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Despite recent advances in immunotherapies targeting single tumor-associated antigens, patients with multiple myeloma eventually relapse. ISB 2001 is a CD3+ T cell engager (TCE) co-targeting BCMA and CD38 designed to improve cytotoxicity against multiple myeloma. Targeting of two tumor-associated antigens by a single TCE resulted in superior cytotoxic potency across a variable range of BCMA and CD38 tumor expression profiles mimicking natural tumor heterogeneity, improved resistance to competing soluble factors and exhibited superior cytotoxic potency on patient-derived samples and in mouse models. Despite the broad expression of CD38 across human tissues, ISB 2001 demonstrated a reduced T cell activation profile in the absence of tumor cells when compared to TCEs targeting CD38 only. To determine an optimal first-in-human dose for the ongoing clinical trial ( NCT05862012 ), we developed an innovative quantitative systems pharmacology model leveraging preclinical data, using a minimum pharmacologically active dose approach, therefore reducing patient exposure to subefficacious doses of therapies.

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The management of endometrial cancer involves a multidisciplinary team (MDT) approach, with immunohistochemistry playing an important role in management and prognosis. Markers investigated include estrogen receptor (ER), progesterone receptor (PR), tumor protein 53 (p53), and mismatch repair(MMR) protein. Additionally, polymerase epsilon (POLE) mutations indicate treatment-responsive tumors, often with excellent prognosis. We aimed to improve the reporting of immunohistochemistry and introduce POLE testing, with a sustainable change in the long-term management of endometrial cancer at Royal Cornwall Hospitals Trust (RCHT). An initial sample of 53 patients with endometrial cancer from 2022 was analyzed. Endometrial biopsy reports were reviewed for immunohistochemistry reporting, with delays of reporting over 10 days documented. In initial results, a mean of 15.5% of cases failed to report p53 (12/53), ER (9/53), PR (10/53), and MMR (2/53). The interventions implemented in February 2023 were an immunohistochemistry proforma, the introduction of POLE testing, and departmental presentations. Data was re-collected between March and September 2023. After the project, there was a 100% (39/39) rate of reporting immunohistochemistry correctly. POLE testing was introduced to the department. In addition, the proforma developed is now standard practice in the reporting of endometrial cancer cases and is utilized in the gynae-oncology MDT meetings.

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Objectives: Sjögren's disease (SjD) is a common exocrine disorder typified by chronic inflammation and dryness, but also profound fatigue, suggesting a pathological basis in cellular bioenergetics. In healthy states, damaged or dysfunctional mitochondrial components are broken down and recycled by mitophagy, a specialized form of autophagy. In many autoimmune disorders, however, evidence suggests that dysfunctional mitophagy allows poorly functioning mitochondria to persist and contribute to a cellular milieu with elevated reactive oxygen species. We hypothesized that mitophagic processes are dysregulated in SjD and that dysfunctional mitochondria contribute to overall fatigue. We sought to link fatigue with mitochondrial dysfunction directly in SjD, heretofore unexamined, and further sought to assess the pathogenic extent and implications of dysregulated mitophagy in SjD. Methods: We isolated pan T cells via negative selection from the peripheral blood mononuclear cells of 17 SjD and 8 age-matched healthy subjects, all of whom completed fatigue questionnaires prior to phlebotomy. Isolated T cells were analyzed for mitochondrial oxygen consumption rate (OCR) and glycolysis using Seahorse, and linear correlations with fatigue measures were assessed. A mitophagy transcriptional signature in SjD was identified by reanalysis of whole-blood microarray data from 190 SjD and 32 healthy subjects. Differential expression analyses were performed by case/control and subgroup analyses comparing SjD patients by mitophagy transcriptional cluster against healthy subjects followed by bioinformatic interpretation using gene set enrichment analysis. Results: Basal OCR, ATP-linked respiration, maximal respiration, and reserve capacity were significantly lower in SjD compared to healthy subjects with no observed differences in non-mitochondrial respiration, basal glycolysis, or glycolytic stress. SjD lymphocytic mitochondria show structural alterations compared to healthy subjects. Fatigue scores related to pain/discomfort in SjD correlated with the altered OCR. Results from subgroup analyses by mitophagic SjD clusters revealed highly variable inter-cluster differentially expressed genes (DEGs) and expanded the number of SjD-associated gene targets by tenfold within the same dataset. Conclusion: Mitochondrial dysfunction, associated with fatigue, is a significant problem in SjD and warrants further investigation.

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Over the past two decades, therapeutic antibodies have emerged as a rapidly expanding domain within the field of biologics. In silico tools that can streamline the process of antibody discovery and optimization are critical to support a pipeline that is growing more numerous and complex every year. High-quality structural information remains critical for the antibody optimization process, but antibody-antigen complex structures are often unavailable and in silico antibody docking methods are still unreliable. In this study, DeepAb, a deep learning model for predicting antibody Fv structure directly from sequence, was used in conjunction with single-point experimental deep mutational scanning (DMS) enrichment data to design 200 potentially optimized variants of an anti-hen egg lysozyme (HEL) antibody. We sought to determine whether DeepAb-designed variants containing combinations of beneficial mutations from the DMS exhibit enhanced thermostability and whether this optimization affected their developability profile. The 200 variants were produced through a robust high-throughput method and tested for thermal and colloidal stability (Tonset, Tm, Tagg), affinity (KD) relative to the parental antibody, and for developability parameters (nonspecific binding, aggregation propensity, self-association). Of the designed clones, 91% and 94% exhibited increased thermal and colloidal stability and affinity, respectively. Of these, 10% showed a significantly increased affinity for HEL (5- to 21-fold increase) and thermostability (>2.5C increase in Tm1), with most clones retaining the favorable developability profile of the parental antibody. Additional in silico tests suggest that these methods would enrich for binding affinity even without first collecting experimental DMS measurements. These data open the possibility of in silico antibody optimization without the need to predict the antibody-antigen interface, which is notoriously difficult in the absence of crystal structures.

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Introduction: External fixation devices are commonly used in orthopaedic surgery to manage a range of pathologies. In this patient population, there is currently no consensus on optimal rehabilitation techniques. There exists a large variation in practice, with a limited understanding of how these affect treatment outcomes. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a systematic review was conducted of Allied and Complementary Medicine Database (AMED), Cumulative Index to Nursing and Allied Health Literature (CINAHL), MEDLINE, PEDro, and COCHRANE databases, grey literature sources and forward and backward searching of included articles. Studies were selected following rigorous screening with predefined inclusion criteria. Data quality was assessed using validated appraisal tools. Articles were synthesised by rehabilitation type and descriptive analysis was subsequently performed. Results: From 1,156 articles identified, 18 were eligible for inclusion. The overall quality was low, with clinical commentaries and case studies being the most common study type. Studies were synthesised by rehabilitation type, the most common themes being gait re-education, strengthening, therapy-assisted, active exercises and weight-bearing exercises. Conclusion: There is a lack of high-quality evidence to support meaningful recommendations and guide rehabilitation practices for this patient cohort. Further research for patients being treated in external fixation, especially related to the potential effects of physical rehabilitation on bone healing, return of strength, mobility and independent function is likely to have transferability within wider orthopaedic populations. Clinical significance: This systematic review is unable to provide clinical recommendations due to the poor quality of the available literature. However, it is hoped this paper will provide a foundation for further research to improve rehabilitation for patients being treated with external fixation. How to cite this article: Pawson JR, Church D, Fletcher J, et al. Rehabilitation Techniques for Adults Undergoing External Fixation Treatment for Lower Limb Reconstruction: A Systematic Review. Strategies Trauma Limb Reconstr 2024;19(1):45-55.

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The neuronal membrane glycoprotein M6B (Gpm6b) gene encodes a membrane glycoprotein that belongs to the proteolipid protein family, and is enriched in neurons, oligodendrocytes, and subset of astrocytes in the central nervous system. GPM6B is thought to play a role in neuronal differentiation, myelination, and inactivation of the serotonin transporter via internalization. Recent human genome-wide association studies (GWAS) have implicated membrane glycoproteins (both GPM6B and GPM6A) in the regulation of traits relevant to psychiatric disorders, including neuroticism, depressed affect, and delay discounting. Mouse studies have implicated Gpm6b in sensorimotor gating and regulation of serotonergic signaling. We used CRISPR to create a mutant Glycoprotein M6B (Gpm6b) allele on a C57BL/6J mouse background. Because Gpm6b is located on the X chromosome, we focused on male Gpm6b mutant mice and their wild-type littermates (WT) in two behavioral tests that measured aspects of impulsive or flexible decision-making. We found that Gpm6b deletion caused deficits in a delay discounting task. In contrast, reward sensitivity was enhanced thereby facilitating behavioral flexibility and improving performance in the probabilistic reversal learning task. Taken together these data further delineate the role of Gpm6b in decision making behaviors that are relevant to multiple psychiatric disorders.

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Two factors intrinsic to health are diet and sleep. These two behaviors may well influence one another. Indeed, that insufficient sleep adversely impacts dietary intakes is well documented. On the other hand, diet may influence sleep via melatonin and its biosynthesis from tryptophan. Experimental data exist indicating that provision of specific foods rich in tryptophan or melatonin can improve sleep quality. Whole diets rich in fruits, vegetables, legumes, and other sources of dietary tryptophan and melatonin have been shown to predict favorable sleep outcomes. Although clinical trials are needed to confirm a causal impact of dietary patterns on sleep and elucidate underlying mechanisms, available data illustrate a cyclical relation between these lifestyle factors. We recommend adopting a healthful diet to improve sleep, which may further promote sustained favorable dietary practices.

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BACKGROUND: Patients with metastatic non-small cell lung cancer (NSCLC) harboring a sensitizing EGFR mutation have effective targeted therapy options initially but most patients eventually progress and receive cytotoxic chemotherapy. In this single-institution phase II study, we evaluated the role of nab-paclitaxel monotherapy in this patient population. PATIENTS AND METHODS: Patients with metastatic NSCLC with an activating EGFR mutation whose disease progressed after frontline tyrosine kinase inhibitor therapy and who were chemotherapy naïve received nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint was response rate per RECIST 1.1 and secondary endpoints were duration of response, progression free survival, toxicity and overall survival. RESULTS: A total of 27 patients were enrolled and 21 patients were evaluable for response. Median age was 65 (range 52-81), 69% of patients were women, 42% of patients did not having a smoking history. 31% of patients had central nervous system (CNS) metastatic disease at baseline. Confirmed partial response was documented in 9 of 26 patients (35%, 95% CI 17-56) and disease control rate was 58% (95% CI 35-73). CNS was a common first site of progression. Median progression free survival was 4.0 months (95% CI 1.8-5.2). No new safety signals were observed. CONCLUSION: Single agent nab-paclitaxel showed modest antitumor activity in patients with EGFR mutation positive NSCLC and may be an option in patients who are platinum ineligible. Patients often progressed in the CNS and the results underscores the importance of CNS activity of systemic therapies in this patient population.

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AIM: Prenatal experiences, including maternal stress, depression and anxiety, form crucial building blocks affecting the maturation of the foetal central nervous system. Previous research has examined foetal movements without considering effects of maternal mental health factors critical for healthy foetal development. The aim of this research is to assess the effects of maternal mental health factors on foetal twin compared with singleton movement profiles. METHOD: We coded foetal touch and head movements in 56 ultrasound scans, from a prospective opportunity sample of 30 mothers with a healthy pregnancy (mean gestational age 27.8 weeks for singleton and 27.2 for twins). At the ultrasound scan appointment, participants completed questionnaires assessing their stress, depression and anxiety. RESULTS: Maternal depression increased foetal self-touch significantly. In foetal twins, maternal stress significantly decreased and maternal depression significantly increased other twin touch. Maternal mental health factors affected the head movements of twins significantly more than singletons, with maternal depression decreasing head movement frequency for twins significantly. CONCLUSION: These results indicate that maternal mental health might have an impact on types of body schemata formed in utero, in twin compared with singleton pregnancies. Future research needs to examine whether these prenatal effects affect postnatal differences in body awareness.

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BACKGROUND: Stillbirth is an extremely traumatic and distressing experience for parents, with profound and long-lasting negative impacts. Cultural beliefs and practices surrounding death vary considerably across different contexts and groups, and are a key influence on individual experiences, impacting grief, adjustment, and support needs. Few studies have explored cultural influences surrounding stillbirth in an African context. This study explored the influence of cultural beliefs and practices on the experiences of bereaved parents and health workers after stillbirth in urban and rural settings in Kenya and Uganda. METHODS: A qualitative descriptive study design was employed. Face to face interviews were conducted with parents (N = 134) who experienced a stillbirth (≤ 1 year) and health workers (N = 61) at five facilities in Uganda and Kenya. Interviews were conducted in English or the participants' local language, audio-recorded and transcribed verbatim. Analysis was conducted using descriptive thematic analysis. RESULTS: Commonalities in cultural beliefs and practices existed across the two countries. Three main themes were identified: 1) Gathering round, describes the collective support parents received from family and friends after stillbirth. 2)'It is against our custom' addresses cultural constraints and prohibitions impacting parents' behaviour and coping in the immediate aftermath of the baby's death. 3) 'Maybe it's God's plan or witchcraft' summarises spiritual, supernatural, and social beliefs surrounding the causes of stillbirth. CONCLUSIONS: Kinship and social support helped parents to cope with the loss and grief. However, other practices and beliefs surrounding stillbirth were sometimes a source of stress, fear, stigma and anxiety especially to the women. Conforming to cultural practices meant that parents were prevented from: holding and seeing their baby, openly discussing the death, memory-making and attending the burial. The conflict between addressing their own needs and complying with community norms hindered parents' grief and adjustment. There is an urgent need to develop culturally sensitive community programmes geared towards demystifying stillbirths and providing an avenue for parents to grieve in their own way.

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Female genital mutilation (FGM) is a global issue, with 200 million women and girls thought to be affected. FGM is defined as removal of female external genitalia, either partial or total, for non-medical purposes. FGM is embedded in tradition, including cultural beliefs about sexual behaviour. Associated risks include haemorrhage, infection, death, dyspareunia, childbirth complications and psychological issues. Although FGM negatively impacts on women's psychological wellbeing, little is known about the impact on pregnancy experiences. Psychological consequences of FGM are likely to be intensified during pregnancy when women have concerns about their own and their baby's wellbeing. This mixed-method systematic review aimed to provide insight into the psychological impact of FGM on women who subsequently become pregnant. Nine electronic databases were searched, using a search strategy to identify relevant studies. Studies were considered for inclusion if they were primary studies (qualitative, quantitative or mixed-method) involving pregnant women of any age who have previously undergone FGM. Relevant studies were evaluated using the MMAT appraisal tool. Analysis was guided by the review questions and the evidence identified. One quantitative and 9 qualitative papers were included. Qualitative data were analysed using meta-ethnography. Narrative analysis of the quantitative study was conducted. Findings relate to power of choice linked to reinfibulation, deinfibulation, birth procedures and pain management; importance of knowledgeable and sensitive health care professionals; and relived trauma experienced during childbirth. These findings could inform the development of supportive interventions for women with FGM within maternity services.

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SLE is a clinically heterogeneous disease characterized by an unpredictable relapsing-remitting disease course. Although the etiology and mechanisms of SLE flares remain elusive, Epstein-Barr virus (EBV) reactivation is implicated in SLE pathogenesis. This study examined the relationships between serological measures of EBV reactivation, disease activity, and interferon (IFN)-associated immune pathways in SLE patients. Sera from adult SLE patients (n = 175) and matched unaffected controls (n = 47) were collected and tested for antibodies against EBV-viral capsid antigen (EBV-VCA; IgG and IgA), EBV-early antigen (EBV-EA; IgG), cytomegalovirus (CMV; IgG), and herpes simplex virus (HSV-1; IgG). Serological evidence of EBV reactivation was more common in SLE patients compared to controls as demonstrated by seropositivity to EBV-EA IgG (39% vs 13%; p = 0.0011) and EBV-VCA IgA (37% vs 17%; p = 0.018). EBV-VCA, CMV1, and HSV-1 IgG seropositivity rates did not differ between SLE patients and controls. Furthermore, concentrations of EBV-VCA (IgG and IgA) and EBV-EA (IgG) were higher in SLE patients. SLE patients with high disease activity had increased concentrations of EBV-VCA IgA (mean ISR 1.34 vs. 0.97; p = 0.041) and EBV-EA IgG levels (mean ISR 1.38 vs. 0.90; p = 0.007) compared with those with lower disease activity. EBV reactivation was associated with enhanced levels of the IFN-associated molecule IP-10 (p < 0.001) and the soluble mediators BLyS (p < 0.001) and IL-10 (p = 0.0011). In addition, EBV-EA IgG responses were enriched in two previously defined patient clusters with robust expression of IFN and inflammatory or lymphoid and monocyte responses. Patients in these clusters were also more likely to have major organ involvement, such as renal disease. This study supports a possible role for EBV reactivation in SLE disease activity.

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During the response to the COVID-19 pandemic, doctors will be redeployed into roles with which they are unfamiliar. Adequate training must be provided to reacquaint doctors with medical ward practice, supporting psychological wellbeing and patient safety. Here we describe a cross-skilling programme in North Bristol NHS Trust designed to address colleague anxiety and support wellbeing during redeployment.

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Multiple mitochondrial quality control pathways exist to maintain the health of mitochondria and ensure cell homeostasis. Here, we investigate the role of the endosomal adaptor Tollip during the mitochondrial stress response and identify its interaction and colocalisation with the Parkinson's disease-associated E3 ubiquitin ligase Parkin. The interaction between Tollip and Parkin is dependent on the ubiquitin-binding CUE domain of Tollip, but independent of Tom1 and mitophagy. Interestingly, this interaction is independent of Parkin mitochondrial recruitment and ligase activity but requires an intact ubiquitin-like (UBL) domain. Importantly, Tollip regulates Parkin-dependent endosomal trafficking of a discrete subset of mitochondrial-derived vesicles (MDVs) to facilitate delivery to lysosomes. Retromer function and an interaction with Tom1 allow Tollip to facilitate late endosome/lysosome trafficking in response to mitochondrial stress. We find that upregulation of TOM20-positive MDVs upon mitochondrial stress requires Tollip interaction with ubiquitin, endosomal membranes and Tom1 to ensure their trafficking to the lysosomes. Thus, we conclude that Tollip, via an association with Parkin, is an essential coordinator to sort damaged mitochondrial-derived cargo to the lysosomes.

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The almost universally-occurring aggregated distributions of helminth burdens in host populations have major significance for parasite population ecology and evolutionary biology, but the mechanisms generating heterogeneity remain poorly understood. For the direct life cycle monogenean Discocotyle sagittata infecting rainbow trout, Oncorhynchus mykiss, variables potentially influencing aggregation can be analysed individually. This study was based at a fish farm where every host individual becomes infected by D. sagittata during each annual transmission period. Worm burdens were examined in one trout population maintained in isolation for 9 years, exposed to self-contained transmission. After this year-on-year recruitment, prevalence was 100% with intensities 10-2628, mean 576, worms per host. Parasite distribution, amongst hosts with the same age and environmental experience, was highly aggregated with variance to mean ratio 834 and negative binomial parameter, k, 0.64. The most heavily infected 20% of fish carried around 80% of the total adult parasite population. Aggregation develops within the first weeks post-infection; hosts typically carried intensities of successive age-specific cohorts that were consistent for that individual, such that heavily-infected individuals carried high numbers of all parasite age classes. Results suggest that host factors alone, operating post-infection, are sufficient to generate strongly overdispersed parasite distributions, rather than heterogeneity in exposure and initial invasion.

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BACKGROUND: Quantity and frequency of drinking may be used to effectively quantify the severity of alcohol-use. Drinking-severity has been related to neurocognitive impairments in such domains as spatial working memory (SWM). Youth drinking has been associated with altered neurofunctional underpinnings of SWM. The current study examined the relationship between drinking-severity and SWM processing. METHODS: One-hundred-and-seventy college drinkers reported the maximum number of drinks in a 24 -h period in the last six-months (quantity) and average number of drinking weeks in the last six-months (frequency). All participants performed a virtual Morris Water Task during fMRI which included trials where the target platform was visible or hidden. RESULTS: Greater quantity was associated with reduced SWM-related activity in the dorsolateral prefrontal cortex (F(1, 167) = 4.15, p = .04). Greater frequency was associated with reduced SWM-related activity in the hippocampus (F(1, 167) = 4.34, p = 0.039). Greater quantity was associated with longer search times (r = 0.21, p = .005) and greater platforms found (r = 0.19, p = .01) in VISIBLE trials. We did not find a relationship between drinking quantity or frequency and gender on SWM-related activity, although men found more platforms in both HIDDEN (F(1, 168) = 11.7, p = 0.0008) and VISIBLE (F(1, 168) = 23.0, p < .0001) trials compared to women. CONCLUSIONS: Altered SWM-related hippocampal function relating to alcohol use in young adults raises questions regarding the impact on young adult health and the nature of the findings. Future studies should examine whether these differences may lead to cognitive deficits later in life.

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In low-income settings, partner engagement in HIV testing during pregnancy is well recognised, but uptake remains low. To understand why men fail to engage, 76 in-depth, individual interviews were conducted with women (n = 23), men (n = 36) and community stakeholders (n = 17) in Malawi and Kenya. Transcribed data were analysed thematically. Male engagement was verbally supported. However, definitions of 'engagement' varied; women wanted a shared experience, whereas men wanted to offer practical and financial support. Women and stakeholders supported couples-testing, but some men thought separate testing was preferable. Barriers to couples-testing were strongly linked to barriers to antenatal engagement, with some direct fear of HIV-testing itself. The major themes identified included diverse definitions of male engagement, cultural norms, poor communication and environmental discomfort - all of which were underpinned by hegemonic masculinity. Couples-testing will only increase when strategies to improve reproductive health care are implemented and men's health is given proper consideration within the process. As social norms constitute a barrier, community-based interventions are likely to be most effective. A multi-pronged approach could include advocacy through social media and community forums, the provision of tailored information, the presence of positive role models and a welcoming environment.

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Marijuana (MJ) is widely used among college students, with peak use between ages 18-22. Research suggests memory dysfunction in adolescent and young adult MJ users, but the neural correlates are unclear. We examined functional magnetic resonance imaging (fMRI) response during a memory task among college students with varying degrees of MJ involvement. Participants were 64 college students, ages 18-20, who performed a visual encoding and recognition task during fMRI. MJ use was ascertained for 3 months prior to scanning; 27 individuals reported past 3-month MJ use, and 33 individuals did not. fMRI response was modeled during encoding based on whether targets were subsequently recognized (correct encoding), and during recognition based on target identification (hits). fMRI response in left and right inferior frontal gyrus (IFG) and hippocampal regions of interest was examined between MJ users and controls. There were no group differences between MJ users and controls on fMRI response during encoding, although single sample t-tests revealed that MJ users failed to activate the hippocampus. During recognition, MJ users showed less fMRI response than controls in right hippocampus (Cohen's d = 0.55), left hippocampus (Cohen's d = 0.67) and left IFG (Cohen's d = 0.61). Heavier MJ involvement was associated with lower fMRI response in left hippocampus and left IFG. This study provides evidence of MJ-related prefrontal and hippocampal dysfunction during recognition memory in college students. These findings may contribute to our previously identified decrements in academic performance in college MJ users and could have substantial implications for academic and occupational functioning.

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