A cost-utility study of elective haemorrhoidectomies in Canada.

AIM: The aim was to estimate the 10-year cost-utility of haemorrhoidectomy surgery with preference-based measures of health using Canadian health utility measures and costs. METHODS: Patients undergoing elective haemorrhoidectomies by general and colorectal surgeons in British Columbia, Vancouver, between September 2015 and November 2022, completed preoperatively and postoperatively the EuroQol five-dimension five-level health-related quality of life questionnaire (EQ-5D-5L). Quality-adjusted life years (QALYs) attributable to surgery were calculated by discounting preoperative and postoperative health utility values derived from the EQ-5D-5L. Costs were measured from a health system perspective which incorporated costs of hospital stay and specialists' fees. Results are presented in 2021 Canadian dollars. RESULTS: Of 94 (47%) patients who completed both the preoperative and postoperative questionnaires, the mean gain in QALYs 10 years after surgery was 1.0609, assuming a 3.5% annual discounting rate. The average cost of the surgery was $3166. The average cost per QALY was $2985 when benefits of the surgery were assumed to accrue for 10 years. The cost per QALY was higher for women ($3821) compared with men ($2485). Participants over the age of 70 had the highest cost per QALY ($8079/QALY). CONCLUSIONS: Haemorrhoidectomies have been associated with significant gains in health status and are inexpensive relative to the associated gains in quality of life based on patients' perspectives of their improvement in health and well-being.

Two alternative methods for the retrieval of somatic cell populations from the mouse ovary.

Many modern techniques employed to uncover the molecular fundamentals underlying biological processes require dissociated cells as their starting point/substrate. Investigations into ovarian endocrinology or folliculogenesis, therefore, necessitate robust protocols for dissociating the ovary into its constituent cell populations. While in the mouse, methods to obtain individual, mature follicles are well-established, the separation and isolation of single cells of all types from early mouse follicles, including somatic cells, has been more challenging. Herein we present two methods for the isolation of somatic cells in the ovary. These methods are suitable for a range of applications relating to the study of folliculogenesis and mouse ovarian development. First, an enzymatic dissociation utilising collagenase and a temporary, primary cell culture step using neonatal mouse ovaries which yields large quantities of granulosa cells from primordial, activating, and primary follicles. Second, a rapid papain dissociation resulting in a high viability single cell suspension of ovarian somatic cells in less than an hour, which can be applied from embryonic to adult ovarian samples. Collectively these protocols can be applied to a broad array of investigations with unique advantages and benefits pertaining to both.

Signal transducer and activator of transcription (STAT) 1 and STAT3 are expressed in the human ovary and have Janus kinase 1-independent functions in the COV434 human granulosa cell line.

Ovarian granulosa cells are fundamental for oocyte maintenance and maturation. Recent studies have demonstrated the importance of members of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway in the granulosa cell population of mouse and horse ovaries, with perturbation of JAK1 signalling in the mouse shown to impair oocyte maintenance and accelerate primordial follicle activation. The presence and role of the JAK/STAT pathway in human granulosa cells has yet to be elucidated. In this study, expression of JAK1, STAT1 and STAT3 was detected in oocytes and granulosa cells of human ovarian sections from fetal (40 weeks gestation) and premenopausal ovaries (34-41 years of age; n=3). To determine the effects of JAK1 signalling in granulosa cells, the human granulosa-like cell line COV434 was used, with JAK1 inhibition using ruxolitinib. Chemical inhibition of JAK1 in COV434 cells with 100nM ruxolitinib for 72h resulted in significant increases in STAT3 mRNA (P=0.034) and p-Y701-STAT1 protein (P=0.0117), demonstrating a role for JAK1 in modulating STAT in granulosa cells. This study implicates a conserved role for JAK/STAT signalling in human ovary development, warranting further investigation of this pathway in human granulosa cell function.

Health and quality of life among a cohort of patients having lateral internal sphincterotomy for anal fissures.

AIM: The aim of this study is to report changes in health-related quality of life attributable to lateral internal sphincterotomy for treatment of anal fissure. There is very little evidence on whether the overall health-related quality of life of patients is detrimentally affected by the condition, or which aspects of self-perceived health status improve after lateral internal sphincterotomy. This study will articulate which aspects of health tend to improve and guide postoperative expectations appropriately. Knowledge gained from this study may also identify gaps in an individual patient's episode of care. METHOD: Patients were prospectively identified when they consented to surgical treatment of their anal fissure and were contacted by phone to participate. Participants completed a number of patient-reported outcomes preoperatively and 6 months postoperatively. Faecal incontinence-related quality of life, pain and depression were measured at both time points. The severity of faecal incontinence was measured at both times. RESULTS: Participants reported high levels of pain preoperatively. Postoperatively, improvement in pain exceeded the threshold of clinical relevance (P < 0.01). Thirty-five per cent of participants reported significant effects of faecal incontinence preoperatively, while 26% did so postoperatively. Participants with multiple comorbidities were more likely to report faecal incontinence postoperatively than preoperatively. CONCLUSION: This study reports that lateral internal sphincterotomy improved pain symptoms without adverse effects on continence. Not all domains of health-related quality of life were similarly positively affected by anal fissure repair.

Discharge destination following hip fracture in Canada among previously community-dwelling older adults, 2004-2012: database study.

Little is known about post-acute care following hip fracture surgery. We investigated discharge destinations from surgical hospitals for nine Canadian provinces. We identified significant heterogeneity in discharge patterns across provinces suggesting different post-acute recovery pathways. Further work is required to determine the impact on patient outcomes and health system costs. INTRODUCTION: To examine discharge destinations by provinces in Canada, adjusting for patient, injury, and care characteristics. METHODS: We analyzed population-based hospital discharge abstracts from a national administrative database for community-dwelling patients who underwent hip fracture surgery between 2004 and 2012 in Canada. Discharge destination was categorized as rehabilitation, home, acute care, and continuing care. Multinomial logistic regression modeling compared proportions of discharge to rehabilitation, acute care, and continuing care versus home between each province and Ontario. Adjusted risk differences and risk ratios were estimated. RESULTS: Of 111,952 previously community-dwelling patients aged 65 years or older, 22.5% were discharged to rehabilitation, 31.6% to home, 27.0% to acute care, and 18.2% to continuing care, with significant variation across provinces (p < 0.001). The proportion of discharge to rehabilitation ranged from 2.4% in British Columbia to 41.0% in Ontario while the proportion discharged home ranged from 20.3% in Prince Edward Island to 52.2% in British Columbia. The proportion of discharge to acute care ranged from 15.2% in Ontario to 58.8% in Saskatchewan while the proportion discharged to continuing care ranged from 9.3% in Manitoba and Prince Edward Island to 22.9% in New Brunswick. Adjusting for hospital type changed the direction of the provincial effect on discharge to continuing care in two provinces, but statistical significance remained consistent with the primary analysis. CONCLUSIONS: Discharge destination from the surgical hospital after hip fracture is highly variable across nine Canadian provinces. Further work is required to determine the impact of this heterogeneity on patient outcomes and health system costs.

Time to surgery after hip fracture across Canada by timing of admission.

The extent of Canadian provincial variation in hip fracture surgical timing is unclear. Provinces performed a similar proportion of surgeries within three inpatient days after adjustment. Time to surgery varied by timing of admission across provinces. This may reflect different approaches to providing access to hip fracture surgery. INTRODUCTION: The aim of this study was to compare whether time to surgery after hip fracture varies across Canadian provinces for surgically fit patients and their subgroups defined by timing of admission. METHODS: We retrieved hospitalization records for 140,235 patients 65 years and older, treated surgically for hip fracture between 2004 and 2012 in Canada (excluding Quebec). We studied the proportion of surgeries on admission day and within 3 inpatient days, and times required for 33%, 66%, and 90% of surgeries across provinces and by subgroups defined by timing of admission. Differences were adjusted for patient, injury, and care characteristics. RESULTS: Overall, provinces performed similar proportions of surgeries within the recommended three inpatient days, with all provinces requiring one additional day to perform the recommended 90% of surgeries. Prince Edward Island performed 7.0% more surgeries on admission day than Ontario irrespective of timing of admission (difference = 7.0; 95% CI 4.0, 9.9). The proportion of surgeries on admission day was 6.3% lower in Manitoba (difference = - 6.3; 95% CI - 12.1, - 0.6), and 7.7% lower in Saskatchewan (difference = - 7.7; 95% CI - 12.7, - 2.8) compared to Ontario. These differences persisted for late weekday and weekend admissions. The time required for 33%, 66%, and 90% of surgeries ranged from 1 to 2, 2-3, and 3-4 days, respectively, across provinces by timing of admission. CONCLUSIONS: Provinces performed similarly with respect to recommended time for hip fracture surgery. The proportion of surgeries on admission day, and time required to complete 33% and 66% of surgeries, varied across provinces and by timing of admission. This may reflect different provincial approaches to providing access to hip fracture surgery.

Waiting for surgery: is waiting bad for anyone or everyone?

PURPOSE: For Canadians, as in many countries, waiting for elective surgery is expected. The duration of the wait raises questions about the maximum amount of time patients should wait for their surgery. The primary objective of this study was to test for a relationship between the length of time patients waited for elective hernia repair surgery and change in patients' self-reported health. METHODS: This study was based on a prospectively recruited longitudinal cohort of patients waiting for elective hernia repair surgery. Participants completed the PHQ-9, PEG, EQ-5D(3L) generic instruments, and the condition-specific COMI-hernia. Multivariate regression models explored associations between patient-reported outcomes and potential confounders, including age, sex, socio-economic status, and medical comorbidities. RESULTS: There were 118 participants and the modal age group was 61-70 years. The average wait time for participants was 22.5 weeks. There were no relationships between the duration of participants' wait for hernia repair and the change in patients' self-reported health for hernia-specific outcomes or overall health-related quality of life. DISCUSSION: There are gains in health-related quality of life to be realized by prioritizing symptomatic patients. Participants with greater pre-operative depression, pain, and hernia-related symptoms experienced an improvement in health prior to surgery, though more clarity is needed on the mechanisms that led to improved health. CONCLUSION: Many countries face problems with wait lists for elective surgery-and few have effective processes for triaging patients. This study shows that duration of time on the wait list was not associated with change in hernia patients' self-reported health.

Damaging legacy: maternal cigarette smoking has long-term consequences for male offspring fertility.

STUDY QUESTION: What are the effects on fertility of cigarette smoke-induced toxicity on male offspring exposed during the gestational/weaning period? SUMMARY ANSWER: Maternal cigarette smoke exposure during the gestational/weaning period causes long-term defects in male offspring fertility. WHAT IS KNOWN ALREADY: Cigarette smoke is a well-known reproductive toxicant which is particularly harmful to both fetal and neonatal germ cells. However, recent studies suggest a significant portion of young mothers in the developed world still smoke during pregnancy. In the context of male reproductive health, our understanding of the effects of in utero exposure on offspring fertility is limited. STUDY DESIGN, SIZE, DURATION: In this study, 27 C57BL/6 5-week-old female mice were exposed via the nose-only to cigarette smoke (treatment) or 27 were exposed to room air (control) for 6 weeks before being housed with stud males to produce litters. In the treatment group, smoke exposure continued throughout mating, pregnancy and lactation until weaning of pups at 21 days post birth. Male offspring were examined at post-natal days 3, 6, 12, 21 and 98 (adult). PARTICIPANTS/MATERIALS, SETTING, METHODS: Approximately 108 maternal smoke-exposed C57BL/6 offspring and controls were examined. Spermatogenesis was examined using testicular histology and apoptosis/DNA damage was assessed using caspase immunohistochemistry and TUNEL. Sertoli cell morphology and fluctuations in the spermatogonial stem cell population were also examined using immunohistochemistry. Microarray and QPCR analysis were performed on adult testes to examine specific long-term transcriptomic alteration as a consequence of maternal smoke exposure. Sperm counts and motility, zona/oolemma binding assays, COMET analysis and mitochondrial genomic sequencing were also performed on spermatozoa obtained from adult treated and control mice. Fertility trials using exposed adult male offspring were also performed. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal cigarette smoke exposure caused increased gonocyte and meiotic spermatocyte apoptosis (P < 0.01) as well as germ cell depletion in the seminiferous tubules of neonatal and juvenile offspring. Aberrant testicular development characterized by abnormal Sertoli and germ cell organization, a depleted spermatogonial stem cell population (P < 0.01), atrophic seminiferous tubules and increased germ cell DNA damage (P < 0.01) persisted in adult offspring 11 weeks after exposure. Microarray analysis of adult offspring testes associated these defects with meiotic germ cell development, sex hormone metabolism, oxidative stress and Sertoli cell signalling. Next generation sequencing also revealed a high mitochondrial DNA mutational load in the testes of adult offspring (P < 0.01). Adult maternal smoke-exposed offspring also had reduced sperm counts with spermatozoa exhibiting morphological abnormalities (P < 0.01), affecting motility and fertilization potential. Odf2, a spermatozoa flagellum component required for coordinated ciliary beating, was also significantly down-regulated (P < 0.01) in maternal smoke-exposed adult offspring, with aberrant localization along the spermatozoa flagellum. Adult maternal smoke-exposed offspring took significantly longer to impregnate control females and had a slight but significant (P < 0.01) reduction in litter size. LIMITATIONS, REASONS FOR CAUTION: This study examined only one species (mouse) using a smoking model which only simulates human cigarette smoke exposure. WIDER IMPLICATIONS OF THE FINDINGS: This study represents the first comprehensive animal model of maternal smoking on male offspring reproductive function, suggesting that exposure during the gestational/weaning period causes long-term defects in male offspring fertility. This is due to a compromised spermatogonial stem cell population resulting from gonocyte apoptosis and impaired spermatogenic development. This results in significant germ cell damage and Sertoli cell dysfunction, impacting germ cell number, tubule organization, DNA damage and spermatozoa in adult offspring. This study strengthens the current literature suggesting that maternal exposure impairs male offspring fertility, which is currently debated due to conflicting studies. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Australian Research Council, Hunter Medical Research Institute, National Health and Medical Research Council of Australia and the Newcastle Permanent Building Society Charitable Trust. The authors declare no conflict of interest.

Scrambled and fried: cigarette smoke exposure causes antral follicle destruction and oocyte dysfunction through oxidative stress.

Cigarette smoke is a reproductive hazard associated with pre-mature reproductive senescence and reduced clinical pregnancy rates in female smokers. Despite an increased awareness of the adverse effects of cigarette smoke exposure on systemic health, many women remain unaware of the adverse effects of cigarette smoke on female fertility. This issue is compounded by our limited understanding of the molecular mechanisms behind cigarette smoke induced infertility. In this study we used a direct nasal exposure mouse model of cigarette smoke-induced chronic obstructive pulmonary disease to characterise mechanisms of cigarette-smoke induced ovotoxicity. Cigarette smoke exposure caused increased levels of primordial follicle depletion, antral follicle oocyte apoptosis and oxidative stress in exposed ovaries, resulting in fewer follicles available for ovulation. Evidence of oxidative stress also persisted in ovulated oocytes which escaped destruction, with increased levels of mitochondrial ROS and lipid peroxidation resulting in reduced fertilisation potential. Microarray analysis of ovarian tissue correlated these insults with a complex mechanism of ovotoxicity involving genes associated with detoxification, inflammation, follicular activation, immune cell mediated apoptosis and membrane organisation. In particular, the phase I detoxifying enzyme cyp2e1 was found to be significantly up-regulated in developing oocytes; an enzyme known to cause molecular bioactivation resulting in oxidative stress. Our results provide a preliminary model of cigarette smoke induced sub-fertility through cyp2e1 bioactivation and oxidative stress, resulting in developing follicle depletion and oocyte dysfunction.

Intracellular signalling during female gametogenesis.

Female reproductive potential is dictated by the size of the primordial follicle pool and the correct regulation of oocyte maturation and activation--events essential for production of viable offspring. Although a substantial body of work underpins our understanding of these processes, the molecular mechanisms of follicular and oocyte development are not fully understood. This review summarizes recent findings which have improved our conception of how folliculogenesis and oocyte competence are regulated, and discusses their implications for assisted reproductive techniques. We highlight evidence provided by genetically modified mouse models and in vitro studies which have refined our understanding of Pi3k/Akt and mTOR signalling in the oocyte and have discovered a role for Jak/Stat/Socs signalling in granulosa cells during primordial follicle activation. We also appraise a novel role for the metal ion zinc in the regulation of meiosis I and meiosis II progression through early meiosis inhibitor (Emi2) and Mos-Mapk signalling, and examine studies which expand our understanding of intracellular calcium signalling and extrinsic Plcζ in stimulating oocyte activation.

Suppressor of cytokine signaling 4 (SOCS4): moderator of ovarian primordial follicle activation.

Mammalian ovarian primordial follicle activation and regulation is considered as one of the most important stages of folliculogenesis and as such requires exquisite control. Selection of quiescent follicles to enter the growing pool determines the rate of supply of maturing follicles over the female reproductive lifespan. To coordinate this process a range of positive and negative input signals contribute to determine follicle fate. This study demonstrates that the cytokine Leukemia Inhibitory Factor (LIF) activates the Janus Kinase 1/Signal Transducers and Activators of Transcription 3 (JAK1/STAT3) signaling pathway in pre-granulosa cells and positively regulates primordial follicle activation. Negative regulation of the JAK/STAT pathway is controlled by the suppressor of cytokine signaling 4 (SOCS4) protein, which target members of negative feedback loops, Cardiotrophin like Cytokine (CLC), Poly (rC) Binding Protein 1 (PCBP1), and Cytosolic Malate Dehydrogenase (MDH1) to suppress follicle growth and development.

Poststroke depression and treatment effects on functional outcomes.

BACKGROUND: Poststroke depression (PSD) is common after stroke; however, the relationship to poststroke function is inconclusive. Our objectives were to 1) determine the relationship between PSD at baseline (1 month poststroke) and function (12 weeks later) and 2) assess the impact of depression improvement on 12-week function among those with depression at baseline. METHODS: We completed a secondary analysis of data from a cohort study of participants with and without PSD. We used logistic regression to identify factors associated with 12-week functional dependence for 1) all 367 participants and 2) the 174 participants with PSD. RESULTS: In the PSD cohort, 3 characteristics were found to be independently associated with 12-week dependence: increased medical comorbidity (odds ratio [OR] 1.10, 95%confidence interval [CI] 1.02-1.22), increased stroke severity (OR 1.42, 95% CI 1.19-1.69), and increased baseline depression severity (OR 1.13, 95% CI 1.03-1.23). Depression severity was significantly different between those considered dependent and independent at 12 weeks (entire cohort, PHQ-9 7.31 vs 5.18, p = 0.008; depressed cohort, PHQ-9 9.94 vs 7.27, p = 0.019). CONCLUSION: Among study participants with PSD, the severity of depression symptoms at baseline was associated with dependence; however, our results are inconclusive as to whether improvement of depression is independently associated with functional recovery at 12 weeks. Even if the treatment and improvement of PSD does not directly influence functional recovery poststroke, it is essential for PSD to be identified and treated due to its high symptom burden and association with other negative health and social outcomes.

Patterns of care in two HIV continuity clinics in Uganda, Africa: a time-motion study.

The study objectives were to identify opportunities to improve the quality of care in resource-limited settings by examining the workflow and patient activities at two large outpatient HIV clinics in Uganda. Using time motion study techniques, we collected detailed data on all activities of patients and clinicians in two government-sponsored HIV clinics in Uganda. Processes measured included amount of time clinicians (physicians, nurse practitioners and clinical officers) spend in clinic, the daily patient census and patient visit-length. We also recorded the time spent on various activities by providers and patients. We found that the mean time in clinic per workday at Masaka was 5.5 hours and at Mbarara 4.9 hours, with about 60% of this time spent in direct and indirect care of patients at both sites. Workday start-times varied by two hours in Masaka and one-and-a half hours in Mbarara and end-times by five and three hours respectively. One-hundred-and-nineteen patients (SD 34) visited Masaka each day and 107 (SD 45) visited Mbarara. The mean duration of the patient visit was 77 minutes at Masaka and 196 minutes at Mbarara, with 66% and 62% of the time spent at respective sites waiting for care. We conclude that clinicians in resource-poor settings spend limited amounts of time at the clinic site, with a large portion of the clinic-time taken up by tasks that do not require specialized patient-care skills. This study demonstrates that opportunities exist to improve clinic productivity and visit experience for patients, and provides a baseline for designing and evaluating the impact of process improvement interventions.

Characterisation of rhizobia from African acacias and other tropical woody legumes using Biolog and partial 16S rRNA sequencing.

A Biolog (sole carbon source utilisation) user database of tropical and temperature rhizobial strains was created and used in conjunction with the partial 16S rRNA sequencing method to characterise 12 rhizobial isolates from African acacias and other tropical woody legumes. There was close agreement between the two methods but also some significant discrepancies. A high degree of diversity was shown in the relatively small sample of isolates, with 4 out of 5 of the currently proposed rhizobial genera represented. This is the first time Biolog has shown congruence with genotypic fingerprinting using a wide selection of rhizobial reference and test strains.

Self-starting Kerr-lens mode-locked femtosecond Cr(4+):YAG and picosecond Pr(3+):YLF solid-state lasers.

We have observed true self-starting Kerr-lens mode locking in two distinct solid-state laser systems operating at room temperature by optimizing the cavity geometry to maximize the amplitude modulation with respect to the intracavity power variation. Pulses of 15 ps have been obtained from a Pr(3+):YLF laser system operating at 607 nm, and 53-fs pulses have been obtained from Cr(4+):YAG at 1.54 microm.

Visible continuous-wave laser transitions in Pr(3+):YLF and femtosecond pulse generation.

Fourteen new cw, visible laser transitions have been observed in Pr(3+):YLF, several of which have exhibited modest tunability. The (3)P(0) - (3)H(6) transition near 613 nm has been shown to have a tunable linewidth of ~1 nm, which, for the first time to our knowledge, has permitted the direct production of femtosecond pulses in the visible from a cw solid-state laser by Kerr-lens mode locking.

A multicenter randomized, placebo-controlled trial of surfactant therapy for respiratory distress syndrome.

We carried out a multicenter randomized, placebo-controlled trial to evaluate the efficacy and safety of surfactant in the treatment of respiratory distress syndrome. The study population was made up of newborn infants weighing 750 to 1750 g who were receiving assisted ventilation with 40 percent or more oxygen. The eligible infants received a single dose of either surfactant (100 mg of phospholipid per kilogram of body weight [4 ml per kilogram]) or an air placebo (4 ml per kilogram), administered into the trachea within eight hours of birth by an investigator not involved in the clinical care of the infant. When compared with the infants who received the placebo (n = 81), the infants who were treated with surfactant (n = 78) had a 0.12 greater average increase in the ratio of arterial to alveolar oxygen tension (P less than 0.0001), a 0.20 greater average decrease in the fractional inspiratory oxygen concentration (P less than 0.0001), and a 0.26-kPa greater average decrease in the mean airway pressure (P less than 0.0001) during the 72 hours after treatment. Pneumothorax was less frequent among the infants treated with surfactant than in the control group (13 percent vs. 37 percent; P = 0.0005). There were no statistically significant differences between the groups in the proportion of infants in each of five ordered clinical-status categories on day 7 (P = 0.08) or day 28 (P = 0.75) after treatment. There were also no significant differences between the groups in the frequency of bronchopulmonary dysplasia, patent ductus arteriosus, necrotizing enterocolitis, or periventricular-intraventricular hemorrhage. In each group, 17 percent of the infants died by day 28. We conclude that treatment with the single-dose surfactant regimen used in this study reduces the severity of respiratory distress during the 72 hours after treatment and decreases the frequency of pneumothorax, but that it does not significantly improve clinical status later in the neonatal period and does not reduce neonatal mortality. Further study of different surfactant regimens and patient-selection criteria will be required to determine whether this initial improvement can be translated into reductions in mortality or serious morbidity.

Occurrence of nodulation in the Leguminosae.

Reports of nodulation in the Leguminosae are examined in the light of current views on the taxonomy of the family. In the subfamily Caesalpinioideae, nodulation is largely restricted to the tribe Caesalpinieae and the genus Chamaecrista from the Cassieae. All nodules studied have rhizobia retained within infection threads during the nitrogen fixing period. In the Mimosoideae, nodulation is general, except for 4 groups within the tribe Mimoseae, and a very few species of Acacia. The only tribe from the Papilionoideae which appears not to nodulate is the Dipterygeae, although the monogeneric Euchresteae has not been examined. A number of genera in the Swartzieae do not nodulate. Taking tile family as a whole, nodulation appears to be very uniform - certain sections nodulate, others do not.