Planar cell polarity proteins mediate ketamine-induced restoration of glutamatergic synapses in prefrontal cortical neurons in a mouse model for chronic stress.

Single administration of low-dose ketamine has both acute and sustained anti-depressant effects. Sustained effect is associated with restoration of glutamatergic synapses in medial prefrontal cortic (mFPC) neurons. Ketamine induced profound changes in a number of molecular pathways in a mouse model for chronic stress. Cell-cell communication analyses predicted that planar-cell-polarity (PCP) signaling was decreased after chronic administration of corticosterone but increased following ketamine administration in most of the excitatory neurons. Similar decrease of PCP signaling in excitatory neurons was predicted in dorsolateral prefrontal cortical (dl-PFC) neurons of patients with major depressive disorder (MDD). We showed that the basolateral amygdala (BLA)-projecting infralimbic prefrontal cortex (IL PFC) neurons regulate immobility time in the tail suspension test and food consumption. Conditionally knocking out Celsr2 and Celsr3 or Prickle2 in the BLA-projecting IL PFC neurons abolished ketamine-induced synapse restoration and behavioral remission. Therefore, PCP proteins in IL PFC-BLA neurons mediate synapse restoration induced by of low-dose ketamine.

Case report: Successful treatment of refractory immune thrombocytopenia in chronic lymphocytic leukaemia with venetoclax monotherapy.

In chronic lymphocytic leukaemia (CLL), immune dysregulation is common and can manifest as immune thrombocytopenia (ITP). Corticosteroids are the mainstay for front-line management of CLL-associated ITP. Therapy refractoriness represents a clinical challenge and is an indication to commence CLL-directed treatment, historically with anti-CD20 antibody-based chemoimmunotherapy. There is a small but growing body of evidence supporting the use of Bruton's tyrosine kinase (BTK) inhibitors in this setting, but not the B-cell lymphoma-2 inhibitor, venetoclax. Here, we describe two cases of refractory ITP in patients with CLL who successfully achieved and sustained complete remission with fixed-duration venetoclax monotherapy. Responses were rapid and durable and not explained by the concomitant use of an anti-CD20 antibody. This supports a dual role for single-agent venetoclax in managing active CLL and associated ITP as an alternative to BTK inhibitors and anti-CD20 monoclonals.

Value of a UK medical degree for international students (VISION): a cross-sectional study.

OBJECTIVES: It is estimated that NHS staff consist of over 200 different nationalities, with a reported 30.7% of doctors holding a nationality other than British. Despite this, international medical students represent 7.5% of all medical students studying in the UK and pay on average, 4-6 times more in tuition fees when compared with the £9250 per annum (Great British Pounds (£) in 2021) paid by home students. This study's aim and objective are to evaluate the perception of the financial cost and value of the UK medical degree for international students and their motivations for pursuing such a degree. METHODS: This is a cross-sectional observational study enquiring about international premedical, medical and medical school graduates' perception of the value of the UK medical degree and factors influencing their decision to study in the UK.A questionnaire was developed and distributed to 24 medical schools and 64 secondary schools both internationally and across the UK. RESULTS: A total of 352 responses from 56 nationalities were recorded. 96% of international students identified clinical and academic opportunities as the most important factors to study medicine in the UK, closely followed by quality of life (88%). The least important factor was family reasons, with 39% of individuals identifying this factor. Only 4.82% of graduates in our study considered leaving the UK after training. Overall, 54% of students felt the UK degree was value for money. This belief was significantly higher in premedical students compared with existing students and graduates (71% vs 52% and 20%, p<0.001 for all comparisons). CONCLUSION: The quality of medical education and international prestige are attractive factors for international students to study medicine in the UK. However, further work is needed to ascertain reasons for the differing perceptions of the value by international students at different stages in their clinical training.

A critical care outreach team under strain - Evaluation of the service provided to patients with haematological malignancy during the Covid-19 pandemic.

PURPOSE: Critical Care Outreach Teams (CCOTs) have been associated with improved outcomes in patients with haematological malignancy (HM). This study aims to describe CCOT activation by patients with HM before and during the Covid-19 pandemic, assess amny association with worse outcomes, and examine the psychological impact on the CCOT. MATERIALS AND METHODS: A retrospective, mixed-methods analysis was performed in HM patients reviewed by the CCOT over a two-year period, 01 July 2019 to 31 May 2021. RESULTS: The CCOT increased in size during the surge period and reviewed 238 HM patients, less than in the pre- and post-surge periods. ICU admission in the baseline, surge and the non-surge periods were 41.7%, 10.4% and 47.9% respectively. ICU mortality was 22.5%, 0% and 21.7% for the same times. Time to review was significantly decreased (p = 0.012). Semi-structured interviews revealed four themes of psychological distress: 1) time-critical work; 2) non-evidence based therapies; 3) feelings of guilt; 4) increased decision-making responsibility. CONCLUSIONS: Despite the increase in total hospital referrals, the number of patients with HM that were reviewed during the surge periods decreased, as did their ICU admission rate and mortality. The quality of care provided was not impaired, as reflected by the number of patients receiving bedside reviews and the shorter-than-pre-pandemic response time.

Addressing the Quality of Hospital Care of Colorectal Cancer Patients Undergoing Surgery: What Can We Learn From the National Bowel Cancer Audit?

Introduction The National Bowel Cancer Audit (NBOCA) is the largest database in the United Kingdom that audits real-world data and allows comparison of the quality of care for colorectal cancer patients. This study aimed to highlight relevant clinical factors in the NBOCA that contribute to variation in the quality of care provided in different hospitals. Methods Data from 36,116 patients with colorectal cancer who had undergone surgery were obtained from the NBOCA. These were patients from 145 and 146 hospitals from the years 2016 and 2017, respectively. A validated multiple linear regression was performed to compare the identified clinical factors with various quality outcomes. The quality outcomes defined in this study were the length of hospital stay of more than five days, two-year mortality, 30-day unplanned readmission rate, 90-day mortality, and 18-month stoma rate. Results Four clinical factors (laparoscopy rate, abdominal-perineal-resection-of-rectum, pre-operative radiotherapy, and patients with distant metastases) were shown to have a significant (p < 0.05) impact on the length of hospital stay of more than five days and the 18-month stoma rate. The 18-month stoma rate was also a significant predictor (p < 0.001) with two-year mortality. Conclusion The NBOCA should consider adjusting for these factors when reporting the quality of care provided in hospitals. Hospitals should monitor the four clinical factors for colorectal cancer patients during perioperative care. When formulating a management plan for patients with colorectal cancer, clinicians should consider these factors along with the individual patient's history.

Targeting the Non-Canonical NF-κB Pathway in Chronic Lymphocytic Leukemia and Multiple Myeloma.

In this study, we evaluated an NF-κB inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B- and T-lymphocytes. Basal NF-κB subunit activity was characterized using an enzyme linked immunosorbent assay (ELISA), and the effects of NIK inhibition were then assessed in terms of cytotoxicity and the expression of nuclear NF-κB subunits following monoculture and co-culture with CD40L-expressing fibroblasts, as a model of the lymphoid niche. CW15337 induced a dose-dependent increase in apoptosis, and nuclear expression of the non-canonical NF-κB subunit, p52, was correlated with sensitivity to CW15337 (p = 0.01; r2 = 0.39). Co-culture on CD40L-expressing cells induced both canonical and non-canonical subunit expression in nuclear extracts, which promoted in vitro resistance against fludarabine and ABT-199 (venetoclax) but not CW15337. Furthermore, the combination of CW15337 with fludarabine or ABT-199 showed cytotoxic synergy. Mechanistically, CW15337 caused the selective inhibition of non-canonical NF-κB subunits and the transcriptional repression of BCL2L1, BCL2A1 and MCL1 gene transcription. Taken together, these data suggest that the NIK inhibitor, CW15337, exerts its effects via suppression of the non-canonical NF-κB signaling pathway, which reverses BCL2 family-mediated resistance in the context of CD40L stimulation.

The Effect of Ophthalmic Surgery for Graves' Orbitopathy on Quality of Life: A Systematic Review and Meta-Analysis.

Background: Graves' orbitopathy (GO) has a profound negative impact on quality of life. Surgery is undertaken to preserve vision, correct diplopia, and improve aesthetics. We sought to quantify the effect of different surgical approaches on quality of life. Methods: Electronic databases Ovid-MEDLINE and EMBASE were used from inception until March 22, 2021, to identify studies assessing quality of life pre- and postsurgical intervention for GO. Two reviewers independently extracted data and performed quality assessments. Random-effects and Bayesian models for meta-analyses were utilized. Results: Ten articles comprising 632 patients with a mean age of 48.4 years (range 16-85 years) were included. All used the Graves' Ophthalmopathy Quality of Life (GO-QOL) questionnaire. For GO-QOL appearance, the pooled standardized mean improvement for patients after surgery was +0.72 (95% confidence interval [CI 0.50-0.94]), I2 = 69% [CI 52-80%]. For GO-QOL visual functioning, the pooled standardized mean difference (SMD) for patients after surgery was +0.41 [CI 0.25-0.58], I2 = 60% [CI 36-74%]. For visual appearance, orbital decompression yielded the greatest improvement (SMD +0.84 [CI 0.54-1.13]) followed by eyelid surgery (SMD +0.38 [CI 0.05-0.70]), while strabismus correction had no significant effect (SMD +0.94 [CI -0.10 to 1.99]). Conversely strabismus correction was associated with the greatest improvement (SMD +1.25 [CI 0.29-2.21]) in visual functioning, outperforming orbital decompression (SMD +0.29 [CI 0.15-0.43]) and eyelid surgery (SMD +0.12 [CI -0.18 to 0.41]). A mean improvement in GO-QOL of greater than 10 points after orbital decompression surgery was achieved in 12/14 (86%) patient groups for appearance and 5/14 (36%) patient groups for visual functioning. A mean improvement of greater than 6 points was achieved in 5 of 6 (83%) patient groups for strabismus surgery for both appearance and visual functioning. A mean improvement of greater than 6 points after eyelid surgery was achieved in 2/3 (67%) patient groups and 0/3 patient groups for visual appearance and functioning, respectively. Conclusion: Ophthalmic surgery results in substantial improvements in quality of life in patients with GO, with greater perceived effects on appearance than visual function. Orbital decompression has particular impact on visual appearance; strabismus surgery may benefit both visual appearance and function equally, whereas eyelid surgery benefits appearance alone.

Motivations of medical students and doctors leaving the NHS explored in a residency training application webinar series.

BACKGROUND: Recent reports show that about 10% of UK-graduate doctors leave the country to pursue specialty training elsewhere. Our article aims to evaluate the motivating factors for UK graduates to leave the National Health Service (NHS), especially during the COVID-19 pandemic and Brexit. STUDY DESIGN: Cross-sectional study. METHOD: A novel 22-item questionnaire was disseminated at a webinar series regarding the application process to pursue residency training in six different countries/regions from 2 August 2020 to 13 September 2020. The data was analysed using Kruskal-Wallis rank-sum with post-hoc Wilcoxon test to compare the difference in significance among the motivating factors. RESULTS: 1118 responses from the UK medical students and doctors were collected; of which, 1001 (89.5%) were medical students, and 88 (7.9%) were junior doctors. There was a higher propensity for leaving after the Foundation Programme compared with other periods (p<0.0001 for all comparisons). There was no difference between desire for leaving after core surgical/medical training and specialty training (p=0.549). However, both were significantly higher than leaving the NHS after medical school (p<0.0001). Quality of life and financial prospects (both p<0.0001) were the most agreed reasons to leave the NHS, followed by clinical and academic opportunities and, subsequently, family reasons. CONCLUSION: Future work on the quality of life for doctors in the UK should be explored, especially among those considering leaving the NHS. Policymakers should focus on assessing the difference in working hours, on-call hours and wages that may differ among healthcare systems.

Changing Student Perception of an Online Integrated Structured Clinical Examination During the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic has created a hiatus in in-person clinical assessments due to safety and logistical concerns. We aimed to evaluate student perception and utility of an online Integrated Structured Clinical Examinations (ISCEs) during the pandemic. METHODS: Final-year medical students from a single institution were offered an online mock ISCE through a student-to-student ("near-peer") teaching-programme. A questionnaire-based cross-sectional study was conducted pre- and post-online mock ISCE. RESULTS: Sixty-four students completed the study. Pre- and post-data showed an increase in confidence (p<0.0001), less worry regarding the online format (p<0.0001) and less anxiety about excelling in ISCEs (p<0.001). Students felt that having done the mock, an online format would more positively affect their overall performance (p=0.007). CONCLUSION: This study demonstrates a positive change in student perception and confidence in online ISCEs. Online ISCEs are thus feasible, though sole reliance on this format may provide an incomplete assessment of student's overall clinical competency.

Anti-HTLV-1/2 IgG Antibodies in the Breastmilk of Seropositive Mothers.

BACKGROUND: HTLV-1/2 mother-to-child transmission (MTCT) is an important route for the maintenance of HTLV-1/2 within populations and disproportionally contributes to the burden of HTLV-1-associated diseases. Avoidance of breastfeeding is the safest recommendation to prevent MTCT. Due to the benefits of breastfeeding, alternative methods that would allow seropositive mothers to breastfeed their babies are needed. There is limited knowledge about HTLV-1/2 infection and breastmilk. METHODS: Paired blood and milk samples collected from HTLV-1/2 seropositive mothers were tested for HTLV-1 proviral load (PVL) quantification and for the detection of anti-HTLV-1/2 IgG. RESULTS: All breastmilk samples had detectable anti-HTLV-1/2 IgG. HTLV-1/2 proviral DNA was detected in all samples except for one. HTLV-1 PVL and IgG binding ratio (BR) was similar in milk and plasma. However, antibody titer was significantly higher in blood (Median (95%CI): Milk:128 (32-512); Plasma:131,584 (16,000-131,584), p < 0.05). There was a strong correlation between HTLV-1 PVL, anti-HTLV-1/2 IgG BR, and titer when comparing milk and blood. PVL did not correlate with antibody BR nor titer in blood or milk. CONCLUSIONS: Anti-HTLV-1/2 IgG are present in milk in the same proportion as blood but in lower quantity. PVL in milk correlates with blood.

Intraspecific interactions affect outcomes of pulse toxicity at different Daphnia magna population phases.

Traditional toxicity tests assess stressor effects on individuals, while protection goals are focused on the population-level and above. Additionally, these tests ignore common ecological factors such as resource levels and population growth phase. The objective of this research was to explore effects of - and interactions between - resource availability and stress response at the individual and population levels using Daphnia magna as a model. We hypothesized that density-dependent changes in resources at various phases of population growth would cause different population responses to the same toxicant stress. Laboratory populations of Daphnia magna were exposed to a 48-h pulse of 20 or 30 µg/l pyraclostrobin in one of four distinct phases of laboratory population cycles: growth, peak, decline, and stable. Population size and recovery were observed throughout the 51-day study. Populations exposed to pyraclostrobin during the growth phase had the least mortality and fastest recovery, while populations in the peak phase had the greatest mortality and slowest recovery. These data suggested that high density and low food at the peak phase resulted in more sensitive daphnids. To further test this hypothesis, a resource-amended acute toxicity study was conducted to quantify the effects of food resource on pyraclostrobin toxicity to Daphnia magna. Three age classes of Daphnia magna (neonate, subadult, adult) were fed low or high food levels and exposed to pyraclostrobin for 48 h. Toxicity was greater, as shown by lower 48 h LC50s, for smaller Daphnia magna age classes and lower food levels comporting results in the population study. Importantly, the acute toxicity studies generally yielded lower effect levels than the population studies suggesting that while the standard acute studies are ecologically unrealistic, they may be protective of toxicity under some circumstances. Collectively, these data point to the importance of population phase and the resource environment in modulating toxicity.

Noninvasive Detection of Antibodies to Human T-Cell Lymphotropic Virus Types 1 and 2 by Use of Oral Fluid.

Human T-lymphotropic viruses type 1 and 2 (HTLV-1/2) are prevalent in endemic clusters globally, and HTLV-1 infects at least 5 to 10 million individuals. Infection can lead to inflammation in the spinal cord, resulting in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), or adult T cell leukemia/lymphoma (ATL). Obtaining venous blood for serological screening, typically performed using enzyme immunoassays (EIAs), is invasive, sometimes socially unacceptable, and has restricted large-scale seroprevalence studies. Collecting oral fluid (OF) is a noninvasive alternative to venesection. In this study, an IgG antibody capture EIA was developed and validated to detect anti-HTLV-1/2 IgG in OF. OF and plasma specimens were obtained from seropositive HTLV-1/2-infected patients attending the National Centre for Human Retrovirology (n = 131) and from HTLV-1/2-uninfected individuals (n = 64). The assay showed good reproducibility and high diagnostic sensitivity (100%) and specificity (100%) using both OF and plasma. The Murex HTLV I+II commercial assay was evaluated and did not detect anti-HTLV-1/2 IgG in 14% (5/36) of OF specimens from seropositive donors. The reactivities of OF and plasma in the IgG capture correlated strongly (r = 0.9290) and were not significantly affected by delayed extraction when held between 3°C and 45°C for up to 7 days to simulate field testing. The use of OF serological screening for HTLV-1/2 infection could facilitate large-scale seroprevalence studies, enabling active surveillance of infection on a population level.

Radiographic/MR Imaging Correlation of Spinal Bony Outlines.

The human spine is a highly specialized structure that protects the neuraxis and supports the body during movement, but its complex structure is a challenge for imaging. Radiographs can provide fine bony detail, but lack soft tissue definition and can be complicated by overlying structures. MR imaging allow(s) excellent soft tissue contrast, but some bony abnormalities can be difficult to discern. This makes the 2 modalities highly complementary. In this article, the authors discuss the correlation between radiographic and MR imaging appearances focusing first on disease affecting the vertebral body itself, its surrounding structures, and finally global spinal alignment.

Imaging of Upper Limb Tumors and Tumorlike Pathology.

Bone and soft tissue sarcomas are uncommon tumors that can occur within the upper extremity as well as elsewhere within the body. However, certain histopathological subtypes have increased affinity for the upper limb and even certain sites within the arm and hand. Other benign masses and tumor mimics, such as infection and traumatic lesions, are more common and imaging appearances can sometimes overlap with malignant lesions making diagnosis difficult. In this article, we explore the current options for imaging of these lesions as well as typical imaging appearances of the more common upper limb tumors.