2023 Undetectable = Untransmittable global policy roundtable report: a multistakeholder perspective on Undetectable = Untransmittable research and policy priorities.

Background Launched in 2016 by Prevention Access Campaign, the 'Undetectable=Untransmittable' (U=U) campaign empowers people living with HIV to live full social, sexual and reproductive lives, dismantle stigma, promote increased treatment access, and advocate for updated HIV guidelines. Methods Key priorities for promoting improvements to community-centred, evidence-informed U=U policy and research were the focus of a half-day global roundtable held in 2023 alongside the 12th International AIDS Society Conference in Brisbane, Australia. After a series of presentations, experts in U=U research, policymaking, advocacy and HIV clinical care participated in facilitated discussions, and detailed notes were taken on issues related to advancing U=U policy and research. Results Expert participants shared that knowledge and trust in U=U remains uneven, and is largely concentrated among people living with HIV, particularly those connected to gay and bisexual networks. It was agreed that there is a need to ensure all members of priority populations are explicitly included in U=U policies that promote U=U. Participants also identified a need for policymakers, healthcare professionals, advocates and researchers to work closely with community-based organisations to ensure the U=U message is relevant, useful, and utilised in the HIV response. Adopting language, such as 'zero risk', was identified as crucial when describing undetectable viral load as an effective HIV prevention strategy. Conclusion U=U can have significant benefits for the mental and physical wellbeing of people living with HIV. There is an urgent need to address the structural barriers to HIV care and treatment access to ensure the full benefits of U=U are realised.

Influence of artificial drainage system design on the nitrogen attenuation potential of gley soils: Evidence from hydrochemical and isotope studies under field-scale conditions.

In North Atlantic Europe intensive dairy farms have a low nitrogen (N) use efficiency, with high N surpluses often negatively affecting water quality. Low feed input systems on heavy textured soils often need artificial drainage to utilise low cost grassland and remain profitable. Heavy textured soils have high but variable N attenuation potential, due to soil heterogeneity. Furthermore, drainage system design can influence the potential for N attenuation and subsequent N loadings in waters receiving drainage from such soils. The present study utilises end of pipe, open ditch and shallow groundwater sampling points across five sites in SW Ireland to compare and rank sites based on N surplus, water quality and "net denitrification", and to develop a conceptual framework for the improved management of heavy textured dairy sites to inform water quality N sustainability. This includes both drainage design and "net denitrification" criterion, as developed within this study.N surplus ranged from 211 to 292 kg N/ha (mean of 252 kg N/sourha) with a common source of organic N across all locations. The predicted soil organic matter (SOM) N release potential from top-subsoil layers was high, ranging from 115 to >146 kg N/ha. Stable isotopes analyses showed spatial variation in the extent of specific N-biotransformation processes, according to drainage location and design. Across all sites, nitrate (NO3-N) was converted to ammonium (NH4+-N), which migrated offsite through open ditch and shallow groundwater pathways. Using the ensemble data the potential for soil N attenuation could be discriminated by 3 distinct groups reflecting the relative dominance of in situ N-biotransformation processes deduced from water composition: Group 1 (2 farms, ranked with high sustainability, NH4+ < 0.23 mg N/l, δ15N-NO3- > 5‰ and δ18O-NO3- > 10‰), low NH4+-N concentration coupled with a high denitrification potential; Group 2 (1 farm with moderate sustainability, NH4+ < 0.23 mg N/l, δ15N-NO3- < 8‰ and δ18O-NO3- < 8‰), low NH4+-N concentration with a high nitrification potential and a small component of complete denitrification; Group 3 (2 farms, ranked with low sustainability, NH4+ > 0.23 mg N/l, 14‰ > Î´15N-NO3- > 5‰ and 25‰ > Î´18O-NO3- > -2‰), high NH4+-N concentration due to low denitrification. The installation of a shallow drainage system (e.g. mole or gravel moles at 0.4 m depth) reduced the "net denitrification" ranking of a site, leading to water quality issues. From this detailed work an N sustainability tool for any site, which presents the relationship between drainage class, drainage design (if present), completeness of denitrification, rate of denitrification and NH4-N attenuation was developed. This tool allows a comparison or ranking of sites in terms of their N sustainability. The tool can also be used pre-land drainage and presents the consequences of future artificial land drainage on water quality and gaseous emissions at a given site.

Warming and redistribution of nitrogen inputs drive an increase in terrestrial nitrous oxide emission factor.

Anthropogenic nitrogen inputs cause major negative environmental impacts, including emissions of the important greenhouse gas N2O. Despite their importance, shifts in terrestrial N loss pathways driven by global change are highly uncertain. Here we present a coupled soil-atmosphere isotope model (IsoTONE) to quantify terrestrial N losses and N2O emission factors from 1850-2020. We find that N inputs from atmospheric deposition caused 51% of anthropogenic N2O emissions from soils in 2020. The mean effective global emission factor for N2O was 4.3 ± 0.3% in 2020 (weighted by N inputs), much higher than the surface area-weighted mean (1.1 ± 0.1%). Climate change and spatial redistribution of fertilisation N inputs have driven an increase in global emission factor over the past century, which accounts for 18% of the anthropogenic soil flux in 2020. Predicted increases in fertilisation in emerging economies will accelerate N2O-driven climate warming in coming decades, unless targeted mitigation measures are introduced.

Origin of whales in epicontinental remnant seas: new evidence from the early eocene of pakistan.

Pakicetus inachus from the early Eocene of Pakistan is the oldest and most primitive cetacean known. The dentition of Pakicetus resembles that of carnivorous mesonychid land mammals as well as middle Eocene cetaceans. The otic region of the cranium lacks characteristic specializations of whales necessary for efficient directional hearing under water. Pakicetus occurs with a land-mammal fauna in fluvial sediments bordering epicontinental Eocene remnants of the eastern Tethys seaway. Discovery of Pakicetus strengthens earlier inferences that whales originated from terrestrial carnivorous mammals and suggests that whales made a gradual transition from land to sea in the early Eocene, spending progressively more time feeding on planktivorous fishes in shallow, highly productive seas and embayments associated with tectonic closure of eastern Tethys.

Order of function of the budding-yeast mitotic exit-network proteins Tem1, Cdc15, Mob1, Dbf2, and Cdc5.

The Dbf2 protein kinase functions as part of the mitotic-exit network (MEN), which controls the inactivation of the Cdc28-Clb2 kinase in late mitosis [1]. The MEN includes the Tem1 GTP binding protein; the kinases Cdc15 and Cdc5; Mob1, a protein of unknown function; and the phosphatase Cdc14 [2]. Here we have used Dbf2 kinase activity to investigate the regulation and order of function of the MEN. We find that Tem1 acts at the top of the pathway, upstream of Cdc15, which in turn functions upstream of Mob1 and Dbf2. The Cdc5 Polo-like kinase impinges at least twice on the MEN since it negatively regulates the network, probably upstream of Tem1, and is also required again for Dbf2 kinase activation. Furthermore, we find that regulation of Dbf2 kinase activity and actin ring formation at the bud neck are causally linked. In metaphase-arrested cells, the MEN inhibitor Bub2 restrains both Dbf2 kinase activity [3] and actin ring formation [4]. We find that the MEN proteins that are required for Dbf2 kinase activity are also required for actin ring formation. Thus, the MEN is crucial for the regulation of cytokinesis, as well as mitotic exit.

Anthropometric trends from 1997 to 2012 in infants born at ⩽28 weeks' gestation or less.

OBJECTIVE: Postnatal growth failure is common after preterm birth, in particular for infants born at ⩽28 weeks' gestation, but it is unknown if growth-to-term equivalent age has improved over the years as neonatal intensive care in general, and infant nutrition in particular, have improved. The objective of the study was to evaluate anthropometric trends at NICU discharge for infants born at ⩽28 weeks' gestation using a large national database. STUDY DESIGN: Analysis of growth in weight, length, head circumference and body mass index (kg m2) in 23 005 infants born in 1997 to 2012 who survived to neonatal intensive care unit discharge at ⩽41 weeks' postmenstrual age. RESULTS: Discharge weight, length, head circumference and body mass index were converted to Z-scores using a reference database, and growth trends over the 16 years were summarized. Discharge results also were summarized for common neonatal morbidities, including chronic lung disease. Gestational age at birth and postmenstrual age at discharge were similar across the 16 years. Discharge weight, length and head circumference Z-scores were all below the median, but head circumference Z-scores consistently were closer to the median than were weight and length. In 1997 compared with 2012, the weight Z-score improved from -1.5 to -0.6; the length Z-score increased the least, from -1.68 to just -1.16; the head circumference Z-score improved from -0.68 to -0.30; and the body mass index Z-score increased from -0.66 to 0.19. Percent small-for-gestational age at birth was stable across the years at 8.4 to 9.3%, and the frequency of postnatal growth failure at discharge improved from 55.4% in 1997 to 19.6% in 2012. CONCLUSIONS: Growth-to-discharge progressively improved from 1997 to 2012, but Z-scores remained below the reference median for weight, length and head circumference. Length Z-scores were consistently significantly less than for weight, and body mass index Z-scores have been above the reference median since 2002. Prospective studies are needed to quantify anthropometric trends in relation to body composition and to current nutritional strategies.

Towards quantifying the role of hydrogen bonding within amphiphile self-association and resultant aggregate formation.

Herein, we present a series of five tetrabutylammonium (TBA) sulfonate-urea amphiphilic salts. In solution these amphiphilic salts have been shown to form a variety of self-associated species. The proportion and type of which are both solvent and concentration dependent. In DMSO-d6 a variety of NMR experiments provide evidence towards the formation of mainly dimeric over larger aggregate species. Increasing the percentage of water was shown to increase the concentration of the larger aggregates over dimers in solution. A correlation was established between critical micelle concentration (CMC) values obtained in a 1 : 19 EtOH : H2O mixture, dimeric self-association constants obtained in a DMSO-d6 - 0.5% H2O and the results of simple semi-empirical PM6 computational modelling methods. This approach begins to quantify the role of hydrogen bonding in amphiphile self-association and the effects it imparts on surfactant properties. This consequently provides preliminary evidence that these properties maybe predicted by simple low level computational modelling techniques.

The US radiation dosimetry standards for 60Co therapy level beams, and the transfer to the AAPM accredited dosimetry calibration laboratories.

This work reports the transfer of the primary standard for air kerma from the National Institute of Standards and Technology (NIST) to the secondary laboratories accredited by the American Association of Physics in Medicine (AAPM). This transfer, performed in August of 2003, was motivated by the recent revision of the NIST air-kerma standards for 60Co gamma-ray beams implemented on July 1, 2003. The revision involved a complete recharacterization of the two NIST therapy-level 60Co gamma-ray beam facilities, resulting in new values for the air-kerma rates disseminated by the NIST. Some of the experimental aspects of the determination of the new air-kerma rates are briefly summarized here; the theoretical aspects have been described in detail by Seltzer and Bergstrom ["Changes in the U.S. primary standards for the air-kerma from gamma-ray beams," J. Res. Natl. Inst. Stand. Technol. 108, 359-381 (2003)]. The standard was transferred to reference-class chambers submitted by each of the AAPM Accredited Dosimetry Calibration Laboratories (ADCLs). These secondary-standard instruments were then used to characterize the 60Co gamma-ray beams at the ADCLs. The values of the response (calibration coefficient) of the ADCL secondary-standard ionization chambers are reported and compared to values obtained prior to the change in the NIST air-kerma standards announced on July 1, 2003. The relative change is about 1.1% for all of these chambers, and this value agrees well with the expected change in chambers calibrated at the NIST or at any secondary-standard laboratory traceable to the new NIST standard.

Physiological regulation of eukaryotic topoisomerase II.

Topoisomerase II is an essential enzyme in all organisms with several independent roles in DNA metabolism. In this article we review our knowledge on the regulation of the expression and catalytic activity of topoisomerase II in both lower and higher eukaryotes. Current data indicate that the regulation of topoisomerase II gene expression is complex, with positive and negative controls in evidence at the level of both promoter activity and mRNA stability. Similarly, the activity of the mature enzyme can be regulated by the action of several different protein kinases. Of particular interest is the cell cycle-dependent phosphorylation of topoisomerase II, including multiple, mitosis-specific modifications, which are proposed to regulate the essential chromosome decatenation activity of the enzyme.

Smart, reusable labels for assessing self-cleaning films.

Novel, reversible (reusable) photocatalyst activity indicator labels, which undergo a rapid colour change when in contact with a photocatalytic film via the photoreduction of methylene blue contained within the label's adhesive, are explored as a method for assessing the activity of self-cleaning glass in situ and the laboratory, using digital photography.

The real costs of emesis--an economic analysis of ondansetron vs. metoclopramide in controlling emesis in patients receiving chemotherapy for cancer.

The cost effectiveness of ondansetron was compared with that of metoclopramide in the prevention of acute emesis due to highly emetogenic chemotherapy in an open, randomised, parallel group pilot study. Ondansetron was given as three 8 mg intravenous doses (0, 4 and 8 h) and metoclopramide as an intravenous loading dose (3 mg/kg) followed by a maintenance dose of 0.5 mg/kg/h for 8 h. Therapeutic outcomes and full utilisation costs, that is nursing time, material costs, in addition to drug acquisition prices were recorded for each antiemetic for 24 h following chemotherapy. The cost per successfully treated patient (< or = 1 emetic episode and no adverse events) was 95.20 pounds for ondansetron and 92.18 pounds for metoclopramide. The results of the study therefore suggest that for the control of acute emesis due to highly emetogenic chemotherapy ondansetron and metoclopramide are equally cost-effective treatments.

Clinical economics review: irritable bowel syndrome.

The ubiquitous nature of irritable bowel syndrome (IBS), coupled with a lack of good treatment options, has created the impression that the condition must represent a large drain on health-care resources. The literature certainly appears to support this view but is largely based on patients seen in referral centres (10-15%) and it may not be appropriate to extrapolate these data to the IBS population as a whole (85-90%). In addition to reviewing such literature that exists on the economics of IBS, this paper contains some new data, which suggest that the direct costs of the condition, certainly in the UK, may not be quite as high as has previously been assumed. This may be partly due to factors such as the low cost of the drugs used to treat the condition and the tendency for many patients to stop consulting because of disenchantment with the inadequacies of current therapy. Conversely, the indirect and intangible costs of the disorder appear to be much greater, but these burdens obviously do not have such an impact on those responsible for purchasing and providing health care for IBS sufferers. Paradoxically, if a new, effective therapy for IBS were forthcoming, the situation could change dramatically, especially if it involved a new drug. Any such agent would inevitably be more expensive than anything available today, leading to a potentially dramatic escalation in the direct costs of this disorder.

Economic and social impact of migraine.

We sent an anonymous self-administered questionnaire to 4200 employees of a Trust hospital, 1903 of whom returned it. We identified 158 migraine sufferers according to International Headache Society (IHS) criteria. These sufferers estimated 2.0 days/year absence from work, and an equivalent of 5.5 days/year lost by reduced effectiveness at work, caused by their migraine at an estimated financial cost of over 50,000 pounds to the Trust. An additional 220 individuals who had received a diagnosis of migraine from a doctor but fulfilled only 3/4 IHS criteria lost the equivalent of 6.7 days off work at a further cost of 63,000 pounds). Few patients had consulted their general practitioner about their migraines in the last 3 months. Most (78%) were using only over-the-counter medication. Migraine patients should be encouraged to seek medical attention.

Housing quality and mental health.

This study examined the potential link between housing quality and mental health. First, the development of a psychometrically sound, observer-based instrument to assess physical housing quality in ways conceptually relevant to psychological health is reported. Then 2 different studies, including a prospective longitudinal design, demonstrate that physical housing quality predicts mental health. Possible underlying psychosocial processes for the housing quality-psychological distress link are discussed.

Use of a multileaf collimator as a dynamic missing-tissue compensator.

A dynamic multileaf collimator (D-MLC) was used to investigate the feasibility of producing missing-tissue compensators. The modulation of the x-ray field in two dimensions produced by conventional physical compensators was mimicked by delivering a sequence of D-MLC-shaped subfields. A method is introduced to calculate monitor units (MU) for dynamically compensated fields that is analogous to and expands upon methods used for conventional compensating filter MU calculations. In this investigation, the tissue deficit at the surface of an anatomical phantom was measured using a Moiré camera. The tissue deficit data were used to generate a series of D-MLC subfields that, delivered in sequence, provided the compensated treatment. Film was used to integrate the dose delivered to a specified depth of compensation. Isodose distributions were measured for uncompensated fields, fields compensated with a conventional lead or plastic filter, and fields compensated with the D-MLC. A comparison of the dose distributions shows the compensation achieved with the dynamic compensating filter is comparable to that achieved using conventional physical compensating filters.

Rotational kernels for conformal therapy.

Conformal therapy treatment planning involves determining an irradiation strategy to deliver a dose distribution which is optimized for a given tumor volume. A technique proposed by Brahme restricts the search for the optimal treatment strategy to x-ray distributions in which points within the target volume are irradiated uniformly under rotation of the beam source around the patient. The dose distribution in this case may be calculated as a convolution of an irradiation weighting distribution with an invariant kernel. A procedure is described for calculating three-dimensional kernels to be used for clinical treatment planning with x rays produced by an electron accelerator. The convolution kernel is calculated as the sum of pencil beams irradiating the center of a cylindrical phantom uniformly from all angles. The shape of the kernel at points off the center of the phantom is investigated by means of numerical calculations which support the assumption that the kernel is invariant with respect to position within the phantom. The calculated kernels are verified by comparison with experimentally measured rotational arc dose distributions.

Potential and limitations of invariant kernel conformal therapy.

A treatment planning methodology was developed to investigate the invariant kernel form of conformal therapy proposed by Brahme. Three-dimensional dose distributions were calculated by convolving a rotationally symmetric, invariant kernel with weighting distributions. Fourier transform convolution techniques implemented on an array processor were used to achieve high calculation speeds, thereby allowing iterative techniques in the spatial and frequency domains for computing dose distributions that asymptotically approach a desired dose distribution. To use rotationally symmetric kernels, the generality of the solution is traded for a fast, deterministic, inverse planning approach. The limitations imposed on the dose distributions by this loss of generality are characterized and tentative conclusions are drawn about the potentials and limits of clinical application of this form of the methodology. Further developments of the concept are suggested.

Dosimetry of effective wedge fields produced by an internal wedge.

A procedure is described to calculate the monitor unit ratios required to produce effective wedge fields having a desired wedge angle by combining an internal 60 degrees wedge with an open field. Complementary procedures are derived and demonstrated for calculating the effective wedge dose distributions with wedge angles of 15 degrees, 30 degrees, and 45 degrees using the central axis depth dose data and off-axis ratios of the open field and the 60 degrees wedged field. Measurements at five points on and off the central axis within each field and measurements of the effective wedge factor demonstrated that the calculated wedge distributions were correctly delivered to within 2% in all cases.

Development of a short version of the Barriers Questionnaire.

Among the reasons that cancer pain is not controlled adequately are patient-related barriers. Patient beliefs that may contribute to poor outcome have been measured in previous research with the Barriers Questionnaire (BQ). The purpose of this study was to examine the internal consistency of a shortened version of the BQ. A sample of 217 outpatients with cancer completed a 17-item version of the scale. Factor analysis suggested two subscales, one reflecting beliefs about communication about pain and the other reflecting beliefs about the use of analgesics. Both subscales demonstrated adequate internal consistency. Beliefs did not differ between patients who had and those who had not experienced pain within the previous two weeks. Findings suggest the shortened BQ provides an internally consistent measure of two broad patient barriers to pain management.

Different motion sensitive units are involved in recovering the direction of moving lines.

We studied direction discrimination for lines moving obliquely relative to their orientation. Manipulating contrast, length and duration of motion, we found systematic errors in direction discrimination at low contrast, long length and/or short durations. These errors can be accounted for by a competition between ambiguous velocity signals originating from contour motion processing units and signals from line terminator processing units. The dynamic of this competition can be described by a simple model involving two different classes of processing units with different contrast thresholds, different integration time constants and different levels of response saturation.