'Folfirinox' chemotherapy combined with contact x-ray brachytherapy 50kVp and 'CAP50' chemoradiotherapy aiming at organ preservation for selected intermediate distal-middle cT2-T3 rectal cancers: A feasibility study.

PURPOSE: The standard treatment of T2-T3 rectal adenocarcinoma is radical proctectomy by total mesorectal excision often combined with some neoadjuvant treatment. To reduce morbidity of this surgery, organ preservation strategy using various combination of radiotherapy, chemotherapy and local excision is gaining interest. Some randomized trials have proven the feasibility of such approaches. The OPERA trial demonstrated, for T2 T3<5cm diameter low-middle rectum, that a contact X-ray brachytherapy boost of 90Gy in three fractions over 4 weeks was able to achieve a planned organ preservation in 81% of patients at 3years with 97% success for tumour smaller than 3cm treated with contact X-ray brachytherapy boost first. To try to expand organ preservation to larger tumours we set up a feasibility trial in T2-T3 tumours using total neoadjuvant treatment and a contact X-ray brachytherapy boost. MATERIAL AND METHOD: The trial was approved by the institutional review board of Nice. Inclusion criteria were operable patients, 75years or less, adenocarcinoma of the low-middle rectum staged T2c-T3N0 larger than 3.5cm and less than 6cm in diameter or T2-T3N1 less than 6cm in diameter. Treatment started in all cases with neoadjuvant chemotherapy associating 5-fluoro-uracile, irinotecan and oxaliplatin ('folfirinox' regimen, four to six cycles). In case of good tumour response after four cycles, a contact X-ray brachytherapy boost (delivering 90Gy in three fractions) was given followed by chemoradiotherapy (external beam radiotherapy delivering 50Gy, with concurrent capecitabine). After six cycles if only a partial response (tumour still larger than 3cm) was seen, chemoradiotherapy was given and contact X-ray brachytherapy boost was delivered after that. At the end of this total neoadjuvant treatment a watch and wait strategy was decided in case of clinical complete response or radical proctectomy by total mesorectal excision for partial response. RESULTS: Between July 2019 and October 2022, 14 patients were included; median age was 66years (range: 51-77years), there were nine male and five female, two T2 N1 tumours, seven T3N0, and five T3N1, all were M0. Median tumour diameter was 40mm (range: 11-50mm); three tumours had a circumferential extension greater than 50%. Seven patients received four folfirinox cycles and seven had six cycles. Contact X-ray brachytherapy boost was given during folfirinox chemotherapy before chemoradiotherapy in 11 patients (and after in three). The tolerance was good, with no grade 4-5 toxicity. The main grade 3 early toxicity was in relation with the folfirinox regimen. A clinical complete response was seen in 12 patients at the end of the total neoadjuvant treatment (85%). All these patients are alive and have preserved their rectum with a mean follow-up time of 17.8months (range: 6-48months) and a good bowel function (low anterior rectal resection syndrome score below 30). The main contact X-ray brachytherapy boost toxicity was radiation ulceration in three patients that usually healed within 6 months, sometimes necessitating hyperbaric oxygen. CONCLUSION: The preliminary results of this feasibility study show that early tolerance of these intensive total neoadjuvant treatment is compatible with an acceptable toxicity. The high rate of organ preservation in this intermediate group of T2-T3 tumours is encouraging and is a good argument to start the next randomized TRESOR trial that will aim at achieving a 65% of 3-year survival with organ preservation in this intermediate tumour group.

[Success factors and obstacles in the implementation of competence-oriented teaching in surgery]. / Erfolgsfaktoren und Hindernisse bei der Implementierung kompetenzorientierter Lehre in der Chirurgie.

BACKGROUND AND OBJECTIVES: For successful competence-oriented teaching at the medical faculties it is important to identify the factors that influence its implementation in order to benefit from the strengths and balance out weaknesses. The present study examined the success factors and obstacles of the implementation of competence-oriented teaching in the surgical discipline from the point of view of students and lecturers. METHODS: After implementation of competence-oriented teaching based on the teaching goals of the NKLM, in clinical examination courses (bedside teaching and block internship, BP) at two hospitals, a qualitative content analysis and quantification of the answers were performed using focus group interviews and questionnaires with students (S) and lecturers (D). RESULTS: During the summer semester 2022 a total of 31 students and 14 lecturers were interviewed in focus groups and 143 questionnaires (123 S, 20 D) were analyzed. For the students the presence of concrete competences/teaching goals, guidelines for the lesson, transparent goals and ability to demand teaching goals as well as structured lessons and mentoring were the main success factors. Lecturers on the other hand reported the presence of concrete goals, assistance for the lesson preparation and the activity of the students as success factors. The results of the questionnaires showed that the majority (88% S, 75% D) were informed about the teaching goals and considered them to be followed (84%S, 95% D). Obstacles were the factors "time", "mentoring" and "information". Factors that were between negative and positive (indifferent factors) were "uncertainty about competence-orientation" and "uncertainty how to examine the teaching success". DISCUSSION: Transparent structure and teaching goals as well as a mentoring system are the success factors for the implementation of competence-oriented lessons and should be used as strengths. Indifferent factors represent weaknesses and need to be addressed by training and instruction. Restricted time and personnel resources are the immanent problems that hamper the implementation and require fulminant structural changes.

Dysregulation of the renin-angiotensin system in vascular dementia.

The renin-angiotensin system (RAS) regulates systemic and cerebral blood flow and is dysregulated in dementia. The major aim of this study was to determine if RAS signalling is dysregulated in vascular dementia. We measured markers of RAS signalling in white matter underlying the frontal and occipital cortex in neuropathologically confirmed cases of vascular dementia (n = 42), Alzheimer's disease (n = 50), mixed AD/VaD (n = 50) and age-matched controls (n = 50). All cases were stratified according to small vessel disease (SVD) severity across both regions. ACE-1 and ACE-2 protein and activity was measured by ELISA and fluorogenic peptide assays respectively, and angiotensin peptide (Ang-II, Ang-III and Ang-(1-7)) levels were measured by ELISA. ACE-1 protein level and enzyme activity, and Ang-II and Ang-III, were elevated in the white matter in vascular dementia in relation to SVD severity. ACE-1 and Ang-II protein levels were inversely related to MAG:PLP1 ratio, a biochemical marker of brain tissue oxygenation that when reduced indicates cerebral hypoperfusion, in a subset of cases. ACE-2 level was elevated in frontal white matter in vascular dementia. Ang-(1-7) level was elevated across all dementia groups compared to age-matched controls but was not related to SVD severity. RAS signalling was not altered in the white matter in Alzheimer's disease. In the overlying frontal cortex, ACE-1 protein was reduced and ACE-2 protein increased in vascular dementia, whereas angiotensin peptide levels were unchanged. These data indicate that RAS signalling is dysregulated in the white matter in vascular dementia and may contribute to the pathogenesis of small vessel disease.

Stereotactic body radiation therapy to postpone systemic therapy escalation for castration-resistant prostate cancer: A multicenter retrospective analysis.

Purpose: To evaluate the oncological outcome after stereotactic body radiation therapy (SBRT) for oligoprogressive metastatic castration-resistant prostate cancer (omCRPC) patients. Materials-Methods: In this retrospective, observational, multi-institutional study, omCRPC patients (≤5 metastases) underwent SBRT. Primary endpoint was systemic therapy escalation-free survival (STE-FS) after SBRT. Local relapse (LR), distant (DP) and isolated biochemical (iBP) progressions were reported with progression-free survival (PFS) and overall survival (OS). Prognostic factors for STE-FS were investigated. Toxicity was reported. Results: From 01/07 to 09/19, 50 pts with omCRPC underwent SBRT. With a MFU of 23 months [3---100], median STE-FS was 13.1 months (95 %CI 10.8 - 36.4). Median OS was not reached and PFS was 13 months (CI95% 10.1 - 20.8). Post-SBRT PSA remained stable or decreased in 19 pts (38 %). Progression events (LR, DP, iBP) were observed in 34 pts (68 %), among whom 6 relapsed in the irradiated area (local control rate: 88 %). DP and iBP were observed in 28 pts (56 %) and 4 pts (8 %) respectively. In multivariate analysis, post-SBRT biochemical response was an independent prognostic factor for STE-FS. Grade ≥ 3 toxicity occurred in 2 pts. Conclusion: With excellent local control and tolerance, SBRT for omCRPC patients represents an acceptable approach to defer systemic therapeutic escalation and prevent its side effects. Accurate patient selection for SBRT requires more data with longer follow-up and higher numbers of patients pending the results of upcoming randomized trials.

Systemic therapy escalation after stereotactic body radiation therapy for oligometastatic hormone-sensitive prostate cancer.

Purpose: To evaluate the oncological outcome after stereotactic body radiation therapy (SBRT) for oligometastatic hormone-sensitive prostate cancer (omHSPC) patients. Materials-Methods: In this retrospective, observational, multi-institutional study, omHSPC patients (≤5 metastases) underwent SBRT. Primary endpoint was systemic therapy escalation-free survival (STE-FS) after SBRT. Local (LR), distant (DR), prostatic (PR) and isolated biochemical (iBR) relapses were reported with progression-free survival (PFS) and overall survival (OS). Prognostic factors for STE-FS were investigated. Toxicity was reported. Results: From 01/07 to 09/19, 119 pts with omHSPC underwent SBRT. With a MFU of 34 months [12-97], median STE-FS was 33.4 months (95%CI 26.6---40.1). Median OS was not reached and PFS was 22.7 months (CI95% 18.6---32.3). Post-SBRT-PSA remained stable or decreased in 87 pts (73.1%). Progression events (LR, MR, PR, iBR) were observed in 72 pts (60.5%), among whom 6 relapsed in the irradiated area (local control rate: 95%). DR, BR, PR were observed in 44 pts (37%), 21pts (17.7%) and 2 pts (1.7%) respectively. In multivariate analysis, post-SBRT biochemical response was an independent prognostic factor for STE-FS. Grade ≥ 3 toxicity occurred in 1pt. Conclusion: With excellent local control and tolerance, SBRT for omHSPC patients represents an attractive approach to defer systemic therapeutic escalation and prevent its side effects. Accurate patient selection for SBRT requires more data with longer follow-up and higher numbers of patients pending the results of upcoming randomized trials.

Prevalence and Risk Factors of PrEP Use Stigma Among Adolescent Girls and Young Women in Johannesburg, South Africa and Mwanza, Tanzania Participating in the EMPOWER Trial.

Adolescent girls and young women (AGYW) in sub-Saharan Africa may benefit from pre-exposure prophylaxis (PrEP), yet stigma may limit PrEP acceptance and continuation. We examined factors associated with PrEP use stigma among 307 participants of the EMPOWER trial (2016-2018), an unblinded randomized controlled trial among HIV-negative, AGYW, aged 16-24, in South Africa and Tanzania. The 6-item, brief-PrEP use stigma scale (B-PSS) had high internal reliability. At the end of the trial, 34.2% of study participants reported any PrEP use stigma. Three latent classes were observed, reflecting low (46.9%), medium (31.9%), and high (21.2%) reported PrEP use stigma. Disclosure of PrEP use to sexual partner and belief that PrEP prevents HIV were associated with less reported PrEP use stigma. Conversely, participants who reported fear and shame about people living with HIV were more likely to report PrEP use stigma. Our validated tool and findings will enable practitioners to identify AGYW at high risk of PrEP use stigma who may benefit from additional support.Pan African clinical trials registry PACTR202006754762723, 5 April 2020, retrospectively registered.

[The role of radiotherapy to the primary tumor and metastases in patients with oligometastatic prostate cancer]. / Place de la radiothérapie de la tumeur primitive et/ou des métastases du cancer de la prostate oligométastatique.

Oligometastatic prostate cancer is among the most studied oligometastatic cancers in the literature. However few prospective studies have assessed stereotactic body radiotherapy (SBRT) for prostate cancer oligometastases. Two randomised phase II trials show a progression-free survival benefit compared with observation. Prospective registry data show very good local control and low toxicity too. Inclusion in ongoing trials should be strongly encouraged to define the role of SBRT in addition to systemic therapy. Radiation therapy to the primary tumour has been studied in randomised trials and provides an overall survival benefit in patients with low metastatic burden. The benefit is inversely correlated with the number of bone lesions using conventional imaging, up to three metastases. Radiotherapy to the primary tumour is recommended by the learned societies for patients with low metastatic burden. Its role in combination with second generation anti androgen therapy needs to be clarified.

Molecular neuro-biological and systemic health benefits of achieving dopamine homeostasis in the face of a catastrophic pandemic (COVID- 19): A mechanistic exploration.

In the face of the global pandemic of COVID 19, approaching 1.75 Million infected worldwide (4/12/2020) and associated mortality (over 108, 000 as of 4/12/2020) as well-as other catastrophic events including the opioid crisis, a focus on brain health seems prudent [1] (https://www.coronavirus.gov). This manuscript reports on the systemic benefits of restoring and achieving dopamine homeostasis to reverse and normalize thoughts and behaviors of Reward Deficiency Syndrome (RDS) dysfunctional conditions and their effects on behavioral physiology; function of reward genes; and focuses on digestive, immune, eye health, and the constellation of symptomatic behaviors. The role of nutrigenomic interventions on restoring normal brain functions and its benefits on these systems will be discussed. We demonstrate that modulation of dopamine homeostasis using nutrigenomic dopamine agonists, instead of pharmaceutical interventions, is achievable. The allied interlinking with diverse chronic diseases and disorders, roles of free radicals and incidence of anaerobic events have been extensively highlighted. In conjunction, the role of dopamine in aspects of sleep, rapid eye movement and waking are extensively discussed. The integral aspects of food indulgence, the influence of taste sensations, and gut-brain signaling are also discussed along with a special emphasis on ocular health. The detailed mechanistic insight of dopamine, immune competence and the allied aspects of autoimmune disorders are also highlighted. Finally, the integration of dopamine homeostasis utilizing a patented gene test and a research-validated nutrigenomic intervention are presented. Overall, a cutting-edge nutrigenomic intervention could prove to be a technological paradigm shift in our understanding of the extent to which achieving dopamine homeostasis will benefit overall health.

Sequencing seismograms: A panoptic view of scattering in the core-mantle boundary region.

Scattering of seismic waves can reveal subsurface structures but usually in a piecemeal way focused on specific target areas. We used a manifold learning algorithm called "the Sequencer" to simultaneously analyze thousands of seismograms of waves diffracting along the core-mantle boundary and obtain a panoptic view of scattering across the Pacific region. In nearly half of the diffracting waveforms, we detected seismic waves scattered by three-dimensional structures near the core-mantle boundary. The prevalence of these scattered arrivals shows that the region hosts pervasive lateral heterogeneity. Our analysis revealed loud signals due to a plume root beneath Hawaii and a previously unrecognized ultralow-velocity zone beneath the Marquesas Islands. These observations illustrate how approaches flexible enough to detect robust patterns with little to no user supervision can reveal distinctive insights into the deep Earth.

Patient blood management during the COVID-19 pandemic: a narrative review.

As COVID-19 disease escalates globally, optimising patient outcome during this catastrophic healthcare crisis is the number one priority. The principles of patient blood management are fundamental strategies to improve patient outcomes and should be given high priority in this crisis situation. The aim of this expert review is to provide clinicians and healthcare authorities with information regarding how to apply established principles of patient blood management during the COVID-19 pandemic. In particular, this review considers the impact of the COVID-19 pandemic on blood supply and specifies important aspects of donor management. We discuss how preventative and control measures implemented during the COVID-19 crisis could affect the prevalence of anaemia, and highlight issues regarding the diagnosis and treatment of anaemia in patients requiring elective or emergency surgery. In addition, we review aspects related to patient blood management of critically ill patients with known or suspected COVID-19, and discuss important alterations of the coagulation system in patients hospitalised due to COVID-19. Finally, we address special considerations pertaining to supply-demand and cost-benefit issues of patient blood management during the COVID-19 pandemic.

Biotechnical development of genetic addiction risk score (GARS) and selective evidence for inclusion of polymorphic allelic risk in substance use disorder (SUD).

Research into the neurogenetic basis of addiction identified and characterized by Reward Deficiency Syndrome (RDS) includes all drug and non-drug addictive, obsessive and compulsive behaviors. We are proposing herein that a new model for the prevention and treatment of Substance Use Disorder (SUD) a subset of RDS behaviors, based on objective biologic evidence, should be given serious consideration in the face of a drug epidemic. The development of the Genetic Addiction Risk Score (GARS) followed seminal research in 1990, whereby, Blum's group identified the first genetic association with severe alcoholism published in JAMA. While it is true that no one to date has provided adequate RDS free controls there have been many studies using case -controls whereby SUD has been eliminated. We argue that this deficiency needs to be addressed in the field and if adopted appropriately many spurious results would be eliminated reducing confusion regarding the role of genetics in addiction. However, an estimation, based on these previous literature results provided herein, while not representative of all association studies known to date, this sampling of case- control studies displays significant associations between alcohol and drug risk. In fact, we present a total of 110,241 cases and 122,525 controls derived from the current literature. We strongly suggest that while we may take argument concerning many of these so-called controls (e.g. blood donors) it is quite remarkable that there are a plethora of case -control studies indicating selective association of these risk alleles ( measured in GARS) for the most part indicating a hypodopaminergia. The paper presents the detailed methodology of the GARS. Data collection procedures, instrumentation, and the analytical approach used to obtain GARS and subsequent research objectives are described. Can we combat SUD through early genetic risk screening in the addiction field enabling early intervention by the induction of dopamine homeostasis? It is envisaged that GARS type of screening will provide a novel opportunity to help identify causal pathways and associated mechanisms of genetic factors, psychological characteristics, and addictions awaiting additional scientific evidence including a future meta- analysis of all available data -a work in progress.

The association of pre-operative anaemia with survival after orthotopic liver transplantation.

Anaemia is common in patients with end-stage liver disease. Pre-operative anaemia is associated with greater mortality after major surgery. We analysed the association of pre-operative anaemia (World Health Organization classification) with survival and complications after orthotopic liver transplantation using Cox and logistic regression models. We included patients undergoing their first orthotopic liver transplantation between 2004 and 2016. Out of 599 included patients, 455 (76%) were anaemic before transplantation. Pre-operative anaemia was not associated with the survival of 485/599 (81%) patients to 1 year after liver transplantation, OR (95%CI) 1.04 (0.64-1.68), p = 0.88. Pre-operative anaemia was associated with higher rates of intra-operative blood transfusions and acute postoperative kidney injury on multivariable analysis, OR (95%CI) 1.70 (0.82-2.59) and 1.72 (1.11-2.67), respectively, p < 0.001 for both. Postoperative renal replacement therapy was associated with pre-operative anaemia on univariate analysis, OR (95%CI) 1.87 (1.11-3.15), p = 0.018.

Understanding the Scientific Basis of Post-traumatic Stress Disorder (PTSD): Precision Behavioral Management Overrides Stigmatization.

Post-traumatic stress disorder (PTSD) is a severe polygenic disorder triggered by environmental factors. Many polymorphic genes, particularly the genetic determinants of hypodopaminergia (low dopamine function), associate with a predisposition to PTSD as well as substance use disorder. Support from the National Institutes of Health for neuroimaging research and molecular, genetic applied technologies has improved understanding of brain reward circuitry functions that have inspired the development of new innovative approaches to their early diagnosis and treatment of some PTSD symptomatology and addiction. This review presents psychosocial and genetic evidence that vulnerability or resilience to PTSD can theoretically be impacted by dopamine regulation. From a neuroscience perspective, dopamine is widely accepted as a major neurotransmitter. Questions about how to modulate dopamine clinically in order to treat and prevent PTSD and other types of reward deficiency disorders remain. Identification of genetic variations associated with the relevant genotype-phenotype relationships can be characterized using the Genetic Addiction Risk Score (GARS®) and psychosocial tools. Development of an advanced genetic panel is under study and will be based on a new array of genes linked to PTSD. However, for now, the recommendation is that enlistees for military duty be given the opportunity to voluntarily pre-test for risk of PTSD with GARS, before exposure to environmental triggers or upon return from deployment as part of PTSD management. Dopamine homeostasis may be achieved via customization of neuronutrient supplementation "Precision Behavioral Management" (PBM™) based on GARS test values and other pro-dopamine regulation interventions like exercise, mindfulness, biosensor tracking, and meditation.

Insurance Companies Fighting the Peer Review Empire without any Validity: the Case for Addiction and Pain Modalities in the face of an American Drug Epidemic.

The United States are amid an opioid overdose epidemic; we are challenged to provide non-addicting/non-pharmacological alternatives to assist in pain attenuation. There are proven strategies available to manage chronic pain effectively without opioids. Utilization review providers for insurance companies often ignore medicine based scientific peer-reviewed studies that warn against the chronic use of opioid medications, as well as the lack of evidence to support long-term use of opioids for pain. This paradigm must change if we are to indeed change the drug-embracing culture in American chronic pain management. A barrier to treatment is pushback on the part of insurance companies especially as it relates to fighting against pain relief alternatives compared to classical analgesic agents. Pain specialists in the U.S., are compelled to find alternative solutions to help pain victims without promoting unwanted tolerance to analgesics and subsequent biological induction of the "addictive brain." It is noteworthy that reward center of the brain plays a crucial role in the modulation of nociception, and that adaptations in dopaminergic circuitry may affect several sensory and affective components of chronic pain syndromes. Possibly knowing a patient's genetic addiction risk score (GARS™) could eliminate guessing as it relates to becoming addicted.

Would induction of dopamine homeostasis via coupling genetic addiction risk score (GARS®) and pro-dopamine regulation benefit benzodiazepine use disorder (BUD)?

Prescriptions for Benzodiazepines (BZDs) have risen continually. According to national statistics, the combination of BZDs with opioids has increased since 1999. BZDs (sometimes called "benzos") work to calm or sedate a person by raising the level of the inhibitory neurotransmitter GABA in the brain. In terms of neurochemistry, BZDs act at the GABAA receptors to inhibit excitatory neurons, reducing VTA glutaminergic drive to reduce dopamine release at the Nucleus accumbens. Benzodiazepine Use Disorder (BUD) is very difficult to treat, partly because BZDs are used to reduce anxiety which paradoxically induces hypodopaminergia. Considering this, we are proposing a paradigm shift. Instead of simply targeting chloride channel direct GABAA receptors for replacement or substitution therapy, we propose the induction of dopamine homeostasis. Our rationale is supported by the well-established notion that the root cause of drug and non-drug addictions (i.e. Reward Deficiency Syndrome [RDS]), at least in adults, involve dopaminergic dysfunction and heightened stress. This proposition involves coupling the Genetic Addiction Risk Score (GARS) with a subsequent polymorphic matched genetic customized Pro-Dopamine Regulator known as KB220ZPBM (Precision Behavioral Management). Induction of dopamine homeostasis will be clinically beneficial in attempts to combat BUD for at least three reasons: 1) During detoxification of alcoholism, the potential induction of dopamine regulation reduces the need for BZDs; 2) A major reason for BZD abuse is because people want to achieve stress reduction and subsequently, the potential induction of dopamine regulation acts as an anti-stress factor; and 3) BUD and OUD are known to reduce resting state functional connectivity, and as such, potential induction of dopamine regulation enhances resting state functional connectivity. Future randomized placebo-controlled studies will investigate this forward thinking proposed novel modality.

Fast- and slow-exploring pigeons differ in how they use previously learned rules.

Several studies report a correlation between exploratory behaviour and performance on tests of cognitive ability. Exploration may influence learning because less exploratory animals are less likely to come in contact with to-be-learned stimuli. Alternatively, the way information available in the environment is processed could influence the rate of exploration. Pigeons are one of the most-studied species used to examine the mechanisms underlying cognitive abilities, but have not been used to examine the relationship between these abilities and animal personality. Here, twelve pigeons were first tested in a novel environment to assess repeatability in exploratory behaviour. Pigeons were then trained to discriminate between two visual stimuli: lines oriented at 90° (vertical, the S+) and 135° (the S-). After training pigeons underwent generalization testing with ten additional visual line orientation stimuli. We found exploratory behaviour was related to generalization performance: fast-explorers had steeper generalization gradients compared to slow-explorers. This effect was only seen in the direction towards the S-. These results suggest that birds with different exploratory styles differ in how they use previously learned information. Further testing is needed to confirm which cue(s) (S+ or S-) control the behaviour of fast-explorers.