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Rectal cancer treatment has evolved during the past 40 years with the use of a standardized surgical technique for tumour resection: total mesorectal excision. A dramatic reduction in local recurrence rates and improved survival outcomes have been achieved as consequences of a better understanding of the surgical oncology of rectal cancer, and the advent of adjuvant and neoadjuvant treatments to compliment surgery have paved the way for a multidisciplinary approach to disease management. Further improvements in imaging techniques and the ability to identify prognostic factors such as tumour regression, extramural venous invasion and threatened margins have introduced the concept of decision-making based on preoperative staging information. Modern treatment strategies are underpinned by accurate high-resolution imaging guiding both neoadjuvant therapy and precision surgery, followed by meticulous pathological scrutiny identifying the important prognostic factors for adjuvant chemotherapy. Included in these strategies are organ-sparing approaches and watch-and-wait strategies in selected patients. These pathways rely on the close working of interlinked disciplines within a multidisciplinary team. Such multidisciplinary forums are becoming standard in the treatment of rectal cancer across the UK, Europe and, more recently, the USA. This Review examines the essential components of modern-day management of rectal cancer through a multidisciplinary team approach, providing information that is essential for any practising colorectal surgeon to guide the best patient care.Rectal cancer treatment has evolved towards a multidisciplinary approach to disease management. This Review examines the essential components of rectal cancer management through a multidisciplinary team, with a focus on the effect of this approach and the elements used for staging and developing the treatment plan.

Inflammatory bowel disease (IBD)-related colorectal cancer (CRC) is responsible for approximately 2% of the annual mortality from CRC overall, but 10–15% of the annual deaths in IBD patients. IBD-related CRC patients are also affected at a younger age than sporadic CRC patients, and have a 5-year survival rate of 50%. Despite optimal medical treatment, the chronic inflammatory state inherent in IBD increases the risk for high-grade dysplasia and CRC, with additional input from genetic and environmental risk factors and the microbiome. Recognizing risk factors, implementing appropriate surveillance, and identifying high-risk patients are key to managing the CRC risk in IBD patients. Chemoprevention strategies exist, and studies evaluating their efficacy are underway. Once dysplasia or invasive cancer is diagnosed, appropriate surgical resection and postoperative treatment and surveillance are necessary. Here, we discuss the current state of IBD-related CRC, prevalence, risk factors, and evidence for surveillance, prophylaxis, and treatment recommendations.

Endothelial nitric oxide synthase (eNOS, NOS3) is responsible for producing nitric oxide (NO)—a key molecule that can directly (or indirectly) act as a vasodilator and anti-inflammatory mediator. In this review, we examine the structural effects of regulation of the eNOS enzyme, including post-translational modifications and subcellular localization. After production, NO diffuses to surrounding cells with a variety of effects. We focus on the physiological role of NO and NO-derived molecules, including microvascular effects on vessel tone and immune response. Regulation of eNOS and NO action is complicated; we address endogenous and exogenous mechanisms of NO regulation with a discussion of pharmacological agents used in clinical and laboratory settings and a proposed role for eNOS in circulating red blood cells.

The unintended consequences of polypharmacy pose significant risks to older adults. The complexities of managing numerous medications from multiple prescribers demand a comprehensive approach to mitigate harms. Pharmacist-led clinics have been shown to improve outcomes in patients with diabetes and hypertension. Pharmacist-led clinics focused on broader issues of polypharmacy have the potential to lead to better outcomes for older patients. We describe the design and the pre-post evaluation of a polypharmacy clinic. We conducted a retrospective standardized chart review of polypharmacy visits during October and November 2022. Systematic data collection was completed by March 2023. Our review included 84 polypharmacy visits; the average patient age was 80. Patients were on 17.3 (range: 7–33) medications at-visit and 15.9 (range: 4–30) medications post-visit, with an average of 1.4 medications deprescribed per visit. In patients with many medications (range: 17–33 medications) at the polypharmacy consult visit, 2.6 medications were deprescribed post-visit. In patients with a moderate number of medications (range: 7–16 medications) at-visit, 0.9 medications were deprescribed post-visit. Medication list accuracy increased to 72% at follow-up visits compared to initial visits (66%). 44% of patients were on 1 or more Potentially Inappropriate Medications (PIMs) and 24% were on 1 or more Drugs with Strong Anticholinergic Properties (DSAPs) at initial visits. At follow-up visit, the proportion of patients with PIMs decreased by 28%, and the proportion of patients with DSAPs decreased by 54%. Our evaluation demonstrates the value of a polypharmacy clinic in improving medication list accuracy and deprescribing PIMs and DSAPs.

Attention is the gate through which sensory information enters our conscious experiences. Oftentimes, patients with major depressive disorder (MDD) complain of concentration difficulties that negatively impact their day-to-day function, and these attention problems are not alleviated by current first-line treatments. In spite of attention’s influence on many aspects of cognitive and emotional functioning, and the inclusion of concentration difficulties in the diagnostic criteria for MDD, the focus of depression as a disease is typically on mood features, with attentional features considered less of an imperative for investigation. Here, we summarize the breadth and depth of findings from the cognitive neurosciences regarding the neural mechanisms supporting goal-directed attention in order to better understand how these might go awry in depression. First, we characterize behavioral impairments in selective, sustained, and divided attention in depressed individuals. We then discuss interactions between goal-directed attention and other aspects of cognition (cognitive control, perception, and decision-making) and emotional functioning (negative biases, internally-focused attention, and interactions of mood and attention). We then review evidence for neurobiological mechanisms supporting attention, including the organization of large-scale neural networks and electrophysiological synchrony. Finally, we discuss the failure of current first-line treatments to alleviate attention impairments in MDD and review evidence for more targeted pharmacological, brain stimulation, and behavioral interventions. By synthesizing findings across disciplines and delineating avenues for future research, we aim to provide a clearer outline of how attention impairments may arise in the context of MDD and how, mechanistically, they may negatively impact daily functioning across various domains.

Macrophages internalize pathogens for intracellular degradation. An important part of this process is the phagosomal transport from the cell periphery to the perinuclear region. Biochemical factors are known to influence the fate of phagosomes. Here, we show that the size of phagosomes also has a strong influence on their transport. We found that large phagosomes are transported persistently to the nucleus, whereas small phagosomes show strong bidirectional transport. We show that dynein motors play a larger role in the transport of large phagosomes, whereas actin filament-based motility plays a larger role in the transport of small phagosomes. Furthermore, we investigated the spatial distribution of dyneins and microtubules around phagosomes and hypothesize that dynein and microtubule density differences between the nucleus-facing side of phagosomes and the opposite side could explain part of the observed transport characteristics. Our findings suggest that a size-dependent cellular sorting mechanism might exist that supports macrophages in their immunological roles.

BackgroundIn the era of competency-based surgical education, VBC has gained increased attention and may enhance the efficacy of surgical education. The objective of this systematic review was to summarize the existing evidence of video-based coaching (VBC) and compare VBC to traditional master-apprentice-based surgical education.MethodsWe performed a systematic review and meta-analysis of randomized controlled trials (RCT) assessing VBC according to the PRISMA and Cochrane guidelines. The MEDLINE, EMBASE, and COCHRANE and Researchgate databases were searched for eligible manuscripts. Standard mean difference (SMD) of performance scoring scales was used to assess the effect of VBC versus traditional training without VBC (control).ResultsOf 627 studies identified, 24 RCTs were eligible and evaluated. The studies included 778 surgical trainees (n = 386 VBC vs. n = 392 control). 13 performance scoring scales were used to assess technical competence; OSATS-GRS was the most common (n = 15). VBC was provided preoperative (n = 11), intraoperative (n = 1), postoperative (n = 10), and perioperative (n = 2). The majority of studies were unstructured, where identified coaching frameworks were PRACTICE (n = 1), GROW (n = 2) and Wisconsin Coaching Framework (n = 1). There was an effect on performance scoring scales in favor of VBC coaching (SMD 0.87, p < 0.001). In subgroup analyses, the residents had a larger relative effect (SMD 1.13; 0.61–1.65, p < 0.001) of VBC compared to medical students (SMD 0.43, 0.06–0.81, p < 0.001). The greatest source of potential bias was absence of blinding of the participants and personnel (n = 20).ConclusionVideo-based coaching increases technical performance of medical students and surgical residents. There exist significant study and intervention heterogeneity that warrants further exploration, showing the need to structure and standardize video-based coaching tools.

Temporal lobe epilepsy (TLE) is a prevalent neurological disorder resulting in disruptive seizures. In the case of drug resistant epilepsy resective surgery is often considered. This is a procedure hampered by unpredictable success rates, with many patients continuing to have seizures even after surgery. In this study we apply a computational model of epilepsy to patient specific structural connectivity derived from diffusion tensor imaging (DTI) of 22 individuals with left TLE and 39 healthy controls. We validate the model by examining patient-control differences in simulated seizure onset time and network location. We then investigate the potential of the model for surgery prediction by performing in silico surgical resections, removing nodes from patient networks and comparing seizure likelihood post-surgery to pre-surgery simulations. We find that, first, patients tend to transit from non-epileptic to epileptic states more often than controls in the model. Second, regions in the left hemisphere (particularly within temporal and subcortical regions) that are known to be involved in TLE are the most frequent starting points for seizures in patients in the model. In addition, our analysis also implicates regions in the contralateral and frontal locations which may play a role in seizure spreading or surgery resistance. Finally, the model predicts that patient-specific surgery (resection areas chosen on an individual, model-prompted, basis and not following a predefined procedure) may lead to better outcomes than the currently used routine clinical procedure. Taken together this work provides a first step towards patient specific computational modelling of epilepsy surgery in order to inform treatment strategies in individuals.

Resistance artery vasodilation in response to hypoxia is essential for matching tissue oxygen and demand. In hypoxia, erythrocytic hemoglobin tetramers produce nitric oxide through nitrite reduction. We hypothesized that the alpha subunit of hemoglobin expressed in endothelium also facilitates nitrite reduction proximal to smooth muscle. Here, we create two mouse strains to test this: an endothelial-specific alpha globin knockout (EC Hba1Δ/Δ) and another with an alpha globin allele mutated to prevent alpha globin’s inhibitory interaction with endothelial nitric oxide synthase (Hba1WT/Δ36–39). The EC Hba1Δ/Δ mice had significantly decreased exercise capacity and intracellular nitrite consumption in hypoxic conditions, an effect absent in Hba1WT/Δ36–39 mice. Hypoxia-induced vasodilation is significantly decreased in arteries from EC Hba1Δ/Δ, but not Hba1WT/Δ36–39 mice. Hypoxia also does not lower blood pressure in EC Hba1Δ/Δ mice. We conclude the presence of alpha globin in resistance artery endothelium acts as a nitrite reductase providing local nitric oxide in response to hypoxia. In mammals, hypoxia causes dilation of small arteries for increased metabolic demand. Keller et al used novel transgenic mice to show alpha hemoglobin in endothelium, once thought only in red blood cells, can regulate hypoxic-mediated dilation.

BackgroundAmid increasing awareness of early-onset colorectal cancer (CRC), guidelines in the United States (US) recently lowered the recommended routine CRC screening age from 50 to 45 in average-risk individuals. There are little data on the number of patients in this age group diagnosed with CRC prior to these changes. Our objective was to audit the historic CRC case trends and impact of CRC in the 45-to-50-year-old category prior to new screening recommendations.MethodsColorectal adenocarcinoma cases in 45-to-50-year-old patients were queried from the NCDB (2004–2017). Cases were stratified by sex, race, and site. The disability-adjusted lost years (DALY) and lost earnings were estimated. The average annual percentage changes (AAPC) of CRC incidence were estimated using jointpoint analysis. The main outcome measures were DALY and lost earnings. Secondary outcome measures were the 2004–2017 AAPC and the cumulative incidence of potential CRC cases in the 45-to-50 cohort through 2030 without guideline changes.Results67,442 CRC patients in the 45-to-50 demographic were identified. The CRC burden resulted 899,905 DALY and $17 billion in lost earnings. The 2004–2017 AAPC was 1.6%, with an estimated 13-year increase of 25%. There were sex-, race-, and anatomic site-specific discrepancies with estimated 13-year increases of 30% for males, 110% for American Indian/ Alaska Natives/ Asian American/ Pacific Islander races, and 31% for rectal cancer by 2030.ConclusionCRC has been steadily increasing in the 45-to-50 age group, with tremendous disability and cost ensuing. There is great potential benefit from lowering the recommended routine CRC screening age to 45. Targeted intervention could ensure the most vulnerable segments benefit from the new guidelines, in both reducing the incidence and improving survivorship in CRC patients.