Effect of hormone replacement therapy on intervertebral disc height.

OBJECTIVE: Intervertebral discs act as shock absorbers, thereby helping to reduce the risk of vertebral body fractures. Previous studies have shown that estrogen loss following menopause is associated with disc height reduction whereas treatment with hormone replacement therapy (HRT) helps to maintain disc height. This study reports the effect of HRT on disc height from a post hoc analysis of a prospective randomized clinical trial of the effect of HRT on bone density. METHODS: A total of 355 healthy postmenopausal women aged (mean ± standard deviation) 55.4 ± 4.8 years were randomized to HRT with oral 1 mg or 2 mg estradiol plus dydrogesterone or placebo. Dual-energy X-ray absorptiometry measurements (Lunar DPX) were obtained at baseline and following 2 years of treatment. Intervertebral disc height was measured in discs between T12 and L3 using the bone densitometer ruler. RESULTS: Compared with baseline, treatment with HRT resulted in a significant increase in total disc height with 1 mg estradiol (0.16 ± 0.65 cm, p = 0.015) and with 2 mg estradiol (0.21 ± 0.86 cm, p = 0.006) whilst there was no significant increase with placebo (0.13 ± 0.65 cm, p = 0.096). Between-group differences were not statistically significant. CONCLUSIONS: These results are consistent with previous findings of a beneficial effect of estrogen on discs. This may be in part responsible for the anti-fracture efficacy of HRT on vertebral fractures.

Cardiometabolic health in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is an increasing public health problem with a prevalence now approaching 4%. POI results in adverse effects on the skeleton and central nervous system as well as disturbances of metabolic and cardiological factors that predispose to a major increased risk of cardiovascular disease (CVD). This article reviews the effects of the premature loss of ovarian function on lipids and lipoproteins, glucose and insulin metabolism, body composition, hemostasis and blood pressure, together with effects on the development of metabolic syndrome and diabetes mellitus. The article examines the effects of POI on vascular endothelial function and inflammation that result in arterial disease, and reviews the effects of hormone replacement therapy (HRT) on these various metabolic processes and on cardiovascular outcomes. It is essential that women with POI receive hormonal treatment to help prevent the development of CVD, and that this treatment is continued at least until the normal age of menopause. It appears that HRT has a more favorable effect than the combined oral contraceptive, but larger clinical trials are needed to establish the optimal treatment. Other therapeutic measures may need to be added to correct existing metabolic abnormalities and, in particular, attention to lifestyle factors such as diet and exercise must be encouraged.

Luteolysis, progesterone, and pregnancy per insemination after modifying the standard 7-day Ovsynch program in Holstein-Friesian and Holstein cows.

Two experiments were conducted with Holstein-Friesian cows in the Republic of North Macedonia and with Holstein cows in Kansas. We hypothesized that 1 dose of PGF2α administered on d 8 (Ov-8×1) instead of d 7 (Ov-7×1) in an Ovsynch program [GnRH-1 (d 0)-7 d-PGF2α-56 h-GnRH-2-16 h-timed artificial insemination (AI)] would increase the proportion of cows with complete luteolysis compared with controls receiving a single dose on d 7. Cows were treated with Ov-7×1 or with Ov-8×1 in experiment 1 (n = 347), using only a single dose of PGF2α. In experiment 2 (n = 452), a third treatment was added (Ov-7×2), in which a second dose of PGF2α was administered on d 8. Progesterone was measured in blood samples collected before the first or only PGF2α administration and 72 h later before insemination. Complete luteolysis was defined as having occurred when progesterone was ≥1 ng/mL before PGF2α and ≤0.3 ng/mL 72 h later (time of AI). Follicles and luteal structures were mapped before GnRH-1 and PGF2α administrations. The results of experiment 1 demonstrated a greater percentage of multiparous cows in OV-8×1 having complete luteal regression compared with multiparous Ov-7×1 cows, whereas treatments were equally effective in primiparous cows, as reflected in the concentrations of progesterone before AI. Furthermore, pregnancy per AI did not differ between treatments. Results in experiment 2 revealed that 99.3% of cows in the Ov-7×2 treatment receiving the second dose of PGF2α had complete luteolysis, regardless of parity, compared with significantly fewer cows in the Ov-7×1 and Ov-8×1 treatments (91.2 and 90.6%, respectively). Neither concentrations of progesterone, which averaged <0.4 ng/mL at AI, nor pregnancy per AI differed among the 3 treatments. In both experiments, when status of luteal function before PGF2α treatment was examined [cows with no corpus luteum (CL) before GnRH-1 but which had formed a new CL in response to ovulation after GnRH-1; cows with an older CL (the same CL that was detected before GnRH-1); or cows with both a new and an older CL], treatments did not differ in causing complete luteolysis. Furthermore, complete luteolysis in experiment 2 did not differ regardless of whether cows had 1, 2, or 3 or more CL before PGF2α administration. Pregnancy per AI did not differ among treatments, indicating that any of the 3 treatments might produce similar pregnancy outcomes with the flexibility of applying either of the 7- or the 8-d treatments.

Global surgery and burn injuries; experience from a 25 year partnership in Malawi.

The Incidence of Burn Injuries - especially in Children - remains high in LMICs; The Lancet Commission on Global Surgery highlights the important role for increased investment to support surgically treatable conditions - including Trauma - in Developing Countries; the emphasis on delivering Funding for Healthcare improvement in Developing countries through a long-term Partnership is illustrated; encouraging early results in managing the challenge of Paediatric Burns are presented.

An investigation into the impact of nine catchment characteristics on the accuracy of two phosphorus load apportionment models.

Phosphorus (P) load apportionment models (LAMs), requiring only spatially and temporally paired P and flow (Q) measurements, provide outputs of variable accuracy using long-term monthly datasets. Using a novel approach to investigate the impact of catchment characteristics on accuracy variation, 91 watercourses' Q-P datasets were applied to two LAMs, BM and GM, and bootstrapped to ascertain standard errors (SEs). Random forest and regression analysis on data pertaining to catchments' land use, steepness, size, base flow and sinuosity were used to identify the individual relative importance of a variable on SE. For BM, increasing urban cover was influential on raising SEs, accounting for c.19% of observed variation, whilst analysis for GM found no individually important catchment characteristic. Assessment of model fit evidenced BM consistently outperformed GM, modelling P values to ±10% of actual P values in 85.7% of datasets, as opposed to 17.6% by GM. Further catchment characteristics are needed to account for SE variation within both models, whilst interaction between variables may also be present. Future research should focus on quantifying these possible interactions and should expand catchment characteristics included within the random forest. Both LAMs must also be tested on a wide range of high temporal resolution datasets to ascertain if they can adequately model storm events in catchments with diverse characteristics.

Recurrent outbreaks of mumps in Lothian and the impact of waning immunity.

Another large outbreak of mumps occurred in Lothian from October 2017, which coincided with the commencement of the higher education term. During this period 324 cases were notified, most of whom were aged 18-22 years old. Although previous outbreaks had a focus in student populations, 43% of current cases reported that they were not a student. There has been increases in private student housing where students from all universities live, which may have contributed to the wide spread of the outbreak and complicated outbreak control. Information on vaccination status was available for 244 cases (75%), of whom the majority (75.8%) reported having two MMR doses. To investigate potential waning vaccine immunity the mean length of time since last mumps containing vaccine was calculated as 14.3 years. The outbreak was declared over in May 2018 after case numbers returned to background levels. This outbreak highlighted that mumps outbreaks occur cyclically coinciding with new cohorts of susceptible students entering the Lothian population. The lessons from this outbreak are to encourage students to have two MMR doses and also be prepared for mumps outbreaks in the near future. In future outbreaks the utility of a third MMR for outbreak control could be examined.

Spatial relationships of ovarian follicles and luteal structures in dairy cows subjected to ovulation synchronization: Progesterone and risks for luteolysis, ovulation, and pregnancy.

Objectives were to determine relative ovary location of follicles, GnRH-induced corpora lutea (CL), and older CL present in ovaries as part of ovulation synchronization and their associations with progesterone concentration and risk for luteolysis, ovulation, and pregnancy. Cows were exposed to a timed artificial insemination (AI) program [GnRH-1-7 d-PGF2α (1 dose or 2 doses 24 h apart)-56 h after first or only dose of PGF2α-GnRH-2-16 h-timed AI at 72 ± 3 d in milk]. Blood was collected to assess progesterone when ovarian structures were mapped in 694 cows before GnRH-1 and before and 48 h after PGF2α and, in a subset of cows, size of CL (n = 599) and progesterone (n = 380) at 6 d after AI. Dominant follicles and CL in single-ovulating cows were detected more often in right than left ovaries (follicles before GnRH-1: 60.6% right and GnRH-2: 61.2% right; and CL before GnRH-1: 58.6% right and GnRH-2: 66.4% right). Dominant follicles in single-ovulating cows before GnRH-1 tended to be ipsilateral to the CL more often than contralateral (54.8 vs. 45.2%) with co-dominant follicles identified in both ovaries (19.3%). In response to GnRH-1 or GnRH-2, more left-ovary follicles ovulated contralateral to CL (left to right, 54.7%; right to left, 34.7%) than right-ovary follicles, but fewer left-ovary follicles ovulated ipsilateral to CL (left to left: 45.3%) than right-ovary follicles ovulated ipsilateral (right to right: 65.3%). Preovulatory follicles in single-ovulating cows before PGF2α tended to be detected more often ipsilateral than contralateral to CL induced by GnRH-1 (younger CL; 56.5 vs. 43.6%), but were of equal frequency ipsilateral or contralateral to older CL present before GnRH-1. Luteolytic risk was less in cows bearing co-dominant follicles in both ovaries compared with those in either right or left ovaries. Luteolytic risk in single-ovulating cows did not differ between ovaries. Luteolytic risk was greater for cows bearing older CL (86.5%) than for cows bearing younger GnRH-1-induced CL (65.3%) or both (79.6%). Pregnancy risk at 60 d after AI was or tended to be greater in cows having both CL types compared with either younger or older CL, respectively, partly because of greater embryonic loss in the latter 2 cases. More female calves tended to be carried in right horns when conception occurred after first service, whereas the opposite greater female frequency occurred in left horns after repeat services. Right-ovary dominance is evident before and after GnRH treatment.

Impact of specialist management on survival from radiation-associated angiosarcoma of the breast.

BACKGROUND: Radiation-associated angiosarcoma of the breast (RAAS) is a rare complication of adjuvant radiotherapy associated with poor survival. The British Sarcoma Group guidelines recommend that all angiosarcomas are referred to a sarcoma multidisciplinary team, although there is no recommendation that patients are managed within a sarcoma service. The aims of this study were to compare survival, complete excision rates and local recurrence rates of patients managed within a sarcoma service and those managed within local hospitals. METHODS: All patients with RAAS referred to a regional sarcoma service between 1998 and 2015 were identified from prospective databases. Patient records, and radiology, pathology and operation notes were reviewed retrospectively. RESULTS: Thirty-six patients were operated on with curative intent; 26 were managed by the sarcoma service (of whom 21 underwent radical excision of the irradiated field followed by chest wall reconstruction) and ten were managed locally. Median age was 69·5 (range 43-85) years. Disease-specific survival was significantly longer in patients managed by the sarcoma service than in those managed locally: median 91·1 (range 69·2-113·0) versus 48·8 (18·6-79·1) months respectively (P = 0·012). Overall survival rates were similar (P = 0·112). There was no difference in complete excision rate (18 of 26 in sarcoma service versus 5 of 10 in local services; P = 0·456), although the local recurrence rate was significantly lower among patients managed by the sarcoma service (9 of 26 versus 8 of 10; P = 0·015). CONCLUSION: Specialist management of RAAS leads to fewer local recurrences and improved disease-specific survival. Early referral and management within specialist units is recommended.

Imported case of measles in a university setting leading to an outbreak of measles in Edinburgh, Scotland from September to December 2016.

In September 2016, an imported case of measles in Edinburgh in a university student resulted in a further 17 confirmed cases during October and November 2016. All cases were genotype D8 and were associated with a virus strain most commonly seen in South East Asia. Twelve of the 18 cases were staff or students at a university in Edinburgh and 17 cases had incomplete or unknown measles mumps rubella (MMR) vaccination status. The public health response included mass follow-up of all identified contacts, widespread communications throughout universities in Edinburgh and prompt vaccination clinics at affected campuses. Imported cases of measles pose a significant risk to university student cohorts who may be undervaccinated, include a large number of international students and have a highly mobile population. Public health departments should work closely with universities to promote MMR uptake and put in place mass vaccination plans to prevent rapidly spreading measles outbreaks in higher educational settings in future.

Dose frequency of prostaglandin F2α administration to dairy cows exposed to presynchronization and either 5- or 7-day Ovsynch program durations: Ovulatory and luteolytic risks.

We hypothesized (1) that neither duration of the Ovsynch program nor dose frequency of PGF2α would change the proportion of cows with complete luteolysis (progesterone <0.4 ng/mL 72 h after PGF2α) and (2) that the additional GnRH treatment administered as part of a presynchronization program would not alter the proportion of anovulatory cows starting the timed artificial insemination (AI) program compared with an alternative shorter presynch program including only 1 GnRH treatment. Lactating Holstein cows (n = 406) were milked 3 times daily and enrolled in a 2 × 2 × 2 factorial experiment consisting of 8 treatments before the first postpartum AI. Treatments were used to test ovulatory, luteal, and luteolytic outcomes to 3 main effects: (1) 2 GnRH-PGF2α presynchronization programs (PG-3-G vs. Double Ovsynch), (2) 2 Ovsynch program durations [5 d: GnRH (GnRH-1)-5 d-PGF2α-24 h-PGF2α-32 h-GnRH (GnRH-2)-16 h-timed AI; 7 d: GnRH-1-7 d-PGF2α-56 h-GnRH-2-16 h-timed AI], and (3) 2 PGF2α dose frequency treatments (2 × 25 mg) 24 h apart versus 1 dose (1 × 50 mg) of PGF2α administered 72 h before timed AI. The presynchronization treatments of PG-3-G and Double Ovsynch had no effect on the proportion of cows with luteal function at the onset of the Ovsynch treatments (87.9 vs. 86.2%). Although ovulatory responses were similar after GnRH-1 (>60%), Double Ovsynch cows tended to have greater ovulatory responses than PG-3-G after GnRH-2 (95.3 vs. 90.6%). The 2 × 25-mg doses of PGF2α and the 1 × 50-mg dose induced luteolysis in both Ovsynch treatment durations, but the 1 × 50-mg dose was less effective in the 5-d program. More pregnancy per AI (P/AI; 49.2%) tended to occur in the PG-3-G cows in the 7-d program compared with the other treatment combinations (range: 32.4-37.4%; Ovsynch × presynch interaction). In addition, an Ovsynch × PGF2α dose frequency interaction resulted in cows receiving the 1 × 50-mg dose in the 7-d program having the greatest P/AI (46.1%) and cows receiving the 1 × 50-mg dose in the 5-d program having the least P/AI (30.6%). We conclude that complete luteolysis was less effective in the 5-d program when the 1 × 50-mg dose was applied, but both PGF2α dose frequencies (1 × 50 mg and 2 × 25 mg 24 h apart) effectively induced complete luteolysis in the 7-d program. Treatments producing complete luteolysis tended to be related to subsequent pregnancy outcomes.

Invited review: Learning from the future-A vision for dairy farms and cows in 2067.

The world's population will reach 10.4 billion in 2067, with 81% residing in Africa or Asia. Arable land available for food production will decrease to 0.15 ha per person. Temperature will increase in tropical and temperate zones, especially in the Northern Hemisphere, and this will push growing seasons and dairy farming away from arid areas and into more northern latitudes. Dairy consumption will increase because it provides essential nutrients more efficiently than many other agricultural systems. Dairy farming will become modernized in developing countries and milk production per cow will increase, doubling in countries with advanced dairying systems. Profitability of dairy farms will be the key to their sustainability. Genetic improvements will include emphasis on the coding genome and associated noncoding epigenome of cattle, and on microbiomes of dairy cattle and farmsteads. Farm sizes will increase and there will be greater lateral integration of housing and management of dairy cattle of different ages and production stages. Integrated sensors, robotics, and automation will replace much of the manual labor on farms. Managing the epigenome and microbiome will become part of routine herd management. Innovations in dairy facilities will improve the health of cows and permit expression of natural behaviors. Herds will be viewed as superorganisms, and studies of herds as observational units will lead to improvements in productivity, health, and well-being of dairy cattle, and improve the agroecology and sustainability of dairy farms. Dairy farmers in 2067 will meet the world's needs for essential nutrients by adopting technologies and practices that provide improved cow health and longevity, profitable dairy farms, and sustainable agriculture.

Phase II randomized trial of carboplatin, paclitaxel, bevacizumab with or without cixutumumab (IMC-A12) in patients with advanced non-squamous, non-small-cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3508).

BACKGROUND: Cixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor that can potentially reverse resistance and enhance the efficacy of chemotherapy. METHODS: Bevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small-cell lung cancer and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of six cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg i.v. weekly (arm B). RESULTS: Of 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI 5.4-7.1) in arm A versus 7 months (95% CI 5.7-7.6) in arm B (P = 0.33); hazard ratio 0.92 (95% CI 0.65-1.31). Objective response was 46.2% versus 58.7% in arm A versus arm B (P = 0.15). The median overall survival was 16.2 months in arm A versus 16.1 months in arm B (P = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab. CONCLUSIONS: The addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in non-small-cell lung cancer. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II trials. CLINICALTRIALS.GOV IDENTIFIER: NCT00955305.

Defining and quantifying frustration in the energy landscape: Applications to atomic and molecular clusters, biomolecules, jammed and glassy systems.

The emergence of observable properties from the organisation of the underlying potential energy landscape is analysed, spanning a full range of complexity from self-organising to glassy and jammed systems. The examples include atomic and molecular clusters, a ß-barrel protein, the GNNQQNY peptide dimer, and models of condensed matter that exhibit structural glass formation and jamming. We have considered measures based on several different properties, namely, the Shannon entropy, an equilibrium thermodynamic measure that uses a sample of local minima, and indices that require additional information about the connections between local minima in the form of transition states. A frustration index is defined that correlates directly with key properties that distinguish relaxation behaviour within this diverse set. The index uses the ratio of the energy barrier to the energy difference with reference to the global minimum. The contributions for each local minimum are weighted by the equilibrium occupation probabilities. Hence we obtain fundamental insight into the connections and distinctions between systems that cover the continuum from efficient structure-seekers to landscapes that exhibit broken ergodicity and rare event dynamics.

The menopausal hot flush: a review.

The hot flush is the most characteristic and often the most distressing symptom of the menopause. It is a unique feature and yet the mechanism and health implications are still not fully understood. This review summarizes some of the current thoughts on factors contributing to flushing, the physiological, vascular and neuroendocrine changes associated with flushing and the possible cardiovascular and other health implications for women experiencing hot flushes. Therapy is not discussed.

A 100-Year Review: Practical female reproductive management.

Basic knowledge of mechanisms controlling reproductive processes in mammals was limited in the early 20th century. Discoveries of physiologic processes and mechanisms made early in the last century laid the foundation to develop technologies and programs used today to manage and control reproduction in dairy cattle. Beyond advances made in understanding of gonadotropic support and control of ovarian and uterine functions in basic reproductive biology, advancements made in artificial insemination (AI) and genetics facilitated rapid genetic progress of economically important traits in dairy cattle. Technologies associated with management have each contributed to the evolution of reproductive management, including (1) hormones to induce estrus and ovulation to facilitate AI programs; (2) pregnancy diagnosis via ultrasonography or by measuring conceptus-derived pregnancy-associated glycoproteins; (3) estrus-detection aids first devised for monitoring only physical activity but that now also quantitate feeding, resting, and rumination times, and ear temperature; (4) sex-sorted semen; (5) computers and computerized record software packages; (6) handheld devices for tracking cow location and retrieving cow records; and (7) genomics for increasing genetic progress of reproductive and other economically important traits. Because of genetic progress in milk yield and component traits, the dairy population in the United States has been stable since the mid 1990s, with approximately 9 to 9.5 million cows. Therefore, many of these technologies and changes in management have been developed in the face of increasing herd size (4-fold since 1990), and changes from pastoral or dry-lot dairies to increased housing of cows in confinement buildings with freestalls and feed-line lockups. Management of groups of "like" cows has become equally important as management of the one. Management teams, including owner-managers, herdsmen, AI representatives, milkers, and numerous consultants dealing with health, feeding, and facilities, became essential to develop working protocols, monitor training and day-to-day chores, and evaluate current trends and revenues. Good management teams inspect and follow through with what is routinely expected of workers. As herd size will undoubtedly increase in the future, practical reproductive management must evolve to adapt to the new technologies that may find more herds being milked robotically and applying technologies not yet conceived or introduced.

Increasing estrus expression in the lactating dairy cow.

Using an activity monitoring system (AMS) equipped with an accelerometer, 2 experiments were conducted to test the hypotheses that (1) enhancing progesterone before inducing luteolysis or (2) exposing cows to estradiol cypionate (ECP) or testosterone propionate (TP) after luteolysis would increase occurrence and intensity of estrus. Our goal was to determine if more cows could be detected in estrus by an AMS compared with other estrus-detection aids. In experiment 1, cows (n=154) were fitted with both an AMS collar and a pressure-sensitive, rump-mounted device (HeatWatch; HW) and assigned to 3 treatments: (1) no CL + progesterone insert (CIDR) for 5d, (2) CL only, or (3) CL + 2 CIDR inserts for 5d to achieve a range in concentrations of progesterone. Prostaglandin F2α was administered to all cows upon CIDR insert removal or its equivalent. Progesterone concentration up to 72h posttreatment was greatest in CL + 2 CIDR, followed by CL only, and no CL + CIDR cows. Estrus occurred 14 to 28h earlier in no CL + CIDR compared with CL-bearing cows. Estrus intensity was greater for CL + 2 CIDR than for CL-only cows. The AMS and HW detected 70 and 59% of cows defined to be in estrus, respectively. In experiment 2, cows (n=203) were equipped with both an AMS and a friction-activated, rump-mounted patch (Estrotect patch) and assigned to receive 1mg of ECP, 2mg of TP, or control 24h after PGF2α. Concentrations of estradiol 24 and 48h after treatment were greater in ECP cows compared with controls. Estrus expression detected by AMS or patches in cows defined to be in estrus tended to be greater or was greater for ECP compared with controls, respectively. Compared with controls and in response to TP or ECP, estrus occurred 8 to 18h earlier and was of greater intensity for ECP cows, respectively. The AMS and patches determined 73 and 76% of cows defined to be in estrus, respectively. Of cows exposed to the AMS, HW, or patches, 70, 61, and 75%, respectively, were detected in estrus and more than 93% of these subsequently ovulated. In contrast, of the residual cows not detected in estrus, 62 to 77% ovulated in the absence of detected estrus. Only ECP was successful in inducing more expression and intensity of estrus, and proportions of cows detected in estrus exceeded 80%. Given the large proportion of cows equipped with AMS collars ovulating in the absence of estrus, further research is warranted to determine if more pregnancies can be achieved by inseminating those cows not detected in estrus at an appropriate time when PGF2α is administered to induce luteolysis.

Detection of an undersea acoustic communications network by an energy detector.

A theory is presented for the upper bound on the mean time τ to the detection of an undersea acoustic communications network by an energy detector whose initial position and heading are uniformly distributed random variables. The network is an infinite square grid of omnidirectional transmit-receive nodes on a flat bottom. Each node transmits to one nearest neighbor at a bit-rate R equal to Shannon's capacity, maximizing τ. The network sets a signaling bandwidth W and node-spacing D. The detector sets a false-alarm rate, integration time, height above the bottom, and speed. For W = 5 kHz and D = 1 km, τ is computed as a function of R in 200 -m water with propagation varying from spherical to cylindrical spreading, volume absorption of 2 dB per km (corresponding approximately to 15 kHz), and illustrative values for other parameters.