Liver transplantation as an alternative for the treatment of non-resectable liver colorectal cancer: Advancing the therapeutic algorithm.

Colorectal cancer is a leading cause of cancer-related mortality, with nearly half of the affected patients developing liver metastases. For three decades, liver resection (LR) has been the primary curative strategy, yet its applicability is limited to about 20% of cases. Liver transplantation (LT) for unresectable metastases was attempted unsuccessfully in the 1990s, with high rates of perioperative death and recurrence. There is now more interest in this strategy due to improvements in systemic therapies and surgical techniques. A significant study conducted by the Oslo group showed that patients receiving liver transplants had a 60% chance of survival after five years. Significantly better results have been achieved by using advanced imaging for risk stratification and further refining selection criteria, especially in the Norvegian SECA trials. This review carefully charts the development and history of LT as a treatment option for colorectal cancer liver metastases. The revolutionary path from the early days of exploratory surgery to the current situation of cautious optimism is traced, highlighting the critical clinical developments and improved patient selection standards that have made LT a potentially curative treatment for such challenging very well selected cases.

Selected adjuvants increase the efficacy of foliar biofortification of iodine in bread wheat (Triticum aestivum L.) grain.

Agronomic biofortification of crops is a promising approach that can improve the nutritional value of staple foods by alleviating dietary micronutrient deficiencies. Iodine deficiency is prevalent in many countries, including Australia, but it is not clear what foliar application strategies will be effective for iodine fortification of grain. This study hypothesised that combining adjuvants with iodine in foliar sprays would improve iodine penetration in wheat, leading to more efficient biofortification of grains. The glasshouse experiment included a total of nine treatments, including three reference controls: 1) Water; 2) potassium iodate (KIO3) and 3) potassium chloride (KCl); and a series of six different non-ionic surfactant or oil-based adjuvants: 4) KIO3 + BS1000; 5) KIO3 + Pulse® Penetrant; 6) KIO3 + Uptake®; 7) KIO3 + Hot-Up®; 8) KIO3 + Hasten® and 9) KIO3 + Synerterol® Horti Oil. Wheat was treated at heading, and again during the early milk growth stage. Adding the organosilicon-based adjuvant (Pulse®) to the spray formulation resulted in a significant increase in grain loading of iodine to 1269 µg/kg compared to the non-adjuvant KIO3 control at 231µg/kg, and the water and KCl controls (both 51µg/kg). The second most effective adjuvant was Synerterol® Horti Oil, which increased grain iodine significantly to 450µg/kg. The Uptake®, BS1000, Hasten®, and Hot-Up® adjuvants did not affect grain iodine concentrations relative to the KIO3 control. Importantly, iodine application and the subsequent increase in grain iodine had no significant effects on biomass production and grain yield relative to the controls. These results indicate that adjuvants can play an important role in agronomic biofortification practices, and organosilicon-based products have a great potential to enhance foliar penetration resulting in a higher translocation rate of foliar-applied iodine to grains, which is required to increase the iodine density of staple grains effectively.

The role of multidisciplinary team and stepwise pelvic devascularization to minimize blood loss during total pelvic exenteration for patients refusing blood transfusion.

Key Clinical Message: Radical gynecology oncology surgeries are feasible in patients refusing blood transfusion, when performed with careful preoperative (with hemoglobin optimization and patients' counseling), intraoperative (with hemostasis and stepwise devascularization, hemodilution, and autologous cell salvage) and postoperative (considering iron infusion or erythropoietin) planning with a multidisciplinary team involvement. Abstract: We describe the case of a female Jehovah's Witness patient in her 60s undergoing pelvic exenteration, focusing on the preoperative, intraoperative, and postoperative measures that allowed an uncomplicated surgery without blood transfusion. Blood transfusions are common in the surgical management of gynecology oncology patients, up to 93% of patients undergoing pelvic exenteration may require blood products. However, increasingly more patients are cautious in receiving blood products, either for fear of potential risks or for religious believes. It is therefore vital to optimize the management of these patients in order to avoid blood transfusions. In this case, we summarize the management of a lady in her 60s who underwent laparotomy, pelvic exenteration, Bricker colicureterostomy, and end colostomy formation for recurrent endometrial carcinoma, despite previous total abdominal hysterectomy and bilateral salpingo-oophorectomy followed by brachytherapy, chemotherapy, and external beam radiotherapy for high-grade serous carcinoma. Preoperatively, an advance decision to refuse blood products was discussed to ascertain all the options that were suitable. As her preoperative hemoglobin was acceptable (127 g/L), no further intervention was required. Intraoperatively, blood loss was effectively minimized with meticulous hemostasis, stepwise pelvic devascularization, intraoperative hemodilution, and cell salvage. Despite these interventions, total blood loss was 1030 mL and postoperative hemoglobin was 113 g/L. Postoperative measures therefore included intravenous iron infusion, minimization of phlebotomy, and optimization of cardiopulmonary status. Erythropoietin was also considered, but was not necessary as patient responded to the previous measures well and was successfully discharged after an uncomplicated recovery. Only few cases of total pelvic exenteration have been described in the literature for Jehovah's Witness patients. However, our case shows that laparotomy and pelvic exenteration is feasible in patients refusing blood products, if performed under a multidisciplinary team and with careful preoperative, intraoperative, and postoperative planning, also in the setting of previous radical hysterectomy and co-adjuvant therapy.

Targeting Synovial Lymphatic Function as a Novel Therapeutic Intervention for Age-Related Osteoarthritis in Mice.

OBJECTIVE: The synovial lymphatic system (SLS) removes catabolic factors from the joint. Vascular endothelial growth factor C (VEGF-C) and its receptor, VEGFR-3, are crucial for lymphangiogenesis. However, their involvement in age-related osteoarthritis (OA) is unknown. This study was undertaken to determine whether the SLS and the VEGF-C/VEGFR-3 pathway contribute to the development and progression of age-related OA, using a murine model of naturally occurring joint disease. METHODS: SLS function was assessed in the knees of young (3-month-old) and aged (19-24-month-old) male and female C57BL/6J mice via a newly established in vivo IVIS-dextran imaging approach, which, in addition to histology, was used to assess the effects of VEGF-C treatment on SLS function and OA pathology in aged mice. RNA-sequencing of synovial tissue was performed to explore molecular mechanisms of the disease in the mouse knee joints. RESULTS: Results showed that aged mice had impaired SLS function, including decreases in joint clearance (mean T1/2 of signal intensity clearance, 2.8 hours in aged mice versus 0.5 hours in young mice; P < 0.0001), synovial influx (mean ± SD 1.7 ± 0.8% in aged mice versus 4.1 ± 1.9% in young mice; P = 0.0004), and lymph node draining capacity (mean ± SD epifluorescence total radiant intensity ([photons/second]/[µW/cm2 ]) 1.4 ± 0.8 in aged mice versus 3.7 ± 1.2 in young mice; P < 0.0001). RNA-sequencing of the synovial tissue showed that Vegf-c and Vegfr3 signaling genes were decreased in the synovium of aged mice. VEGF-C treatment resulted in improvements in SLS function in aged mice, including increased percentage of signal intensity joint clearance (mean ± SD 63 ± 9% in VEGF-C-treated aged mice versus 52 ± 15% in vehicle-treated aged mice; P = 0.012), increased total articular cartilage cross-sectional area (mean ± SD 0.38 ± 0.07 mm2 in VEGF-C-treated aged mice versus 0.26 ± 0.07 mm2 in vehicle-treated aged mice; P < 0.0001), and decreased percentage of matrix metallopeptidase 13-positive staining area within total synovial area in 22-month-old VEGF-C-treated mice versus 22-month-old vehicle-treated mice (mean ± SD decrease 7 ± 2% versus 4 ± 1%; P = 0.0004). CONCLUSION: SLS function is reduced in the knee joints of aged mice due to decreased VEGF-C/VEGFR-3 signaling. VEGF-C treatment attenuates OA joint damage and improves synovial lymphatic drainage in aged mice. The SLS and VEGF-C/VEGFR-3 signaling represent novel physiopathologic mechanisms that could potentially be used as therapeutic targets for age-related OA.

Persistent popliteal lymphatic muscle cell coverage defects despite amelioration of arthritis and recovery of popliteal lymphatic vessel function in TNF-Tg mice following anti-TNF therapy.

While rheumatoid arthritis patients and tumor necrosis factor transgenic (TNF-Tg) mice with inflammatory-erosive arthritis display lymphatic drainage deficits, the mechanisms responsible remain unknown. As ultrastructural studies of joint-draining popliteal lymphatic vessels (PLVs) in TNF-Tg mice revealed evidence of lymphatic muscle cell (LMC) damage, we aimed to evaluate PLV-LMC coverage in TNF-Tg mice. We tested the hypothesis that alpha smooth muscle actin (αSMA)+ PLV-LMC coverage decreases with severe inflammatory-erosive arthritis, and is recovered by anti-TNF therapy facilitated by increased PLV-LMC turnover during amelioration of joint disease. TNF-Tg mice with established disease received anti-TNF monoclonal antibody (mAb) or placebo IgG isotype control mAb therapy (n = 5) for 6-weeks, while wild-type (WT) littermates (n = 8) received vehicle (PBS). Bromodeoxyuridine (BrdU) was also administered daily during the treatment period to monitor PLV-LMC turnover. Effective anti-TNF therapy was confirmed by longitudinal assessment of popliteal lymph node (PLN) volume via ultrasound, PLV contraction frequency via near-infrared imaging of indocyanine green, and ankle bone volumes via micro-computed tomography (micro-CT). Terminal knee micro-CT, and ankle and knee histology were also performed. PLVs were immunostained for αSMA and BrdU to evaluate PLV-LMC coverage and turnover, respectively, via whole-mount fluorescent microscopy. Anti-TNF therapy reduced PLN volume, increased talus and patella bone volumes, and reduced tarsal and knee synovial areas compared to placebo treated TNF-Tg mice (p < 0.05), as expected. Anti-TNF therapy also increased PLV contraction frequency at 3-weeks (from 0.81 ± 1.0 to 3.2 ± 2.0 contractions per minute, p < 0.05). However, both anti-TNF and placebo treated TNF-Tg mice exhibited significantly reduced αSMA+ PLV-LMC coverage compared to WT (p < 0.05). There was no correlation of αSMA+ PLV-LMC coverage restoration with amelioration of inflammatory-erosive arthritis. Similarly, there was no difference in PLV-LMC turnover measured by BrdU labeling between WT, TNF-Tg placebo, and TNF-Tg anti-TNF groups with an average of < 1% BrdU+ PLV-LMCs incorporated per week. Taken together these results demonstrate that PLV-LMC turnover in adult mice is limited, and that recovery of PLV function during amelioration of inflammatory-erosive arthritis occurs without restoration of αSMA+ LMC coverage. Future studies are warranted to investigate the direct and indirect effects of chronic TNF exposure, and the role of proximal inflammatory cells on PLV contractility.

Farmers' fertilizer use gaps relative to government recommendations in the saline coastal zone of the Ganges Delta.

Overuse or underuse of nutrients relative to recommendations is a likely cause of crop yield gaps and an impediment to the achievement of food security. Government-endorsed recommendations are developed to deliver the best evidence-based advice on balanced fertilizer; however, deviations of farmers' nutrient use from the recommendations are rarely examined. This study chose the salt-affected coastal zone of the Ganges Delta, where low crop productivity and cropping intensity by smallholders limit their income, to determine current nutrient use gaps for the first time of three cropping patterns in two representative districts of Bangladesh. A total of 246 farms were surveyed from three farm sizes. Farmers' nutrient use gaps were compared with Fertilizer Recommendation Guides published in 2012 (FRG-2012) and 2018 (FRG-2018). Relative to FRG-2012 recommendations, farmers used 12%, 70%, and 11% overdoses of N, P, and K, respectively, under two fully rice-based cropping patterns, but the level of overdoses increased with farm size. Rates of K (14%), S (28%), and Zn use were below the FRG-2012 recommendations, especially for the smallest category of farms. However, the FRG-2018, increased recommended N (5%), K (62%), S (12%), and Zn rates but reduced P (25%) rates for fully rice-based cropping patterns. In contrast with rice, regardless of farm size, farmers applied overdose nutrients to watermelon but compensated with underdoses in the subsequent monsoon rice implying that farmers prioritized fertilizer expenditure on the most profitable crop. For the cropping pattern with watermelon, farmers could reduce the use of N (69%) and P (46%) and increase the use of K (48%), S (5%), and B. Reducing NPK use gaps can save treasury for both the farmers and the governments by 39.1 and 73.8 USD ha-1, respectively, under fully rice-based cropping patterns. Finally, our findings suggest there is scope to promote crop yields and sustainable intensification through balanced fertilizer use in a vulnerable saline region. Supplementary Information: The online version contains supplementary material available at 10.1007/s13593-022-00797-1.

A Randomized Controlled Trial Comparing Epidural Analgesia Versus Continuous Local Anesthetic Infiltration Via Abdominal Wound Catheter in Open Liver Resection.

AIM: To compare outcomes following open liver resection (OLR) between patients receiving thoracic epidural (EP) versus abdominal wound catheters plus patient-controlled analgesia (AWC-PCA). METHOD: Patients were randomized 1:1 to either EP or AWC-PCA within an enhanced recovery protocol. Primary outcome was length of stay (LOS), other variables included functional recovery, pain scores, peak flow, vasopressor and fluid requirements, and postoperative complications. RESULTS: Between April 2015 and November 2017, 83 patients were randomized to EP (n = 41) or AWC-PCA (n = 42). Baseline demographics were comparable. No difference was noted in LOS (EP 6 d (3-27) vs AWC-PCA 6 d (3-66), P = 0.886). Treatment failure was 20% in the EP group versus 7% in the AWC-PCA (P = 0.09). Preoperative anesthetic time was shorter in the AWC-PCA group, 49 minutes versus 62 minutes (P = 0.003). EP patients required more vasopressor support immediately postoperatively on day 0 (14% vs 54%, P = <0.001) and day 1 (5% vs 23%, P = 0.021). Pain scores were greater on day 0, afternoon of day 1 and morning of day 2 in the AWC-PCA group however were regarded as low at all time points. No other significant differences were noted in IV fluid requirements, nausea/sedation scores, days to open bowels, length of HDU, and postoperative complications. CONCLUSION: AWC-PCA was associated with reduced treatment failure and a reduced vasopressor requirement than EP up to 2 days postoperatively. While the use of AWC-PCA did not translate into a shorter LOS in this study, it simplified patient management after OLR. EP cannot be routinely recommended following open liver resections.

Targeting lymphatic function as a novel therapeutic intervention for rheumatoid arthritis.

Although clinical outcomes for patients with rheumatoid arthritis (RA) have greatly improved with the use of biologic and conventional DMARDs, approximately 40% of patients do not achieve primary clinical outcomes in randomized trials, and only a small proportion achieve lasting remission. Over the past decade, studies in murine models point to the critical role of the lymphatic system in the pathogenesis and therapy of inflammatory-erosive arthritis, presumably by the removal of catabolic factors, cytokines and inflammatory cells from the inflamed synovium. Murine studies demonstrate that lymphatic drainage increases at the onset of inflammatory-erosive arthritis but, as inflammation progresses to a more chronic phase, lymphatic clearance declines and both structural and cellular changes are observed in the draining lymph node. Specifically, chronic damage to the lymphatic vessel from persistent inflammation results in loss of lymphatic vessel contraction followed by lymph node collapse, reduced lymphatic drainage, and ultimately severe synovitis and joint erosion. Notably, clinical pilot studies in patients with RA report lymph node changes following treatment, and thus draining lymphatic vessels and nodes could represent a potential biomarker of arthritis activity and response to therapy. Most importantly, targeting lymphatics represents an innovative strategy for therapeutic intervention for RA.

Rat animal models for screening medications to treat alcohol use disorders.

The purpose of this review is to present animal research models that can be used to screen and/or repurpose medications for the treatment of alcohol abuse and dependence. The focus will be on rats and in particular selectively bred rats. Brief introductions discuss various aspects of the clinical picture, which provide characteristics of individuals with alcohol use disorders (AUDs) to model in animals. Following this, multiple selectively bred rat lines will be described and evaluated in the context of animal models used to screen medications to treat AUDs. Next, common behavioral tests for drug efficacy will be discussed particularly as they relate to stages in the addiction cycle. Tables highlighting studies that have tested the effects of compounds using the respective techniques are included. Wherever possible the Tables are organized chronologically in ascending order to describe changes in the focus of research on AUDs over time. In general, high ethanol-consuming selectively bred rats have been used to test a wide range of compounds. Older studies usually followed neurobiological findings in the selected lines that supported an association with a propensity for high ethanol intake. Most of these tests evaluated the compound's effects on the maintenance of ethanol drinking. Very few compounds have been tested during ethanol-seeking and/or relapse and fewer still have assessed their effects during the acquisition of AUDs. Overall, while a substantial number of neurotransmitter and neuromodulatory system targets have been assessed; the roles of sex- and age-of-animal, as well as the acquisition of AUDs, ethanol-seeking and relapse continue to be factors and behaviors needing further study. This article is part of the Special Issue entitled "Alcoholism".

Epidural versus local anaesthetic infiltration via wound catheters in open liver resection: a meta-analysis.

BACKGROUND: This meta-analysis was designed to systematically analyse all published studies comparing local anaesthetic infiltration with wound catheters and epidural catheters in open liver resection. METHODS: A literature search was performed using the Cochrane Colorectal Cancer Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in the Cochrane Library, MEDLINE, Embase and Science Citation Index Expanded. Randomized trials, and prospective and retrospective studies comparing wound catheters with epidural catheters were included. Statistical analysis was performed using Review Manager Version 5.2 software. The primary outcome measures were pain scores in the post-operative period operation. Secondary outcome measures were hospital stay, time to opening bowels, overall complications and analgesia-specific complications. RESULTS: Four studies including 705 patients were included in the analysis. The pain scores were significantly lower in those patients with epidural on the first post-operative day (POD) (mean difference of -0.90 [-1.29, -0.52], Z = 4.61) (P < 0.00001) with comparable pain scores on PODs 2 and 3. There was no significant difference in the time to opening bowels, opioid use and hospital stay between the techniques. The post-operative complication rate was higher in the epidural group (risk ratio 1.40 [1.07, 1.83]; χ(2) = 0.60, df = 1) (P = 0.44); I(2) = 0%; Z = 2.42 (P = 0.02). CONCLUSION: Local anaesthetic infiltration via wound catheters combined with patient-controlled opiate analgesia provides comparable pain relief to epidural catheters except for the first POD. Both techniques are associated with similar hospital stay and opioid use with wound catheters associated with lower complication rate.

Applicability of passive compost bioreactors for treatment of extremely acidic and saline waters in semi-arid climates.

Extremely acidic and saline groundwater occurs naturally in south-western Australia. Discharge of this water to surface waters has increased following extensive clearing of native vegetation for agriculture and is likely to have negative environmental impacts. The use of passive treatment systems to manage the acidic discharge and its impacts is complicated by the region's semi-arid climate with hot dry summers and resulting periods of no flow. This study evaluates the performance of a pilot-scale compost bioreactor treating extremely acidic and saline drainage under semi-arid climatic conditions over a period of 2.5 years. The bioreactor's substrate consisted of municipal waste organics (MWO) mixed with 10 wt% recycled limestone. After the start-up phase the compost bioreactor raised the pH from ≤3.7 to ≥7 and produced net alkaline outflow for 126 days. The bioreactor removed up to 28 g/m(2)/d CaCO3 equivalent of acidity and acidity removal was found to be load dependent during the first and third year. Extended drying over summer combined with high salinity caused the formation of a salt-clay surface layer on top of the substrate, which was both beneficial and detrimental for bioreactor performance. The surface layer prevented the dehydration of the substrate and ensured it remained waterlogged when the water level in the bioreactor fell below the substrate surface in summer. However, when flow resumed the salt-clay layer acted as a barrier between the water and substrate decreasing performance efficiency. Performance increased again when the surface layer was broken up indicating that the negative climatic impacts can be managed. Based on substrate analysis after 1.5 years of operation, limestone dissolution was found to be the dominant acidity removal process contributing up to 78-91% of alkalinity generation, while bacterial sulfate reduction produced at least 9-22% of the total alkalinity. The substrate might last up to five years before the limestone is exhausted and would need to be replenished. The MWO substrate was found to release metals (Zn, Cu, Pb, Ni and Cr) and cannot be recommended for use in passive treatment systems unless the risk of metal release is addressed.

Molecular targets of alcohol action: Translational research for pharmacotherapy development and screening.

Alcohol abuse and dependence are multifaceted disorders with neurobiological, psychological, and environmental components. Research on other complex neuropsychiatric diseases suggests that genetically influenced intermediate characteristics affect the risk for heavy alcohol consumption and its consequences. Diverse therapeutic interventions can be developed through identification of reliable biomarkers for this disorder and new pharmacological targets for its treatment. Advances in the fields of genomics and proteomics offer a number of possible targets for the development of new therapeutic approaches. This brain-focused review highlights studies identifying neurobiological systems associated with these targets and possible pharmacotherapies, summarizing evidence from clinically relevant animal and human studies, as well as sketching improvements and challenges facing the fields of proteomics and genomics. Concluding thoughts on using results from these profiling technologies for medication development are also presented.

Development and resolution of brain lesions caused by pyrithiamine- and dietary-induced thiamine deficiency and alcohol exposure in the alcohol-preferring rat: a longitudinal magnetic resonance imaging and spectroscopy study.

Wernicke's encephalopathy (WE) is characterized by lesions in thalamus, hypothalamus (including mammillary nuclei), and inferior colliculi, results in serious disabilities, has an etiology of thiamine deficiency, is treatable with thiamine, and occurs most commonly with alcoholism. Despite decades of study, whether alcohol exposure exacerbates the neuropathology or retards its resolution remains controversial. To examine patterns of brain damage and recovery resulting from thiamine deprivation with and without alcohol exposure, we conducted in vivo magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) at 3 T in alcohol-preferring (P) rats, which had voluntarily consumed large amounts of alcohol before thiamine manipulation. A total of 18 adult male P rats (nine alcohol-exposed) received a thiamine-deficient diet for 2 weeks: 10 (five alcohol-exposed) received intraperitoneal (i.p.) pyrithiamine (PT) and eight (four alcohol-exposed) received i.p. thiamine supplementation. Neurological signs developed by day 14. Rats were scanned before thiamine depletion and 18 and 35 days after thiamine repletion. Two-dimensional J-resolved MRS single-voxel spectra with water reference were collected in a voxel subtending the thalamus; metabolite quantification was corrected for voxel tissue content. MRI identified significant enlargement of dorsal ventricles and increase in signal intensities in thalamus, inferior colliculi, and mammillary nuclei of PT compared with thiamine-treated (TT) groups from MRI 1-2, followed by significant normalization from MRI 2-3 in thalamus and colliculi, but not mammillary nuclei and lateral ventricles. Voxel-by-voxel analysis revealed additional hyperintense signal clusters in the dorsal and ventral hippocampus and enlargement of the fourth ventricle. MRS showed a significant decline and then partial recovery in thalamic N-acetylaspartate, a marker of neuronal integrity, in PT compared with TT rats, with no change detected in creatine, choline, or glutamate. PT rats with prior alcohol exposure exhibited attenuated recovery in the thalamus and arrested growth of the corpus callosum; further, two of the five alcohol-exposed PT rats died prematurely. Parenchymal and ventricular changes with thiamine manipulation concur with human radiological signs of WE. The enduring macrostructural and neurochemical abnormalities involving critical nodes of Papez circuit carry liabilities for development of amnesia and incomplete recovery from other cognitive and motor functions subserved by the affected neural systems.

Adjuvant hyperbaric oxygen therapy in the management of crush injury and traumatic ischemia: an evidence-based approach.

Hyperbaric oxygen therapy (HBO) has been recommended as an adjunct treatment in acute traumatic ischemia and crush injury. Several animal models have shown better outcomes when HBO is used in crush injury and compartment syndrome. Animal and in vitro models have suggested that these beneficial effects may be mediated by attenuation of ischemia-reperfusion injury. We did a systematic review of the literature using the Eastern Association for the Surgery of Trauma (EAST) recommendations for evidence-based reviews. An electronic search using Medline, OVID technologies, and the Cochrane database was performed. Only clinical papers published between 1966 and December 2003 with at least five patients that included enough information to evaluate were selected. A group of trauma experts reviewed the selected articles and scored them applying the instrument developed by the EAST practice management guidelines committee. Nine documents fulfilled the inclusion criteria for a total of approximately 150 patients. Most documents were retrospective, uncontrolled, and case series lacking a standardized methodology (class III). There was one prospective controlled randomized trial with some limitations on its design. We determined that eight of nine studies showed a beneficial effect from HBO with only one major complication. We concluded that adjunctive HBO is not likely to be harmful and could be beneficial if administered early. Well designed clinical studies are warranted.