Predictors of Acute and Late Toxicity in Patients Receiving Chemoradiation for Unresectable Pancreatic Cancer.

Purpose: Patients with pancreatic cancer undergoing chemoradiation therapy may experience acute and chronic side effects. We conducted an exploratory analysis of patients with locally advanced pancreatic cancer (LAPC) undergoing definitive chemoradiation to identify factors influencing the occurrence of gastrointestinal (GI) bleeding, short-term radiation side effects, patterns of failure, and survival. Methods and Materials: Under an institutional review board-approved protocol, we retrospectively studied patients with LAPC treated with chemoradiation. Statistical models were used to test associations between clinical characteristics and outcomes, including upper GI bleeding, radiation treatment breaks, and weight loss during therapy. Results: Between 1999 and 2012, 211 patients were treated with radiation for pancreatic cancer. All patients received concurrent chemotherapy with either gemcitabine (174) or 5-fluorouracil (27), and 67 received intensity modulated radiation therapy (IMRT). Overall, 18 patients experienced an upper GI bleed related to treatment, with 70% of bleeds occurring in the stomach or duodenum, and among those patients, 11 (61%) patients had a pancreatic head tumor and 17 (94%) patients had a metallic biliary stent. IMRT was associated with decreased risk of postradiation nausea (odds ratio, 0.27 [0.11, 0.67], P = .006) compared with 3-dimensional conformal radiation. Regarding long-term toxicities, patients with a metallic biliary stent at the time of radiation therapy were at a significantly higher risk of developing upper GI bleeding (unadjusted hazard ratio [HR], 15.41 [2.02, 117.42], P = .008), even after controlling for radiation treatment modality and prescribed radiation dose (adjusted HR, 17.38 [2.26, 133.58], P = .006). Furthermore, biliary stent placement was associated with a higher risk of death (HR, 1.99 [1.41, 2.83], P < .001) after adjusting for demographic, treatment-related, and patient-related variables. Conclusions: Metallic biliary stents may be associated with an increased risk of upper GI bleeding and mortality. Furthermore, IMRT was associated with less nausea and short-term toxicity compared with 3-dimensional conformal therapy.

MAIP: An Open-Source Tool to Enrich High-Throughput Screening Output and Identify Novel, Druglike Molecules with Antimalarial Activity.

Efforts to tackle malaria must continue for a disease that threatens half of the global population. Parasite resistance to current therapies requires new chemotypes that are able to demonstrate effectiveness and safety. Previously, we developed a machine-learning-based approach to predict compound antimalarial activity, which was trained on the compound collections of several organizations. The resulting prediction platform, MAIP, was made freely available to the scientific community and offers a solution to prioritize molecules of interest in virtual screening and hit-to-lead optimization. Here, we experimentally validate MAIP and demonstrate how the approach was used in combination with a robust compound selection workflow and a recently introduced innovative high-throughput screening (HTS) cascade to select and purchase compounds from a public library for subsequent experimental screening. We observed a 12-fold enrichment compared with a randomly selected set of molecules, and the eight hits we ultimately selected exhibit good potency and absorption, distribution, metabolism, and excretion (ADME) profiles.

Ruptured subclavian artery pseudoaneurysm following a shoulder massage on a background of clavicle non-union.

We present an unusual case of ruptured subclavian artery pseudoaneurysm following hydrotherapy and shoulder massage session on a background of clavicle non-union.Following a clavicle fracture 16 years ago, which was managed conservatively, a woman in her 30s presents over a decade later with a ruptured subclavian artery pseudoaneurysm.The original midshaft clavicle fracture was sustained 16 years ago. Conservative management was agreed, and she was discharged. Six years ago, she developed a small subclavian artery pseudoaneurysm which was kept under surveillance for 12 months with no active intervention required.Over the following years, she continued to have intermittent shoulder girdle discomfort and neuropathic symptoms. On this presentation, after a sports massage, she presented with rapid-onset supraclavicular and axillary swelling. This was diagnosed as a ruptured subclavian artery pseudoaneurysm and was treated with emergency radiological-guided stenting and subsequent internal fixation of the clavicle non-union.The patient then attended regular orthopaedic and vascular follow-up to ensure her clavicle fracture unites and the graft remains patent.We discuss the case presentation and management of this unusual injury.

Optimal initial diet in mild acute pancreatitis: A comprehensive meta-analysis of randomized control trials.

OBJECTIVE: We performed a comprehensive systematic review and meta-analysis comparing initiation of full solid diet (FSD) versus stepwise diet to better define the management of patients with mild acute pancreatitis (AP). METHODS: Electronic databases were searched through August 2, 2021 for trials comparing initial FSD versus stepwise advancement in patients with mild AP on length of hospital stay (LOHS). We stratified by whether diet was initiated early (within 24 h or immediately upon presence of bowel sounds). RESULTS: We identified seven RCTs that compared LOHS in AP patients who received initial oral intake with solid diet versus stepwise diet. Across the studies a total of 305 patients were randomized to immediate FSD and 308 patients to sequential advancement. Patients who were initiated on a FSD had a significant reduction in total LOHS (Standardized Mean Difference (SMD) -0.52 [95% CI -0.69, -0.36]). There was no difference in post refeeding abdominal pain, tolerance of diet, or necessity to cease diet between the two groups. Sub-analysis of three studies that initiated FSD early reduced total LOHS (OR -0.95 [95% CI -1.26, -0.65]) compared to those who received graded diet advancement as well as higher likelihood of tolerating the assigned diet (OR 6.8 [95% CI 1.2, 39.2]). CONCLUSIONS: Our meta-analysis shows that initiation of FSD reduces total LOHS in patients with mild AP and does not increase post refeeding abdominal pain. Though additional high-quality studies are needed, these findings support initial solid diet for AP and consideration of feeding within the first 24 h.

Convolvulus pluricaulis extract can modulate synaptic plasticity in rat brain hippocampus.

The memory-boosting property of Indian traditional herb, Convolvulus pluricaulis, has been documented in literature; however, its effect on synaptic plasticity has not yet been reported. Two important forms of synaptic plasticity known to be involved in the processes of memory formation are long-term potentiation (LTP) and long-term depression (LTD). In the present study, the effect of C. pluricaulis plant extract on LTP and LTD were evaluated. The adult male Wistar rats were fed orally with 250, 500 and 1000 mg/kg of this extract for 4 weeks and the effect was determined on LTP and LTD in the Schaffer collaterals of the hippocampal cornu ammonis region CA1. We found that the 500 mg/kg dose of the extract could significantly enhance LTP compared to the vehicle treated ones. Moreover, the same dose could also reduce LTD while used in a separate set of animals. Also, a fresh group of animals treated with the effective dose (500 mg/kg) of plant extract were examined for memory retention in two behavioral platforms namely, contextual fear conditioning (CFC) and novel object recognition test (NORT). Increased fear response to the conditioned stimulus and enhanced recognition of objects were observed in CFC and NORT, respectively, both indicating strengthening of memory. Following up, ex-vivo electrophysiology experiments were performed with the active single molecule scopoletin, present in C. pluricaulis extract and similar patterns in synaptic plasticity changes were obtained. These findings suggest that prolonged treatment of C. pluricaulis extract, at a specific dose in healthy animals, can augment memory functions by modulating hippocampal plasticity.

A pilot randomized controlled trial (RCT) of daily versus weekly interactive voice response calls to support adherence among antiretroviral treatment patients in India.

BACKGROUND: There are more than two million people living with HIV (PLH) in India, with more than 30% on antiretroviral treatment (ART) estimated to be non-adherent. This study aimed to (I) document adherence rates and related factors among ART patients in a large ART clinic in India, and (II) pilot test daily and weekly interactive voice response (IVR) calls to improve ART adherence and related outcomes. METHODS: ART patients reporting missing at least one dose in prior 6 months (N=362) were enrolled and assessed via self-report and medical record review. Participants were randomized to one of two conditions: (I) twice-daily IVR call reminders with self-management support messaging, plus a weekly IVR adherence assessment; or (II) an attention control, with only weekly IVR adherence assessment. Participants completed study assessments at baseline, 2-, 4-, and 6-months with high retention (88% to 96%). RESULTS: Intention-to-treat analyses found limited support for intervention effects for improving or maintaining ART adherence or CD4 counts between the two study arms over 6-months follow-up. Adherence increased significantly in the six months prior to baseline from about 65% to >95% with perfect adherence based on pill counts from medical records and consistent with patient self-report measures, which presented ceiling effects for detecting improvements in ART adherence in response to IVR intervention exposure. There was also limited support for intervention effects on secondary, self-management outcomes. CONCLUSIONS: High levels of adherence were sustained throughout the 6-month RCT. IVR regulation changes in India delayed study launch for 6 months, which likely allowed mobilization of improved adherence at the clinic, provider and patient levels in anticipation of the study launch. Therefore, ceiling effects limited inferences on intervention effects to improve adherence. Results suggest that clinic-level adherence monitoring may be sufficient to mobilize adherence improvements by providers and patients. TRIAL REGISTRATION: ClinicalTrials.gov registration #NCT02118454.

The effects of temporary intraocular pressure spikes after intravitreal dexamethasone implantation on the retinal nerve fiber layer.

Background and objective: The dexamethasone (DEX) implant is known to cause temporary intraocular pressure (IOP) spikes after implantation. The purpose of this study is to determine if IOP spikes after DEX implant cause significant thinning in the retinal nerve fiber layer (RNFL). Study design, patients, and methods: A total of 306 charts were reviewed with 48 and 21 patients meeting inclusion criteria for the cross-sectional and prospective groups, respectively. Cross-sectional inclusion criteria: IOP spike ≥22 mmHg up to 16 weeks after DEX implant, DEX implant in only 1 eye per patient, and spectral-domain optical coherence tomography (OCT) RNFL imaging of both eyes ≥3 months after IOP spike. Prospective inclusion criteria: OCT RNFL performed within 1 year prior to DEX implantation, IOP spike ≥22 mmHg up to 16 weeks after DEX implant, and OCT RNFL performed ≥3 months after IOP spike. The average RNFL thickness in the contralateral eye was used as the control in the cross-sectional group. Institutional review board approval was obtained. Results: In the cross-sectional group, there was no statistically significant difference in the mean RNFL thicknesses in the treated vs untreated eyes (80.4±15.5 µm and 82.6±15.8 µm, respectively; P=0.33) regardless of treatment diagnosis, magnitude of IOP spike, or history of glaucoma. In the prospective group, mean RNFL thicknesses before and after IOP spikes ≥22 mmHg were similar (78.0±14.8 µm and 75.6±13.6 µm, respectively; P=0.13). Conclusion and relevance: Temporary elevation of IOP after DEX implantation when treated with topical IOP lowering drops does not appear to lead to a meaningful change in RNFL thickness.

Correction: Gender disparities in depression severity and coping among people living with HIV/AIDS in Kolkata, India.

[This corrects the article DOI: 10.1371/journal.pone.0207055.].

Gender disparities in depression severity and coping among people living with HIV/AIDS in Kolkata, India.

People living with HIV/AIDS (PLH) experience high rates of depression and related psychosocial risk factors that vary by gender. This study examines gender differences in depression severity among antiretroviral therapy (ART) patients (n = 362) from a large government ART clinic in Kolkata, India. Hypotheses for multiple linear regression models were guided by an integrated gendered stress process model focusing on variables reflecting social status (age, partner status), stressors (stigma), and resources (income, social support). Depressive symptoms were assessed with the Hospital Anxiety and Depression Scale (HADS); 22% of the sample reached the cutoff for severe depression, 56% moderate, and 13% mild depression. Compared to men, women reported lower income, education (50% no formal education vs. 20% men), availability of emotional and instrumental support, and were less likely to be married or cohabiting (53% women vs. 72% of men). However, more women had partners who were HIV-positive (78% women vs. 46% men). Overall, depression severity was negatively associated with availability of emotional support and self-distraction coping, and positively associated with internalized HIV/AIDS stigma, availability of instrumental support, and behavioral disengagement coping. Interactions for instrumental support by income and partner status by age varied significantly by gender. Analyses stratified by gender indicated that: 1) Frequently seeking instrumental support from others was protective for men at all income levels, but only for high-income women; and 2) having a partner was protective for men as they aged, but not for women. These results suggest that gender disparities in depression severity are created and maintained by women's lower social status and limited access to resources. The effect of stigma on depression severity did not vary by gender. These findings may inform the tailoring of future interventions to address mental health needs of PLH in India, particularly gender disparities in access to material and social resources for coping with HIV. Trial Registration: ClinicalTrials.gov registration #NCT02118454, registered April 2014.

Chronic but not acute immobilization stress stably enhances hippocampal CA1 metabotropic glutamate receptor dependent Long-Term Depression.

Acute stress has been shown to facilitate but not increase metabotropic glutamate receptor (mGluR) mediated Long-Term Depression (LTD) in the hippocampus. However, the effect of chronic stress on mGluR dependent LTD has not been investigated. Moreover, whether stress leads to a transient modification LTD threshold or a more stable change in synaptic plasticity needs to be addressed. In the present study, we have explored the effects of both a ten-day long and a single day immobilization stress protocol on mGluR-LTD at the CA3:CA1synapse in the hippocampus of adult male Sprague-Dawley rats, a day after applying stress. Bath application of the selective group 1 mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) promoted robust LTD in hippocampal slices from control (i.e. un-stressed) animals. Administration of immobility stress for two hours per day for ten days significantly elevated this LTD to a level almost twice that of control, when observed 24h following the last stress event. Acute stress i.e. a single day of two hours of immobilization, however, failed to significantly enhance LTD, 24h later. These results demonstrate for the first time, that repeated exposure to stress, but not a single stress event, is required to bring about a stable alteration in mGluR mediated synaptic plasticity.

Two-stage Revision for Periprosthetic Hip and Knee Joint Infections.

BACKGROUND: Periprosthetic joint infection (PJI) continues to be one of the leading causes of failure following hip and knee surgery. The diagnostic workflow of PJI includes detailed clinical examination, serum markers, imaging and aspiration/biopsy of the affected joint. The goals of treatment are eradication of the infection, alleviation of pain, and restoration of joint function. Surgical management of PJI consists of debridement, antibiotics and implant retention (DAIR) and single or two-stage revision procedures. Two-stage revision remains the gold standard for treatment of PJIs. We aim to discuss the two stage procedure in this article and report the outcomes. METHODS: The first stage of the two stages consists of removal of all components and associated cement with aggressive debridement and placement of an antibiotic-loaded cement spacer. Patients are then treated with variable periods of parenteral antibiotics, followed by an antibiotic free period to help ensure the infection has been eradicated. If the clinical evaluation and serum inflammatory markers suggest infection control, then the second stage can be undertaken and this involves removal of the cement spacer, repeat debridement, and placement of a new prosthesis. RESULTS: Common themes around the two-stage revision procedure include timing of the second stage, antibiotics used in the interim period, length of the interim period before consideration of reimplantation and close liaising with microbiologists. CONCLUSION: Successful eradication of infection and good functional outcome using the two stage procedure is dependent on a multidisciplinary approach and having a standard reproducible startegy.

Approaches to isolation and molecular characterization of disseminated tumor cells.

Micrometastatic cells in the bone marrow, now usually referred to as "disseminated tumor cells (DTCs)", can be detected in early stage cancer patients. It has been hypothesized that DTCs represent key intermediates in the metastatic process as possible precursors of bone and visceral metastases, and are indicators of metastatic potential. Indeed, multiple clinical studies have unequivocally demonstrated the prognostic value of these cells in breast and other cancers, as DTCs have been associated with adverse outcomes, including inferior overall and disease-free survival. Despite this established clinical significance, the molecular nature of DTCs remains elusive. The complexity of the bone marrow poses a unique challenge in the isolation and direct characterization of these rare cells. However, recent advances in rare-cell technology along with technical improvements in analyzing limited cell inputs have enabled the molecular profiling of DTCs. In this review, we discuss research featuring the isolation and genomic analysis of DTCs. Emerging work on the molecular characterization of DTCs is now providing new insights into the biology of these cells.