The value of predicting restriction of fetal growth and compromise of its wellbeing: Systematic quantitative overviews (meta-analysis) of test accuracy literature

Background

Improving maternal health by reducing maternal mortality constitutes the fifth Millennium Development Goal and represents a key public health challenge in the United Republic of Tanzania. In response to the need to evaluate and monitor safe motherhood interventions, this study aims at assessing the coverage of obstetric care according to the Unmet Obstetric Need (UON) concept by obtaining information on indications for, and outcomes of, major obstetric interventions. Furthermore, we explore whether this concept can be operationalised at district level.

Methods

A two year study using the Unmet Obstetric Need concept was carried out in three districts in Tanga Region, Tanzania. Data was collected prospectively at all four hospitals in the region for every woman undergoing a major obstetric intervention, including indication and outcome. The concept was adapted to address differentials in access to emergency obstetric care between districts and between rural and urban areas. Based upon literature and expert consensus, a threshold of 2% of all deliveries was used to define the expected minimum requirement of major obstetric interventions performed for absolute maternal indications.

Results

Protocols covering 1,260 complicated deliveries were analysed. The percentage of major obstetric interventions carried out in response to an absolute maternal indication was only 71%; most major obstetric interventions (97%) were caesarean sections. The most frequent indication was cephalo-pelvic-disproportion (51%). The proportion of major obstetric interventions for absolute maternal indications performed amongst women living in urban areas was 1.8% of all deliveries, while in rural areas it was only 0.7%. The high proportion (8.3%) of negative maternal outcomes in terms of morbidity and mortality, as well as the high perinatal mortality of 9.1% (still birth 6.9%, dying within 24 hours 1.7%, dying after 24 hours 0.5%) raise concern about the quality of care being provided.

Conclusion

Based on the 2% threshold, Tanga Region – with an overall level of major obstetric interventions for absolute maternal indications of 1% and a caesarean section rate of 1.4% – has significant unmet obstetric need with a considerable rural-urban disparity. The UON concept was found to be a suitable tool for evaluating and monitoring the coverage of obstetric care at district level.     

Hepatic sarcoidosis complicating treatment-naive viral hepatitis

Hepatic sarcoidosis is usually asymptomatic but rarely leads to adverse liver-related outcome.Co-existence of viral hepatitis and hepatic sarcoidosis is a rare,but recognised phenomenon.Obtaining a balance between immune suppression and anti-viral therapy may be problematic.Immunosuppression in the presence of viral hepatitis can lead to rapid deterioration of liver disease.Similarly,anti-viral therapy may exacerbate granulomatous hepatitis.Here we present two cases of viral hepatitis co-existing with sarcoidosis that illustrate successful management strategies.In one,hepatitis B replication was suppressed with oral antiviral therapy before commencing prednisolone.In the second,remission of hepatic sarcoidosis was achieved with prednisolone,before treating hepatitis C and obtaining a sustained virological response with pegylated interferon and ribavirin therapy.     

Vacuolation in hepatocyte nuclei is a marker of senescence

Hepatocyte nuclear vacuolation is considered benign and associated with non-alcohol-related fatty liver disease. Vacuolated hepatocyte nuclei were compared with non-vacuolated hepatocyte nuclei in eight patients with advanced fibrosis and a spectrum of liver disease to explore the hypothesis that such nuclei represent senescence. Age- and sex-matched liver donors served as normal tissue. In normal liver <0.01% hepatocytes showed nuclear vacuolation. In contrast, nuclear vacuolation was present in all patients with liver disease, ranging from 0.1% to 11.7% hepatocytes, irrespective of the aetiology of liver disease and independent of insulin resistance. There was a close association between nuclear vacuolation and increased nuclear area, p21 expression, γ H(2)AX expression and the absence of Mcm-2, consistent with senescence and cell cycle arrest. Nuclear vacuolation in hepatocytes is a marker of senescence and likely to be a consequence of liver injury, unrelated to insulin resistance.     

The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis

STUDY QUESTION: Is there an association between high levels of sperm DNA damage and miscarriage? SUMMARY ANSWER: Miscarriage rates are positively correlated with sperm DNA damage levels. WHAT IS KNOWN ALREADY: Most ejaculates contain a subpopulation of sperm with DNA damage, also referred to as DNA fragmentation, in the form of double or single-strand breaks which have been induced in the DNA prior to or following ejaculation. This DNA damage may be particularly elevated in some subfertile men, hence several studies have examined the link between sperm DNA damage levels and conception and miscarriage rates. STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis of studies which examined the effect of sperm DNA damage on miscarriage rates was performed. Searches were conducted on MEDLINE, EMBASE and the Cochrane Library without any language restrictions from database inception to January 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used the terms 'DNA damage' or 'DNA fragmentation' combined with 'miscarriage', 'abortion' or 'pregnancy' to generate a set of relevant citations. Data extraction was performed by two reviewers. Study quality was assessed using the Newcastle-Ottawa Scale. Meta-analysis of relative risks of miscarriage was performed with a random effects model. Subgroup analyses were performed by the type of DNA damage test, whether the sperm examined were prepared or from raw semen and for pregnancies resulting from IVF or ICSI treatment. MAIN RESULTS AND THE ROLE OF CHANCE: We identified 16 cohort studies (2969 couples), 14 of which were prospective. Eight studies used acridine orange-based assays, six the TUNEL assay and two the COMET assay. Meta-analysis showed a significant increase in miscarriage in patients with high DNA damage compared with those with low DNA damage [risk ratio (RR) = 2.16 (1.54, 3.03), P < 0.00001)]. A subgroup analysis showed that the miscarriage association is strongest for the TUNEL assay (RR = 3.94 (2.45, 6.32), P < 0.00001). LIMITATIONS, REASONS FOR CAUTION: There is some variation in study characteristics, including the use of different assays and different thresholds for DNA damage and the definition of pregnancy loss. WIDER IMPLICATIONS OF THE FINDINGS: The use of methods which select sperm without DNA damage for use in assisted conception treatment may reduce the risk of miscarriage. This finding indicates that assays detecting DNA damage could be considered in those suffering from recurrent pregnancy loss. Further research is necessary to study the mechanisms of DNA damage and the potential therapeutic effects of antioxidant therapy. STUDY FUNDING/COMPETING INTEREST(S): None.     

A systematic review and thematic synthesis of qualitative studies on maternal emergency transport in low- and middle-income countries

Background

Most maternal deaths are preventable with emergency obstetric care; therefore, ensuring access is essential. There is little focused information on emergency transport of pregnant women.

Objectives

The literature on emergency transport of pregnant women in low- and middle-income countries (LMICs) was systematically reviewed and synthesized to explore current practices, barriers, and facilitators for transport utilization.

Search strategy

MEDLINE, EMBASE, BNI, Cochrane Library, CINAHL, African Index Medicus, ASSIA, QUALIDATA, RHL, and Science Citation Index (inception to April 2012) were searched without language restriction.Selection criteria: Studies using qualitative methodology and reporting on emergency transportation in LMICs were included.

Data collection and analysis

Thematic framework and synthesis through examination and translation of common elements were used to analyze and synthesize the data.

Main results

Twenty-nine articles were included. Eight major themes were identified: time for transport; transport options; geography; local support; autonomy; culture; finance; and ergonomics. Key issues were transport availability; transport speed; terrain; meteorology; support; dependence for decision making; cultural issues; cost; and lack of safe, comfortable positioning during transport.

Conclusion

Themes should be appreciated within local contexts to illuminate barriers and facilitators. Potential solutions include motorcycle ambulance programs, collaboration with taxi services, community education, subsidies, and vehicle maintenance.     

Sensory determinants of behavioral dynamics in Drosophila thermotaxis

Complex animal behaviors are built from dynamical relationships between sensory inputs, neuronal activity, and motor outputs in patterns with strategic value. Connecting these patterns illuminates how nervous systems compute behavior. Here, we study Drosophila larva navigation up temperature gradients toward preferred temperatures (positive thermotaxis). By tracking the movements of animals responding to fixed spatial temperature gradients or random temperature fluctuations, we calculate the sensitivity and dynamics of the conversion of thermosensory inputs into motor responses. We discover three thermosensory neurons in each dorsal organ ganglion (DOG) that are required for positive thermotaxis. Random optogenetic stimulation of the DOG thermosensory neurons evokes behavioral patterns that mimic the response to temperature variations. In vivo calcium and voltage imaging reveals that the DOG thermosensory neurons exhibit activity patterns with sensitivity and dynamics matched to the behavioral response. Temporal processing of temperature variations carried out by the DOG thermosensory neurons emerges in distinct motor responses during thermotaxis.Navigation toward environmental conditions that improve survival and fitness is of near-universal importance in motile biological organisms. Quantitative analysis of such animal behaviors to defined sensory inputs is a powerful approach to elucidate how behavior is encoded in underlying neurons and circuits. The advantage of studying navigation in small, optically transparent, genetically modifiable animals like Caenorhabditis elegans (1) or Drosophila larvae (2) is the opportunity to dissect sensory, neuronal, and behavioral dynamics in live animals by using optical neurophysiology and optogenetics throughout the nervous system.The Drosophila melanogaster larva navigates gradients of many sensory cues, including light, temperature, odors, and tastes, but with fewer neurons in its sensory periphery and brain than the adult. Moreover, the simpler body plan and crawling movements of the larva facilitate the precise quantification of behavioral dynamics. Poikilotherms like C. elegans or Drosophila use sensitive thermosensory mechanisms to navigate moderate temperature ranges, thereby enabling them to use their environments to regulate their own body temperatures (3, 4). Here, we study sensory and behavioral dynamics during positive thermotaxis (i.e., cool avoidance) by the Drosophila larva. Tracking the movements of Drosophila exploring temperature, olfactory, or gaseous gradients has shown that their navigation is generated by a sequence of two alternating motor programs: runs involving peristaltic forward movement that are interrupted by turns involving probing side-to-side head sweeps until the initiation of a new run (5–8). Larvae negotiating temperature gradients stochastically transition between runs and turns by strategies that cause runs pointed in favorable directions to be more frequent and longer than runs pointed in unfavorable directions. These transitions between runs and turns are dependent on temporal variations in ambient temperature. Warming over time is favorable and cooling is unfavorable during positive thermotaxis. However, the sensitivity and dependence of these transitions on measurements of temperature variations by the nervous system is not known.The sensory basis for positive thermotaxis in the Drosophila larva is also poorly understood. In adult Drosophila, separate sensory neurons in the arista of the antennae contribute to cold and warm avoidance (9). These sensory neurons project to distinct glomeruli in the brain, suggesting labeled lines from the sensory periphery to the brain that drive flies toward preferred temperatures. In addition, dTRPA1-expressing neurons in the central brain function as internal temperature sensors that also contribute to warm avoidance (10). Several genes that can affect the range of preferred temperatures in larvae have been identified, which include transient receptor potential (trp) channels and rhodopsin (11, 12). However, none of these genes are required for driving larval movement toward preferred temperatures. It has been suggested that the larva’s terminal organ ganglion (TOG) is activated by temperature changes, but specific neurons that might be required for positive thermotaxis were not identified (13).In earlier work, we used imaging systems that tracked individual larvae to uncover general rules for thermotactic behavioral strategy (5). Here, we used high-throughput/high-resolution behavioral assays to define the patterns of sensorimotor processing that produce these behavioral rules. We tracked the movements of large numbers of animals responding to fixed spatial gradients or defined random thermal fluctuations. Reverse-correlation methods yielded the temperature sensitivity as functions of time between stimulus history and motor responses that dictate how the larva uses its sensory experience to modulate behavior. We sought the relevant thermosensory neurons and discovered three neurons that are necessary for positive thermotaxis in each dorsal organ ganglion (DOG). We characterized the dynamics of the DOG thermosensory neurons by imaging calcium dynamics using GCaMP and voltage dynamics using ArcLight in response to defined temperature waveforms: sine waves, ramps, and random thermal fluctuations (14). Reverse-correlation methods showed that the transformations from temperature dynamics into neuronal dynamics are well matched to behavioral response. Finally, we used random optogenetic stimulation of the DOG neurons combined with reverse-correlation methods to connect neuronal dynamics with behavior. We confirmed that both activation and deactivation of the DOG neurons—which signify cooling and warming, respectively—drive distinct motor state transitions during thermotaxis.     

Bidirectional thermotaxis in Caenorhabditis elegans is mediated by distinct sensorimotor strategies driven by the AFD thermosensory neurons

The nematode Caenorhabditis elegans navigates toward a preferred temperature setpoint (T_s) determined by long-term temperature exposure. During thermotaxis, the worm migrates down temperature gradients at temperatures above T_s (negative thermotaxis) and performs isothermal tracking near T_s. Under some conditions, the worm migrates up temperature gradients below T_s (positive thermotaxis). Here, we analyze positive and negative thermotaxis toward T_s to study the role of specific neurons that have been proposed to be involved in thermotaxis using genetic ablation, behavioral tracking, and calcium imaging. We find differences in the strategies for positive and negative thermotaxis. Negative thermotaxis is achieved through biasing the frequency of reorientation maneuvers (turns and reversal turns) and biasing the direction of reorientation maneuvers toward colder temperatures. Positive thermotaxis, in contrast, biases only the direction of reorientation maneuvers toward warmer temperatures. We find that the AFD thermosensory neuron drives both positive and negative thermotaxis. The AIY interneuron, which is postsynaptic to AFD, may mediate the switch from negative to positive thermotaxis below T_s. We propose that multiple thermotactic behaviors, each defined by a distinct set of sensorimotor transformations, emanate from the AFD thermosensory neurons. AFD learns and stores the memory of preferred temperatures, detects temperature gradients, and drives the appropriate thermotactic behavior in each temperature regime by the flexible use of downstream circuits.Navigational behaviors provide a framework for exploring the interplay among sensorimotor circuits, learning, and memory. During a navigational task, animals eventually reach their goals by implementing strategies composed of sensorimotor rules. Experience can modify navigational goals, so memory can also be integrated into sensorimotor pathways. Studying navigation in the nematode Caenorhabditis elegans offers the possibility of understanding the plasticity and programming of sensorimotor circuits from input to output in a small nervous system (1).Previous studies established C. elegans thermotaxis as a model for experience-dependent navigation (2–6). When worms are exposed to specific temperatures between 15 °C and 25 °C for at least 4 h, they adopt those temperatures as their thermotactic setpoint (T_s) (2, 3, 5, 7). When placed on a spatial temperature gradient, worms seek the T_s. When arriving near T_s, worms track isotherms. Genetic analysis of thermotaxis has yielded mutants that are athermotactic (crawling randomly on temperature gradients), cryophilic (crawling to the coldest point on a temperature gradient irrespective of T_s), or thermophilic (crawling to the warmest point on a temperature gradient). This observation led to the suggestion that thermotaxis might involve separate circuits for negative thermotaxis (movement down gradients) and positive thermotaxis (movement up gradients) that balance near T_s (2, 4).Systematic laser ablation analysis uncovered an interconnected neural circuit for thermotaxis behavior composed of one pair of thermosensory neurons (AFD) and three pairs of interneurons (AIY, AIZ, and RIA) (Fig. 1A) (4). Ablation of AFD or AIY led to cryophilic behavior. Ablation of AIZ led to thermophilic behavior. Ablation of RIA led to athermotactic behavior. Ablation of the AWC olfactory neuron, which is presynaptic to AIY and RIA, has also been found to mildly disrupt negative thermotaxis (8). These findings suggested that candidate circuit pathways converging on RIA might drive positive and negative thermotaxis (Fig. 1A).Open in a separate windowFig. 1.Bidirectional thermotaxis in C. elegans. (A) A proposed neural circuit for thermotaxis showing chemical synaptic connectivity between the AFD and AWC sensory neurons and downstream interneurons. (B) Navigation trajectories over 15 min of 50 wild-type (N2) worms grown at 15 °C (blue) or 25 °C (red) and started near 20 °C on a 0.2 °C/cm linear spatial temperature gradient on a 22- × 22-cm agar plate (Fig. S1). Trajectories are aligned to the same starting point (white circle) for presentation purposes. (C) Mean x displacement ± 1 SD for trajectories shown in B. (D) A navigational index was computed for each trajectory using the component of velocity in the direction of the gradient divided by the mean crawling speed along each trajectory. Positive and negative thermotaxis corresponds to positive and negative indices, respectively. The magnitude of the index for negative thermotaxis is significantly larger than that for positive thermotaxis (P < 0.0005 using Student t test). All data points in C and D represent mean ± 1 SEM. Each calculation is based on at least 241 worm trajectories.Recently, movie microscopy has enabled high-resolution and high-content tracking of worm navigation (5, 9–12). Tracking negative thermotaxis and isothermal tracking have uncovered components of the worms’ underlying behavioral strategies (12–14). Negative thermotaxis involves modulation of run length that is reminiscent of the biased random walk that was originally observed in bacterial chemotaxis (15, 16). In isotropic environments, worms move in a sequence of forward movements (runs) interrupted by turns and reversal turns (also called pirouettes) generating exploration that resembles an unbiased random walk. During negative thermotaxis, if worms sense negative temperature gradients, they suppress turns and reversal turns, yielding long runs in the favorable cooler direction. If worms sense positive temperature gradients, they exhibit short runs. Thus, net migration is down temperature gradients (13). Isothermal tracking is deterministic, a steering behavior in which the worm continuously makes temperature comparisons and movement corrections with every undulation to maintain isothermal alignment (14).The strategy for positive thermotaxis has not yet been analyzed because this behavior is restricted to certain growth and stimulus conditions. If worms are grown at ∼23 °C or higher, they will crawl up temperature gradients toward their T_s as long as they are within ∼5 °C and navigating gradients are shallower than 0.5 °C/cm. Lower setpoints, steeper gradients, and greater distances from the T_s lead to athermotactic behavior (17). Now that we know specific conditions that evoke positive thermotaxis, we can use these conditions to compare and contrast the strategies for positive and negative thermotaxis.Genetic methods provide tools to inactivate or remove specific neurons from C. elegans that yield larger numbers of animals than is possible with laser ablation. Cell-specific expression of reconstituted caspase (recCaspase) induces programmed cell death and thus the removal of specific neurons during development (18). Expression and irradiation of the protein KillerRed with intense green light remove cells acutely (19, 20). Here, we combine these methods with quantitative behavioral tracking to assess how each neuron in the proposed circuit for thermotaxis (AFD-AWC-AIY-AIZ-RIA) contributes to movement up or down temperature gradients.We find that positive thermotaxis involves biased reorientation toward the T_s: the worm uses turns and reversal turns to point itself toward warmer temperatures. We find that negative thermotaxis also involves biased reorientation toward the T_s: the worm uses turns and reversal turns to point itself toward colder temperatures. As observed earlier, negative thermotaxis also involves a biased random walk toward the T_s, with longer runs toward colder temperatures and shorter runs toward warmer temperatures. These results suggest an asymmetry in the sensorimotor strategies for positive and negative thermotaxis, where run-length modulation makes negative thermotaxis more efficient by prolonging favorable orientations. We find that AFD drives both positive and negative thermotaxis. AIY is necessary to exhibit positive instead of negative thermotaxis below T_s. Although AWC, AIZ, and RIA might have minor contributions to thermotaxis, none of these neurons is required for either positive or negative thermotaxis. In summary, bidirectional thermotaxis emanates from the AFD neurons, achieved by coupling sensory input to motor output in different patterns to drive thermotaxis up gradients below T_s and down gradients above T_s.