Synthetic Approaches to the New Drugs Approved During 2022.

In 2022, 23 new small molecule chemical entities were approved as drugs by the United States FDA, European Union EMA, Japan PMDA, and China NMPA. This review describes the synthetic approach demonstrated on largest scale for each new drug based on patent or primary literature. The synthetic routes highlight practical methods to construct molecules, sometimes on the manufacturing scale, to access the new drugs. Ten additional drugs approved in 2021 and one approved in 2020 are included that were not covered in the previous year's review.

Quantifying the clinical and economic burden of desquamating dermatological conditions: Implications for a supraregional burns centre.

INTRODUCTION: This study aimed to identify the spectrum of desquamating skin diseases referred for tertiary burns care and quantify the care requirements and expenses associated with caring for these patients within the burns service. METHODS: Patient records were identified with nonburn-induced skin loss between 2016 and 2022. Data was extracted from inpatient records, operative notes, and dressing clinic records. A cost analysis was conducted using figures from the National Schedule of National Health Service Costs and our own unit-specific costs. RESULTS: Twenty patients were identified, with a median age of 46.5 and a median total body surface area of 30%. The mean length of stay was 21.2 days, with 8/20 patients requiring intensive care. Overall mortality was 30%, rising to 50% if patients required intensive treatment unit (ITU) admission. Patients had a mean of 1.5 procedures under general anaesthesia and a mean operative time of 169 min per patient. Postoperatively, a mean of 8.3 dressing changes was required per patient (range 1-21). Of 75% of patients referred as suspected toxic epidermal necrolysis syndrome (TENS), only 32% of patients histologically had TENS (32%), with linear IgA disease, pemphigus vulgaris and bullous lupus comprising the other diagnoses. Cost analysis predicted a total cost to the unit of £1,422,106. CONCLUSION: Desquamating dermatological diseases are life-threatening conditions with exhaustive care requirements. Our experiences highlight the importance of awareness of the range of desquamating skin conditions beyond TENS to enable optimum management and the need to ensure adequate financial provisions to accommodate the care requirements mandated by these patients.

Synthetic Approaches to the New Drugs Approved During 2021.

Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021.

Factor structure and measurement invariance of the Mood and Feelings Questionnaire: a cross-cultural study among Thai and British adolescents.

The Mood and Feelings Questionnaire-child self-report (MFQ-C) is a widely used measure of child and adolescent depression. This study evaluated possible factor solutions and examined the measurement invariance of the MFQ-C as a prerequisite for its use in cross-cultural comparisons between Thai (N = 1272) and British samples (N = 1817) by using multigroup confirmatory factor analysis (MGCFA). The latent means of Thai and British samples were also examined. A five-factor structure of the MFQ-C was confirmed through confirmatory factor analysis. A partial scalar invariant model was supported, and thus latent means were compared, with British adolescents reporting significantly higher mean MFQ-C scores than Thai adolescents on four of the five factors (Vegetative Symptoms, Suicidality, Cognitive Symptoms, Agitated Distress). There was no difference for the Core Symptoms factor. The findings also suggest that the MFQ-C is a valid measure to assess depression in Thai and British adolescents and maybe useful in cross-cultural comparisons of adolescent depression.

A qualitative study exploring the benefits of involving young people in mental health research.

INTRODUCTION: It is increasingly accepted that young people need to be centrally involved in research on issues that affect them. The aim of this study was to explore young people's perceptions of the benefits for them of being involved in mental health research and the processes that enabled these benefits. METHODS: Qualitative interviews were conducted by co-researchers (young people with lived experience and/or interest in mental health) with 13 young people (aged 13-24 years) who had experience of being involved in mental health research when they were between 11 and 16 years of age. Reflective thematic analysis was used to identify important aspects of young people's experiences. RESULTS: Four main themes were identified: (1) opportunity to have a meaningful impact, (2) opportunity to be part of a supportive community, (3) opportunity to learn and grow and (4) increasing opportunities for young people. CONCLUSION: This study highlights young people's experiences of being involved in mental health research and identifies ways in which researchers can ensure that involvement opportunities bring benefits to both the young people and the research. PATIENT OR PUBLIC CONTRIBUTION: This research was a response to issues raised by young people involved in research. The project was supported by co-researchers throughout, including design, data collection, analysis and write-up.

Challenging stigma and attitudes towards ECT via an educational video.

While electroconvulsive therapy (ECT) is an effective therapeutic modality for the treatment of mental illness, negative attitudes and stigma exist about ECT in the general community and even within health services. Investigating interventions that improve the attitudes of health professionals towards ECT is beneficial as this reduces stigma and increases the acceptability of ECT for consumers. The primary aim of this study was to evaluate the change in attitude of nursing graduates and medical students towards ECT by watching an educational video. The secondary aim was to compare health professional attitudes to those of the general community. An educational video was co-designed with consumers and members of the mental health Lived Experience (Peer) Workforce Team about ECT outlining the procedure, side effects, treatment considerations and lived experiences. Nursing graduates and medical students completed the ECT Attitude Questionnaire (EAQ) prior to and after watching the video. Descriptive statistics, paired samples t-tests and one sample t-tests were completed. One hundred and twenty-four participants completed pre- and post- questionnaires. Attitudes towards ECT significantly improved after watching the video. Positive responses towards ECT increased from 67.09% to 75.72%. Participants in this study reported higher positive attitudes towards ECT than members of the general public before and after watching the intervention. Results indicated that the video educational intervention was effective in improving attitudes towards ECT for nursing graduates and medical students. While the video is promising as an educational tool, further research is required to explore the use of the video in reducing stigma for consumers and carers.

Mifepristone induced liver injury in a patient with Cushing syndrome: a case report and review of the literature.

BACKGROUND: Mifepristone, also known as RU-486, is an anti-progestational steroid with similar chemical structure to anabolic steroids. Given as a single dose in conjunction with misoprostol, mifepristone is used to induce medical abortion. Mifepristone administered chronically at a higher dose is also approved for the management of hypercortisolism. There have been only 2 reported cases of mifepristone associated liver injury, in both cases, in the setting of Cushing syndrome. We report a third patient with Cushing syndrome with mifepristone induced liver injury with unique histological findings that provide insight to the pathophysiology of liver injury in mifepristone and anabolic steroids. CASE PRESENTATION: Patient is a 63-year-old Caucasian female Cushing disease with no prior history of liver disease. She was started on mifepristone and semaglutide. Ninety days after initiating mifepristone, she developed deep jaundice, severe pruritus, fatigue, and nausea. Liver tests revealed a mixed hepatocellular/cholestatic pattern. Viral and autoimmune serologies were negative and there was no biliary dilatation on imaging. Liver biopsy showed severe cholestasis but no bile duct injury. Focal endothelialitis was present within a central venule. Cholestatic symptoms persisted for one month after presentation before slowly subsiding. Four months after stopping mifepristone, the patient's symptoms completely resolved, and liver tests became normal. Compilation of Roussell Uclaf Causality Assessment Method score indicated probable causality. CONCLUSIONS: Mifepristone shares a similar chemical structure as synthetic anabolic/androgenic steroids and there are many similarities in the clinical presentation of liver injury. This case and the 2 other reported cases share similar clinical characteristics. The observation of endothelialitis in our patient may provide a mechanistic link between mifepristone, or anabolic steroids in general, and the development of vascular complications such as peliosis.

A series of diabetic ketoacidosis associated with the use of sodium-glucose co-transporter-2 inhibitors in secondary care.

BACKGROUND AND AIMS: Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) are associated with diabetic ketoacidosis (DKA), however limited case series are published. METHODS: We evaluated the characteristics of patients admitted with SGLT-2i associated DKA. RESULTS: Over 4 months, 22 patients were identified; 45.5% of DKA was not associated with concurrent illness. CONCLUSION: DKA is not uncommonly associated with SGLT2i with no clear patient factors associated with severity.

A series of patients with hospital-acquired diabetic ketoacidosis (HADKA): a descriptive analysis.

BACKGROUND: Hospital-acquired diabetic ketoacidosis (HADKA) can complicate hospital admission in people with type 1 diabetes (T1D) and type 2 diabetes (T2D). We aimed to determine the characteristics of such patients and the reasons for HADKA. METHODS: A retrospective analysis of patients referred to diabetes services with HADKA at Morriston Hospital between January 2016 and January 2022 was undertaken. Patients that were included were admitted without diabetic ketoacidosis (DKA), were aged 18 years and over, and who subsequently developed DKA in hospital. RESULTS: Twenty-five patients were included with a mean age of 65.2 years; nine (32.0%) were men, 13 (52.0%) had T1D and 12 (48.0%) had T2D. Patients had a mean pre-admission glycated haemoglobin of 84.7 mmol/mol, and 17 (68.0%) were insulin-treated. Most were admitted under medicine (n=14; 56.0%) and the remainder under surgery (n=11; 44.0%). More common reasons for HADKA were erroneous insulin administration (n=9; 36.0%), infection (n=7; 28.0%) and surgery (n=5; 20.0%).Five (20.0%) patients required intensive care admission, and the mean length of hospital stay was 42.6 days (range 2-173). Three (12.0%) patients died during the hospital admission. CONCLUSION: HADKA was identified in a significant number of patients at our hospital and was associated with significant mortality. Earlier recognition of ketonaemia and associated medication use may prevent HADKA and improve outcomes.

Synthetic Approaches to the New Drugs Approved During 2020.

New drugs introduced to the market are privileged structures that have affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates (ADCs), provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This Review is part of a continuing series presenting the most likely process-scale synthetic approaches to 44 new chemical entities approved for the first time anywhere in the world during 2020.

Barriers and facilitators to physical activity participation for child, adolescent, and young adult cancer survivors: a systematic review.

PURPOSE: The aim of this systematic review is to explore and describe the barriers and facilitators to physical activity (PA) participation for child, adolescent, and young adult cancer survivors. METHODS: MEDLINE, Embase, AMED, CINAHL, Cochrane, and Web of Science were searched for manuscripts published between January 2000 and February 2021. To be included in this review, studies had to report qualitative or quantitative data on barriers and facilitators to PA participation in child (4 to < 10 years), adolescent (10 to 19 years), and young adult (> 19 to < 40 years) cancer survivors. Six independent reviewers assessed methodological quality using the Mixed Methods Appraisal Tool (MMAT-version 18) in duplicate. RESULTS: Fifteen studies were included in this systematic review. Fatigue and psychological factors were the most prevalent barriers shared between children, adolescents, and young adults. Support from others was a shared facilitator between age groups. CONCLUSION: Psychological barriers and social support are important to address in younger cancer survivors. Clinicians can use these findings to create exercise interventions to facilitate and overcome barriers to PA participation. IMPLICATIONS FOR CANCER SURVIVORS: While PA is beneficial for cancer survivors of all ages, different barriers and facilitators to PA participation exist depending on a survivors age and life stage. Survivors should discuss PA with their healthcare team at all timepoints in the cancer treatment trajectory in order to gain the associated benefits during and after treatment.

Erratum: Prior upregulation of interferon pathways in the nasopharynx impacts viral shedding following live attenuated influenza vaccine challenge in children.

[This corrects the article DOI: 10.1016/j.xcrm.2021.100465.].

Effects of early-life antibiotics on the developing infant gut microbiome and resistome: a randomized trial.

Broad-spectrum antibiotics for suspected early-onset neonatal sepsis (sEONS) may have pronounced effects on gut microbiome development and selection of antimicrobial resistance when administered in the first week of life, during the assembly phase of the neonatal microbiome. Here, 147 infants born at ≥36 weeks of gestational age, requiring broad-spectrum antibiotics for treatment of sEONS in their first week of life were randomized 1:1:1 to receive three commonly prescribed intravenous antibiotic combinations, namely penicillin + gentamicin, co-amoxiclav + gentamicin or amoxicillin + cefotaxime (ZEBRA study, Trial Register NL4882). Average antibiotic treatment duration was 48 hours. A subset of 80 non-antibiotic treated infants from a healthy birth cohort served as controls (MUIS study, Trial Register NL3821). Rectal swabs and/or faeces were collected before and immediately after treatment, and at 1, 4 and 12 months of life. Microbiota were characterized by 16S rRNA-based sequencing and a panel of 31 antimicrobial resistance genes was tested using targeted qPCR. Confirmatory shotgun metagenomic sequencing was executed on a subset of samples. The overall gut microbial community composition and antimicrobial resistance gene profile majorly shift directly following treatment (R2 = 9.5%, adjusted p-value = 0.001 and R2 = 7.5%, adjusted p-value = 0.001, respectively) and normalize over 12 months (R2 = 1.1%, adjusted p-value = 0.03 and R2 = 0.6%, adjusted p-value = 0.23, respectively). We find a decreased abundance of Bifidobacterium spp. and increased abundance of Klebsiella and Enterococcus spp. in the antibiotic treated infants compared to controls. Amoxicillin + cefotaxime shows the largest effects on both microbial community composition and antimicrobial resistance gene profile, whereas penicillin + gentamicin exhibits the least effects. These data suggest that the choice of empirical antibiotics is relevant for adverse ecological side-effects.

Early-life viral infections are associated with disadvantageous immune and microbiota profiles and recurrent respiratory infections.

The respiratory tract is populated by a specialized microbial ecosystem, which is seeded during and directly following birth. Perturbed development of the respiratory microbial community in early-life has been associated with higher susceptibility to respiratory tract infections (RTIs). Given a consistent gap in time between first signs of aberrant microbial maturation and the observation of the first RTIs, we hypothesized that early-life host-microbe cross-talk plays a role in this process. We therefore investigated viral presence, gene expression profiles and nasopharyngeal microbiota from birth until 12 months of age in 114 healthy infants. We show that the strongest dynamics in gene expression profiles occurred within the first days of life, mostly involving Toll-like receptor (TLR) and inflammasome signalling. These gene expression dynamics coincided with rapid microbial niche differentiation. Early asymptomatic viral infection co-occurred with stronger interferon activity, which was related to specific microbiota dynamics following, including early enrichment of Moraxella and Haemophilus spp. These microbial trajectories were in turn related to a higher number of subsequent (viral) RTIs over the first year of life. Using a multi-omic approach, we found evidence for species-specific host-microbe interactions related to consecutive susceptibility to RTIs. Although further work will be needed to confirm causality of our findings, together these data indicate that early-life viral encounters could impact subsequent host-microbe cross-talk, which is linked to later-life infections.

Image challenge: Beware of diagnostic anchoring - An offshore vessel welding inspector with eosinophilia and a cough productive of 'worms'.

A 38-year old male was referred from an Acute Medical Unit to a regional Tropical Infectious Disease Unit with a seven-week history of dyspnoea, wheeze and cough reportedly productive of worms. The patient had taken photographs of the expectorated substance which allowed macroscopic examination by a consultant in infectious diseases. Fresh samples were also sent for histological examination. Initial investigations showed a prominent eosinophilia of 2.5 × 109/ml (0.0-0.4 × 109/ml).

Clinical Features and Severity of Leptospirosis Cases Reported in the Hawke's Bay Region of New Zealand.

AIMS: To record demographics, symptoms, signs, and laboratory features of confirmed leptospirosis cases in the Hawke's Bay area of New Zealand to aid clinicians in diagnosis and recognition of severity. METHODS: Review of suspected leptospirosis cases referred to the reference laboratory from hospitals in the Hawke's Bay region between March 2003 and March 2012. Inclusion criteria were IgM positivity and diagnosis confirmed with either polymerase chain reaction (PCR) or microscopic agglutination test (MAT). A retrospective systematic review of case notes was completed for demographic and laboratory data. RESULTS: Forty-three cases were included. Most common presenting symptoms were pyrexia (93%), myalgia, and headache (both 86%). 93% of patients worked in the farming or meat industries. The most common biochemical abnormalities were elevated CRP (100%) and abnormal urinalysis (93%). There was no difference in disease severity between icteric and anicteric patients. Compared to other studies, patients in New Zealand have less severe disease. CONCLUSION: Contrary to popular understanding, this study has not found icteric leptospirosis to be related to more severe disease. Anicteric leptospirosis should be a differential diagnosis in patients presenting with pyrexia, myalgia, and headache who have elevated CRP and abnormal urinalysis.

What do people hospitalised with COVID-19 think about their care? Results of a satisfaction survey during the first wave of COVID-19 in Liverpool.

Despite huge advances in vaccines, testing and treatments for COVID-19, there is negligible evidence on the perceptions of people hospitalised with COVID-19 about the care they received. To address this, we developed a satisfaction survey for people with COVID-19 admitted to our hospital during the first COVID-19 wave in Liverpool. Of those invited, 98/160 (61%) responded, of whom 94/98 (96%) completed the survey. Respondents rated overall care highly (mean 4.7/5) and 89/94 (95%) reported that they would recommend the hospital to friends and/or family. Most respondents felt safe on the ward (94%), with privacy maintained (93%) and pain well managed (90%). Fewer than two-thirds (63%) of respondents considered themselves adequately consulted regarding medications and side effects. Sleep and food/drink quality were also highlighted as areas for improvement. To overcome the issues raised, we generated a 'COVID-19 practice pointers' poster within an integrated educational bundle on COVID-19 wards. The impact of the bundle on perceptions of people hospitalised with COVID-19 will be evaluated in people hospitalised with COVID-19 in Liverpool in 2021. Whether hospitalised for COVID-19 or other conditions, our survey results are a timely reminder of the importance of involving patients in shaping the care that they receive.

Development and validation of a new adolescent self-report scale to measure loss of interest and pleasure: The Anhedonia Scale for Adolescents.

Anhedonia, the loss of interest and pleasure in previously enjoyable experiences, is a core symptom of depression and a characteristic of other mental health and physical health problems. Most self-report measures of anhedonia has been developed for use with adults and their suitability for adolescents is questionable. In this article, we describe the development and psychometric qualities of a new measure, the Anhedonia Scale for Adolescents (ASA), designed specifically for use with adolescents aged 11-18 years. Items were generated from in-depth qualitative interviews with depressed young people, and then reviewed by an independent group of young people and clinically qualified experts in adolescent mental health. After piloting the new scale (n = 66), we established the structural validity of the measure with two groups of young people using exploratory (n = 1057) and confirmatory (n = 1041) factor analysis. The final scale consisted of 14 items, with 1 general factor and 3 specific factors producing the best fit to the data, (1) Enjoyment, Excitement, and Emotional Flattening (negatively framed); (2) Enthusiasm, Connection, and Purpose (positively framed); and (3) Effort, Motivation, and Drive (negatively framed). The ASA had high test-retest reliability and converged with standardized measures of depression, negative symptoms of schizophrenia, pleasure, and positive affect. Findings from these analyses provided evidence of incremental validity, as the ASA was a stronger predictor of clinical group (high vs. low depressive symptoms) than existing measures used to assess anhedonia. The ASA has potential as a new clinical and research tool to assess adolescent anhedonia. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A qualitative study exploring adolescents' experience of brief behavioural activation for depression and its impact on the symptom of anhedonia.

OBJECTIVES: Anhedonia, the loss of interest and pleasure, is a core symptom of depression and is associated with deficits in reward processing. Behavioural Activation for depression may address this symptom due to its focus on identifying and increasing intrinsically rewarding activities. DESIGN: This was a qualitative study employing reflexive thematic analysis (TA). METHODS: Participants were eight treatment-seeking adolescents with a recent primary diagnosis of depression who had received eight sessions of Brief Behavioural Activation. Qualitative semi-structured interviews were conducted after treatment was completed. RESULTS: Three main themes emerged: (1) connecting, reviewing, and taking action: 'focus on getting better rather than what you're feeling'; (2) struggles, restrictors, and motivators: 'it seemed really unachievable'; and (3) feeling, acting, or seeing things differently: 'looking forwards in a more healthy way'. CONCLUSIONS: Both specific Brief Behavioural Activation strategies (e.g., connecting with values) and more generic therapeutic strategies (e.g., self-monitoring) may be helpful in treating the symptom of anhedonia in adolescent depression. Motivational aspects of anhedonia, as well as anxiety, fatigue, and academic pressures act as potential barriers to recovery. This highlights the need for psychological treatments for adolescent depression to include explicit and targeted strategies to enhance motivation. PRACTITIONER POINTS: Young people reported that specific Brief Behavioural Activation strategies (e.g., connecting with values) and more generic therapeutic techniques (e.g., self-monitoring) had a role in treating anhedonia. Barriers to engaging in Brief BA included: motivational anhedonia, fatigue, and academic demands.

A patient satisfaction survey and educational package to improve the care of people hospitalised with COVID-19: a quality improvement project, Liverpool, UK.

Background: The perspectives and experiences of people hospitalised with COVID-19 have been under-reported during the coronavirus pandemic. We developed and conducted a COVID-19 patient satisfaction survey in a large university-affiliated secondary healthcare centre in Liverpool, UK, during Europe's first coronavirus wave (April-June 2020). The survey found that care was rated highly, including among people of Black Asian and Minority Ethnic (BAME) background. However, sleep-quality and communication about medications and discharge-planning were identified as areas for improvement.   Methods: To improve care for people with COVID-19 admitted to our centre, we designed an educational package for healthcare professionals working on COVID-19 wards. The package, implemented in August 2020, included healthcare worker training sessions on providing holistic care and placement of "Practice Pointers" posters. Patient satisfaction was re-evaluated during the second/third COVID-19 waves in Liverpool (September 2020 - February 2021). Results: Across waves, most (95%) respondents reported that they would recommend our hospital to friends and/or family and rated overall care highly. Comparison of the responses of second/third-wave respondents (n=101) with first-wave respondents (n=94) suggested improved patient satisfaction across most care domains but especially those related to having worries and fears addressed and being consulted about medications and their side-effects. Conclusions: People admitted with COVID-19 to our centre in Liverpool, including those from BAME background, rated the care they received highly. A simple education package improved the feedback on care received by respondents between the first and second/third waves. These UK-first findings are informing regional strategies to improve person-centred care of hospitalised people with COVID-19.