Microbial composition, rumen fermentation parameters, enteric methane emissions, and lactational performance of phenotypically high and low methane-emitting dairy cows.

This experiment was designed to investigate the relation of high and low methane-yield phenotypes with body weight (BW), dry matter intake (DMI), lactation performance, enteric CH4 emissions, and rumen fermentation parameters in lactating dairy cows. A total of 130 multi- and primiparous Holstein cows were screened for enteric CH4 emissions using the GreenFeed system (C-Lock Inc.). Out of these 130 cows, 5 were identified as phenotypically high (HM) and 5 as phenotypically low (LM) CH4 emitters. Cows in the LM group had lower daily enteric CH4 emissions than cows in the HM group (on average 346 vs. 439 g/d, respectively), lower CH4 yield (15.5 vs. 20.4 g of CH4/kg of DMI), and CH4 intensity (13.2 vs. 17.0 g of CH4/ kg of energy-corrected milk yield). Enteric emissions of CO2 and H2 did not differ between HM and LM cows. These 10 cows were blocked by parity, days in milk, and milk production, and were used in a 5-wk randomized complete block design experiment. Milk composition, production, and BW were also not different between LM and HM cows. The concentration of total volatile fatty acids in ruminal contents did not differ between CH4 phenotypes, but LM cows had a lower molar proportion of acetate (57 vs. 62.1%), a higher proportion of propionate (27.5 vs. 21.6%, respectively), and therefore a lower acetate-to-propionate ratio than HM cows. Consistently, the 16S cDNA analysis revealed the abundance of Succinivibrionaceae and unclassified Veillonellaceae to be higher in LM cows compared with HM cows, bacteria that were positively correlated with ruminal propionate concentration. Notably, Succinivibrionaceae trigger the formation of propionate via oxaloacetate pathway from phosphoenolpyruvate via Enzyme Commission: 4.1.1.49, which showed a trend to be higher in LM cows compared with HM cows. Additionally, LM cows possessed fewer transcripts of a gene encoding for methyl-CoM reductase enzyme compared with HM. In this study, low and high CH4-yield cows have similar production performance and milk composition, but total-tract apparent digestibility of organic matter and fiber fractions was lower in the former group of animals.

Reproductive outcomes following recurrent first-trimester miscarriage: a retrospective cohort study.

STUDY QUESTION: What are the subsequent reproductive outcomes (livebirths, miscarriages or other adverse pregnancy outcomes or no further pregnancy) of women with recurrent miscarriage (RM) attending a dedicated clinic? SUMMARY ANSWER: Of women with RM, 77% had a subsequent pregnancy, and among these pregnancies, the livebirth rate was 63%. WHAT IS KNOWN ALREADY: RM affects ∼1-3% of women of reproductive age. RM has known associations with advanced maternal age, obesity, diabetes, inherited thrombophilias, thyroid dysfunction, endometriosis and parental balanced translocations. However, ∼ 50% of women or couples will be left without an explanation for their pregnancy loss, even after completing investigations. RM is also associated with secondary infertility and adverse pregnancy outcomes including preterm birth and perinatal death. STUDY DESIGN SIZE DURATION: We undertook a retrospective cohort study to identify subsequent pregnancy outcomes in women with RM, defined as three consecutive first-trimester miscarriages. Women attending the RM clinic at a tertiary university hospital in the Republic of Ireland over 12 years (2008-2020) with a confirmed diagnosis of primary or secondary first-trimester RM were eligible for inclusion. In total, 923 charts were identified for review against the eligibility criteria. PARTICIPANTS/MATERIALS SETTING METHODS: Women with non-consecutive first-trimester miscarriages or ectopic pregnancy were excluded. Epidemiological and clinical information regarding medical history, investigation and management was gathered from paper and electronic medical records. Data were analysed using SPSS (Version 27). Associations between maternal characteristics and outcomes were explored using the χ2 test, with significance set at P < 0.05. Multinomial regression analysis was performed using a stepwise approach. MAIN RESULTS AND THE ROLE OF CHANCE: There were 748 women who were included; 332 (44%) had primary RM and 416 (56%) had secondary RM. The median age was 36 years (range 19-47). Foetal aneuploidy was the most common investigative finding (15%; n = 111/748); 60% had unexplained RM. In addition to supportive care, most women were prescribed aspirin (96%) and folic acid (75%). Of the 748 women, 573 had a subsequent pregnancy (77%) and 359 (48% of all women; 63% of pregnancies) had a livebirth, while 208 had a further pregnancy loss (28% of all women; 36% of pregnancies) and 6 were still pregnant at the end of the study. Women aged 35-39 years were more likely to have a livebirth than no further pregnancy (relative risk ratio (RRR): 2.29 (95% CI: 1.51-5.30)). Women aged 30-34 years were more likely to have a livebirth (RRR: 3.74 (95% CI: 1.80-7.79)) or a miscarriage (RRR: 2.32 (95% CI: 1.07-4.96)) than no further pregnancy. Smokers were less likely to have a livebirth (RRR: 0.37 (95% CI: 0.20-0.69)) or a miscarriage (RRR: 0.45 (95% CI: 0.22-0.90)) than no further pregnancy. Couples with an abnormal parental karyotype were less likely to have a miscarriage than no further pregnancy (RRR: 0.09 (95% CI: 0.01-0.79)). Including successive pregnancies conceived over the study period, the overall livebirth rate was 63% (n = 466/742), but this was reduced to 44% in women aged ≥40 years and 54% in women with infertility. LIMITATIONS REASONS FOR CAUTION: This work covers 13 years; however, those included in the later years have a shorter follow-up time. Although electronic health records have improved data availability, data collection in this cohort remains hampered by the absence of a formal booking visit for women presenting with miscarriage and a national miscarriage database or register. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are largely reassuring as most women with RM and hoping to conceive achieved a livebirth. In addition to older age, smoking and parental balanced translocations were associated with a reduced likelihood of further pregnancy. No investigation or treatment was associated with pregnancy outcome, reiterating the importance of the supportive aspects of care for women and their partners after RM and counselling regarding individual risk factors. This contributes to the limited international data on the investigative findings and treatment of women with RM. The high rate of prescribed medications merits greater scrutiny, in conjunction with other pregnancy outcomes, and reiterates the need for a national guideline on RM. STUDY FUNDING/COMPETING INTERESTS: L.A.L. is a PhD scholar funded through the Pregnancy Loss Research Group, Department of Obstetrics and Gynaecology, University College Cork. M.H. and C.F. are Postdoctoral Researchers on a project funded by the Health Research Board Ireland [ILP-HSR-2019-011] and led by K.O.D., titled: 'Study of the impact of dedicated recurrent miscarriage clinics in the Republic of Ireland'. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no conflicts of interests to declare. TRIAL REGISTRATION NUMBER: N/A.

An exploration of the impact of ethanol diluent on breath alcohol concentration in patients receiving paclitaxel chemotherapy.

PURPOSE: This study aimed to provide a better understanding of the impact of paclitaxel chemotherapy on breath alcohol in an Irish population. METHODS: Patients attending the Oncology Day Unit at Beaumont Hospital were invited to participate on the day of their treatment. The brand of paclitaxel used was Actavis Pharma Inc and contained 6 mg/mL paclitaxel in 50% Ethanol/ 50% Cremophor EL. Breath alcohol concentration was measured using the AlcoSense ™ Breathalyser on three separate visits. The primary end-point was the number of patients who were above the legal threshold for drink driving in Ireland. RESULTS: In total, 50 patients were recruited. 36 (68%) were female. The most common diagnosis was breast cancer (56%). Ten (20%) patients had metastatic disease and 4 (8%) had liver metastases. The mean paclitaxel dose administered was 118 mg. The mean amount of ethanol infused was 7.7 g. 27 patients had a detectable breath alcohol level on at least one visit. The mean breath alcohol concentration was 2 mcg/100 mL or 0.02 mg/L of breath. The maximum concentration of ethanol in exhaled breath was 11 mcg/100 mL or 0.11 mg/L which is 50% of the statutory limit for drink driving in Ireland. A weak correlation was observed between ethanol concentration in exhaled breath and the total amount of ethanol administered. Although no patient exceeded the general limit for drink driving in Ireland, three (6%) participants had a breath alcohol concentration above the threshold for professional, learner or novice drivers. CONCLUSION: Although definitive conclusions are limited by relatively small numbers, it seems unlikely that weekly paclitaxel infusions pose any significant risk to patients driving.

Optimizing and simplifying post-traumatic amnesia testing after moderate-severe traumatic brain injury despite common confounders in routine practice.

The duration of post-traumatic amnesia (PTA) following traumatic brain injury (TBI) is a key diagnostic and outcome indicator. However, concerningly, different PTA paradigms record different PTA durations: some over-estimate, others under-estimate, PTA. Thus, a compromise is implied. The potential effect of in-hospital confounders including opioids is unknown. Three clinical groups were prospectively recruited. Group-1: in-patients with moderate-severe-TBI (MS-TBI), considered likely 'in-PTA'. Group-2: patients rehabilitating after recent MS-TBI, considered 'out-of-PTA'. Group-3: orthopaedic in-patients without TBI undergoing elective surgery. Only Groups 1&3 were taking opioids. All were administered the Westmead Post-traumatic Amnesia Scale (WPTAS) and the Galveston Orientation and Amnesia Test (GOAT). Results were obtained in n = 56 (Group-1:n = 18, Group-2:n = 13 and Group-3:n = 25). On WPTAS, Groups 1&3 scored similarly, but significantly lower than, Group-2 (χ2 = 8.2, P = 0.017). Contrariwise, on GOAT, Group-1 scored significantly lower than Groups 2&3 (χ2 = 23.99, P < 0.001): however, no patient scored GOAT <75. WPTAS showed moderate sensitivity (72%) but poor specificity (40%) in distinguishing Group-1 from Groups 2&3. Contrariwise, GOAT showed 100% specificity but 0% sensitivity. WPTAS 'day of week' and 'pictures' combined with GOAT 'transport medium to hospital', 'anterograde amnesia' and 'retrograde amnesia' maximized sensitivity (100%), specificity (85-88%), PPV (77-83%) and NPV (100%) in distinguishing Group-1 from Groups 2&3. CONCLUSIONS: Confounders including opioids likely affected WPTAS overall, but not GOAT specificity. A merger, whereby WPTAS sensitivity augmented GOAT specificity, was therefore sought. Favourable items from WPTAS (4/12) and GOAT (3/10) together optimized, and yet simplified, PTA testing; despite prevalent clinical confounders. Less, not more, 'PTA' items would benefit both patients and staff alike.

Optimal Timing of CT Scanning in the Rapid Access Lung Cancer Clinic.

Aims To investigate whether a 'CT first' approach to Rapid Access Lung Cancer Clinic (RALC) review could be feasible in an Irish context. Methods A retrospective review of our institution's Lung Cancer Database was performed. All RALC first attendances from 2012-2018 were identified. Timing of CT was assessed as well as CT imaging findings. Results Total first attendances in this period were 2372, of whom 91% had CT thorax as part of their evaluation. 866 patients (37%) were diagnosed with lung cancer, all had an abnormal CT. 1290 patients (54%) underwent CT but did not have lung cancer after clinical work up. 34% of patients diagnosed with Lung Cancer had their CT scan post RALC. Time to diagnosis was longer in those who had post RALC CT (34.5 versus 21 days) Conclusion CT scanning plays a vital role in the RALC pathway. Initial delays in obtaining CT can result in delayed time to diagnosis. These findings warrant close consideration when devising future national lung cancer policy.

Gastric ulceration and perforation secondary to large trichobezoar - A case report describing the role of magnetic resonance imaging in diagnosis.

INTRODUCTION: Trichotillomania and trichotillophagia can result in huge intraluminal coagulations of hair. Rarely, these can present with gastric perforation. This work has been reported in line with the SCARE criteria (Agha et al., 2016) [1]. PRESENTATION OF CASE: We report the case of a 15 year old girl who attended the emergency department with abdominal pain and vomiting. Ultrasound abdomen and pelvis identified free fluid within the pelvis concerning for inflammatory bowel disease. A subsequent magnetic resonance enterography (MRE) demonstrated a giant gastric trichobezoar which resulted in gastric perforation necessitating laparotomy and gastrotomy. The patient recovered well from the surgery and was reviewed by the psychiatry service prior to discharge. DISCUSSION: Trichobezoar is a challenging diagnosis and as clinician, we must always include it in our differential diagnosis. The clinical presentation, signs and symptoms depend on the size of the trichobezoar and the presence of complications. Management is almost always surgical. CONCLUSION: This case illustrates the infrequent perforation risk of gastric bezoars and the important role of magnetic resonance imaging in diagnosis, particularly in a population who must not be exposed to excessive radiation.

Efficacy of the nanoparticle-drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I-IIa clinical trial.

BACKGROUND: Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. CRLX101 is an investigational camptothecin-containing nanoparticle-drug conjugate (NDC), which durably inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab. PATIENTS AND METHODS: Patients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of CRLX101 (12, 15 mg/m(2)) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1. RESULTS: Twenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade ≥3 AEs related to CRLX101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months. CONCLUSIONS: CRLX101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol's predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing.

Differential interactions of antiretroviral agents with LXR, ER and GR nuclear receptors: potential contributing factors to adverse events.

BACKGROUND AND PURPOSE: Antiretroviral (ARV) drugs activate pregnane X receptors and constitutive androstane receptors, increasing the risk of drug interactions due to altered drug metabolism and disposition. The closely related liver X receptors (LXRα/ß), oestrogen receptors (ERα/ß) and glucocorticoid receptor (GR) regulate many endogenous processes such as lipid/cholesterol homeostasis, cellular differentiation and inflammation. However, ARV drug activation of these nuclear receptors has not been thoroughly investigated. EXPERIMENTAL APPROACH: The ability of an ARV drug library to activate LXRα/ß, ERα/ß and GR was assessed using a combined in silico and in vitro approach encompassing computational docking and molecular descriptor filtering, cell-free time-resolved fluorescence resonance energy transfer co-activator assays to assess direct binding to ligand-binding domains (LBDs), cell-based reporter assays and target gene expression. KEY RESULTS: Direct LBD interactions with LXRα and/or LXRß were predicted in silico and confirmed in vitro for darunavir, efavirenz, flavopiridol, maraviroc and tipranavir. Likewise, efavirenz was also predicted and confirmed as a ligand of ERα-LBD. Interestingly, atazanavir and ritonavir also activated LXRα/ß in reporter assays, while tipranavir enhanced transcriptional activity of ERα. Effects on ER and LXR target gene expression were confirmed for efavirenz and tipranavir. CONCLUSIONS AND IMPLICATIONS: There was good agreement between in silico predictions and in vitro results. However, some nuclear receptor interactions identified in vitro were probably due to allosteric effects or nuclear receptor cross-talk, rather than direct LBD binding. This study indicates that some of the adverse effects associated with ARV use may be mediated through 'off-target' effects involving nuclear receptor activation.

A primer on the mechanics of P-glycoprotein the multidrug transporter.

P-glycoprotein (P-gp) the multidrug transporter is a well-characterised member of the super-family of ATP-binding cassette (ABC) transporters, and mediates the clearance of xenotoxins against steep concentration gradients at the expense of ATP hydrolysis. The primary function of this protein is to prevent the uptake of toxic compounds from the gut into the body, and to protect vital structures such as the brain, cerebrospinal fluid, testis, foetus and bone marrow against toxins. Although P-gp transports a wide range of compounds, which is advantageous, it can also be a disadvantage and may interfere with the delivery of drugs to target tissues resulting in multidrug resistance. In the present review: (i) we consider our current understanding of the structure of P-glycoprotein, (ii) discuss substrate binding and its coupling to ATPase activity, (iii) provide insight into key features which define P-glycoprotein substrates/inhibitors and the ability to predict potential substrates in silico, (iv) provide an overview of existing models of pump function and (v) present emerging concepts into the regulation of P-glycoprotein expression, with particular reference to multidrug resistance.

The role of MRI and ultrasound imaging in Morton's neuroma and the effect of size of lesion on symptoms.

We investigated 29 cases, diagnosed clinically as having Morton's neuroma, who had undergone MRI and ultrasound before a neurectomy. The accuracy with which pre-operative clinical assessment, ultrasound and MRI had correctly diagnosed the presence of a neuroma were compared with one another based on the histology and the clinical outcome. Clinical assessment was the most sensitive and specific modality. The accuracy of the ultrasound and MRI was similar and dependent on size. Ultrasound was especially inaccurate for small lesions. There was no correlation between the size of the lesion and either the pre-operative pain score or the change in pain score following surgery. Reliance on single modality imaging would have led to inaccurate diagnosis in 18 cases and would have only benefited one patient. Even imaging with both modalities failed to meet the predictive values attained by clinical assessment. There is no requirement for ultrasound or MRI in patients who are thought to have a Morton's neuroma. Small lesions, < 6 mm in size, are equally able to cause symptoms as larger lesions. Neurectomy provides an excellent clinical outcome in most cases.

VNS in patients with previous unsuccessful resective epilepsy surgery: antiepileptic and psychotropic effects.

OBJECTIVES: To assess the efficacy of vagus nerve stimulation (VNS) in patients with medically and surgically intractable complex partial seizures (CPS). PATIENTS AND METHODS: Sixteen patients with previous temporal [15] and frontal [one] resections were treated with VNS between 1994 and 1999 at King's College Hospital, London, UK. Post-operative video-electroencephalogram telemetry had shown that CPS started from the operated side in 12 patients, contralaterally in three and bilaterally independently in one. RESULTS: Three patients (18.75%) had 50% or more reduction in seizure frequency, but one showed severe worsening of epilepsy, which remitted upon VNS discontinuation. The antiepileptic effect of VNS was not different with respect to the type of operation (anterior temporal lobectomy vs amygdalohippocampectomy), the side of operation, or the side of seizure onset. We observed psychotropic effects in two patients with post-ictal psychosis, in two others with depression, and in a child with severe behavioral disorder. CONCLUSIONS: VNS may have a rather limited antiepileptic role to play in patients with persistent seizures following epilepsy surgery, but may independently possess useful antipsychotic and mood-stabilizing properties.

Postictal psychosis after temporal lobectomy.

Three of 282 consecutive patients who had temporal resections for intractable epilepsy developed postoperative postictal psychosis. These three patients had seizure recurrence contralateral to the resection, whereas none of the patients with ipsilateral seizure recurrence developed any psychiatric symptoms after surgery. Two had left amygdalo-hippocampectomy and one right temporal lobectomy. The de novo occurrence of postoperative postictal psychosis is a well-defined complication of surgery for temporal lobe epilepsy, and may relate to contralateral epileptogenesis.

Calcaneal osteotomy and transfer of the tendon of flexor digitorum longus for stage-II dysfunction of tibialis posterior. Three- to five-year results.

The treatment of acquired flat foot secondary to dysfunction of the posterior tibial tendon (PTT) of stage II, as classified by Johnson and Strom, remains controversial. Joint sparing and soft-tissue reconstructive procedures give good early results, but few studies describe those in the medium-term. We studied prospectively the outcome of surgery in 51 patients with classical stage-II dysfunction of the PTT treated by a medial displacement calcaneal osteotomy and transfer of the tendon of flexor digitorum longus. We reviewed 44 patients with a mean follow-up of 51 months (38 to 62). The mean American Orthopaedic Foot and Ankle Society ankle/hindfoot rating scale improved from 48.8 before operation to 88.5 at follow-up. The operation failed in two patients who later had a calcaneocuboid fusion. The outcome in 43 patients was rated as good to excellent for pain and function, and in 36 good to excellent for alignment. There were no poor results.

Effect of high-altitude exposure on myopic laser in situ keratomileusis.

PURPOSE: To study the effect of high-altitude exposure on visual acuity after myopic laser in situ keratomileusis (LASIK). SETTING: Aconcagua, Mendoza, Argentina. METHODS: In the early postoperative period after uneventful myopic LASIK, 2 physicians prospectively assessed their visual acuity during an ascent of Aconcagua (22841 feet). The distance uncorrected visual acuity (UCVA) and peripheral oxygenation were measured at approximately every 2000 feet of altitude. RESULTS: Both climbers developed a moderate loss of distance UCVA but described normal near and pinhole acuity consistent with a myopic shift. The distance UCVA diminished to 20/100 in the right eye and 20/125 in the left eye of Climber A and to 20/160 and 20/30, respectively, of Climber B. The vision loss worsened with increased altitude, duration of exposure, and decreased peripheral oxygenation. One week after the climb, the manifest refraction demonstrated a small myopic shift in both eyes of Climber A; these subsequently resolved. CONCLUSIONS: Two climbers, 8 and 14 weeks after myopic LASIK, experienced vision loss consistent with a temporary myopic shift in the refractive error with ascent to high altitude. Climbers who have LASIK, particularly those in the early postoperative period, should be prepared for visual acuity fluctuations with high-altitude exposure.

Prognostic factors in the surgical treatment of medically intractable epilepsy associated with mesial temporal sclerosis.

OBJECTIVES: To assess the prognostic factors determining seizure remission after temporal lobectomy for intractable epilepsy associated with mesial temporal sclerosis (MTS) at pathology. METHODS: The clinical and investigative features of 116 consecutive patients who had temporal lobe surgery for drug-resistant epilepsy and MTS at pathology were assessed using actuarial statistics and logistic regression analysis. RESULTS: At a median follow-up of 63 months the probability of achieving at least a 1-year period of continuous seizure freedom was 67%. Factors contributing to a favourable outcome were interictal EEG localization to the operated lobe and the absence of secondarily generalized seizures. These were also selected in the multivariate analysis, although at lower statistical significance (P=0.08 and 0.09, respectively). Perinatal complications were associated with a significantly worse outcome but overall, complicated febrile convulsions and congruent neuropsychological deficits were not significantly predictive variables. CONCLUSIONS: The present findings may aid in the non-invasive presurgical assessment of patients with intractable TLE and clinical and neuroimaging evidence of MTS.