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Adoptive cell therapy (ACT) utilizing γδ T cells is becoming a promising option for the treatment of cancer, because it offers an off-the-shelf allogeneic product that is safe, potent, and clinically effective. Approaches to engineer or enhance immune-competent cells for ACT, like expression of chimeric antigen receptors (CARs) or combination treatments with bispecific T cell engagers, have improved the specificity and cytotoxic potential of ACTs and have shown great promise in preclinical and clinical settings. Here, we test whether electroporation of γδ T cells with CAR or secreted bispecific T cell engager (sBite) mRNA is an effective approach to improve the cytotoxicity of γδ T cells. Using a CD19-specific CAR, approximately 60% of γδ T cells are modified after mRNA electroporation and these cells show potent anticancer activity in vitro and in vivo against two CD19-positive cancer cell lines. In addition, expression and secretion of a CD19 sBite enhances γδ T cell cytotoxicity, both in vitro and in vivo, and promotes killing of target cells by modified and unmodified γδ T cells. Taken together, we show that transient transfection of γδ T cells with CAR or sBite mRNA by electroporation can be an effective treatment platform as a cancer therapeutic.

Hepatic gene transfer with adeno-associated viral (AAV) vectors shows much promise for the treatment of the X-linked bleeding disorder hemophilia B in multiple clinical trials. In an effort to further innovate this approach and to introduce alternative vector designs with potentially superior features into clinical development, we recently built a vector platform based on AAV serotype 3 because of its superior tropism for human hepatocytes. A vector genome with serotype-matched inverted terminal repeats expressing hyperactive human coagulation factor IX (FIX)-Padua was designed for clinical use that is optimized for translation using hepatocyte-specific codon-usage bias and is depleted of immune stimulatory CpG motifs. Here, this vector genome was packaged into AAV3 (T492V + S663V) capsid for hepatic gene transfer in non-human primates. FIX activity within or near the normal range was obtained at a low vector dose of 5 × 1011 vector genomes/kg. Pre-existing neutralizing antibodies, however, completely or partially blocked hepatic gene transfer at that dose. No CD8+ T cell response against capsid was observed. Antibodies against the human FIX transgene product formed at a 10-fold higher vector dose, albeit hepatic gene transfer was remarkably consistent, and sustained FIX activity in the normal range was nonetheless achieved in two of three animals for the 3-month duration of the study. These results support the use of this vector at low vector doses for gene therapy of hemophilia B in humans.

Background: Sensory over-responsivity (SOR) refers to excessively intense and/or prolonged behavioral responses to environmental stimuli typically perceived as non-aversive. SOR is prevalent in several neurodevelopmental disorders, including chronic tic disorders (CTDs) and obsessive-compulsive disorder (OCD). Few studies have examined the extent and clinical correlates of SOR across disorders, limiting insights into the phenomenon's transdiagnostic clinical and biological relevance. Such cross-disorder comparisons are of particular interest for CTDs and OCD given their frequent co-occurrence. Objective: We sought to compare the magnitude of SOR between adults with CTD and adults with OCD and to identify the clinical factors most strongly associated with SOR across these disorders. Methods: We enrolled 207 age- and sex-matched participants across four diagnostic categories: CTD without OCD (designated “CTD/OCD-”; n = 37), CTD with OCD (“CTD/OCD+”; n = 32), OCD without tic disorder (“OCD”; n = 69), and healthy controls (n = 69). Participants completed a self-report battery of rating scales assessing SOR (Sensory Gating Inventory, SGI), obsessive-compulsive symptoms (Dimensional Obsessive-Compulsive Scale, DOCS), inattention and hyperactivity (Adult ADHD Self-Report Screening Scale for DSM-5, ASRS-5), anxiety (Generalized Anxiety Disorder-7), and depression (Patient Health Questionnaire-9). CTD participants were also administered the Yale Global Tic Severity Scale (YGTSS). To examine between-group differences in SOR, we compared SGI score across all groups and between pairs of groups. To examine the relationship of SOR with other clinical factors, we performed multivariable linear regression. Results: CTD/OCD-, CTD/OCD+, and OCD participants were 86.7%, 87.6%, and 89.5%, respectively, more likely to have higher SGI total scores than healthy controls. SGI total score did not differ between CTD/OCD-, CTD/OCD+, and OCD groups. In the regression model of log-transformed SGI total score, OCD diagnosis, DOCS score, and ASRS-5 score each contributed significantly to model goodness-of-fit, whereas CTD diagnosis and YGTSS total tic score did not. Conclusion: SOR is prevalent in adults with CTD and in adults with OCD but does not significantly differ in magnitude between these disorders. Across CTD, OCD, and healthy control adult populations, SOR is independently associated with both obsessive-compulsive and ADHD symptoms, suggesting a transdiagnostic relationship between these sensory and psychiatric manifestations. Future cross-disorder, longitudinal, and translational research is needed to clarify the role and prognostic import of SOR in CTDs, OCD, and other neurodevelopmental disorders.

Potency is a key optimization parameter for hemophilia A gene therapy product candidates. Optimization strategies include promoter engineering to increase transcription, codon optimization of mRNA to improve translation, and amino-acid substitution to promote secretion. Herein, we describe both rational and empirical design approaches to the development of a minimally sized, highly potent AAV-fVIII vector that incorporates three unique elements: a liver-directed 146-nt transcription regulatory module, a target-cell-specific codon optimization algorithm, and a high-expression bioengineered fVIII variant. The minimal synthetic promoter allows for the smallest AAV-fVIII vector genome known at 4,832 nt, while the tissue-directed codon optimization strategy facilitates increased fVIII transgene product expression in target cell types, e.g., hepatocytes, over traditional genome-level codon optimization strategies. As a tertiary approach, we incorporated ancient and orthologous fVIII sequence elements previously shown to facilitate improved biosynthesis through post-translational mechanisms. Together, these technologies contribute to an AAV-fVIII vector that confers sustained, curative levels of fVIII at a minimal dose in hemophilia A mice. Moreover, the first two technologies should be generalizable to all liver-directed gene therapy vector designs. Keywords: vector optimization, AAV, hemophilia, factor VIII, codon optimization, promoter design

Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV.

Clinical data support the feasibility and safety of adeno-associated viral (AAV) vectors in gene therapy applications. Despite several clinical trials of AAV-based gene transfer for hemophilia B, a unique set of obstacles impede the development of a similar approach for hemophilia A. These include (i) the size of the factor VIII (fVIII) transgene, (ii) humoral immune responses to fVIII, (iii) inefficient biosynthesis of human fVIII, and (iv) AAV vector immunity. Through bioengineering approaches, a novel fVIII molecule, designated ET3, was developed and shown to improve biosynthetic efficiency 10- to 100-fold. In this study, the utility of ET3 was assessed in the context of liver-directed, AAV-mediated gene transfer into hemophilia A mice. Due to the large size of the expression cassette, AAV-ET3 genomes packaged into viral particles as partial genome fragments. Despite this potential limitation, a single peripheral vein administration of AAV-ET3 into immune-competent hemophilia A mice resulted in correction of the fVIII deficiency at lower vector doses than previously reported for similarly oversized AAV-fVIII vectors. Therefore, ET3 appears to improve vector potency and mitigate at least one of the critical barriers to AAV-based clinical gene therapy for hemophilia A.

Sustainable crop production requires nutrient inputs to replace what was removed or lost. Replenishing nutrients using fertilizers and animal wastes is one of the most common input practices. While there is considerable research evaluating the efficacy of fertilizer and manure-based inputs for crop performance, nutrient use efficiency, and the subsequent impact to the environment, the influence of these inputs on soil health properties is less understood. The goals of this review are to summarize the state of literature on the influence of chemical fertilizer and manure-based inputs on soil health and to identify research gaps to refine efforts toward improved soil health, sustainability, and soil carbon storage. Conclusions suggest that chemical fertilizer inputs can increase soil organic matter and soil health provided that additions are not beyond what a plant can utilize. Manure-based inputs contribute to soil organic carbon and associated metrics; however, direct comparison of products is difficult as they are generally applied on a nutrient basis rather than carbon basis, which differentially affects their influence on soil health. Overall, nutrient-containing inputs show beneficial influences on soil health metrics; however, more focused research into their influence on soil health is needed.

Background: Only 12% of Kenyan women use breast cancer (BC) screening programs. Early detection is critical for reducing the condition's associated morbidity and mortality. Unfortunately, few studies have been conducted on the screening program's implementation and the causes for the low usage rates in Turbo Sub-County, Kenya. The purpose of this study was to learn about women of reproductive age's (WRA) practices, attitudes, and knowledge regarding BC screening programs, as well as to investigate the potential association between lifestyle factors and BC screening service utilization. Methods: Mixed-method approaches were used in an analytical cross-sectional study design. The study included 317 participants selected randomly. An interviewer-administered questionnaire was used to collect quantitative data while focus group discussion (FGD) and key informant interview (KII) guides were used for collecting qualitative data. The Statistical Package for Social Sciences (SPSS) version 26 was used to manage quantitative data, whereas NVivo version 12 was used to analyze qualitative data. Chi-square, Fisher's exact test, and multiple logistic regression were used to assess the degree of relationship between BC screening service uptake and independent variables. The qualitative data was transcribed verbatim, and the transcripts were automatically coded to generate themes. Results: The participants' mean age was 30.14 (9.64). Breast cancer screening services were used by 10.21% of the population. Women who were aware of the signs and symptoms of BC were 71.5 times more likely to undergo screening than their counterparts. Similarly, those with positive attitudes toward BC and screening programs were 84 times more likely to get screened than those with negative attitudes. Breastfeeding increased the likelihood of BC screening by OR = 37 (95% CI: 0.00–0.32), physical activity by OR = 37 (95% CI: 0.00–0.25), and chronic illnesses by OR = 37 (95% CI: 0.00–0.17). Conclusion: Knowledge of signs and symptoms of BC and a positive attitude towards perceived barriers enhanced the probabilities of BC screening. Being physically active, breastfeeding, and having a chronic disease all increased the odds of BC screening uptake. To improve screening rates, it is necessary to provide sufficient information to those who are least likely to be screened.

The nutritional value versus toxicity was conducted in muscles, gonads, livers, and skin of Tetraodon lineatus from Lake Nasser, Egypt, during 2018. Its overall moisture was 74.92 ± 2.27 muscles, 72.45 ± 2.887 gonads and 35.49 ± 5.55 % livers. The livers recorded the highest crude protein (23.66 ± 3.48%) and total lipids (36.45 ± 6.32%). The annual total protein in muscles was 16.91 ± 2.54%, while the annual total lipids were 3.39 ± 1.05 %. Leucine was the most abundant (0.548 mg/g) ˃ isoleucine (0.284 mg/g) of the essential amino acids. Sixteen fatty acids were recorded (12: SFAs, 4: MUSFAs), with butyric acid predominating. Assessment of tetrodotoxin (TTX) as mouse per unit (MU/g), gave the highest toxic abundant for skin (53.13%) ˃ gonads (34.6) ˃ muscles (12.9) and no detection in the livers. The average toxicity in all organs is at a low level and lower than the maximum permissible limits (

The present investigation describes the biology of penaeid shrimps and their fishery studies on morphometric length-weight relationships estimated during the two monsoon seasons from Malindi–Ungwana Bay in Kenya. A total of 1238 penaeid shrimps belonging to Fenneropenaeus indicus, Penaeus monodon, Marsupenaeus japonicus, Metapenaeus monoceros, Penaeus canaliculatus and Penaeus semisulcatus were collected from the two seasons with South East Monsoon (SEM) recording more diverse species than the North East Monsoon (NEM). The length-weight relationship analyses of most penaeid species exhibited positive allometric growth significantly different from 3.0 (p

A total of 52 samples of finished fish feeds and ingredients were collected from smallholder farmers in Kenya, Tanzania, Rwanda and Uganda, and analyzed. Culture and molecular techniques were used to identify fungal isolates from the feedstock, and mycotoxin profiles were determined using liquid chromatography–tandem mass spectrometry. The most prevalent fungal species recovered in the samples was Asperigillus flavus (54.5%). Other fungal species recovered from the samples were Aspergillus tamarii (9.1%), Mucor velutinosus (9%), Phoma sp. (6.1%), Aspergillus niger (6%), Eurotium rubrum (3%) and Penicillium chrysogenum (3%). Fourteen mycotoxins were identified: aflatoxins B1, B2, G1 and G2, fumonisin B1 and B3, deoxynivalenol (DON) and acetyldeoxynivalenol (sum of 3-ADONand 15-ADON), ochratoxin A, roquefortine C, alternariol, T-2 toxin, and nivalenol. DON (92.9%), aflatoxins (64.3%) and fumonisins (57.1%) were the most prevalent within locally manufactured feeds, while no contamination was found in imported feed. Samples from Kenya were the most contaminated with aflatoxin (maximum 806.9 μg·kg−1). The high levels of aflatoxin and trichothecene type A and B contamination found in this study point to potential risks to fish performance and to the health of consumers of the fish and derived products.

A 7-month experiment was carried out to determine the effects of different levels of probiotics (baker's yeast (Saccharomyces cerevisiae) and Bacillus subtilis) on Nile tilapia (Oreochromis niloticus) reared in low input ponds. Monosex male fingerlings (40 g) were randomly distributed into 28, 1.25 m3 net cages at 50 fish m−3 and fed twice daily at 3% body weight on seven isonitrogenous (28% crude protein) diets supplemented with either Saccharomyces cerevisiae (1 × 1010 CFU g−1) or Bacillus subtilis (1 × 109 CFU g−1) at different levels: Diet 0 (control); Diet 1–3 were supplemented with S. cerevisiae at 2 g kg −1 (Diet 1); 4 g kg−1 (Diet 2) and 6 g kg −1 (Diet 3) whereas Diet 4–6 were supplemented with B. subtilis at 5 g kg−1 (Diet 4); 10 g kg−1 (Diet 5) and 15 g kg−1 (Diet 6). Higher final weight (255.31 ± 3.19), Specific Growth rates (SGR) (0.77±0.01) and better Feed Conversion Ratio (FCR) (1.61 ± 0.02) were recorded in fish fed on Diet 2 followed by fish fed on Diet 5. Fish fed on probiotic- supplemented diets had significantly better growth, nutrient utilization and FCR compared to fish fed on the control diet (P < 0.05). Probiotic supplementation significantly affected the body composition of the fish (P < 0.05). S. cerevisiae led to significantly high protein (86.06%) at 4 g kg−1 (Diet 2) (P < 0.05) while B. subtilis led to significantly higher protein (89.40%) at 5 g kg−1 (Diet 4) (P < 0.05). Crude lipid and ash content were significantly lower in the fish fed on probiotic supplemented diets (P < 0.05) compared to the control. This study has demonstrated that the application of probiotics in diets of Nile tilapia in low input ponds promotes growth and enhances body composition. The two probiotics have got different effects depending on the level of application. S. cerevisiae exhibited the best performance at 4 g kg−1 while B. subtilis had the best performance at 10 g kg−1. Keywords: Bacillus subtilis, Nile tilapia, Probiotics, Saccharomyces cerevisiae, Growth, Nutrient utilization

Abstract: With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate interstudy comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group-European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to (1) account for gender-specific differences in determining hemoglobin levels for eligibility criteria; (2) revise the definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices; and (3) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks before study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs non-TDA) and graded (major vs minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Females are at greater risk of developing patellofemoral pain (PFP) than males, and an excessive patellofemoral joint reaction force (PFJRF) may contribute to this discrepancy. It is unknown if the PFJRF differs between males and females during stair ascent. Additionally, body height may also influence the PFJRF. This study investigated PFJRF differences between males and females and explored relationships between body height and PFJRF during stair ascent., Methods: Thirty males (25.6 (2.7) yr) and thirty females (23.7 (2.2) yr) ascended stairs (96 steps/min). Three-dimensional kinematics (200 Hz) and kinetics (2000 Hz) were recorded and used to calculate biomechanical dependent variables., Results: Females experienced a greater PFJRF magnitude (mean difference (MD) = 3.2 N/kg; 95% CI = 0.5, 5.9; p = 0.022) and rate (MD = 23.8 N/kg/sec; 95% CI = 2.7, 45.1; p = 0.029), quadriceps muscle force (3.1 N/kg; 95% CI = 0.2, 6.0; p = 0.036), and knee flexion angle (MD = 2.3°; 95% CI = 0.3, 4.3; p = 0.026). Females exhibited shorter quadriceps lever arm length (MD = -0.1 cm; 95% CI = -0.2, 0.0; p = 0.024) and body height (MD = -16.9 cm; 95% CI = -20.5, -13.2, p < 0.001) compared to males. Body height was inversely correlated with PFJRF magnitude (r = -0.31; p = 0.017), rate (r = -0.28; p = 0.032), and knee flexion angle (r = -0.54; p < 0.001)., Conclusion: Females experienced a greater PFJRF than males. Additionally, the PFJRF and body height were inversely correlated. This observed difference may contribute to the PFP sex discrepancy and be due, at least in part, to body height differences., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Studies report interaction difficulties between patients with polycystic ovary syndrome (PCOS) and healthcare professionals (HCP). This systematic review and qualitative evidence synthesis aimed to collate and synthesize the existing peer-reviewed literature investigating challenges for people with PCOS when interacting with HCP. Medline, PsycInfo, EMBASE, All EBM and CINAHL were searched from 1990 to September 2022. Study risk of bias (RoB) was performed and all textual data relevant to challenging interactions between patients with PCOS and HCP were extracted and analysed using thematic synthesis. Of the 6353 studies identified, 28 were included. Two were appraised as high, four as moderate and 22 as low RoB. Four analytic themes were derived illustrating that interactions were challenging when: (i) medical information (PCOS, its management) was not shared in the best way; (ii) information provision and deliberation opportunities were insufficient to achieve outcomes that mattered to patients; (iii) interactions prompted but did not support patient activation; and (iv) health system-level barriers (e.g. policies and guidelines) were present or made worse by HCP behaviour. Future research should examine methods for the implementation and evaluation of established frameworks for sharing medical information and supporting patient agency in the context of PCOS care., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Laboratory resurrection of ancient coagulation factor (F) IX variants generated through ancestral sequence reconstruction led to the discovery of a FIX variant, designated An96, which possesses enhanced specific activity independent of and additive to that provided by human p.Arg384Lys, referred to as FIX-Padua., Objectives: The goal of the current study was to identify the amino acid substitution(s) responsible for the enhanced activity of An96 and create a humanized An96 FIX transgene for gene therapy application., Methods: Reductionist screening approaches, including domain swapping and scanning residue substitution, were used and guided by one-stage FIX activity assays. In vitro characterization of top candidates included recombinant high-purity preparation, specific activity determination, and enzyme kinetic analysis. Final candidates were packaged into adeno-associated viral (AAV) vectors and delivered to hemophilia B mice., Results: Five of 42 total amino acid substitutions in An96 appear sufficient to retain the enhanced activity of An96 in an otherwise human FIX variant. Additional substitution of the Padua variant further increased the specific activity 5-fold. This candidate, designated ET9, demonstrated 51-fold greater specific activity than hFIX. AAV2/8-ET9 treated hemophilia B mice produced plasma FIX activities equivalent to those observed previously for AAV2/8-An96-Padua, which were 10-fold higher than AAV2/8-hFIX-Padua., Conclusion: Starting from computationally inferred ancient FIX sequences, novel amino acid substitutions conferring activity enhancement were identified and translated into an AAV-FIX gene therapy cassette demonstrating high potency. This ancestral sequence reconstruction discovery and sequence mapping refinement approach represents a promising platform for broader protein drug and gene therapy candidate optimization., Competing Interests: Declaration of competing interests H.C.B., G.D., S.N.G., C.B.D., H.T.S., K.A.K., and C.W.C. are inventors on patents and patent applications describing the ancestral FIX technology filed by Expression Therapeutics, Emory University, Children’s Healthcare of Atlanta, and Georgia Institute of Technology. C.B.D., H.T.S., and H.C.B. are inventors on liver-directed codon-optimization and promoter technology filed by Emory University and Children’s Healthcare of Atlanta. H.T.S. and C.B.D. are cofounders of Expression Therapeutics, Inc, and own equity in the company. H.C.B., G.D., and S.N.G. are employees of Expression Therapeutics, Inc and own equity in the company. Expression Therapeutics, Inc has obtained licenses for FIX-An96, liver codon-optimized FIX, and synthetic liver-directed promoter intellectual property. K.C.C., P.C.S., and G.M.B. declare no conflicts of interest. The terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict of interest policies., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Abstract: Although myeloproliferative neoplasms (MPNs) are traditionally considered diseases of adults in their sixth or seventh decade, these conditions do occur in young patients; for example, for essential thrombocythemia, in particular, there is a second peak in women of reproductive age. Therefore, pregnancy is an uncommon but not rare occurrence and clinical challenge in some scenarios. Here, we discuss in detail our local approach to the management of pregnancy in patients with MPN while taking a case-based approach. We include relevant updates in the field and point to a future research strategy that should be internationally focused to obtain as much information in as short a time as possible., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: There is a lack of established clinical outcomes for patients with myelofibrosis (MF) receiving fedratinib following ruxolitinib failure. This study examined real-world patient characteristics, treatment patterns, and clinical outcomes of patients with MF treated with fedratinib following ruxolitinib failure in US clinical practice., Patients and Methods: This retrospective patient chart review included adults with a physician-reported diagnosis of MF, who initiated fedratinib after discontinuing ruxolitinib. Descriptive analyses characterized patient characteristics, clinical outcomes, and treatment patterns from MF diagnosis through ruxolitinib and fedratinib treatment., Results: Twenty-four physicians abstracted data for 150 eligible patients. Approximately 55.3% of the patients were male, 68.0% were White, and median age at MF diagnosis was 68 (range, 35-84) years. Median duration of ruxolitinib therapy was 7.6 (range, 0.7-65.5) months. At initiation of fedratinib, 88.0% of patients had palpable spleen and a mean spleen size of 16.0 (standard deviation [SD], 5.9) cm. Spleen size decreased by 19.4% to 13.2 (SD, 7.9) cm at month 3 (P = .0001) and by 53.4% to 7.2 (SD, 7.4) cm at month 6 (P = .01) of fedratinib treatment, respectively. Almost one-third (26.8%) of patients had achieved ≥ 50% spleen reduction by month 6. Mean number of symptoms also decreased significantly at month 3 (P < .0001) and month 6 (P = .01)., Conclusion: Fedratinib appears to deliver spleen and symptom benefits in real-world patients with MF previously treated with ruxolitinib., Competing Interests: Disclosure J.M. reports research funding paid to institution from AbbVie, BMS, CTI BioPharm, Geron, Incyte, Kartos, Novartis, PharmaEssentia, and Roche; consulting fees from AbbVie, BMS, CTI BioPharm, Galecto, Geron, GSK, Incyte, Kartos, Karyopharm, MorphoSys, Novartis, PharmaEssentia, Roche, and Sierra Oncology. C.H. reports research funding from BMS/Celgene, Constellation Pharmaceuticals, a MorphoSys Company, and Novartis; and advisory role and speaker funding from Abbvie, AOP Orphan Pharmaceuticals, BMS/Celgene, CTI BioPharma, Galacteo, Geron, Gilead, Janssen, Keros, Novartis, Promedior, Roche, and Shire. T.A.S., D.L., M.G., and T.A.M. report employment with Cardinal Health. S.M. and A.M. report employment with BMS. D.T. and I.S.D. report employment with and stock ownership in BMS. P.A. reports no conflicts of interest. J.K. reports employment with and stock ownership in Cardinal Health at the time this study was conducted. B.A.F. reports research funding from BMS; and stock ownership in and employment with Cardinal Health. A.T.G. reports consulting for AbbVie, BMS/Celgene, CTI BioPharma, Constellation Pharmaceuticals, a MorphoSys Company, GSK/Sierra Oncology, Incyte, Kartos, Novartis, and PharmaEssentia., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Nonmelanoma skin cancers (NMSCs) in ruxolitinib-treated patients with myeloproliferative neoplasms behave aggressively, with adverse features and high recurrence. In our cohort, mortality from metastatic NMSC exceeded that from myelofibrosis. Vigilant skin assessment, counseling on NMSC risks, and prospective ruxolitinib-NMSC studies are crucial., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Research on family communication of germline genome sequencing (GS) results (versus of genetic results after targeted genetic testing) is still emerging, yet potentially complex results increase the importance of communicating risk to relatives. Promoting equity by ensuring patients have sufficient health literacy to interpret results is important in this context. This study aimed to identify cancer patients' perceived importance of result disclosure, predictors of perceptions, and perspectives on family communication., Methods: This explanatory-sequential, cross-sectional mixed-methods study involved participants (n = 246) completing a questionnaire and (n = 20) a semi-structured interview. Ordinal logistic regressions determined associations between potential predictors and perceived importance of result disclosure. Interview transcripts were analysed thematically using a constant-comparative approach., Results: More participants intended disclosing to nuclear (77.4%) than to extended family (42.7%). More than half (59.3%) felt results were family information; 62.7% believed it was important to disclose results to family members. Nuclear and extended family communication scores and education level were significantly positively associated with perceived importance of disclosure (p < 0.05). Six qualitative themes were identified: i) Responsibility to inform, ii) Choice, iii) Autonomy, iv) Family Communication, v) Significance of results, and vi) Health professional role., Conclusion: Low health literacy and family conflict can complicate communication of GS results. Patients seek clear, interpretable information in a format they can easily communicate., Practice Implications: Healthcare professionals can facilitate discussion of GS results by offering written information, encouraging disclosure, exploring existing family dynamics and communication patterns, and offering strategies to improve family communication. Centralised genetic communication offices and chatbots can also be helpful., Competing Interests: Declaration of Competing Interest BM has a remunerated consultant role with the company Astrazeneca with respect to an unrelated project. The other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Non-melanoma skin cancer (NMSC) is the most common cancer type and incidence increases with age. As a consequence, an increasing number of frail patients are being referred for consideration of skin cancer surgery. However, some of these patients may not live long enough to experience benefit from surgery, while being at risk of postoperative complications., Objectives: To investigate the treatment burden of surgical excision of skin cancers in frail individuals., Methods: We conducted a single-center retrospective cohort study analyzing outcomes of skin cancer excision in frail versus non-frail patients., Results: Eighty-eight patients were included. The complication rate was higher in frail versus non-frail patients: 12 (27.9%) versus 9 (18.8%), with 5 unplanned postoperative hospital attendances leading to 3 hospital admissions in the frail cohort. Nine patients in the frail group (21%) died within 6 months of their procedure versus no deaths in the non-frail group (p < 0.001 Fisher's Exact test), with no deaths attributed to skin cancer., Conclusion: Treatment-related complications and mortality are common in frail patients after surgical excision of skin lesions clinically suspicious for skin cancer. Careful consideration should be given, and patients should be adequately counseled about treatment risks and alternative management options, including active surveillance, in particular, if the lesions are expected to remain asymptomatic., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Letters of recommendation play an important role in resident selection. While plastic surgery's Standardized Letter of Recommendation (SLOR) form most commonly serves as an adjunct to narrative letters, the SLOR provides objective data in the review process and could eventually replace narrative letters. The utility of the SLOR in predicting Match outcomes has not been studied., Methods: Applicant data from 225 first-time residency applicants in 2020-21 were collected. Logistic regression modeling was used to predict Match outcomes. This model was validated using 100 randomly selected applicants from 2019-20., Results: Rank placement (SLOR Question 6) was the most important factor when predicting Match outcomes (p<0.0001). All other SLOR questions were not predictive and subject to notable score inflation. No SLOR score differences were noted based on race; female applicants were rated higher in two of ten domains (p<0.05)., Conclusions: One question on the plastic surgery SLOR was highly predictive of an applicant matching. However, the remaining SLOR questions had little utility and were subject to gross score inflation. Further work should be done to optimize the utility of the SLOR in differentiating applicants. This has important implications in ensuring the selection of professional, competent residents according to the aims of the Accreditation Council of Graduate Medical Education., (Copyright © 2023 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: Insufficient physical activity (PA) and prolonged sitting time (ST) increase the risk of chronic disease and mortality. Caring for young children can potentially impact maternal PA and sedentary behaviours. The aims of this study were to explore the levels of PA and ST in women with young children (infants, toddlers and preschoolers) and sociodemographic and behavioural factors associated with these., Study Design: This was a population-based cross-sectional study., Methods: Survey 5 data collected in 2009 (n = 4290) of the 1973-1978 birth cohort of the Australian Longitudinal Study on Women's Health were used. Multiple linear and logistic regression models were used to examine associations., Results: In adjusted models, compared with women with preschoolers, women whose youngest child was an infant aged 0-6 months, aged >6-12 months or toddler had lower PA (-321.3 MET.min/week [95% confidence interval (CI) -416.2, -226.4], -147.9 MET.min/week [95% CI -237.6, -58.1] and -106.4 MET.min/week [95% CI -172.3, -40.5]). ST was higher in women whose youngest child was an infant aged 0-6 months (0.48 h/day; 95% CI 0.19, 0.77) but lower with infants aged >6-12 months (-0.33 h/day; 95% CI -0.60, -0.05) and toddlers (-0.40 h/day; 95% CI -0.60, -0.20) than in those with preschoolers. The findings were similar in the logistic model. Sociodemographic and behavioural factors such as occupation and marital status also influenced PA and ST., Conclusions: Women with infants and toddlers have lower PA than women with preschoolers. Women are more likely to sit more in the first 6 months after childbirth. These findings can inform resources and intervention development to improve activity levels in women with young children through consideration of the age of the youngest child, sociodemographic and behavioural factors., (Copyright © 2022 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

General practitioner (GP) prescribing of psychotropic medicines to paediatric patients is increasing across countries, sparking the need for additional research into this field. We examined prescribing rates, GP and patient characteristics and indications associated with prescribing psychotropic medicines to paediatric patients in Australian general practice, using data from the Bettering the Evaluation and Care of Health (BEACH) program. We extracted all encounters with children aged 3 to 17 from 2000 to 2016. Psychotropic medicines were defined as those in the ATC codes N05 (Psycholeptics) and N06 (Psychoanaleptics). Of the 144,397 encounters, GPs prescribed 1829 psychotropic medicines to paediatric patients at an average rate of 1.16 prescriptions per 100 encounters (95% confidence interval 1.09-1.23). We found that the rate of psychotropic medicines prescribed to paediatric patients in Australian general practice increased. Patients who were adolescent, female, socio-economically disadvantaged or from an English-speaking background were significantly more likely to be prescribed a psychotropic medicine. GP practices in remote or regional areas and Australian graduate GPs were more likely to prescribe psychotropic medicines to paediatric patients. Depression, attention deficit hyperactivity disorder, anxiety and autism were the most common psychiatric indications managed with psychotropic medicines. Antidepressants, psychostimulants, benzodiazepines, antipsychotics and other psychotropic medicines were prescribed, signifying a high rate of off-label use. Sertraline was the most common psychotropic medicine prescribed, followed by fluoxetine and methylphenidate. Future studies involving data from other prescribers, e.g. paediatricians and psychiatrists, and studies linking prescribed medicines to their indications may widen our understanding of psychotropic medicine prescribing in Australian paediatric patients., Competing Interests: Declaration of Competing Interest L.T., C.H., P.S.N., T.F.C.: There are no competing interests to declare., (Copyright © 2022 Elsevier B.V. and ECNP. All rights reserved.)

Background: Acute subdural hematoma is a neurosurgical emergency. Thrombocytopenia poses a management challenge for these patients. We aimed to determine the impact of thrombocytopenia on preoperative hemorrhage expansion and postoperative outcomes., Methods: This retrospective study evaluated patients presenting at our institution with acute subdural hematoma between 2009 and 2019. Patients who underwent surgery, had thrombocytopenia (platelets <150,000/μL), and had multiple preoperative computed tomography scans were included. Case control 1:1 matching was performed to generate a matched cohort with no thrombocytopenia. Univariate analyses were conducted to determine changes in subdural thickness and midline shift, postoperative Glasgow Coma Scale score, mortality, length of stay, and readmission rates., Results: We identified 19 patients with both thrombocytopenia and multiple preoperative computed tomography scans. Median platelet count was 112,000/μL (Q1 69,000, Q3 127,000). Comparing the thrombocytopenia cohort with the control group, there was a statistically significant difference in change in subdural thickness (median 5 mm [Q1 2, Q3 7.4] vs. 0 mm [Q1 0, Q3 1.5]; P = 0.001) and change in midline shift (median 3 mm [Q1 0, Q3 9.5] vs. median 0.5 mm [Q1 0, Q3 1.5]; P = 0.018). The thrombocytopenia cohort had higher in-hospital mortality (10 [52.6%] vs. 2 [10.5%]; P = 0.003). No significant differences were found in postoperative Glasgow Coma Scale score, length of stay, number of readmissions, and number of reoperations., Conclusions: Thrombocytopenia is significantly associated with expansion of hematoma preoperatively in patients with acute subdural hematoma. While the benefit of early platelet correction cannot be determined from this study, patients who present with thrombocytopenia will benefit from close monitoring, a low threshold to obtain repeat imaging, and anticipating early surgical evacuation after platelet optimization., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Cerebral arteriovenous malformations (AVMs) are complex vascular lesions at perpetual risk for rupture, which can lead to significant morbidity and mortality. This study sought to evaluate the dynamic relationship between comorbidities and post-procedure complications to quantify the risk of poor discharge outcomes to create a predictive outcomes model., Methods: The National Inpatient Sample (NIS) data from 2012 to 2015 was queried for AVM treatment using International Classification of Diseases, Ninth Revision codes. The Neurovascular Comorbidities Index (NCI) quantified patient comorbidity burden. In-hospital complications included surgical and medical complications or seizures. The primary outcome was the NIS Subarachnoid Hemorrhage Outcome Measure (NIS-SOM)., Results: A total of 1363 patients were included. A total of 1330 patients (98%) underwent embolization, 28 (2%) underwent resection, and 9 (0.7%) underwent radiosurgery. A higher NCI was associated with the occurrence of any complication (odds ratio [OR], 1.30 if NCI = 2; P &lt; 0.001). Higher NCI was also significantly associated with a poor NIS-SOM outcome (OR, 2.45 if NCI = 2 and no complications; P &lt; 0.001). A ruptured AVM with intracranial hemorrhage (ICH) increased the risk of in-hospital complications (OR, 2.16; P = 0.007) and a poor NIS-SOM outcome (OR, 3.18; P &lt; 0.001). Various hypothetical patient scenarios and the predicted outcomes are also presented., Conclusion: Neurovascular comorbidities have a significant impact on poor functional outcomes at discharge in patients with and without complications following procedural management of AVMs. At the time of initial patient assessment, risk stratification strategies should take into account neurovascular comorbidities and potential complications. Such an approach would ultimately optimize patient outcomes and increase the value of care provided., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Cutaneous basal cell carcinoma (BCC) is the commonest cancer in the United Kingdom and United States. Surgical excision is the most common treatment. This review summarises all published outcomes of observational/non-interventional management of cutaneous BCC., Methods: This PRISMA-compliant systematic review searched MEDLINE, EMBASE and CENTRAL databases from inception-June 2021. All studies reporting outcomes of observational management for BCC were included., Results: We identified 2529 titles, from which 4 full-text articles were eligible, reporting on 2298 individuals. Two studies were randomised controlled trials (RCTs) comparing histological clearance rates and adverse events following treatment with an inactive strategy (placebo cream) versus topical 5%-imiquimod (at different frequencies) for 6-12 weeks. Clearance rates ranged from 52-100% for imiquimod and 2-19% for placebo, with more adverse events associated with imiquimod. The other two studies used prospective cohort designs. One study assessed the natural history of BCCs managed expectantly in 39 individuals aged ≥80years. During the 15.8-month follow-up, 46.2% of lesions did not increase in size and 10.3% resolved. The remaining study compared treatment patterns of 1360 patients with non-melanoma skin cancer (NMSC) in individuals with or without limited life-expectancy (LLE). The LLE subgroup had a 5-year mortality rate of 43.3%, with no deaths attributed to NMSC. Only 3.3% of individuals with LLE underwent observational treatment. No study examined quality-of-life or cost-effectiveness., Conclusion: There has been limited investigation of observational management of BCC, despite possible advantages of this strategy. Future RCTs should compare quality-of-life outcomes and utility-adjusted survival following interventional or observational management of BCC., Competing Interests: Conflicts None to disclose., (Copyright © 2022 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Introduction: Burn injury remains a serious cause of morbidity and mortality worldwide. Severity of burns is determined by the percentage of burned area compared to the body surface area, age of patient, and by the depth of skin and soft tissue involvement; these factors determine management as well as prospective outcomes. The pathophysiology of partial- to full-thickness burn conversion remains poorly understood and is associated with a worse overall prognosis. Recent studies have demonstrated that an altered inflammatory response may play a significant role in this conversion and therefore a reduction in early inflammation is crucial to ultimately decreasing burn severity and morbidity. We hypothesize that the application of a microcapillary gelatin-alginate hydrogel loaded with anti-TNF-α (infliximab) monoclonal antibodies to a partial-thickness burn will reduce inflammation within partially burned skin and prevent further progression to a full-thickness burn., Methods: Assembly of the microfluidic hydrogels is achieved by embedding microfibers within a hydrogel scaffold composed of a gelatin-alginate blend, which is then soaked in a solution containing anti-TNF-α antibodies for drug loading. 12 young (2-4 months) and 12 old (>16 months) mice were given partial thickness burns. The treatment cohort received the anti-TNF-α infused hydrogel with an occlusive dressing and the control cohort only received an occlusive dressing. Mice were euthanized at post-burn day 3 and skin samples were taken. Burn depth was evaluated using Vimentin immunostaining., Results: All mice in the treatment cohort demonstrated decreased conversion of burn from partial to full thickness injury (old = p < 0.01, young = p < 0.001) as compared to the control group. Old mice had greater depth of burn than young mice (p < 0.001). There were greater eosinophils in the treatment cohort for both young and old mice, but it did not reach statistical significance., Conclusion: The application of a novel microcapillary gelatin-alginate hydrogel infused with anti-TNF-α antibody to partial thickness burns in mice showed reduction in partial to full thickness burn secondary progression as compared to controls using this murine model; this promising finding might help decrease the high morbidity and mortality associated with burn injuries., (Copyright © 2021 Elsevier Ltd and ISBI. All rights reserved.)

Objectives: The FACE-Q Skin Cancer module is a patient-reported outcome measure (PROM) for facial skin cancer. It has been anglicised for the UK population and undergone psychometric testing using classical test theory. In this study, further evaluation of construct validity using Rasch measurement theory and hypothesis testing was performed., Methods: Patients were prospectively recruited to the Patient-Reported Outcome Measures In Skin Cancer Reconstruction (PROMISCR) study and asked to complete the anglicised FACE-Q Skin Cancer module. The scalability and unidimensionality of the data were assessed with a Mokken analysis prior to Rasch analysis. Response thresholds, targeting, fit statistics, local dependency, and internal consistency were examined for all items and subscales. Four a priori hypotheses were tested to evaluate the convergent and divergent validity. We additionally hypothesised that the median 'cancer worry' score would be lower in post-operative than pre-operative patients., Results: 239 patients self-completed the questionnaire between August 2017 and May 2019. Of the ten subscales assessed, five showed relative fit to the Rasch model. Unidimensionality was present for all five subscales, with most demonstrating ordered item thresholds and appropriate fit statistics. Two items in the 'cancer worry' subscale had either disordered or very close response thresholds. Subscales of the FACE-Q Skin Cancer module demonstrated convergent and divergent validity with relevant Skin Cancer Index comparators (p < 0.001). Median 'cancer worry' was lower in post-operative patients (44 vs 39, p < 0.001)., Conclusion: The anglicised FACE-Q Skin Cancer module shows psychometric validity through hypothesis testing, and both classical and modern test theory., (Copyright © 2021 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group., Methods: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance., Results and Conclusion: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic., Competing Interests: DIsclosure CB reports honoraria from Roche/Genentech, Janssen, BeiGene, Novartis, Pfizer, Incyte, AbbVie, Gilead Sciences, Celltrion, MorphoSys, Regeneron; he reports consulting or advisory role: Gilead Sciences, Janssen, Roche, Pfizer, BeiGene, Celltrion, AbbVie, Incyte, Regeneron, MorphoSys, Novartis; he reports speaker’s engagement: Roche, Janssen, BeiGene, Celltrion, AbbVie, Pfizer, Gilead Sciences; he reports research funding: Roche/Genentech, Janssen, Celltrion, Merck Sharp & Dohme (MSD), Pfizer, Amgen. MD reports honoraria as Advisory Board Member of AstraZeneca, Bayer, BeiGene, Celgene, Genmab, Gilead, Incyte, Janssen, Lilly, MorphoSys, Novartis, Roche; he reports honoraria for speaker’s engagement from Amgen, AstraZeneca, Bayer, Celgene, Gilead, Janssen, Novartis, Roche; he reports institutional research grants from AbbVie, Bayer, Gilead, Celgene, Janssen, Roche. AA-L has declared no conflicts of interest. JA reports personal financial interests as advisory board and invited speaker from Incyte, advisory board from Mallinckrodt, advisory board and invited speaker from Novartis, advisory board and invited speaker from Pfizer; she reports non-financial interests as principal investigator from Incyte, principal investigator from Novartis. LA received advisory honoraria from Roche, Celgene, Janssen-Cilag, Verastem, Eusa Pharma, Incyte, ADC Therapeutics and Gilead; research support from Gilead, and travel expenses from Roche, Celgene, Janssen-Cilag, and Eusa Pharma; speakers bureau from Novartis. CB has declared no conflicts of interest. LB reports Advisory Committee activities for AbbVie, Amgen, Astellas, Bristol Myers Squibb (BMS), Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Sanofi, Seattle Genetics and has research support from Bayer and Jazz Pharmaceuticals. PC has declared no conflicts of interest. MGDP has declared no conflicts of interest. MD reports personal fees from Amgen, personal fees from Takeda, personal fees from Janssen, personal fees from BeiGene, personal fees from BMS, outside the submitted work. SD reports personal financial interests as advisory board, invited speaker, fellow funding, and coordinating PI from BeiGene, writing engagement from Karger, advisory board and coordinating PI from Sanofi, funding, and other from Janssen; she reports non-financial interests as advisory role at British Society for Haematology Lymphoma Special Interest Group, advisory role at Lymphoma Action, member of board of directors at WMUK Charity. HTE has declared no conflicts of interest. RF reports honoraria for advisory boards and/or speaker bureau from Janssen, Gilead, AbbVie, Amgen, Novartis, Roche, Incyte, Pfizer, all outside the submitted work. PG reports grants and personal fees from AbbVie, grants and personal fees from Acerta/AstraZeneca, personal fees from BeiGene, personal fees from Celgene/Juno/BMS, grants and personal fees from Janssen, personal fees from Lilly/Loxo, personal fees from MEI, personal fees from Roche, personal fees from Sanofi, personal fees from ArQule/MSD, outside the submitted work; MGdS reports grants, personal fees, non-financial support and other from Gilead Sciences, grants from AstraZeneca, personal fees, non-financial support, and other from Janssen Cilag, personal fees and non-financial support from Roche, non-financial support from AbbVie, personal fees and non-financial support from BMS, personal fees and non-financial support from MSD, personal fees and non-financial support from Takeda, personal fees from Novartis, personal fees from ADC Therapeutics, outside the submitted work. JG reports personal fees from AbbVie, grants and personal fees from AstraZeneca, grants and personal fees from BMS/Celgene, grants and personal fees from Janssen, personal fees from Kite/Gilead, personal fees from MorphoSys, personal fees from Novartis, personal fees from TG Therapeutics, outside the submitted work. RH has had a consultant or advisory relationship with Janssen, Amgen, Celgene, AbbVie, BMS, Novartis, PharmaMar, and Takeda; has received honoraria from Janssen, Amgen, Celgene, BMS, PharmaMar, and Takeda; has received research funding from Janssen, Amgen, Celgene, BMS, Novartis, and Takeda. CH reports grants and personal fees from Novartis, grants and personal fees from BMS, personal fees from Sierra Oncology, personal fees from CTI pharmaceuticals, personal fees from Jannsen, personal fees from Geron, grants and personal fees from AOP Orphan Pharma, personal fees from Galecto, grants, personal fees and other from Constellation, outside the submitted work. MH reports personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from AbbVie, personal fees from Daiichi Sankyo, personal fees from Bayer Pharma AG, personal fees from Jazz Pharmaceuticals, personal fees from BMS, personal fees from Tolremo, outside the submitted work. BK has received honoraria for lectures from Ipsen, Novartis and MSD (all outside of the submitted work). J-JK reports consulting fees and honoraria from Novartis, consulting fees from AbbVie, honoraria from AOP Orphan Pharma, participation on a monitoring board or advisory board from BMS/Celgene, participation on a monitoring board or advisory board from Incyte. NK reports grants and honoraria from Neovii, honoraria from Sanofi, grants and honoraria from Jazz, grants and honoraria from Celgene, grants and honoraria from Riemser, honoraria from Gilead/Kite, honorarium from AOP Oprhan Pharma, grants and honorarium from Novartis, honorarium from Amgen. PM reports personal fees from Celgene, Amgen, Janssen, AbbVie, Sanofi, outside the submitted work. JP has declared no conflicts of interest. FP has declared no conflicts of interest. DR received honoraria from Incyte, Novartis Pharma, Pfizer; clinical trial steering committee membership: Novartis; membership on advisory boards: Incyte, Novartis Pharma, Pfizer. J-MR reports grants and honoraria from Novartis, Amgen, Pfizer, Takeda, Incyte, and Servier. TR has declared no conflicts of interest. JF-M reports consulting and advisory boards honoraria (received by CUN ) from AbbVie, Amgen, BMS, Celgene, Janssen, GlaxoSmithKline, Karyopharm, MSD, Novartis, Takeda, Sanofi, SecuraBio, Regeneron, Roche, outside the submitted work. VS has declared no conflicts of interest. GFS reports personal fees and other from AbbVie, other from Amgen, other from Astellas, other from Boehringer-Ingelheim, grants, personal fees and other from Celgene, other from Helsinn Healthcare, grants, personal fees, and other from Janssen-Cilag, grants and other from Novartis, other from Onconova, grants, personal fees and other from Roche, and other from Takeda, outside the submitted work. PS reports honoraria from Amgen, Celgene, Janssen, Karyopharm, SkylineDx, Takeda, and research support from Celgene, Janssen, Amgen, Takeda, BMS, SkylineDx, Karyopharm, all outside the submitted work. MvL-T has received travel grants and honoraria from Celgene, Gilead, Chugai, Janssen, Novartis, Amgen, Takeda, BMS, Medac, Oncopeptides, Merck, CDDF, Pfizer, Medac, Thermo Fisher, AstraZeneca; is a consultant for Celgene, Gilead, Oncopeptides, MSD, 4D Pharma, Janssen, Shionogi and received research funding from BMBF, Deutsche Jose Carreras Leukämie-Stiftung, IZKF Jena, Novartis, Gilead, Deutsche Krebshilfe, Celgene, Oncopeptides, Deutsche Forschungsgemeinschaft (DFG). CW has declared no conflicts of interest. GP reports grants from Amgen, grants, personal fees and non-financial support from Merck, grants and non-financial support from AstraZeneca, grants and personal fees from Roche, grants and personal fees from BMS, grants from Lilly, grants and personal fees from MSD, grants and personal fees from Novartis, outside the submitted work. FP reports grants from Novartis, Celgene, BMS, Abbvie, Karyopharma, Janssen., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patients with underlying psychiatric conditions are vulnerable to the experience of sexual violence. Barriers and facilitators to disclosure exist, at the level of the individual, healthcare system, legal system and society in general. Management requires a trauma-informed approach with a focus on avoidance of stigma, optimisation of pre-existing psychiatric conditions and appropriate treatment of psychological sequalae. Preventive strategies by the patient, practitioner and healthcare system, may assist to reduce the risk of future sexual violence., (Copyright © 2022 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Primary endocrine therapy as treatment of breast cancer is only recommended in older women with limited life expectancy. However, many older women opt for endocrine therapy due to concerns regarding frailty and potential decline in function after surgery. A decline in functional status after surgery is documented in some cancer types, such as colorectal, however, the full impact of breast cancer surgery is less understood. A systematic review was performed to examine the evidence for impact of breast cancer surgery on functional status in older women. PubMed and Embase databases were searched. Studies were eligible if performed within the last 10 years; included patients over the age of 65 years undergoing breast cancer surgery; included stratification of results by age; measured functional status pre-operatively and at least six months following surgery. A total of 11 studies including 12 030 women were appraised. Two studies represented level-II and nine level-IV evidence. Overall, physical activity level was negatively impacted by breast cancer surgery and this was compounded by the extent of surgery. Evidence for impact of breast cancer surgery on quality of life, fatigue and cognition, was conflicting. The possibility of decline in functional status after breast cancer surgery should be discussed in all older women considering surgery. A structured exercise program may improve the negative effects of surgery on physical activity. Further work is required in the areas of quality of life, fatigability and cognition., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to declare., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Deep brain stimulation (DBS) is an effective treatment for motor disturbance in people with primary dystonia (PWD). Numerous factors are considered by an interdisciplinary consensus conference before deciding candidacy for DBS surgery (e.g., demographic, medical, cognitive, and behavioral factors). However, little is known about which of these factors are associated with PWD DBS surgery consensus conference decisions., Objective: Our goal was to examine whether pre-operative demographic, medical, and cognitive/behavioral variables are associated DBS consensus conference decisions in patients with dystonia., Methods: Thirty-two PWD completed comprehensive presurgery workup included neurological and neuropsychological exams, and neuroimaging in consideration for DBS surgery. An interdisciplinary conference committee either recommended or did not recommend DBS surgery based upon these data. Demographic and medical data (e.g., dystonia disease characteristics, medical comorbidities, medications) were also collected. We also examined impact from cardiovascular disease factors, using a Revised Cardiac Risk Index. PWD were grouped based on DBS conference decision (eligible: n = 21, ineligible: n = 11) and compared across demographic, medical, and cognitive/behavioral variables., Results: Across clinical variables, PWD who were deemed ineligible for DBS surgery had a higher Revised Cardiac Risk Index. PWD who were classified as ineligible displayed lower global cognitive functioning, working memory, phonemic fluency, memory retrieval, and cognitive flexibility., Conclusions: Consensus decision making regarding DBS surgery eligibility involves a multifactorial process. We found that deficits in executive functioning were associated with the DBS consensus committee decision. We also observed elevated cardiac risk among these individuals, likely reflecting the relation between vascular health and cognition. Implications, and clinical and scientific applications of these findings are discussed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: The aim of the study was to describe patterns of referral to podiatrists by general practitioners (GPs) in Australia., Study Design: This is a continuous cross-sectional study of Australian general practice activity., Methods: We analysed data from the Bettering the Evaluation and Care of Health program, collected from April 2000 to March 2016 inclusive. Data were summarised using descriptive statistics with 95% confidence intervals around point estimates. Multivariate logistic regression was used to identify GP and patient characteristics independently associated with referral., Results: The data set included 1,568,100 encounters, including 5,912 podiatry referrals. Referrals increased from 7.0 to 39.5 per 1000 population over the evaluation period. In multivariate analyses, female GPs were more likely than male GPs to refer, and GPs aged ≥55 years were less likely to refer. Patients referred to podiatrists were more likely to be aged ≥85 years, be Indigenous, be from an English-speaking background and have previously been seen at the practice. The problem generating the highest number of referrals was diabetes. After the introduction of Medicare funding, referred patients were more likely to be women, be aged >45 years, have a healthcare card, be socio-economically disadvantaged and have previously been seen at the practice., Conclusions: GP referral to podiatrists in Australia increased markedly after the introduction of Medicare funding and appears to be targeted to those with the greatest need. Further research is required to determine whether this policy has improved outcomes and is cost-effective., (Copyright © 2021 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)