bluuebunny/crossref_metadata_2025 huggingface dataset:
Anatomy education in US Medical Schools: before, during, and beyond COVID-19
Authors: Shin Max , Prasad Aman , Sabo Graham , Macnow Alexander S. R. , Sheth Neil P. , Cross Michael B. , Premkumar Ajay
Published: February 2022

Background

Anatomy education in US medical schools has seen numerous changes since the call for medical education reform in 2010. The purpose of this study was to survey US medical schools to assess recent trends in anatomy education, the impact of the COVID-19 pandemic on anatomy teaching, and future directions of medical school anatomy curricula.

Methods

We sent a 29-item survey to anatomy course directors of 145 AAMC-associated allopathic medical schools inquiring about their schools’ anatomy curricula. The survey contained objective discrete questions concerning the curricula changes preceding COVID-19 and those directly related to COVID-19. We also asked subjective and open-ended questions about the impact of COVID-19 and future directions of anatomy education.

Results

A total of 117/143 course directors (82%) completed the survey. Most schools (60%) reported a major change to their anatomy course within the past five years, including a decrease in total course time (20%), integration of anatomy into other courses (19%), and implementation of a “flipped classroom” (15%) teaching style. Due to COVID-19, there was a decrease in the fraction of course time dedicated to “hands-on” learning (p < 0.01) and teaching of clinical correlates (p = 0.02) and radiology (p < 0.01). Most course directors (79%) reported that COVID-19 had a negative impact on quality of learning due to decreased interactive or in-person (62%) learning and lack of dissection (44%). Incorporation of virtual-reality applications or 3D anatomy software (23%) and a decrease in cadaver dissection (13%) were the most common future anticipated changes.

Conclusion

The constraints conferred by COVID-19 highlight the importance of maximizing interactive learning in the discipline of anatomy. In an era of social distancing and decreased emphasis on conventional anatomy dissection, adaptations of new technologies and teaching modalities may allow for traditional educational rigor to be sustained.
Experiences and attitudes of medical professionals on treatment of end-of-life patients in intensive care units in the Republic of Croatia: a cross-sectional study
Authors: Špoljar Diana , Vučić Marinko , Peršec Jasminka , Merc Vlasta , Kereš Tatjana , Radonić Radovan , Poljaković Zdravka , Nesek Adam Višnja , Karanović Nenad , Čaljkušić Krešimir , Župan Željko , Grubješić Igor , Kopić Jasminka , Vranković Srđan , Krobot Renata , Nevajdić Bojana , Golubić Mia , Grosek Štefan , Kujundžić Tiljak Mirjana , Štajduhar Andrija , Tonković Dinko , Borovečki Ana
Published: February 2022

Background

Decisions about limitations of life sustaining treatments (LST) are made for end-of-life patients in intensive care units (ICUs). The aim of this research was to explore the professional and ethical attitudes and experiences of medical professionals on treatment of end-of-life patients in ICUs in the Republic of Croatia.

Methods

A cross-sectional study was conducted among physicians and nurses working in surgical, medical, neurological, and multidisciplinary ICUs in the total of 9 hospitals throughout Croatia using a questionnaire with closed and open type questions. Exploratory factor analysis was conducted to reduce data to a smaller set of summary variables. Mann–Whitney U test was used to analyse the differences between two groups and Kruskal–Wallis tests were used to analyse the differences between more than two groups.

Results

Less than third of participants (29.2%) stated they were included in the decision-making process, and physicians are much more included than nurses (p < 0.001). Sixty two percent of participants stated that the decision-making process took place between physicians. Eighteen percent of participants stated that ‘do-not-attempt cardiopulmonary resuscitations’ orders were frequently made in their ICUs. A decision to withdraw inotropes and antibiotics was frequently made as stated by 22.4% and 19.9% of participants, respectively. Withholding/withdrawing of LST were ethically acceptable to 64.2% of participants. Thirty seven percent of participants thought there was a significant difference between withholding and withdrawing LST from an ethical standpoint. Seventy-nine percent of participants stated that a verbal or written decision made by a capable patient should be respected. Physicians were more inclined to respect patient’s wishes then nurses with high school education (p = 0.038). Nurses were more included in the decision-making process in neurological than in surgical, medical, or multidisciplinary ICUs (p < 0.001, p = 0.005, p = 0.023 respectively). Male participants in comparison to female (p = 0.002), and physicians in comparison to nurses with high school and college education (p < 0.001) displayed more liberal attitudes about LST limitation.

Conclusions

DNACPR orders are not commonly made in Croatian ICUs, even though limitations of LST were found ethically acceptable by most of the participants. Attitudes of paternalistic and conservative nature were expected considering Croatia’s geographical location in Southern Europe.
The precedence effect in spatial hearing manifests in cortical neural population responses
Authors: Li Kongyan , Auksztulewicz Ryszard , Chan Chloe H. K. , Mishra Ambika Prasad , Schnupp Jan W. H.
Published: February 2022

Background

To localize sound sources accurately in a reverberant environment, human binaural hearing strongly favors analyzing the initial wave front of sounds. Behavioral studies of this “precedence effect” have so far largely been confined to human subjects, limiting the scope of complementary physiological approaches. Similarly, physiological studies have mostly looked at neural responses in the inferior colliculus, the main relay point between the inner ear and the auditory cortex, or used modeling of cochlear auditory transduction in an attempt to identify likely underlying mechanisms. Studies capable of providing a direct comparison of neural coding and behavioral measures of sound localization under the precedence effect are lacking.

Results

We adapted a “temporal weighting function” paradigm previously developed to quantify the precedence effect in human for use in laboratory rats. The animals learned to lateralize click trains in which each click in the train had a different interaural time difference. Computing the “perceptual weight” of each click in the train revealed a strong onset bias, very similar to that reported for humans. Follow-on electrocorticographic recording experiments revealed that onset weighting of interaural time differences is a robust feature of the cortical population response, but interestingly, it often fails to manifest at individual cortical recording sites.

Conclusion

While previous studies suggested that the precedence effect may be caused by early processing mechanisms in the cochlea or inhibitory circuitry in the brainstem and midbrain, our results indicate that the precedence effect is not fully developed at the level of individual recording sites in the auditory cortex, but robust and consistent precedence effects are observable only in the auditory cortex at the level of cortical population responses. This indicates that the precedence effect emerges at later cortical processing stages and is a significantly “higher order” feature than has hitherto been assumed.
Untangling neurodevelopmental disorders in the adulthood: a movement disorder is the clue
Authors: Indelicato Elisabetta , Zech Michael , Amprosi Matthias , Boesch Sylvia
Published: February 2022

Background

The genetic landscape of neurodevelopmental disorders is constantly expanding and children with early-onset neurological phenotypes increasingly receive a genetic diagnosis. Nonetheless, the awareness of the chronic course of these conditions, and consequently their recognition and management in the adult population, is still limited.

Results

Herein, we describe four patients with rare neurodevelopmental disorders (SON, ZMYND11, DNMT1 and YY1-related diseases), who received a genetic assignment only in the adulthood. All these patients had an early developmental delay and displayed a movement disorder (dystonia/ataxia/tremor) which manifested for the first time, or worsened, in the adulthood, prompting the referral to a neurologist. This phenotypic combination led eventually to the genetic testing. We report previously unrecognized features and highlight the peculiarities of the adult presentation of four neurodevelopmental disorders.

Conclusions

This report expands the current knowledge on four rare neurodevelopmental disorders (SON, ZMYND11, DNMT1 and YY1), which was mainly based on reports from paediatric cases. This case series emphasize the importance of a tight neurological surveillance extending beyond the childhood.
Tumor suppression and improvement in immune systems by specific activation of dopamine D1-receptor-expressing neurons in the nucleus accumbens
Authors: Sato Daisuke , Hamada Yusuke , Narita Michiko , Mori Tomohisa , Tezuka Hiroyuki , Suda Yukari , Tanaka Kenichi , Yoshida Sara , Tamura Hideki , Yamanaka Akihiro , Senba Emiko , Kuzumaki Naoko , Narita Minoru
Published: February 2022

Recent research has suggested that the mesolimbic dopamine network that mainly terminates in the nucleus accumbens may positively control the peripheral immune system. The activation of dopamine receptors in neurons in the nucleus accumbens by the release of endogenous dopamine is thus expected to contribute to efferent immune regulation. As in the stimulation of Gs-coupled dopamine D1-receptors or Gi-coupled D2-receptors by endogenous dopamine, we investigated whether specific stimulation of dopamine D1-receptor-expressing neurons or inhibition of dopamine D2-receptor-expressing neurons in the nucleus accumbens could produce anti-tumor effects and improve the immune system in transgenic mice using pharmacogenetic techniques. Repeated stimulation of D1-receptor-expressing neurons in either the medial shell, lateral shell or core regions of the nucleus accumbens significantly decreased tumor volume under a state of tumor transplantation, whereas repeated suppression of D2-receptor-expressing neurons in these areas had no effect on this event. The number of splenic CD8+ T cells was significantly increased following repeated stimulation of D1-receptor-expressing neurons in the nucleus accumbens of mice with tumor transplantation. Furthermore, this stimulation produced a significant reduction in the population of splenic CD8+ T cells that expressed immune checkpoint-related inhibitory receptors, PD-1, TIM-3 and LAG-3. These findings suggest that repeated stimulation of D1-receptor-expressing neurons (probably D1-receptor-expressing medium spiny neurons) in the nucleus accumbens suppressed tumor progression and improved the immune system by suppressing the exhaustion of splenic CD8+ T cells.
Pharmacological modulation of Kv1.3 potassium channel selectively triggers pathological B lymphocyte apoptosis in vivo in a genetic CLL model
Authors: Severin Filippo , Urbani Andrea , Varanita Tatiana , Bachmann Magdalena , Azzolini Michele , Martini Veronica , Pizzi Marco , Tos Angelo Paolo Dei , Frezzato Federica , Mattarei Andrea , Ghia Paolo , Bertilaccio Maria Teresa Sabrina , Gulbins Erich , Paradisi Cristina , Zoratti Mario , Semenzato Gianpietro Carlo , Leanza Luigi , Trentin Livio , Szabò Ildiko
Published: February 2022

Background

Ion channels are emerging as promising oncological targets. The potassium channels Kv1.3 and IKCa are highly expressed in the plasma membrane and mitochondria of human chronic lymphocytic leukemia (CLL) cells, compared to healthy lymphocytes. In vitro, inhibition of mitoKv1.3 by PAPTP was shown to kill ex vivo primary human CLL cells, while targeting IKCa with TRAM-34 decreased CLL cell proliferation.

Methods

Here we evaluated the effect of the above drugs in CLL cells from ibrutinib-resistant patients and in combination with Venetoclax, two drugs used in the clinical practice. The effects of the drugs were tested also in the Eμ-TCL1 genetic CLL murine model, characterized by a lympho-proliferative disease reminiscent of aggressive human CLL. Eμ-TCL1 mice showing overt disease state were treated with intraperitoneal injections of non-toxic 5 nmol/g PAPTP or 10 nmol/g TRAM-34 once a day and the number and percentage of pathological B cells (CD19+CD5+) in different, pathologically relevant body districts were determined.

Results

We show that Kv1.3 expression correlates with sensitivity of the human and mouse neoplastic cells to PAPTP. Primary CLL cells from ibrutinib-resistant patients could be killed with PAPTP and this drug enhanced the effect of Venetoclax, by acting on mitoKv1.3 of the inner mitochondrial membrane and triggering rapid mitochondrial changes and cytochrome c release. In vivo, after 2 week- therapy of Eμ-TCL1 mice harboring distinct CLL clones, leukemia burden was reduced by more than 85%: the number and percentage of CLL B cells fall in the spleen and peritoneal cavity and in the peripheral blood, without signs of toxicity. Notably, CLL infiltration into liver and spleen and splenomegaly were also drastically reduced upon PAPTP treatment. In contrast, TRAM-34 did not exert any beneficial effect when administered in vivo to Eμ-TCL1 mice at non-toxic concentration.

Conclusion

Altogether, by comparing vehicle versus compound effect in different Eμ-TCL1 animals bearing unique clones similarly to CLL patients, we conclude that PAPTP significantly reduced leukemia burden in CLL-relevant districts, even in animals with advanced stage of the disease. Our results thus identify PAPTP as a very promising drug for CLL treatment, even for the chemoresistant forms of the disease.
Adaptive laboratory evolution and shuffling of Escherichia coli to enhance its tolerance and production of astaxanthin
Authors: Lu Qian , Zhou Xiao-Ling , Liu Jian-Zhong
Published: February 2022

Background

Astaxanthin is one of the strongest antioxidants in nature and has been widely used in aquaculture, food, cosmetic and pharmaceutical industries. Numerous stresses caused in the process of a large scale-culture, such as high acetate concentration, high osmolarity, high level of reactive oxygen species, high glucose concentration and acid environment, etc., limit cell growth to reach the real high cell density, thereby affecting astaxanthin production.

Results

We developed an adaptive laboratory evolution (ALE) strategy to enhance the production of chemicals by improving strain tolerance against industrial fermentation conditions. This ALE strategy resulted in 18.5% and 53.7% increases in cell growth and astaxanthin production in fed-batch fermentation, respectively. Whole-genome resequencing showed that 65 mutations with amino acid substitution were identified in 61 genes of the shuffled strain Escherichia coli AST-4AS. CRISPR interference (CRISPRi) and activation (CRISPRa) revealed that the shuffled strain with higher astaxanthin production may be associated with the mutations of some stress response protein genes, some fatty acid biosynthetic genes and rppH. Repression of yadC, ygfI and rcsC, activation of rnb, envZ and recC further improved the production of astaxanthin in the shuffled strain E. coli AST-4AS. Simultaneous deletion of yadC and overexpression of rnb increased the production of astaxanthin by 32% in the shuffled strain E. coli AST-4AS.

Conclusion

This ALE strategy will be powerful in engineering microorganisms for the high-level production of chemicals.
Harnessing the potential use of cellulolytic Klebsiella oxytoca (M21WG) and Klebsiella sp. (Z6WG) isolated from the guts of termites (Isoptera)
Authors: Korsa Gamachis , Masi Chandran , Konwarh Rocktotpal , Tafesse Mesfin
Published: February 2022

Background

For many years, denim-heavy quality cotton twill colored with indigo colors and with a well-worn/faded look has held a lot of appeal. Machine damage, drainage system blockage, and other issues come with the conventional usage of pumice stones for “stone-washing” denims. In view of the abovementioned information, a range of works has been done to investigate the economic prospects of bacterial cellulase enzymes for use in industrial processes, including biopolishing in the textile sector. Ethiopia has excellent termite diversity to isolate bacterial gut-associated cellulose enzymes for biostoning applications. The main purpose of this study was, therfore, to decipher how to isolate and characterize cellulase enzymes from termite (Isoptera) gut bacteria with the intention of employing it for biostoning of textiles.

Purpose

To use cellulolytic enzymes of Klebsiella oxytoca (M21WG) and Klebsiella sp. (Z6WG) isolated from termite guts in biostoning of textiles and improving garment quality.

Methods

Cellulase enzyme-producing bacteria were isolated and screened from the guts of worker termites sampled from Meki and Zeway termite mounds in the Central Rift Valley region of Ethiopia. Bacterial screening, biochemical, morphological, and 16S rRNA sequence identification techniques were employed to characterize the bacterial strains. In addition, the production, optimization, and purification of the associated cellulase enzymes were employed, and the potential application of the enzymes for biostoning of a textile was demonstrated.

Result

The isolated M21WG was found to be 99% identical to the Klebsiella oxytoca (MT104573.1) strain, while the isolated Z6WG showed 97.3% identity to the Klebsiella sp. strain (MN629242.1). At an ideal pH of 7, a temperature of 37 °C, a 72-h incubation time, and a substrate concentration of 1.5% carboxymethylcellulose sodium, the maximum activity of the crude cellulase extract from these bacteria was assessed. These bacteria produced cellulase enzymes that were moderately efficient. Consequently, it was determined that the cellulase enzymes were effective for biostoning of denim cloth.

Conclusion

It was determined that Klebsiella oxytoca (M21WG) and Klebsiella sp. (Z6WG) could be used as a doorway to better understand harnessing the use of these cellulase-producing bacteria from termite (Isoptera) guts. In this study, it was also attempted to assess the effectiveness of the two bacterial isolates in biostoning in anticipation of their potential application in the textile realm.
Synthesising the existing evidence for non-pharmacological interventions targeting outcomes relevant to young people with ADHD in the school setting: systematic review protocol
Authors: Russell Abigail E. , Moore Darren , Sanders Amy , Dunn Barnaby , Hayes Rachel , Kidger Judi , Sonuga-Barke Edmund , Pfiffner Linda , Ford Tamsin
Published: February 2022

Background

Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have impairing levels of difficulty paying attention, impulsive behaviour and/or hyperactivity. ADHD causes extensive difficulties for young people at school, and as a result these children are at high risk for a wide range of poor outcomes. We ultimately aim to develop a flexible, modular ‘toolkit’ of evidence-based strategies that can be delivered by primary school staff to improve the school environment and experience for children with ADHD; the purpose of this review is to identify and quantify the evidence-base for potential intervention components. This protocol sets out our plans to systematically identify non-pharmacological interventions that target outcomes that have been reported to be of importance to key stakeholders (ADHD symptoms, organisation skills, executive-global- and classroom-functioning, quality of life, self-esteem and conflict with teachers and peers). We plan to link promising individual intervention components to measured outcomes, and synthesise the evidence of effectiveness for each outcome.

Methods

A systematic search for studies published from the year 2000 that target the outcomes of interest in children and young people aged 3–12 will be conducted. Titles and abstracts will be screened using prioritisation software, and then full texts of potentially eligible studies will be screened. Systematic reviews, RCTs, non-randomised and case-series studies are eligible designs. Synthesis will vary by the type of evidence available, potentially including a review of reviews, meta-analysis and narrative synthesis. Heterogeneity of studies meta-analysed will be assessed, along with publication bias. Intervention mapping will be applied to understand potential behaviour change mechanisms for promising intervention components.

Discussion

This review will highlight interventions that appear to effectively ameliorate negative outcomes that are of importance for people with ADHD, parents, school staff and experts. Components of intervention design and features that are associated with effective change in the outcome will be delineated and used to inform the development of a ‘toolkit’ of non-pharmacological strategies that school staff can use to improve the primary school experience for children with ADHD.

Trial registration

PROSPERO number CRD42021233924
Are estimates of faces’ ages less accurate when they wear sunglasses or face masks and do these disguises make it harder to later recognise the faces when undisguised?
Authors: Thorley Craig , Acton Benjamin , Armstrong Jesse , Ford Shanade , Gundry Margaret
Published: February 2022

This study examined whether our ability to accurately estimate unfamiliar faces’ ages declines when they are wearing sunglasses or surgical-style face masks and whether these disguises make it harder to later recognise those faces when undisguised. In theory, both disguises should harm age estimation accuracy and later face recognition as they occlude facial information that is used to determine a face’s age and identity. To establish whether this is the case, we had participants estimate the age of unfamiliar faces that were pictured wearing no disguises, sunglasses, or face masks. The participants then completed a face recognition test where they had to distinguish between the previously seen faces and new faces. Importantly, none of faces wore disguises in this latter test. Participants’ estimates of the undisguised faces’ ages were inaccurate by a Median of 5.15 years. Their accuracy barely changed when the faces wore sunglasses but declined by a Median of 1.30 years when they wore face masks. Moreover, subsequent undisguised face recognition was less likely to occur when the faces previously wore sunglasses or face masks, with large effects observed. These findings demonstrate the relative importance of different facial areas when estimating faces’ ages and later recognising them. They also have implications for policing as they suggest it may be harder for eyewitnesses to accurately estimate the age of criminals who wear face masks during offences, and it may be harder for them to later recognise criminals in line-ups if the criminals wear sunglasses or face masks during offences.
Schistosomiasis of the Prostate in Sokoto, Nigeria: a case series
Authors: Khalid Abdullahi , Abdulwahab-Ahmed Abdullah , Mungadi Ismaila Arzika , Abdullahi Kabiru , Agwu Ngwobia Peter , Muhammad Abubakar Sadiq
Published: February 2022

Background

Prostate schistosomiasis is a chronic inflammatory condition of the prostate. In an endemic environment, it may mimic the sinister condition of the prostate in its clinical presentation. Despite the high prevalence of urinary schistosomiasis documented in our environment, prostate involvement is rarely encountered in routine clinical practice. We report and share our experience in the management of two cases of prostate schistosomiasis that presented with abnormal digital rectal examination and elevated prostate-specific antigen suggestive of prostate cancer but proved otherwise by the histology report.

Case presentation

The first patient was a 50-year-old man who presented with a history of voiding and storage lower urinary tract symptoms (LUTS) and urinary retention relieved by urethral catheterization. There was no other significant history except for past childhood terminal hematuria. The remarkable findings on physical examination were in the digital rectal examination which revealed enlarged prostate, hard, nodular, obliterated median groove, and restricted mobility of overlying rectal mucosa. The total serum prostate-specific antigen (PSA) was 1.2 ng/ml. Transrectal ultrasound-guided prostate biopsy and histology confirmed prostate schistosomiasis on a background of nodular hyperplasia. The second patient was an 80-year-old man who presented with a history of voiding and storage lower urinary tract symptoms (LUTS) and urinary retention relieved by urethral catheterization. There was no other significant history and no past childhood terminal hematuria. There were no remarkable findings on physical examination except for the enlarged prostate with benign findings on digital rectal examination. The initial total serum prostate-specific antigen (PSA) was 31.0 ng/ml. The repeated PSA was 7.5 ng/ml after antimicrobial therapy. Transrectal ultrasound-guided prostate biopsy and histology confirmed prostate schistosomiasis on a background of nodular hyperplasia. He had two sessions of Bipolar Transurethral Resection of the Prostate following failed medical treatment.

Conclusions

Schistosomiasis of the prostate may mimic the clinical or biochemical presentation of prostate cancer. The attending physician requires high index of suspicion to arrive at this diagnosis, especially for the urologist practicing in an endemic area.
Salvage of infected cardiac implantable electronic device with taurolidine—a case report
Authors: Borov Stefan , Baldauf Benito , Lau Ernest W. , Bonnemeier Hendrik
Published: February 2022

Background

Cardiac implantable electronic devices (CIEDs) are commonly used to treat cardiac arrhythmias and prevent sudden cardiac death. Complications of CIED therapy include component malfunction, lead dislodgement, skin erosion and infection. Infection can result in significant morbidity and even mortality. The recommended treatment of CIED skin erosion and infection is urgent complete device extraction. When this is infeasible due to patient or resource factors, an attempt could be made to salvage the exposed or infected CIED system by debridement of all the infected necrotic tissues and irrigation of the pocket and contaminated hardware with anti-septic/antibiotic solutions. Taurolidine, when dissolved in an aqueous solution, produces a broad spectrum of antimicrobial actions and may be used as a novel irrigation agent during CIED salvage.

Case presentation

This report describes the first use of a taurolidine-containing solution for pocket irrigation and in situ hardware sterilisation that resulted in the successful salvage of a CIED infected with multi-resistant Staphylococcus epidermidis.

Conclusions

A taurolidine-containing antimicrobial solution can be a safe and effective alternative to traditional antiseptic/antibiotic solutions for pocket irrigation and in situ hardware sterilisation during CIED salvage, and may produce better clinical outcomes by some unique mechanisms of action such as inhibition of biofilm formation and neutralisation of endotoxins, with little risk of inducing and encountering resistance.
Alternate delivery platforms and implementation models for bringing evidence-based behavioral interventions to scale for youth facing adversity: a case study in West Africa
Authors: Bond Laura , Farrar Jordan , Borg Ryan C. , Keegan Katrina , Journeay Katharine , Hansen Nathan , Mac-Boima Emmanuel , Rassin Alimamy , Betancourt Theresa S.
Published: February 2022

Background

Youth Functioning and Organizational Success for West African Regional Development (Youth FORWARD) was launched as an implementation science collaboration focused on scaling out evidence-based mental health interventions for youth exposed to war and other adversities through novel delivery platforms. This implementation science case study examines the use of a collaborative team approach (CTA) as a scale-out strategy to foster the integration of an evidence-based group mental health intervention, the Youth Readiness Intervention, into youth employment programs tied to regional economic development in Sierra Leone.

Methods

A case study methodology is used to explore the feasibility and acceptability of integrating an evidence-based intervention, the Youth Readiness Intervention (YRI), into youth entrepreneurship programs (ENTR) in Sierra Leone, facilitated by the CTA. The authors analyzed field notes logged during program implementation, 8 weeks of supervision notes, 20 interviews with agency leaders and front-line staff delivering the YRI within this alternate delivery platform. Quantitative dissemination and implementation interviews administered to youth, facilitators, and agency leaders were analyzed using descriptive statistics and mixed linear models. A linked Hybrid Type II effectiveness-implementation cluster randomized trial is evaluating the clinical effectiveness of the YRI within this delivery platform.

Results

Extant data indicate the strong feasibility and acceptability of integrating the YRI into the ENTR program. Facilitators of integration of the YRI into the ENTR include mission alignment of the organizations with the delivery of psychosocial interventions, shared commitment to serving vulnerable youth, support from local District Youth Councils, and high interest from the youth served. Barriers include perceived competition between frontline organizations seeking funding for psychosocial interventions, and challenges in flexibility between donors and implementation partners operating in a fragile/post-conflict setting. The CTA was a feasible and acceptable strategy to support fidelity and quality improvement while scaling out the YRI.

Conclusions

Youth entrepreneurship and livelihood programs offer a promising mechanism for expanding the reach of evidence-based interventions to youth in fragile and post-conflict settings. Quality improvement and sustainment of evidence-based interventions are novel concepts in such settings. The CTA strategy institutionalizes the integration of an evidence-based intervention into youth entrepreneurship programs.

Trial registration

NCT03603613 (phase 1 pilot, registered May 18, 2018) and NCT03542500 (phase 2 scale-out study, registered May 18, 2018).
Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations.
Authors: Chi Kim N. , Rathkopf Dana E. , Smith Matthew Raymond , Efstathiou Eleni , Attard Gerhardt , Olmos David , Lee Ji Youl , Small Eric Jay , Gomes Andrea Juliana , Roubaud Guilhem , Saad Marniza , Zurawski Bogdan , Sakalo Valerii , Mason Gary , del Corral Adam , Wang George C. , Wu Daphne , Diorio Brooke , Lopez- Gitlitz Angela Mennicke , Sandhu Shahneen Kaur
Published: February 2022

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Background: Approximately 20% of mCRPC has alterations in genes associated with HRR and is responsive to PARP inhibitors (PARPi) such as NIRA. Combined PARPi with androgen receptor pathway targeting may also benefit unselected mCRPC. MAGNITUDE assessed whether adding NIRA to AAP improves outcomes in pts with mCRPC with or without alterations in HRR associated genes. Methods: MAGNITUDE (NCT03748641) is a randomized, double-blind phase 3 study. In eligible mCRPC pts, ≤4 mos of prior AAP for mCRPC was allowed. Pts with (HRR biomarker [BM]+; ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2) and without specified gene alterations (HRR BM-) were randomized 1:1 to receive NIRA 200 mg once daily + AAP or placebo (PBO) + AAP. Primary endpoint was radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) in the BRCA1/2 group followed by all HRR BM+ pts. Secondary endpoints were time to initiation of cytotoxic chemotherapy (TTCC), time to symptomatic progression (TTSP) and overall survival (OS). Other endpoints included time to PSA progression (TTPP) and objective response rate (ORR). Results: 423 HRR BM+ pts were randomized to NIRA + AAP (n = 212) or PBO + AAP (n = 211). Median age was 69, 23% had prior AAP, 21% had visceral metastases, and 53% had BRCA1/2 mutations. Median follow-up was 18.6 mos. NIRA + AAP significantly improved rPFS by BICR in the BRCA1/2 subgroup and in all HRR BM+ pts, reducing the risk of progression or death by 47% (16.6 vs 10.9 mo) and 27% (16.5 vs 13.7 mo) respectively (Table), vs PBO + AAP. Investigator assessed rPFS was consistent with BICR. NIRA + AAP delayed TTCC, TTSP, and TTPP and improved ORR in HRR BM+ pts (Table). First interim analysis of OS is immature. The preplanned futility analysis in 233 HRR BM- pts showed no benefit of adding NIRA to AAP in the prespecified composite endpoint (first of PSA progression or rPFS; HR, 1.09; 95% CI, 0.75-1.57). No new safety signals were seen. In HRR BM+ pts, 67% and 46.4% had grade 3/4 AEs and 9% and 3.8% discontinued treatment in the NIRA + AAP and PBO + AAP arms, respectively. There were no clinically significant differences in overall quality of life (FACT-P). Conclusions: NIRA + AAP improves rPFS and other clinically relevant outcomes in pts with mCRPC and alterations in HRR associated genes. There was no evidence of benefit with the addition of NIRA to AAP in HRR BM- pts with mCRPC. Clinical trial information: NCT03748641. [Table: see text]
Prevalence and natural history of non-metastatic castrate resistant prostate cancer: A population-based analysis.
Authors: Hird Amanda Elizabeth , Dvorani Erind , Saskin Refik , Herschorn Sender , Kodama Ronald , Kulkarni Girish S. , Nam Robert
Published: February 2022

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Background: The natural history of non-metastatic castrate resistant prostate cancer (nmCRPC) prior to the introduction of novel anti-androgen agents in a real-world setting is largely unknown. Methods: This was a retrospective population-based cohort study of men with nmCRPC in Ontario, Canada. Patients with a diagnosis of prostate cancer, castrate level of testosterone ( < 1.7nmol/L) and a PSA > 2.0nmol/L with a subsequent rise > 25% from the nadir, and without diagnostic or treatment codes for metastasis were included. Annual prevalence of nmCRPC was calculated. Crude time from nmCRPC to metastasis and death are presented as medians with interquartile range (IQR). Predictors of time from nmCRPC to prostate cancer death were compared using univariable and multivariable Fine and Gray subdistributional hazard models to account for the competing risk of non-prostate cancer death. Results: From January 2007 until March 2018, we identified 2045 patients with nmCRPC. Median age was 79 years (IQR: 72-84). A total of 984 patients (48.1%) received upfront hormonal therapy while 584 (25.8%) received initial radiotherapy (RT) and 478 (23.4%) underwent radical prostatectomy. Median time from primary treatment to nmCRPC was 6 years (IQR: 3-10). PSA at the time of meeting nmCRPC criteria was a median of 3.0 ng/L. Patients were followed for a median 31.1 months (IQR: 19.8-47.9). The overall annual prevalence of nmCRPC ranged from 1,519-1,913 patients, representing 7-12% of men with prostate cancer prescribed androgen deprivation therapy each year. Crude median time from nmCRPC to all-cause death was 37.6 months (IQR: 22.1-55.4). Median time from nmCRPC to metastasis and metastasis to all-cause death was 20.0 and 8.3 months, respectively. On regression analysis, older age, ADT use with primary treatment, higher PSA at the time of meeting nmCRPC criteria, and grade group predicted time from nmCRPC to prostate cancer death. Conclusions: This is the largest analysis of the prevalence and natural history of nmCRPC. The current study can be used as a historical cohort to compare how novel imaging modalities and advancements in systemic therapy for patients with nmCRPC impact prevalence estimates and disease trajectory over time.
Outcomes of an advanced practice nurse (APN)-led cancer genetics service.
Authors: Aiello Lisa , Petersen Jeffrey , Lynch Julie Ann , Hoffman-Hogg Lori , Damjanov Nevena , Robinson Kyle William , Wong Yu-Ning , Jhala Darshana , Maxwell Kara Noelle
Published: February 2022

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Background: In oncology practice, there are increasing numbers of patients for whom genetic testing is recommended by the National Cancer Care Network (NCCN), including all metastatic and high-risk localized prostate cancer patients. However, there is a critical shortage of genetics services providers. Acuity for these consults can be high, particularly in the context of a treatment related decision. We hypothesized that nurses, particularly advanced practice nurses (APNs), can provide a workforce within VA that can address genetic testing and genetic care needs of prostate cancer patients. Methods: We initiated a cancer genetics service staffed with an advanced practice nurse (APN) geneticist and evaluated the success of the program at a large urban, academic-affiliated Veteran’s Affairs Medical Center (VAMC). Results: In the one year prior to the initiation of the APN geneticist-run program (10/1/2019-9/30/2020), 61 unaffected patients with a family history of cancer and 85 patients with cancer (36 with prostate cancer) were referred to a VA centralized telegenetics service. An average of seven cancer patients (average three with prostate cancer) were referred to VA telegenetics per month. Genetic testing was completed in eleven (18%) of unaffected patients and 21 (25%) of cancer patients. Five (13%) of tested patients were found to have a pathogenic or likely pathogenic mutation or variant of uncertain significance (VUS). In the eight months after initiation of the APN geneticist-run consult service (10/1/2020 - 5/30/2021), 39 unaffected patients with a family history of cancer and 90 patients with cancer (38 with prostate cancer) were referred. An average of 11 cancer patients (average five with prostate cancer) per month were referred. This represents a 57% increase in all cancer patient and a 67% increase in prostate cancer patient referrals. For those patients referred to the APN geneticist-run consult service, genetic testing was completed in three (7%) of unaffected patients and 30 (33%) of cancer patients (including 15 prostate cancer patients). The genetic testing rate therefore improved from 1.7 oncology patients per month to 3.9 oncology patients per month, an 130% increase in genetic testing. For prostate cancer patients, the genetic testing rate improved from 0.8 to 1.9 patients tested per month, representing a 137% increase. Comparison of genetic testing outcomes at one year will be included in the final presentation. Conclusions: Inclusion of an APN geneticist-run consult service embedded in oncology clinics will likely improve access to genetics services and genetic testing rates in cancer patients.
Improvements in symptoms related to bone metastasis in recipients of Lutetium-177 PSMA-617 for prostate cancer.
Authors: Gonzalez Brian D. , Brownstein Naomi C. , Fan Wenyi , Dicker Adam P. , Oswald Laura B. , Dhillon Haryana M. , Jim Heather S.L. , Sandhu Shahneen Kaur , Tagawa Scott T. , Williams Scott , Hofman Michael S
Published: February 2022

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Background: Prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) targeted to prostate-specific membrane antigen (PSMA) is a new targeted treatment for progressive metastatic castration-resistant prostate cancer (mCRPC). PSMA-RLT conjugates a radionuclide to a small molecule ligand with affinity for PSMA. Recent trials, such as TheraP and VISION, established improvements in progression free survival, overall survival, and patient-reported outcomes (PROs) for PSMA-RLT. Less is known about the impact of PSMA-RLT on symptoms related to bone metastasis (BM), commonly causing significant morbidity in men with mCRPC. The optimal tools for PRO collection with PSMA-RLT are also uncertain. We previously reported improvements in Brief Pain Inventory and now report EORTC QLQ-BM22 data to describe change in symptoms related to bone metastasis among men receiving PSMA-RLT for mCRPC. Methods: From 2015 to 2017, 50 patients received up to 4 cycles of 177Lu-PSMA-617 every 6 weeks (trial registration: ACTRN12615000912583). Patients completed a validated assessment of bone metastasis-related pain (EORTC QLQ-BM22) prior to each cycle and 6 or 12 weeks after the last cycle of 177Lu-PSMA. Change in pain over the course of the study was examined using linear mixed effects models. We also examined whether unadjusted changes in PROs exceeded published cutoffs for minimal clinically important difference scores. Results: Patients reported reduced bone metastasis-related pain at various sites over time ( p =.01). Of 44 patients completing this scale before cycle 2, 22 (50%) reported clinically significant improvement in pain at various sites. At follow-up, of the 37 patients alive, 25 provided evaluable data on bone metastasis-related pain. Of these, 10 (40%) reported clinically significant improvement in pain at various sites. Patients also reported less functional interference from pain over time ( p <.01) and lower consistency, intermittency, and difficulty alleviating pain with medication over time ( p =.01). Before cycle 2 and at follow-up, 26% and 38% of respondents reported clinically significant reduction in functional interference from pain. Before cycle 2 and at follow-up, 33% and 42% of respondents reported clinically significant improvement in consistency, intermittency, and difficulty alleviating pain with medication. Conclusions: 177Lu-PSMA RLT resulted in improvements in bone metastasis-related symptoms, supporting prior findings using other PRO measures. At follow-up, 38-42% of patients completing PRO assessment reported clinically meaningful improvements in bone metastasis-related pain, a significant contributor to quality of life. Clinical trial information: ACTRN12615000912583.
The role of sabizabulin in phase 1b/2 clinical trials of men with metastatic castration-resistant prostate cancer who progressed on androgen receptor-targeting agents.
Authors: Markowski Mark Christopher , Eisenberger Mario A. , Pieczonka Christopher Michael , Getzenberg Robert H. , Rodriguez Domingo , Barnette K. Gary , Steiner Mitchell S. , Saltzstein Daniel R. , Antonarakis Emmanuel S. , Tutrone Ronald F.
Published: February 2022

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Background: Sabizabulin is a novel oral cytoskeleton disruptor being developed for use in metastatic castration resistant prostate cancer (mCRPC). A phase 1b/2 clinical study was conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC resistant to androgen receptor targeting agents (ARTAs). Methods: The phase 1b portion of the study in 39 men utilized escalating and expanding dose and duration. The phase 2 portion studied 41 men with mCRPC at the recommended phase 2 dose (RP2D) of 63 mg daily. Based upon the phase 1b/2 data, sabizabulin appears to have both cytotoxic and cytostatic activity. A analysis was conducted evaluating the best clinical response (BCR) defined as either an objective response assessed by PCWG3 criteria and/or stable disease defined as ≥5 cycles (≥15 weeks) of continuous treatment. Results: Of the combined 80 patients in the phase 1b/2 portions of the study, the BCR was 37.5% (30/80) and 5 of the responders remain on study with the longest being treated for more than 30 months. Of the patients with measurable disease at study entry, the BCR was 59% (17/29). Prior to study entry, 11/30 (37%) of those with a BCR had previously been treated with and subsequently progressed on a minimum of 2 ARTAs. The remaining 19/30 (63%) had progressed on a single ARTA agent. 11 (37%) were previously treated with enzalutamide or apalutamide and 8 (27%) with abiraterone as single agents. 8 (27%) received enzalutamide and abiraterone and 3 (10%) patients received more than two ARTAs. As described previously, the safety profile continues to be favorable with no clinically relevant neutropenia or neurotoxicity. Conclusions: In this analysis, sabizabulin has demonstrated not only cytotoxic, but also significant cytostatic activity with similar responses in men that have progressed on a single or multiple ARTA agents. Sabizabulin is a novel agent with the potential provide men with mCRPC a well-tolerated chronic treatment cytostatic option after progressing on an ARTA and is being tested in the open phase 3 VERACITY trial. Clinical trial information: NCT03752099.
Survival of patients with metastatic prostate cancer and comorbid obesity.
Authors: Cheranda Nina , Luo Suhong , Riekhof Forest , Govindan Srinivas , Sanfilippo Kristen Marie , Schoen Martin W.
Published: February 2022

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Background: In metastatic castrate resistant prostate cancer (mCRPC), the oral treatments of enzalutamide (ENZ) and abiraterone (AA) are used interchangeably because there are few large-scale comparative studies of the therapies. However, both drugs have different mechanisms of action, AA being an androgen biosynthesis inhibitor and ENZ being an androgen receptor inhibitor, so there may be therapeutic variance between the two drugs based on their interactions with comorbid conditions like obesity. Obesity not only increases the risk of other comorbidities, like heart disease, diabetes, and stroke, but has also been implicated in the development of CRPC. Methods: Patients treated with abiraterone or enzalutamide from September 10, 2014 to June 2, 2017 in the Veterans Health Administration were identified via pharmacy records. Among this population, patients were separated into body mass index (BMI) categories for underweight ( < 18.5), normal (18.5 to < 25), overweight (25 to < 30), and obese ( > 30). Age, Charlson Comorbidity Index and mCRPC treatments were collected and analyzed for the primary outcome of survival via the Kaplan-Meier method. A multivariate Cox proportional hazard model was performed with the following variables: BMI, Charlson Comorbidity Index, age, Black race, treatment with bone-directed therapy, and baseline PSA. Results: In patients with BMI > 25, there was a significantly improved overall survival for treatment with ENZ (n = 1623) over AA (n = 2159), with medians of 30.0 and 27.0 months respectively (p = 0.002). There was no significant difference in survival for patients with BMI < 25 (p = 0.48), with median survival of 17.7 months for ENZ (n = 589) and 16.1 months for AA (n = 860). The overall survival difference between underweight (n = 113), normal (n = 1336), overweight (n = 1879), and obese (n = 1903) groups shows significant increase in survival with increasing BMI, with the median survival durations of 9.2, 15.9, 23.9, and 29.8 months respectively (p < 0.001). This finding was corroborated by the Cox proportional hazard model, with the data indicating an increased risk of death (aHR = 1.58; 95% CI: 1.29, 1.94; p < 0.001) with the underweight group and decreased risk with the overweight (aHR = 0.75; 95% CI: 0.69, 0.81; p < 0.001) and obese (aHR = 0.64; 95% CI: 0.59, 0.70; p < 0.001) groups. Conclusions: Treatment with ENZ was associated with longer survival for mCRPC patients with overweight and obesity (BMI > 25) over AA. Otherwise, for normal and underweight patients (BMI < 25), there was no significant difference in overall survival between the two drugs. Higher BMI is associated with improved survival, suggesting a protective effect of obesity in mCRPC patients. While the reason for this finding warrants further investigation, similar findings have been seen in obese patients in some hormone driven cancers, like breast cancer and myeloma.