuclear Rac activation, protein interaction with Bmi1, mono-ubiquitination of H2A(K119) (H2AK119Ub) and repression of PRC-1 (PRC1) downstream target loci, of leukemic B-cell progenitors. Vav3 deficiency results in de-repression of negative regulators of cell proliferation and repression of oncogenic transcriptional factors. Mechanistically, we show that Vav3 prevents the Phlpp2-sensitive and Akt (S473)-dependent phosphorylation of Bmi1 on the regulatory residue S314 that, in turn, promotes the transcriptional factor reprogramming of leukemic B-cell progenitors. These results highlight the importance of non-canonical nuclear Rho GTPase signaling in leukemogenesis.

Single ileal segment in a cat-tail configuration for bilateral ureteric strictures.

INTRODUCTION: Management of bilateral long length ureteric strictures is difficult with few options for reconstruction. In this report, we describe our experience with the use of a single, 15- 20 cm ileal segment for reconstruction of bilateral long length (involving more than 2/3rd ureter) ureteric strictures. PATIENTS AND METHODS: A retrospective analysis of 5 cases operated between 2015 and 2020for bilateral long length ureteric strictures, using a single segment ileal interposition in a cat tail configuration was performed. We evaluated renal function, surgical success, incidence of urinary tract infection and complications of the procedure. Surgical success was defined as an asymptomatic patient with no hydronephrosis and/or prompt drainage of the kidney on radiological investigations. RESULTS: The average age of presentation was 42.8 ± 7.4 years (33-53) years). All the cases were secondary to a gynaecological intervention. The mean creatinine prior to surgery was 0.81 ± 0.36 mg % (range 0.5 -1.4 mg%). Mean duration of follow-up was 28.6 ± 20.6 months (Range 10 - 56 months). Mean hospital stay was 14.4 ± 3.36 days (range 12-20 days). Two patients developed ileus and one patient developed deep venous thrombosis in the post-operative period. One patient developed pyelonephritis within one month of surgery. There was no deterioration of renal function with the mean serum creatinine at last follow-up being 0.9 ± 0.36 mg% (range 0.6 - 1.5 mg%). CONCLUSION: The use of an ileal segment in cat-tail configuration for bilateral simultaneous ileal replacement is a feasible and safe option. The medium-term result states that it is effective in the preservation of renal function and provides a good conduit for drainage.

Feasibility, preliminary efficacy, and accessibility of a twitter-based social support group vs Fitbit only to decrease sedentary behavior in women.

BACKGROUND: Health behavior change interventions delivered by social media allow for real-time, dynamic interaction, peer social support, and experimenter-provided content. AIMS: We tested the feasibility, acceptability, and preliminary efficacy of a novel Twitter-based walking break intervention with daily behavior change strategies and prompts for social support, combined with a Fitbit, vs. Fitbit alone. METHODS: In a 2-group pilot, 45 sedentary women from a heart clinic were randomized to Twitter + Fitbit activity tracker (Tweet4Wellness, n = 23) or Fitbit-only (control, n = 22). All received a Fitbit and 13 weeks of tailored weekly step goals. Tweet4Wellness consisted of a private Twitter support group, with daily automated behavior change "tweets" informed by behavior change theory, and encouragement to communicate within the group. Feasibility outcomes included recruitment and enrollment numbers, implementation challenges, and number and type of help requests from participants throughout the study period. Preliminary efficacy outcomes provided by Fitbit data were sedentary minutes, number of hours with >250 steps, maximum sitting bout, weighted sedentary median bout length, total steps, intensity minutes (>3.0 METS), and ratio of time spent sitting-to-moving. Acceptability outcomes included level of Twitter participation within Tweet4Wellness, and Likert scale plus open-ended survey questions on enjoyment and perceived effectiveness of intervention components. Survey data on acceptability of the features of the intervention were collected at 13 weeks (end-of-treatment [EOT]) and 22 weeks (follow-up). RESULTS: The study was feasible, with addressable implementation challenges. Tweet4Wellness participants changed significantly from baseline to EOT relative to control participants on number of active hours p = .018, total steps p = .028, and ratio of sitting-to-moving, p = .014. Only sitting-to-moving was significant at follow-up (p = .047). Among Tweet4Wellness participants, each tweet sent during treatment was associated with a 0.11 increase in active hours per day (p = .04) and a 292-step increase per day (p < .001). Tweet4Wellness participants averaged 54.8 (SD = 35.4) tweets, totaling 1304 tweets, and reported liking the accountability and peer support provided by the intervention. CONCLUSION: A Twitter-delivered intervention for promoting physical activity among inactive women from a heart clinic was feasible, acceptable, and demonstrated preliminary efficacy in increasing daily active hours, daily total steps, and the ratio of sitting-to-moving from pre to post for the intervention compared with the control. Lessons learned from this pilot suggest that the next study should expand the recruitment pool, refine the intervention to increase group engagement, and select active hours, total steps, and ratio of sitting-to-movement as primary sedentary behavior measures.

Pneumothorax following serratus anterior plane block.

Serratus anterior plane blocks may provide analgesia for rib fractures, thoracic surgery and breast surgery. There remains uncertainty regarding the location of injection, be it superficial or deep to the serratus anterior muscle. We describe the case of a 63-year-old ASA physical status 3 woman undergoing a wire-guided wide local excision of a right breast lump. A modified right serratus anterior plane block was performed under ultrasound guidance, injecting 20 ml of bupivacaine 0.25% deep to the serratus anterior muscle. No immediate complications were noted. Intra-operatively the patient developed arterial desaturation associated with high airway pressures. A subsequent chest radiograph in the post-anaesthetic care unit demonstrated a large right-sided pneumothorax which was treated with immediate needle decompression and chest drain insertion. This is the first case of pneumothorax reported from this approach to serratus anterior plane blockade and serves as a reminder of a potential serious complication.

Association between Smoking Exposure, Neoadjuvant Chemotherapy Response and Survival Outcomes following Radical Cystectomy: Systematic Review and Meta-Analysis.

PURPOSE: Studies exploring the association of cigarette smoking and long-term survival outcomes following radical cystectomy have yielded mixed results. We performed a systematic review and meta-analysis to investigate the impact of tobacco smoking exposure, duration, intensity and cessation on response to neoadjuvant chemotherapy and long-term survival outcomes in patients undergoing radical cystectomy for bladder cancer. MATERIALS AND METHODS: We systematically searched PubMed®, MEDLINE®, Embase® and Cochrane® Library databases for original articles published before April 2019. Primary end points were neoadjuvant chemotherapy response, overall and cancer specific mortality, and recurrence-free survival after radical cystectomy. Observational studies reporting Cox proportional hazards regression or logistic regression analysis were independently screened. Available multivariable hazard ratios and corresponding 95% CIs were included in the quantitative analysis. Sensitivity analyses were performed as appropriate. A risk of bias assessment was completed for nonrandomized studies. RESULTS: Our electronic search identified a total of 649 articles. After a detailed review we selected 17 studies that addressed the impact of smoking status on survival outcomes in 13,777 patients after radical cystectomy for bladder cancer. Pooled meta-analysis revealed that active smokers have an increased risk of overall mortality (HR 1.21, 95% CI 1.08-1.36; p=0.001, I2=0%), cancer specific mortality (HR 1.24, 95% CI 1.13-1.36; p <0.00001, I2=0%) and bladder cancer recurrence (HR 1.24, 95% CI 1.12-1.38; p <0.0001, I2=3%). Sensitivity analyses evaluating only patients who underwent neoadjuvant chemotherapy followed by radical cystectomy showed an advantage of non/never smokers in terms of neoadjuvant chemotherapy complete response rate (HR 0.47, 95% CI 0.29-0.75; p=0.001, I2=0%). CONCLUSIONS: Smoking status is associated with lower neoadjuvant chemotherapy response rates and higher overall and cancer specific mortality as well as bladder cancer recurrence after radical cystectomy. Appropriate preoperative counseling, together with tightened followup, may have a pivotal role in improving the smoking-related long-term survival outcomes in patients with bladder cancer.

Best practices in near-infrared fluorescence imaging with indocyanine green (NIRF/ICG)-guided robotic urologic surgery: a systematic review-based expert consensus.

PURPOSE: The aim of the present study is to investigate the impact of the near-infrared (NIRF) technology with indocyanine green (ICG) in robotic urologic surgery by performing a systematic literature review and to provide evidence-based expert recommendations on best practices in this field. METHODS: All English language publications on NIRF/ICG-guided robotic urologic procedures were evaluated. We followed the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement to evaluate PubMed®, Scopus® and Web of Science™ databases (up to April 2019). Experts in the field provided detailed pictures and intraoperative video-clips of different NIRF/ICG-guided robotic surgeries with recommendations for each procedure. A unique QRcode was generated and linked to each underlying video-clip. This new exclusive feature makes the present the first "dynamic paper" that merges text and figure description with their own video providing readers an innovative, immersive, high-quality and user-friendly experience. RESULTS: Our electronic search identified a total of 576 papers. Of these, 36 studies included in the present systematic review reporting the use of NIRF/ICG in robotic partial nephrectomy (n = 13), robotic radical prostatectomy and lymphadenectomy (n = 7), robotic ureteral re-implantation and reconstruction (n = 5), robotic adrenalectomy (n = 4), robotic radical cystectomy (n = 3), penectomy and robotic inguinal lymphadenectomy (n = 2), robotic simple prostatectomy (n = 1), robotic kidney transplantation (n = 1) and robotic sacrocolpopexy (n = 1). CONCLUSION: NIRF/ICG technology has now emerged as a safe, feasible and useful tool that may facilitate urologic robotic surgery. It has been shown to improve the identification of key anatomical landmarks and pathological structures for oncological and non-oncological procedures. Level of evidence is predominantly low. Larger series with longer follow-up are needed, especially in assessing the quality of the nodal dissection and the feasibility of the identification of sentinel nodes and the impact of these novel technologies on long-term oncological and functional outcomes.

Probing the energetic particle environment near the Sun.

NASA's Parker Solar Probe mission1 recently plunged through the inner heliosphere of the Sun to its perihelia, about 24 million kilometres from the Sun. Previous studies farther from the Sun (performed mostly at a distance of 1 astronomical unit) indicate that solar energetic particles are accelerated from a few kiloelectronvolts up to near-relativistic energies via at least two processes: 'impulsive' events, which are usually associated with magnetic reconnection in solar flares and are typically enriched in electrons, helium-3 and heavier ions2, and 'gradual' events3,4, which are typically associated with large coronal-mass-ejection-driven shocks and compressions moving through the corona and inner solar wind and are the dominant source of protons with energies between 1 and 10 megaelectronvolts. However, some events show aspects of both processes and the electron-proton ratio is not bimodally distributed, as would be expected if there were only two possible processes5. These processes have been very difficult to resolve from prior observations, owing to the various transport effects that affect the energetic particle population en route to more distant spacecraft6. Here we report observations of the near-Sun energetic particle radiation environment over the first two orbits of the probe. We find a variety of energetic particle events accelerated both locally and remotely including by corotating interaction regions, impulsive events driven by acceleration near the Sun, and an event related to a coronal mass ejection. We provide direct observations of the energetic particle radiation environment in the region just above the corona of the Sun and directly explore the physics of particle acceleration and transport.

Integrating HIV, syphilis, malaria and anaemia point-of-care testing (POCT) for antenatal care at dispensaries in western Kenya: discrete-event simulation modelling of operational impact.

BACKGROUND: Despite WHO advocating for an integrated approach to antenatal care (ANC), testing coverage for conditions other than HIV remains low and women are referred to distant laboratories for testing. Using point-of-care tests (POCTs) at peripheral dispensaries could improve access to testing and timely treatment. However, the effect of providing additional services on nurse workload and client wait times are unknown. We use discrete-event simulation (DES) modelling to understand the effect of providing four point-of-care tests for ANC on nurse utilization and wait times for women seeking maternal and child health (MCH) services. METHODS: We collected detailed time-motion data over 20 days from one high volume dispensary in western Kenya during the 8-month implementation period (2014-2015) of the intervention. We constructed a simulation model using empirical arrival distributions, activity durations and client pathways of women seeking MCH services. We removed the intervention from the model to obtain wait times, length-of-stay and nurse utilization rates for the baseline scenario where only HIV testing was offered for ANC. Additionally, we modelled a scenario where nurse consultations were set to have minimum durations for sufficient delivery of all WHO-recommended services. RESULTS: A total of 183 women visited the dispensary for MCH services and 14 of these women received point-of-care testing (POCT). The mean difference in total waiting time was 2 min (95%CI: < 1-4 min, p = 0.026) for MCH women when integrated POCT was given, and 9 min (95%CI: 4-14 min, p < 0.001) when integrated POCT with adequate ANC consult times was given compared to the baseline scenario. Mean length-of-stay increased by 2 min (95%CI: < 1-4 min, p = 0.015) with integrated POCT and by 16 min (95%CI: 10-21 min, p < 0.001) with integrated POCT and adequate consult times compared to the baseline scenario. The two nurses' overall daily utilization in the scenario with sufficient minimum consult durations were 72 and 75%. CONCLUSION: The intervention had a modest overall impact on wait times and length-of-stay for women seeking MCH services while ensuring pregnant women received essential diagnostic testing. Nurse utilization rates fluctuated among days: nurses experienced spikes in workload on some days but were under-utilized on the majority of days. Overall, our model suggests there was sufficient time to deliver all WHO's required ANC activities and offer integrated testing for ANC first and re-visits with the current number of healthcare staff. Further investigations on improving healthcare worker, availability, performance and quality of care are needed. Delivering four point-of-care tests together for ANC at dispensary level would be a low burden strategy to improve ANC.

Factors affecting the growth of infants diagnosed with cystic fibrosis by newborn screening.

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) improves nutritional outcomes. Despite early dietetic intervention some children fail to grow optimally. We report growth from birth to 2 years in a cohort of children diagnosed with CF by NBS and identify the variables that influence future growth. METHODS: One hundred forty-four children were diagnosed with CF by the West Midlands Regional NBS laboratory between November 2007 and October 2014. All anthropometric measurements and microbiology results from the first 2 years were collated as was demographic and CF screening data. Classification modelling was used to identify the key variables in determining future growth. RESULTS: Complete data were available on 129 children. 113 (88%) were pancreatic insufficient (PI) and 16 (12%) pancreatic sufficient (PS). Mean birth weight (z score) was 3.17 kg (- 0.32). There was no significant difference in birth weight (z score) between PI and PS babies: 3.15 kg (- 0.36) vs 3.28 kg (- 0.05); p = 0.33. By the first clinic visit the difference was significant: 3.42 kg (- 1.39) vs 4.60 kg (- 0.48); p < 0.0001. Weight and height remained lower in PI infants in the first year of life. In the first 2 years of life, 18 (14%) infants failed to regain their birth weight z score. The median time to achieve a weight z score of - 2, - 1 and 0 was 18, 33 and 65 weeks respectively. The median times to reach the same z scores for height were 30, 51 and 90 weeks. Birth weight z score, change in weight z score from birth to first clinic, faecal elastase, isolation of Pseudomonas aeruginosa, isolation of Staphylococcus aureus and sweat chloride were the variables identified by the classification models to predict weight and height in the first and second year of life. CONCLUSIONS: Babies with CF have a lower birth weight than the healthy population. For those diagnosed with CF by NBS, the weight difference between PI and PS babies was not significantly different at birth but became so by the first clinic visit. The presence of certain factors, most already identifiable at the first clinic visit can be used to identify infant at increased risk of poor growth.

Efficacy of cryotherapy as first line therapy in patients with Barrett's neoplasia: a systematic review and pooled analysis.

Cryotherapy has been used as salvage therapy; however, its efficacy as first line treatment in patients with Barrett's esophagus (BE) neoplasia has not been well studied. The aim of this paper was to perform a systematic review to look at the efficacy of cryotherapy as the primary treatment of BE. An electronic database search was performed (PubMed, Embase, Cochrane, and Google Scholar) to search for studies with cryotherapy as the initial primary modality of ablation in patients with BE neoplasia. Studies that included patients with other prior forms of therapy were excluded. The primary outcomes were the pooled rates of complete eradication of intestinal metaplasia (CE-IM) and CE of neoplasia (CE-N). Secondary outcomes were recurrence rates of neoplasia and intestinal metaplasia (IM) and adverse events. The statistical software OpenMetaAnalyst was used for analysis with pooled estimates reported as proportions (%) with 95% confidence intervals (CI) with heterogeneity (I2) among studies. The search revealed 6 eligible studies with a total of 282 patients (91.5% male, average age 65.3 years) with 459 person years of follow-up. 69.35% [95% CI (52.1%-86.5%)] of patients achieved CE-IM and 97.9% (95% CI: 95.5%-100%) had CE-N. 7.3% of patients had persistent dysplasia with 4% progressing to cancer. The recurrence rate of neoplasia was 10.4 and that of IM was 19.1 per 100 patient years of follow-up. The overall rate of stricture formation was 4.9%. There are scarce data on the use of cryotherapy as the primary modality for the treatment of BE dysplasia. The published data demonstrate efficacy rates of 69% and 98% for complete eradication of metaplasia and neoplasia, respectively. These results need to be assessed in prospective, comparative trials with other forms of therapy.

Intrauterine Growth Restriction Modifies the Accumbal Dopaminergic Response to Palatable Food Intake.

Intrauterine growth restriction (IUGR) associates with increased preference for palatable foods and altered insulin sensitivity. Insulin modulates the central dopaminergic response and changes behavioral responses to reward. We measured the release of dopamine in the accumbens during palatable food intake in IUGR rats both at baseline and in response to insulin. From pregnancy day 10 until birth, gestating Sprague-Dawley rats received either an ad libitum (Control), or a 50% food restricted (FR) diet. In adulthood, palatable food consumption and feeding behavior entropy was assessed using an electronic food intake monitor (BioDAQ®), and dopamine response to palatable food was measured by chronoamperometry recordings in the nucleus accumbens (NAcc). FR rats eat more palatable foods during the dark phase, and their eating pattern has a higher entropy compared to control rats. There was a delayed dopamine release in the FR group in response to palatable food and insulin administration reverted this delayed effect. Western blot showed a decrease in suppressor of cytokine signaling 3 protein (SOCS3) in the ventral tegmental area (VTA) and an increase in the ratio of phospho-tyrosine hydroxylase to tyrosine hydroxylase (pTH/TH) in the NAcc of FR rats. Administration of insulin also abolished this latter effect in FR rats. FR rats showed metabolic alterations and a delay in the dopaminergic response to palatable foods. This could explain the increased palatable food intake and behavioral entropy found in FR rats. IUGR may lead to binge eating, obesity and its metabolic consequences by modifying the central dopaminergic response to sweet food.