Realized impact of COVID-19 related disruptions on the National Bowel Cancer Screening Program.

BACKGROUND: Colorectal cancer is the second most common cause of cancer mortality in Australia (1). The National Bowel Cancer Screening Program (NBCSP) aims to reduce mortality through early detection with a biennial faecal occult blood test for Australians aged 50-74 years (2). Modelling predicted COVID-19 would reduce participation and delay colonoscopies despite the NBCSP continuing during the pandemic (3). This study analyses the realized impact of COVID-19 related disruptions on the NBCSP and the effect on mortality. METHODS: NBCSP participation, time to colonoscopy and annualized mortality were compared before and during COVID-19. The effect on mortality was determined using a validated microsimulation model (4, 5). RESULTS: From 1 January 2018 to 31 December 2019, 2 497 317 people participated in the NBCSP and 168 390 received a colonoscopy, compared to 2 490 265 and 162 573 from 1 January 2020 to 31 December 2021. Relative participation decreased 6 % and the proportion of colonoscopies performed within the recommended 120 days increased 14.5%. A disproportionally greater impact was observed outside major cities and in lower socioeconomic areas. An estimated 98-111 additional colorectal cancer deaths resulted from 3 % fewer colonoscopies performed during the pandemic. CONCLUSION: This study presents the most comprehensive analysis of the realized impact of COVID-19 on the NBCSP. Catch-up screening would be best targeted at Australians from rural and lower socioeconomic areas where participation remains low. Streamlined referral pathways and additional colonoscopy provisioning is required as less than two thirds of screen positive patients receive a colonoscopy within the recommended 120 days.

Combined treatment with naloxone and the alpha2 adrenoceptor antagonist atipamezole reversed brain hypoxia induced by a fentanyl-xylazine mixture in a rat model.

Xylazine, a veterinary tranquillizer known by drug users as "Tranq", is being increasingly detected in people who overdose on opioid drugs, indicating enhanced health risk of fentanyl-xylazine mixtures. We recently found that xylazine potentiates fentanyl- and heroin-induced brain hypoxia and eliminates the rebound-like post-hypoxic oxygen increases. Here, we used oxygen sensors coupled with high-speed amperometry in rats of both sexes to explore the treatment potential of naloxone plus atipamezole, a selective α2-adrenoceptor antagonist, in reversing brain (nucleus accumbens) and periphery (subcutaneous space) hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with naloxone (0.2 mg/kg, IV) fully blocked brain and peripheral hypoxia induced by fentanyl (20 µg/kg, IV), but only partially decreased hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with atipamezole (0.25 mg/kg, IV) fully blocked the hypoxic effects of xylazine (1.0 mg/kg, IV), but not fentanyl. Pretreatment with atipamezole + naloxone was more potent than naloxone alone in blocking the hypoxic effects of the fentanyl-xylazine mixture. Both naloxone and naloxone + atipamezole, delivered at the peak of brain hypoxia (3 min post fentanyl-xylazine exposure), reversed the rapid initial brain hypoxia, but only naloxone + atipamezole decreased the prolonged weaker hypoxia. There were no sex differences in the effects of the different drugs and their combinations on brain and peripheral oxygen responses. Results indicate that combined treatment with naloxone and atipamezole is more effective than naloxone alone in reversing the hypoxic effects of fentanyl-xylazine mixtures. Naloxone + atipamezole treatment should be considered in preventing overdoses induced by fentanyl-xylazine mixtures in humans.

Complete transection of the descending colon following blunt abdominal trauma.

We present the case of a man in his 30s who was crushed between two vehicles sustaining blunt trauma to his lower limbs and torso. The patient was in shock on arrival to the emergency department, and immediate resuscitation was given with massive transfusion protocol activation. Once the patient's haemodynamic status was stabilised, a CT scan revealed a complete colon transection. The patient was taken to the operating theatre where a midline laparotomy was performed, and the transected descending colon was managed with a segmental resection and handsewn anastomosis. The patient followed an unremarkable postoperative course, with bowels opening on day 8 postoperatively. Colon injuries are rare following blunt abdominal trauma, and a delay in diagnosis may lead to increased morbidity and mortality. As such, a low threshold for surgical intervention is recommended.

Xylazine effects on opioid-induced brain hypoxia.

RATIONALE: Xylazine has emerged in recent years as an adulterant in an increasing number of opioid-positive overdose deaths in the United States. Although its exact role in opioid-induced overdose deaths is largely unknown, xylazine is known to depress vital functions and cause hypotension, bradycardia, hypothermia, and respiratory depression. OBJECTIVES: In this study, we examined the brain-specific hypothermic and hypoxic effects of xylazine and its mixtures with fentanyl and heroin in freely moving rats. RESULTS: In the temperature experiment, we found that intravenous xylazine at low, human-relevant doses (0.33, 1.0, 3.0 mg/kg) dose-dependently decreases locomotor activity and induces modest but prolonged brain and body hypothermia. In the electrochemical experiment, we found that xylazine at the same doses dose-dependently decreases nucleus accumbens oxygenation. In contrast to relatively weak and prolonged decreases induced by xylazine, intravenous fentanyl (20 µg/kg) and heroin (600 µg/kg) induce stronger biphasic brain oxygen responses, with the initial rapid and strong decrease, resulting from respiratory depression, followed by a slower, more prolonged increase reflecting a post-hypoxic compensatory phase, with fentanyl acting much quicker than heroin. The xylazine-fentanyl mixture eliminated the hyperoxic phase of oxygen response and prolonged brain hypoxia, suggesting xylazine-induced attenuation of the brain's compensatory mechanisms to counteract brain hypoxia. The xylazine-heroin mixture strongly potentiated the initial oxygen decrease, and the pattern lacked the hyperoxic portion of the biphasic oxygen response, suggesting more robust and prolonged brain hypoxia. CONCLUSIONS: These findings suggest that xylazine exacerbates the life-threatening effects of opioids, proposing worsened brain hypoxia as the mechanism contributing to xylazine-positive opioid-overdose deaths.

The pattern of brain oxygen response induced by intravenous fentanyl limits the time window of therapeutic efficacy of naloxone.

Opioids induce respiratory depression resulting in coma or even death during overdose. Naloxone, an opioid antagonist, is the gold standard reversal agent for opioid intoxication, but this treatment is often less successful for fentanyl. While low dosing is thought to be a factor limiting naloxone's efficacy, the timing between fentanyl exposure and initiation of naloxone treatment may be another important factor. Here, we used oxygen sensors coupled with amperometry to examine the pattern of oxygen responses in the brain and periphery induced by intravenous fentanyl in freely moving rats. At both doses (20 and 60 µg/kg), fentanyl induced a biphasic brain oxygen response-a rapid, strong, and relatively transient decrease (8-12 min) followed by a weaker and prolonged increase. In contrast, fentanyl induced stronger and more prolonged monophasic oxygen decreases in the periphery. When administered before fentanyl, intravenous naloxone (0.2 mg/kg) fully blocked the hypoxic effects of moderate-dose fentanyl in both the brain and periphery. However, when injected 10 min after fentanyl, when most of hypoxia had already ceased, naloxone had minimal effect on central and peripheral oxygen levels, but at a higher dose, it strongly attenuated hypoxic effects in the periphery with only a transient brain oxygen increase associated with behavioral awakening. Therefore, due to the rapid, strong but transient nature of fentanyl-induced brain hypoxia, the time window when naloxone can attenuate this effect is relatively short. This timing limitation is critical, making naloxone most effective when used quickly and less effective when used during the post-hypoxic comatose state after brain hypoxia has already ceased and harm for neural cells already done.

Basic metabolic and vascular effects of ketamine and its interaction with fentanyl.

Ketamine is a short-acting general anesthetic with hallucinogenic, analgesic, and amnestic properties. In addition to its anesthetic use, ketamine is commonly abused in rave settings. While safe when used by medical professionals, uncontrolled recreational use of ketamine is dangerous, especially when mixed with other sedative drugs, including alcohol, benzodiazepines, and opioid drugs. Since synergistic antinociceptive interactions between opioids and ketamine were demonstrated in both preclinical and clinical studies, such an interaction could exist for the hypoxic effects of opioid drugs. Here, we focused on the basic physiological effects of ketamine as a recreational drug and its possible interactions with fentanyl-a highly potent opioid that induces strong respiratory depression and robust brain hypoxia. By using multi-site thermorecording in freely-moving rats, we showed that intravenous ketamine at a range of human relevant doses (3, 9, 27 mg/kg) dose-dependently increases locomotor activity and brain temperature, as assessed in the nucleus accumbens (NAc). By determining temperature differentials between the brain, temporal muscle, and skin, we showed that the brain hyperthermic effect of ketamine results from increased intracerebral heat production, an index of metabolic neural activation, and decreased heat loss due to peripheral vasoconstriction. By using oxygen sensors coupled with high-speed amperometry we showed that ketamine at the same doses increases NAc oxygen levels. Finally, co-administration of ketamine with intravenous fentanyl results in modest enhancement of fentanyl-induced brain hypoxia also enhancing the post-hypoxic oxygen increase. Therefore, in contrast to fentanyl, ketamine increases brain oxygenation but potentiates brain hypoxia induced by fentanyl.

Basic physiological effects of ketamine-xylazine mixture as a general anesthetic preparation for rodent surgeries.

Among the numerous general anesthetics utilized in rodent surgical procedures, the co-administration of ketamine and xylazine is the current standard for induction and maintenance of surgical planes of anesthesia and pain control. In contrast to classical GABAergic anesthetics, which act to inhibit CNS activity, inducing muscle relaxation, sedation, hypothermia, and brain hypoxia, ketamine and xylazine act through different mechanisms to induce similar effects while also providing potent analgesia. By using three-point thermorecording in freely moving rats, we show that the ketamine-xylazine mixture induces modest brain hyperthermia, resulting from increased intra-cerebral heat production due to metabolic brain activation and increased heat loss due to skin vasodilation. The first effect derives from ketamine, which alone increases brain and body temperatures due to brain metabolic activation and skin vasoconstriction. The second effect derives from xylazine, which increases heat loss due to potent skin vasodilation. By using oxygen sensors coupled with amperometry, we show that the ketamine-xylazine mixture modestly decreases brain oxygen levels that results from relatively weak respiratory depression. This tonic pharmacological effect was preceded by a strong but transient oxygen increase that may result from a stressful injection or unknown, possibly peripheral action of this drug combination. This pattern of physiological effects elicited by the ketamine-xylazine mixture differs from the effects of other general anesthetic drugs, particularly barbiturates.

Rapid fluctuations in brain oxygenation during glucose-drinking behavior in trained rats.

Proper inflow of oxygen into brain tissue is essential for maintaining normal neural functions. Although oxygen levels in the brain's extracellular space depend upon a balance between its delivery from arterial blood and its metabolic consumption, the use of high-speed electrochemical detection revealed rapid increases in brain oxygen levels elicited by various salient sensory stimuli. These stimuli also increase intrabrain heat production, an index of metabolic neural activation, but these changes are slower and more prolonged than changes in oxygen levels. Therefore, under physiological conditions, the oxygen inflow into brain tissue exceeds its loss due to consumption, thus preventing any metabolic deficit. Here, we used oxygen sensors coupled with amperometry to examine the pattern of real-time oxygen fluctuations in the nucleus accumbens during glucose-drinking behavior in trained rats. Following the exposure to a glucose-containing cup, oxygen levels rapidly increased, peaked when the rat initiated drinking, and relatively decreased during consumption. Similar oxygen changes but more episodic drinking occurred when Stevia, a calorie-free sweet substance, was substituted for glucose. When water was substituted for glucose, rats tested the water but refused to consume all of it. Although the basic pattern of oxygen changes during this water test was similar to that with glucose drinking, the increases were larger. Finally, oxygen increases were significantly larger when rats were exposed to concealed glucose and made multiple unsuccessful attempts to obtain and consume it. Based on these data, we discuss the mechanisms underlying behavior-related brain oxygen fluctuations and their functional significance.NEW & NOTEWORTHY Oxygen sensors coupled with high-speed amperometry were used to examine brain oxygen fluctuations during glucose-drinking behavior in trained rats. Oxygen levels rapidly increased following presentation of a glucose-contained cup, peaking at the initiation of glucose drinking, and relatively decreasing during drinking. Oxygen increases were larger when rats were exposed to concealed glucose and made multiple attempts to obtain it. We discuss the mechanisms underlying behavior-related brain oxygen fluctuations and their functional significance.

A Novel Virtual Reality Medical Image Display System for Group Discussions of Congenital Heart Disease: Development and Usability Testing.

BACKGROUND: The complex 3-dimensional (3D) nature of anatomical abnormalities in congenital heart disease (CHD) necessitates multidisciplinary group discussions centered around the review of medical images such as magnetic resonance imaging. Currently, group viewings of medical images are constrained to 2-dimensional (2D) cross-sectional displays of 3D scans. However, 2D display methods could introduce additional challenges since they require physicians to accurately reconstruct the images mentally into 3D anatomies for diagnosis, staging, and planning of surgery or other therapies. Virtual reality (VR) software may enhance diagnosis and care of CHD via 3D visualization of medical images. Yet, present-day VR developments for medicine lack the emphasis on multiuser collaborative environments, and the effect of displays and level of immersion for diagnosing CHDs have not been studied. OBJECTIVE: The objective of the study was to evaluate and compare the diagnostic accuracies and preferences of various display systems, including the conventional 2D display and a novel group VR software, in group discussions of CHD. METHODS: A total of 22 medical trainees consisting of 1 first-year, 10 second-year, 4 third-year, and 1 fourth-year residents and 6 medical students, who volunteered for the study, were formed into groups of 4 to 5 participants. Each group discussed three diagnostic cases of CHD with varying structural complexity using conventional 2D display and group VR software. A group VR software, Cardiac Review 3D, was developed by our team using the Unity engine. By using different display hardware, VR was classified into nonimmersive and full-immersive settings. The discussion time, diagnostic accuracy score, and peer assessment were collected to capture the group and individual diagnostic performances. The diagnostic accuracies for each participant were scored by two experienced cardiologists following a predetermined answer rubric. At the end of the study, all participants were provided a survey to rank their preferences of the display systems for performing group medical discussions. RESULTS: Diagnostic accuracies were highest when groups used the full-immersive VR compared with the conventional and nonimmersive VR (χ22=9.0, P=.01) displays. Differences between the display systems were more prominent with increasing case complexity (χ22=14.1, P<.001) where full-immersive VR had accuracy scores that were 54.49% and 146.82% higher than conventional and nonimmersive VR, respectively. The diagnostic accuracies provided by the two cardiologists for each participant did not statistically differ from each other (t=-1.01, P=.31). The full-immersive VR was ranked as the most preferred display for performing group CHD discussions by 68% of the participants. CONCLUSIONS: The most preferred display system among medical trainees for visualizing medical images during group diagnostic discussions is full-immersive VR, with a trend toward improved diagnostic accuracy in complex anatomical abnormalities. Immersion is a crucial feature of displays of medical images for diagnostic accuracy in collaborative discussions.

Novel, 3D Display of Heart Models in the Postoperative Care Setting Improves CICU Caregiver Confidence.

BACKGROUND: Postoperative care delivered in the pediatric cardiac intensive care unit (CICU) relies on providers' understanding of patients' congenital heart defects (CHDs) and procedure performed. Novel, bedside use of virtual, three-dimensional (3D) heart models creates access to patients' CHD to improve understanding. This study evaluates the impact of patient-specific virtual 3D heart models on CICU provider attitudes and care delivery. METHODS: Virtual 3D heart models were created from standard preoperative cardiac imaging of ten patients with CHD undergoing repair and displayed on a bedside tablet in the CICU. Providers completed a Likert questionnaire evaluating the models' value in understanding anatomy and improving care delivery. Responses were compared using two-tailed t test and Mann-Whitney U test and were also compared to previously collected CICU provider responses regarding use of printed 3D heart models. RESULTS: Fifty-three clinicians (19 physicians, 34 nurses/trainees) participated; 49 (92%) of 53 and 44 (83%) of 53 reported at least moderate to high satisfaction with the virtual 3D heart's ability to enhance understanding of anatomy and surgical repair, respectively. Seventy-one percent of participants felt strongly that virtual 3D models improved their ability to manage postoperative problems. The majority of both groups (63% physicians, 53% nurses) felt that virtual 3D heart models improved CICU handoffs. Virtual 3D heart models were as effective as printed models in improving understanding and care delivery, with a noted provider preference for printed 3D heart models. CONCLUSIONS: Virtual 3D heart models depicting patient-specific CHDs are perceived to improve understanding and postoperative care delivery in the CICU.

Impact of poloxamer 188 (Pluronic F-68) additive on cell mechanical properties, quantification by real-time deformability cytometry.

Advances in cellular therapies have led to the development of new approaches for cell product purification and formulation, e.g., utilizing cell endogenous properties such as size and deformability as a basis for separation from potentially harmful undesirable by-products. However, commonly used additives such as Pluronic F-68 and other poloxamer macromolecules can change the mechanical properties of cells and consequently alter their processing. In this paper, we quantified the short-term effect of Pluronic F-68 on the mechanotype of three different cell types (Jurkat cells, red blood cells, and human embryonic kidney cells) using real-time deformability cytometry. The impact of the additive concentration was assessed in terms of cell size and deformability. We observed that cells respond progressively to the presence of Pluronic F-68 within first 3 h of incubation and become significantly stiffer (p-value < 0.001) in comparison to a serum-free control and a control containing serum. We also observed that the short-term response manifested as cell stiffening is true (p-value < 0.001) for the concentration reaching 1% (w/v) of the poloxamer additive in tested buffers. Additionally, using flow cytometry, we assessed that changes in cell deformability triggered by addition of Pluronic F-68 are not accompanied by size or viability alterations.

Structure, viscoelasticity, and interfacial dynamics of a model polymeric bicontinuous microemulsion.

We have systematically studied the equilibrium structure and dynamics of a polymeric bicontinuous microemulsion (BµE) composed of poly(cyclohexylethylene) (PCHE), poly(ethylene) (PE), and a volumetrically symmetric PCHE-PE diblock copolymer, using dynamic mechanical spectroscopy, small angle X-ray and neutron scattering, and transmission electron microscopy. The BµE was investigated over an 80 °C temperature range, revealing a structural evolution and a rheological response not previously recognized in such systems. As the temperature is reduced below the point associated with the lamellar-disorder transition at compositions adjacent to the microemulsion channel, the interfacial area per chain of the BµE approaches that of the neat (undiluted) lamellar diblock copolymer. With increasing temperature, the diblock-rich interface swells through homopolymer infiltration. Time-temperature-superposed linear dynamic data obtained as a function of frequency show that the viscoelastic response of the BµE is strikingly similar to that of the fluctuating pure diblock copolymer in the disordered state, which we associate with membrane undulations and the breaking and reforming of interfaces. This work provides new insights into the structure and dynamics that characterize thermodynamically stable BµEs in the limits of relatively weak and strong segregation.

Risk awareness on uterine cancer among Australian women.

Uterine cancer is the most common invasive gynaecological cancer in Australia. Early detection is a key predictive factor achieved by increasing public awareness and participation in screening. This observational study measures awareness of gynaecological malignancies, particularly uterine, among women in two rural areas of New South Wales, Australia. Patients presenting to gynaecology clinics in January to March 2014 were invited to complete a structured questionnaire. Women with a history of cancer and incomplete questionnaires were excluded. Of the 382 patients invited to participate, 329 (86%) responded with complete feedback. Most respondents were younger than than 50 years (66%) and married with at least 2 children (74%). The majority (94%) of participants had no awareness of uterine cancer and many (46%) were unable to identify common risk factors including obesity, diabetes and hypertension. The ability to identify risk factors was correlated to age, marital status and obesity. The study identifies poor awareness on uterine malignancies in two typical areas of rural Australia. Although external validity is limited by sociological factors, poor awareness of uterine cancer among rural patients in this study represents a valid public health concern. It is imperative to improve awareness of uterine cancer and available screening programs to facilitate early detection and cure.

Recurrent idiopathic painless shoulder weakness in a Navy F/A-18 aviator.

Brachial plexopathies of various etiologies are commonly discussed in the literature; however, recurrent painless shoulder weakness is an uncommon event, especially in an otherwise healthy adult man. A designated Naval F/A-18 E/F aviator presented with acute right-sided, painless shoulder girdle weakness that initially presented 2 yr earlier in a similar fashion. Extensive medical workups during both episodes did not reveal any identifiable cause. This case report discusses the most common etiologies of shoulder weakness. Additionally, we discuss the aviator's most recent presentation and evaluation for acute shoulder weakness. Lastly, we propose a hypothesis as to the cause of the patient's symptoms based on a review of the literature.

Registered 3-D ultrasound and digital stereotactic mammography for breast biopsy guidance.

Large core needle biopsy is a common procedure used to obtain histological samples when cancer is suspected in diagnostic breast images. The procedure is typically performed under image guidance, with freehand ultrasound and stereotactic mammography (SM) being the most common modalities used. To utilize the advantages of both modalities, a biopsy device combining three-dimensional ultrasound (3DUS) and digital SM imaging with computer-aided needle guidance was developed. An implementation of a stereo camera method was applied to SM calibration, providing a target localization error of 0.35 mm. The 3-D transformation between the two imaging modalities was then derived, with a target registration error of 0.52 mm. Finally, the needle guidance error of the device was evaluated using tissue-mimicking phantoms, showing a sample mean and standard deviation of 0.44 +/- 0.22 and 0.49 +/- 0.27 mm for targets planned from 3DUS and SM images, respectively. These results suggest that a biopsy procedure guided using this device would successfully sample breast lesions at a size greater than or equal to the smallest typically detected in mammographic screening (approximately 2 mm).