Current axillary management of patients with early breast cancer and low-volume nodal disease undergoing primary surgery: results of a United Kingdom national practice survey.

PURPOSE: UK NICE guidelines recommend axillary node clearance (ANC) should be performed in all patients with biopsy-proven node-positive breast cancer having primary surgery. There is, however, increasing evidence such extensive surgery may not always be necessary. Targeted axillary dissection (TAD) may be an effective alternative in patients with low-volume nodal disease who are clinically node negative (cN0) but have abnormal nodes detected radiologically. This survey aimed to explore current management of this group to inform feasibility of a future trial. METHODS: An online survey was developed to explore current UK management of patients with low-volume axillary disease and attitudes to a future trial. The survey was distributed via breast surgery professional associations and social media from September to November 2022. One survey was completed per unit and simple descriptive statistics used to summarise the results. RESULTS: 51 UK breast units completed the survey of whom 78.5% (n = 40) reported performing ANC for all patients with biopsy-proven axillary nodal disease having primary surgery. Only 15.7% of units currently performed TAD either routinely (n = 6, 11.8%) or selectively (n = 2, 3.9%). There was significant uncertainty (83.7%, n = 36/43) about the optimal surgical management of these patients. Two-thirds (n = 27/42) of units felt an RCT comparing TAD and ANC would be feasible. CONCLUSIONS: ANC remains standard of care for patients with low-volume node-positive breast cancer having primary surgery in the UK, but considerable uncertainty exists regarding optimal management of this group. This survey suggests an RCT comparing the outcomes of TAD and ANC may be feasible.

A Geospatial Analysis of Social and Structural Determinants of Health and High HIV Prevalence in Alabama, USA.

OBJECTIVE: This study utilizes geospatial analytic techniques to examine HIV hotspots in Alabama leveraging Medicaid utilization data. METHODS: This cross-sectional study leveraged Medicaid utilization data from Alabama's 67 counties, averaging 9,861 Medicaid recipients aged > 18 years old per county. We used Alabama Medicaid administrative claims data from January 1, 2016, to December 31, 2020, to identify individuals with HIV. Using Microsoft SQL Server, we obtained the average annual count of HIV Medicaid claims in each of the 67 Alabama counties (numerator) and the number of adult Medicaid recipients in each county (denominator), and standardized with a multiplier of 100,000. We also examined several other area-level summary variables (e.g., non-high school completion, income greater than four times the federal poverty level, social associations, urbanicity/rurality) as social and structural determinants of health. County-boundary choropleth maps were created representing the geographic distribution of HIV rates per 100,000 adult Medicaid recipients in Alabama. Leveraging ESRI ArcGIS and local indicators of spatial association (LISA), results were examined using local Moran's I to identify geographic hotspots. RESULTS: Eleven counties had HIV rates higher than 100 per 100,000. Three were hotspots. Being an HIV hotspot was significantly associated with relatively low educational attainment and less severe poverty than other areas in the state. CONCLUSIONS: Findings suggesting that the HIV clusters in Alabama were categorized by significantly less severe poverty and lower educational attainment can aid ongoing efforts to strategically target resources and end the HIV epidemic in U.S.' Deep South.

The incidence of malignancy in the residual rectum of IBD patients after colectomy: a systematic review and meta-analysis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) who have had a total colectomy remain with their rectum in situ, and are therefore at risk of rectal carcinoma. It is not clear how high the incidence of rectal cancer is in this cohort. The primary objective of this meta-analysis was to estimate the incidence of rectal cancer in patients with ulcerative colitis or Crohn's disease who have undergone colectomy but have a residual rectum, and to identify the risk factors for its development. In doing so, we explore the current recommendations for screening processes for these patients. METHODS: A systematic review of the literature was performed. Five databases (Medline, Embase, Pubmed, Cochrane Library and Scopus) were searched from inception to 29 October 2021, to identify studies adhering to the population, intervention, control and outcomes (PICO) criteria. The included studies were critically appraised, and the relevant data was extracted. Cancer incidence was estimated from the reported information. Risk stratification was analysed using RevMan. A narrative approach was undertaken for the exploration of the existing screening guidelines. RESULTS: Data from 23 of the 24 identified studies was suitable for analysis. The pooled incidence of rectal carcinoma was calculated to be 1.3%. Subgroup analysis showed an incidence of 0.7% and 3.2% for patients with a de-functioned rectal stump and ileorectal anastomosis, respectively. Patients with a history of a colorectal carcinoma were more likely to have a subsequent diagnosis of rectal carcinoma (RR 7.2, 95% CI 2.4-21.1). Patients with previous colorectal dysplasia were also at higher risk (RR 5.1, 95% CI 3.1-8.2). No universal standardised guidance regarding screening for this cohort could be identified in the available literature. CONCLUSIONS: The overall risk of malignancy was estimated to be 1.3%, which is lower than previously reported. There is a need for clear and standardised screening guidance for this group of patients.

Innovations for the future of breast surgery.

BACKGROUND: Future innovations in science and technology with an impact on multimodal breast cancer management from a surgical perspective are discussed in this narrative review. The work was undertaken in response to the Commission on the Future of Surgery project initiated by the Royal College of Surgeons of England. METHODS: Expert opinion was sought around themes of surgical de-escalation, reduction in treatment morbidities, and improving the accuracy of breast-conserving surgery in terms of margin status. There was emphasis on how the primacy of surgical excision in an era of oncoplastic and reconstructive surgery is increasingly being challenged, with more effective systemic therapies that target residual disease burden, and permit response-adapted approaches to both breast and axillary surgery. RESULTS: Technologies for intraoperative margin assessment can potentially half re-excision rates after breast-conserving surgery, and sentinel lymph node biopsy will become a therapeutic procedure for many patients with node-positive disease treated either with surgery or chemotherapy as the primary modality. Genomic profiling of tumours can aid in the selection of patients for neoadjuvant and adjuvant therapies as well as prevention strategies. Molecular subtypes are predictive of response to induction therapies and reductive approaches to surgery in the breast or axilla. CONCLUSION: Treatments are increasingly being tailored and based on improved understanding of tumour biology and relevant biomarkers to determine absolute benefit and permit delivery of cost-effective healthcare. Patient involvement is crucial for breast cancer studies to ensure relevance and outcome measures that are objective, meaningful, and patient-centred.

This article describes how future innovations in science and technology influence the management of breast cancer from a surgical perspective. This work was undertaken in response to the Commission on the Future of Surgery project initiated by the Royal College of Surgeons of England.

The NeST (Neoadjuvant systemic therapy in breast cancer) study: National Practice Questionnaire of United Kingdom multi-disciplinary decision making.

BACKGROUND: Neoadjuvant systemic therapy (NST) is increasingly used in the treatment of breast cancer, yet it is clear that there is significant geographical variation in its use in the UK. This study aimed to examine stated practice across UK breast units, in terms of indications for use, radiological monitoring, pathological reporting of treatment response, and post-treatment surgical management. METHODS: Multidisciplinary teams (MDTs) from all UK breast units were invited to participate in the NeST study. A detailed questionnaire assessing current stated practice was distributed to all participating units in December 2017 and data collated securely usingREDCap. Descriptive statistics were calculated for each questionnaire item. RESULTS: Thirty-nine MDTs from a diverse range of hospitals responded. All MDTs routinely offered neoadjuvant chemotherapy (NACT) to a median of 10% (range 5-60%) of patients. Neoadjuvant endocrine therapy (NET) was offered to a median of 4% (range 0-25%) of patients by 66% of MDTs. The principal indication given for use of neoadjuvant therapy was for surgical downstaging. There was no consensus on methods of radiological monitoring of response, and a wide variety of pathological reporting systems were used to assess tumour response. Twenty-five percent of centres reported resecting the original tumour footprint, irrespective of clinical/radiological response. Radiologically negative axillae at diagnosis routinely had post-NACT or post-NET sentinel lymph node biopsy (SLNB) in 73.0 and 84% of centres respectively, whereas 16% performed SLNB pre-NACT. Positive axillae at diagnosis would receive axillary node clearance at 60% of centres, regardless of response to NACT. DISCUSSION: There is wide variation in the stated use of neoadjuvant systemic therapy across the UK, with general low usage of NET. Surgical downstaging remains the most common indication of the use of NAC, although not all centres leverage the benefits of NAC for de-escalating surgery to the breast and/or axilla. There is a need for agreed multidisciplinary guidance for optimising selection and management of patients for NST. These findings will be corroborated in phase II of the NeST study which is a national collaborative prospective audit of NST utilisation and clinical outcomes.

Ethnicity-specific pharmacogenetics: the case of warfarin in African Americans.

Using a derivation cohort (N=349), we developed the first warfarin dosing algorithm that includes recently discovered polymorphisms in VKORC1 and CYP2C9 associated with warfarin dose requirement in African Americans (AAs). We tested our novel algorithm in an independent cohort of 129 AAs and compared the dose prediction to the International Warfarin Pharmacogenetics Consortium (IWPC) dosing algorithms. Our algorithm explains more of the phenotypic variation (R(2)=0.27) than the IWPC pharmacogenomics (R(2)=0.15) or clinical (R(2)=0.16) algorithms. Among high-dose patients, our algorithm predicted a higher proportion of patients within 20% of stable warfarin dose (45% vs 29% and 2% in the IWPC pharmacogenomics and clinical algorithms, respectively). In contrast to our novel algorithm, a significant inverse correlation between predicted dose and percent West African ancestry was observed for the IWPC pharmacogenomics algorithm among patients requiring ⩾60 mg per week (ß=-2.04, P=0.02).

LQTS in Northern BC: homozygosity for KCNQ1 V205M presents with a more severe cardiac phenotype but with minimal impact on auditory function.

Long QT syndrome (LQTS), a rare congenital cardiac condition associated with life-threatening ventricular arrhythmias is characterized by a prolonged QT interval on electrocardiograph corrected for heart rate [corrected QT (QTc)]. LQTS has been historically categorized into the autosomal dominant Romano-Ward syndrome (RWS) and the autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS). JLNS is associated with prelingual sensorineural deafness. Both types of LQTS can be caused by mutations in channel genes (e.g. KCNQ1) responsible for potassium homeostasis in cardiac myocytes and cochlea. Autosomal dominant mutations often cause the RWS phenotype and homozygous or compound heterozygous mutations contribute to JLNS. Two First Nations communities in northern British Columbia are affected disproportionately with LQTS largely due to the V205M mutation in KCNQ1, however, the pathology and phenotypic expression for those V205M homozygous has been unknown. Here, we show that four V205M homozygous individuals have a significantly higher 'peak' QTc, and a more severe cardiac phenotype compared with 41 V205M heterozygous carriers and 57 first to third degree relatives without mutations. Given the lack of prelingual deafness the homozygous V205M LQTS patients present with a phenotype more typical of RWS than JLNS.

The establishment of a 3D breast photography service in medical illustration.

This paper aims to describe the development of a 3D breast photography service managed by the Medical Illustration Department, in the Belfast Health and Social Care Trust, Northern Ireland. Dedicated 3D breast photography equipment was installed in Medical Illustration for 18 months. Women were referred for a variety of indications including pre- and post-surgical assessment. A dedicated 3D breast photography protocol was developed locally and this requires further refinement to allow reproducibility in other centres. There are image/data artefacts associated with this technology and special techniques are required to reduce these. Specialist software is necessary for clinicians and scientists to use 3D breast photography data in surgical planning and measurement of surgical outcome.

Tibetans exhibit lower hemoglobin concentration and decreased heart response to hypoxia during poikilocapnia at intermediate altitude relative to Han Chinese.

Background: High-altitude populations exhibit distinct cellular, respiratory, and cardiovascular phenotypes, some of which provide adaptive advantages to hypoxic conditions compared to populations with sea-level ancestry. Studies performed in populations with a history of high-altitude residence, such as Tibetans, support the idea that many of these phenotypes may be shaped by genomic features that have been positively selected for throughout generations. We hypothesize that such traits observed in Tibetans at high altitude also occur in Tibetans living at intermediate altitude, even in the absence of severe sustained hypoxia. Methodology: We studied individuals of high-altitude ancestry (Tibetans, n = 17 females; n = 12 males) and sea-level ancestry (Han Chinese, n = 6 females; n = 10 males), both who had been living at ∼1300 m (∼4327 ft) for at least 18 months. We measured hemoglobin concentration ([Hb]), hypoxic ventilatory response (HVR), and hypoxic heart rate response (HHRR) with end-tidal CO2 (PetCO2) held constant (isocapnia) or allowed to decrease with hypoxic hyperventilation (poikilocapnia). We also quantified the contribution of CO2 on ventilation and heart rate by calculating the differences of isocapnic versus poikilocapnic hypoxic conditions (Δ V˙I/ΔPetCO2 and ΔHR/ΔPetCO2, respectively). Results: Male Tibetans had lower [Hb] compared to Han Chinese males (p < 0.05), consistent with reports for individuals from these populations living at high altitude and sea level. Measurements of ventilation (resting ventilation, HVR, and PetCO2) were similar for both groups. Heart rate responses to hypoxia were similar in both groups during isocapnia; however, HHRR in poikilocapnia was reduced in the Tibetan group (p < 0.03), and the heart rate response to CO2 in hypoxia was lower in Tibetans relative to Han Chinese (p < 0.01). Conclusion: These results suggest that Tibetans living at intermediate altitude have blunted cardiac responses in the context of hypoxia. Hence, only some of the phenotypes observed in Tibetans living at high altitude are observed in Tibetans living at intermediate altitude. Whereas blunted cardiac responses to hypoxia is revealed at intermediate altitudes, manifestation of other physiological adaptations to high altitude may require exposure to more severe levels of hypoxia.

A Phase II, randomized, double-blind study of zibotentan (ZD4054) in combination with carboplatin/paclitaxel versus placebo in combination with carboplatin/paclitaxel in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy (AGO-OVAR 2.14).

BACKGROUND: In platinum-sensitive relapsed ovarian cancer, paclitaxel plus carboplatin is a standard second-line treatment. Zibotentan (ZD4054) is an oral, specific ETA-receptor antagonist with demonstrated antitumour activity in xenograft models of human ovarian cancer. METHODS: In this Phase II, randomized, placebo-controlled study, patients with relapsed ovarian cancer sensitive to platinum-based chemotherapy received zibotentan 10mg or placebo once-daily, plus paclitaxel 175 mg/m(2) iv followed by carboplatin iv (AUC 5) on day 1 of every 3-week cycle for a maximum of eight cycles. The primary endpoint was progression-free survival (PFS), evaluated by Response Evaluation Criteria In Solid Tumours (RECIST). Secondary and exploratory endpoints included objective tumour response rate, tumour size, CA-125/RECIST progression, and safety and tolerability. RESULTS: A total of 120 patients were randomized (zibotentan: n=59; placebo: n=61). Addition of zibotentan 10mg/day to carboplatin and paclitaxel did not improve PFS compared with placebo (median PFS, 7.6 versus 10.0 months, respectively; HR=1.46, [80% CI: 1.10-1.94]; P=0.0870). No improvements in any of the secondary or exploratory efficacy endpoints were observed for patients receiving zibotentan compared with placebo. Median duration of total treatment exposure was 6.7 months. Total chemotherapy dose received was lower for zibotentan-treated versus placebo-treated patients (carboplatin: -16%; paclitaxel: -14%). The most common adverse events in the zibotentan arm were anaemia, nausea, alopecia, headache and neutropenia (43-48% of patients). CONCLUSIONS: Zibotentan 10mg/day plus carboplatin and paclitaxel did not result in an improvement in PFS compared with chemotherapy alone in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy. No unexpected safety concerns were identified.

Medication-assisted treatment and self-help group participation among military veterans with opioid or alcohol use disorder.

INTRODUCTION: Medication-assisted treatment (MAT) is a combination of behavioural therapy and medications to assist with recovery and has been administered to individuals with alcohol and opioid withdrawal symptoms. Military veterans seeking MAT could have barriers preventing them from receiving the care they desire. The present study sought to compare outcomes in individuals who received MAT or those who participated in self-help groups for opioid or alcohol use disorder. In addition, the present study sought to compare outcomes between veterans and non-military-connected individuals. METHODS: We used the 2015-2017 United States Treatment Episode Data Set Discharges data from the Substance Abuse and Mental Health Services Administration. The data set included 138 594 unique discharges. A multinomial logistic regression model was used to examine differences in substance use outcomes for veterans/non-veterans in MAT and a self-help group. RESULTS: Fewer veterans (2.58%) than non-veterans (4.28%) reported usage of MAT. Fewer veterans (38.94%) than non-veterans (40.17%) reported signing up for a self-help group. Finally, those who participated in MAT and a self-help group had a better outcome (66.64%)-defined as no substance use at discharge-than those who only received MAT (43.02%) and those who did not participate in MAT or self-help groups (34.84%). CONCLUSIONS: Recommendations for future research on MAT and implementation for the veteran population would benefit the literature base.

Potential role of vacuum-assisted procedures in resecting breast cancers and highlighting selection criteria to support future trials.

Purpose: The purpose of this study was to evaluate the role of vacuum-assisted biopsy (VAB) in resecting breast cancers. Methods: Retrospective database analysis of 116 cancers [both invasive breast cancers (IC) and ductal carcinoma in situ (DCIS)] diagnosed by VAB submitted to standard surgical treatment with complete histological data from VAB and surgery. Excision following VAB was defined as complete resection (CR) if there was no residual tumor in the surgical specimen, minimal residual disease (MRD) if residual tumor ≤ 3 mm, gross residual disease (GRD) if residual tumor > 3 mm, and upgrade from DCIS on VAB to IC. CR and MRD were combined as potentially resected percutaneously (PRP). GRD and those with upgrade to IC were determined not eligible for percutaneous resection (NPR). Factors predictive of PRP were evaluated. Results: Mean age was 55.6 years (20-91; SD: 12,27). CR was seen in 29 of 116 cases (25%), MRD in 18 of 116 cases (15.5%), GRD in 64 of 116 cases (55.2%), and five of 116 cases (4.3%) were upgraded from DCIS to IC, and those groups combined represented 47 cases of PRP (40.5%) and 69 (59,5%) of NPR. For 77 tumors ≤ 10 mm, 45 (58.5%) were PRP. Multivariate analysis reveals significance for enlarged VAB (EVAB) (p = 0.008, OR: 4.4, 95% CI), low/intermediate nuclear grade (p < 0.001, OR: 12.5, 95% CI) and final tumor size (T) ≤ 10 mm (p = 0.001, OR: 50.1, 95% CI) for PRP. Conclusions: This study showed that lesions completely excised with VAB that were cancer could have been treated with VAB rather than surgery but tumor selection in terms of subtype and size is important.

Expert UK consensus on the definition of high risk of recurrence in HER2-negative early breast cancer: A modified Delphi panel.

BACKGROUND: There is currently no standardised definition for patients at high risk of recurrence of human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC; stages 1-3) after surgery. This modified Delphi panel aimed to establish expert UK consensus on this definition, separately considering hormone receptor (HR)-positive and triple-negative (TN) patients. METHODS: Over three consecutive rounds, results were collected from 29, 24 and 22 UK senior breast cancer oncologists and surgeons, respectively. The first round aimed to determine key risk factors in each patient subgroup; subsequent rounds aimed to establish appropriate risk thresholds. Consensus was pre-defined as ≥70% of respondents. RESULTS: Expert consensus was achieved on need to assess age, tumour size, tumour grade, number of positive lymph nodes, inflammatory breast cancer and risk prediction tools in all HER2-negative patients. There was additional agreement on use of tumour profiling tests and biomarkers in HR-positive patients, and pathologic complete response (pCR) status in TN patients. Thresholds for high recurrence risk were subsequently agreed. In HR-positive patients, these included age <35 years, tumour size >5 cm (as independent risk factors); tumour grade 3 (independently and combined with other high-risk factors); number of positive nodes ≥4 (independently) and ≥1 (combined). For TN patients, the following thresholds reached consensus, both independently and in combination with other factors: tumour size >2 cm, tumour grade 3, number of positive nodes ≥1. CONCLUSIONS: The results may be a valuable reference point to guide recurrence risk assessment and decision-making after surgery in the HER2-negative eBC population.

Post mastectomy radiotherapy in breast cancer: a survey of current United Kingdom practice.

PURPOSE: Radiotherapy (RT) is increasingly used following mastectomy for breast cancer. While indications for post-mastectomy radiotherapy (PMRT) are clear in patient groups at high risk of local recurrence, guidelines are less clear in intermediate-risk patients and patients with ductal carcinoma in situ (DCIS). This study aimed to determine variations in the use of PMRT in the United Kingdom (UK). METHODS: A postal survey of all consultant breast surgeon members of the Association of Breast Surgery in the UK. RESULTS: Tumour size and nodal status were confirmed as the most important indications for PMRT. There was significant variation in the influence of other factors such as tumour grade, lymphovascular invasion and margin status. Nineteen per cent of respondents stated that they would consider the use of PMRT in cases of DCIS alone. CONCLUSIONS: There is significant variation in practice across the UK with regard to the use of PMRT in intermediate risk breast cancer and patients with DCIS. Further work is required to determine which patients in these groups are likely to benefit from the use of PMRT.

Illicit drug use and self-reported vision loss among military service members or veterans.

INTRODUCTION: Little is known about differences in vision loss prevalence among service members or veterans (SMVs) and civilians; further, no study has compared vision loss risk factors in these two populations. As such, we seek to fill this gap in the literature. METHODS: In this cross sectional study, we obtained data on 106 SMVs and 1572 civilians from the 2013-2018 National Health and Nutrition Examination Surveys. We compared the prevalence of or mean values of vision loss risk factors between SMVs and civilians using the Wald χ2 statistic or Kruskal-Wallis test. Further, we examined the relative strength of 17 vision loss risk factors in predicting self-reported vision loss via Firth's logistic regression. RESULTS: SMVs had a significantly higher prevalence of illicit drug use (20.75% vs 13.62%) and HIV (1.89% vs 0.41%), while civilians had a higher prevalence of poor dietary habits (7.61% vs 13.21%). SMVs also had higher mean values of systolic blood pressure (125.85 vs 122.53 mmHg), pack years of cigarette smoking (8.29 vs 4.25), and sedentary minutes per day (379.15 vs 337.07 min). More SMVs (8.49%) self-reported vision loss than civilians (4.48%). After adjustment for covariates, illicit drug use (adjusted ß coefficient=0.72, p=0.02) was associated with self-reported vision loss. CONCLUSIONS: This study indicates that self-reported vision loss among SMVs is more prevalent than among civilians, and vision loss in SMVs is associated with severe or prolonged illicit drug use.

Alcohol screening and brief intervention among military service members and veterans: rural-urban disparities.

BACKGROUND: Access to screening, brief intervention and referral to treatment programmes for alcohol use have been shown to be effective; however, little is known about access to these services among service members and veterans. We examined the association of service member or veteran rural-dwelling area and the following outcomes: recent general health check-up, alcohol screening and alcohol brief intervention. METHODS: Data on 5080 military service members and veterans were obtained from the 2017 Behavioural Risk Factor Surveillance System of the USA. We estimated rural-urban disparities in the receipt of a recent voluntary general health check-up, as well as the receipt of alcohol screening and brief intervention, using a mixed logit model. RESULTS: Of the 5080 participants in the study, a total of 4666 (90.49%, 95% CI 89.39% to 91.48%) reported a general health check-up in the last 2 years. Results showed 7.48% of the sample (95% CI 6.64% to 8.41%) exhibited heavy alcohol consumption patterns. Of the 414 participants who did not undergo a general health check-up, 13.80% (95% CI 9.63% to 19.41%) exhibited a pattern of heavy alcohol consumption. Rural individuals were less likely to report a recent health check-up (adjusted OR=0.82, 95% CI 0.79 to 0.87). Rurality was also independently associated with decreased likelihood of receiving an alcohol screening and brief intervention. CONCLUSION: Greater access to telehealth or other geographically flexible screening and brief intervention programmes is needed in rural areas for service members and veterans.

Trends and prospects of geothermal energy as an alternative source of power: A comprehensive review.

The world has capitalized on numerous renewable energy resources by developing its energy infrastructure mainly around solar, biomass, and hydro energy. However, geothermal energy has not yet been developed at a significant scale, despite reports from 62 wells showing evidence of geothermal gradients ranging from 20.8 °C/km to 48.7 °C/km in various areas of the world. Recent studies suggest that Bangladesh also has a huge potential for geothermal energy. This review extensively reports on exploiting the range of geothermal temperature in various direct and indirect energy application sectors including but not limited to the agriculture and industrial sector of Bangladesh. Additionally, the authors have analyzed and proposed adaptable measures to harness the abundance of geothermal energy. Furthermore, a comparative and possible solution has been discussed extensively for implementing a geothermal powerplant by analyzing techno-economic costs, policies, and systems of other countries in the world. Further, this review also shows the prospect of geothermal energy for Bangladesh as a case study.

Robustness of differential gene expression analysis of RNA-seq.

RNA-sequencing (RNA-seq) is a relatively new technology that lacks standardisation. RNA-seq can be used for Differential Gene Expression (DGE) analysis, however, no consensus exists as to which methodology ensures robust and reproducible results. Indeed, it is broadly acknowledged that DGE methods provide disparate results. Despite obstacles, RNA-seq assays are in advanced development for clinical use but further optimisation will be needed. Herein, five DGE models (DESeq2, voom + limma, edgeR, EBSeq, NOISeq) for gene-level detection were investigated for robustness to sequencing alterations using a controlled analysis of fixed count matrices. Two breast cancer datasets were analysed with full and reduced sample sizes. DGE model robustness was compared between filtering regimes and for different expression levels (high, low) using unbiased metrics. Test sensitivity estimated as relative False Discovery Rate (FDR), concordance between model outputs and comparisons of a 'population' of slopes of relative FDRs across different library sizes, generated using linear regressions, were examined. Patterns of relative DGE model robustness proved dataset-agnostic and reliable for drawing conclusions when sample sizes were sufficiently large. Overall, the non-parametric method NOISeq was the most robust followed by edgeR, voom, EBSeq and DESeq2. Our rigorous appraisal provides information for method selection for molecular diagnostics. Metrics may prove useful towards improving the standardisation of RNA-seq for precision medicine.

Chemical composition and biological effects of kratom (Mitragyna speciosa): In vitro studies with implications for efficacy and drug interactions.

The safety and efficacy of kratom (Mitragyna speciosa) for treatment of pain is highly controversial. Kratom produces more than 40 structurally related alkaloids, but most studies have focused on just two of these, mitragynine and 7-hydroxymitragynine. Here, we profiled 53 commercial kratom products using untargeted LC-MS metabolomics, revealing two distinct chemotypes that contain different levels of the alkaloid speciofoline. Both chemotypes were confirmed with DNA barcoding to be M. speciosa. To evaluate the biological relevance of variable speciofoline levels in kratom, we compared the opioid receptor binding activity of speciofoline, mitragynine, and 7-hydroxymitragynine. Mitragynine and 7-hydroxymitragynine function as partial agonists of the human µ-opioid receptor, while speciofoline does not exhibit measurable binding affinity at the µ-, δ- or ƙ-opioid receptors. Importantly, mitragynine and 7-hydroxymitragynine demonstrate functional selectivity for G-protein signaling, with no measurable recruitment of ß-arrestin. Overall, the study demonstrates the unique binding and functional profiles of the kratom alkaloids, suggesting potential utility for managing pain, but further studies are needed to follow up on these in vitro findings. All three kratom alkaloids tested inhibited select cytochrome P450 enzymes, suggesting a potential risk for adverse interactions when kratom is co-consumed with drugs metabolized by these enzymes.

Molecular regulation of GLUT-4 targeting in 3T3-L1 adipocytes.

Insulin stimulates glucose transport in muscle and adipose tissue by triggering the movement of the glucose transporter GLUT-4 from an intracellular compartment to the cell surface. Fundamental to this process is the intracellular sequestration of GLUT-4 in nonstimulated cells. Two distinct targeting motifs in the amino and carboxy termini of GLUT-4 have been previously identified by expressing chimeras comprised of portions of GLUT-4 and GLUT-1, a transporter isoform that is constitutively targeted to the cell surface, in heterologous cells. These motifs-FQQI in the NH2 terminus and LL in the COOH terminus-resemble endocytic signals that have been described in other proteins. In the present study we have investigated the roles of these motifs in GLUT-4 targeting in insulin-sensitive cells. Epitope-tagged GLUT-4 constructs engineered to differentiate between endogenous and transfected GLUT-4 were stably expressed in 3T3-L1 adipocytes. Targeting was assessed in cells incubated in the presence or absence of insulin by subcellular fractionation. The targeting of epitope-tagged GLUT-4 was indistinguishable from endogenous GLUT-4. Mutation of the FQQI motif (F5 to A5) caused GLUT-4 to constitutively accumulate at the cell surface regardless of expression level. Mutation of the dileucine motif (L489L490 to A489A490) caused an increase in cell surface distribution only at higher levels of expression, but the overall cells surface distribution of this mutant was less than that of the amino-terminal mutants. Both NH2- and COOH-terminal mutants retained insulin-dependent movement from an intracellular to a cell surface locale, suggesting that neither of these motifs is involved in the insulin-dependent redistribution of GLUT-4. We conclude that the phenylalanine-based NH2-terminal and the dileucine-based COOH-terminal motifs play important and distinct roles in GLUT-4 targeting in 3T3-L1 adipocytes.