Delay in the Provision of Antiretroviral Therapy to HIV-infected TB Patients in Nigeria.

BACKGROUND: Nigeria has a high burden of HIV and tuberculosis (TB). To reduce TB-associated morbidity and mortality, the World Health Organization recommends that HIV-positive TB patients receive antiretroviral therapy (ART) within eight weeks of TB treatment initiation, or within two weeks if profoundly immunosuppressed (CD4<50 cell/µL). METHODS: TB and HIV clinical records from facilities in two Nigerian states between October 1st, 2012 and September 30th, 2013 were retrospectively reviewed to assess uptake and timing of ART initiation among HIV-positive TB patients. Healthcare workers were qualitatively interviewed to assess TB/HIV knowledge and barriers to timely ART. RESULTS: Data were abstracted from 4,810 TB patient records, of which 1,249 (26.0%) had HIV-positive or unknown HIV status documented, and the 574 (45.9%) HIV-positive TB patients were evaluated for timing of ART uptake relative to TB treatment. Among 484 (84.3%) HIV-positive TB patients not already on ART, 256 (52.9%, 95% CI: 45.0-60.8) were not initiated on ART during six months of TB treatment. 30.0% of 273 patients with a known CD4≥50cells/µL started ART within eight weeks, and 14.8% of 54 patients with a known CD4<50cells/µL started within the recommended two weeks. Only 42% of health workers interviewed reported knowing to interpret guidelines on when to initiate ART in HIV-positive TB patients based on CD4 cell count results. CD4 cell count significantly predicted timely ART uptake. CONCLUSION: A large proportion of HIV-positive TB patients were not initiated on ART early or even at all during TB treatment. Retraining of staff, and interventions to strengthen referral systems should be implemented to ensure timely provision of ART among HIV-positive TB patients in Nigeria.

Clinical malaria diagnosis in pregnancy in relation to early perinatal mother-to-child transmission of HIV: a prospective cohort study.

OBJECTIVES: We prospectively investigated fever symptoms and maternal diagnosis of malaria in pregnancy (MIP) in relation to child HIV infection among 2368 pregnant HIV-positive women and their infants, followed up from pregnancy until 6 weeks post-delivery in Tanzania. METHODS: Doctors clinically diagnosed and treated MIP and fever symptoms during prenatal health care. Child HIV status was determined via DNA polymerase chain reaction (PCR). Multivariable logistic regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for HIV mother-to-child transmission (MTCT) by the 6th week of life. RESULTS: Mean gestational age at enrolment was 22.2 weeks. During follow-up, 16.6% of mothers had at least one MIP diagnosis, 15.9% reported fever symptoms and 8.7% had both fever and MIP diagnosis. Eleven per cent of HIV-exposed infants were HIV-positive by 6 weeks. The RR of HIV MTCT was statistically similar for infants whose mothers were ever vs. never clinically diagnosed with MIP (RR 1.24; 95% CI 0.94-1.64), were diagnosed with one vs. no clinical MIP episodes (RR 1.07; 95% CI 0.77-1.48) and had ever vs. never reported fever symptoms (RR 1.04; 95% CI 0.78-1.38) in pregnancy. However, the HIV MTCT risk increased by 29% (95% CI 4-58%) per MIP episode. Infants of women with at least two vs. no MIP diagnoses were 2.1 times more likely to be HIV infected by 6 weeks old (95% CI 1.31-3.45). CONCLUSIONS: Clinical MIP diagnosis, but not fevers, in HIV-positive pregnant women was associated with an elevated risk of early HIV MTCT, suggesting that malaria prevention and treatment in pregnant HIV-positive women may enhance the effectiveness of HIV prevention in MTCT programmes in this setting. Future studies using a laboratory-confirmed diagnosis of malaria are needed to confirm this association.

Predictors of stunting, wasting and underweight among Tanzanian children born to HIV-infected women.

BACKGROUND/OBJECTIVES: Children born to human immunodeficiency virus (HIV)-infected women are susceptible to undernutrition, but modifiable risk factors and the time course of the development of undernutrition have not been well characterized. The objective of this study was to identify maternal, socioeconomic and child characteristics that are associated with stunting, wasting and underweight among Tanzanian children born to HIV-infected mothers, followed from 6 weeks of age for 24 months. SUBJECTS/METHODS: Maternal and socioeconomic characteristics were recorded during pregnancy, data pertaining to the infant's birth were collected immediately after delivery, morbidity histories and anthropometric measurements were performed monthly. Multivariate Cox proportional hazards methods were used to assess the association between potential predictors and the time to first episode of stunting, wasting and underweight. RESULTS: A total of 2387 infants (54.0% male) were enrolled and followed for a median duration of 21.2 months. The respective prevalence of prematurity (<37 weeks) and low birth weight (<2500 g) was 15.2% and 7.0%; 11.3% of infants were HIV-positive at 6 weeks. Median time to first episode of stunting, wasting and underweight was 8.7, 7.2 and 7.0 months, respectively. Low maternal education, few household possessions, low infant birth weight, child HIV infection and male sex were all independent predictors of stunting, wasting and underweight. In addition, preterm infants were more likely to become wasted and underweight, whereas those with a low Apgar score at birth were more likely to become stunted. CONCLUSIONS: Interventions to improve maternal education and nutritional status, reduce mother-to-child transmission of HIV, and increase birth weight may lower the risk of undernutrition among children born to HIV-infected women.

Neural circuitry underlying linear representation of wind information in a nonspiking local interneuron of the cockroach.

In the cercal system of the cockroach Periplaneta americana, primary sensory interneurons exhibiting a sharp directional sensitivity respond to wind in a linear manner whereas those exhibiting an omnidirectional sensitivity respond nonlinearly. For example, the wind-evoked response in an identifiable, nonspiking local interneuron, 101, which responds preferentially to wind from the left versus the right, is characterized exclusively by a differential first-order (linear) kernel. However, the slow potential response in a cercal giant interneuron, GI-1, is omnidirectional, and characterized by a second-order (nonlinear) kernel with an elongated depolarizing peak on the diagonal with two off-diagonal valleys. We here examined the neural circuitry underlying the linear and nonlinear representations of wind information by the deprivation of inputs from particular sets of cercal hair afferents. Electrical stimulation of the ipsilateral (related to the soma) cercal nerve elicited a depolarizing potential in 101, which was followed by delayed hyperpolarization. A continuous flow of 10(-4) M picrotoxin, which selectively blocked this delayed hyperpolarization, resulted in a significant change in the 101 response from linear to nonlinear. Because no frequency-doubling response was observed, the nonlinearity is due to signal compression (or rectification) that reflects the mechanical property of cercal afferents. This is consistent with the hypothesis that the linear representation in 101 is based on a subtraction process between two subsets of particular column hairs, whose best optimal directions are opposite to each other.

Neural computation of motion in the fly visual system: quadratic nonlinearity of responses induced by picrotoxin in the HS and CH cells.

1. A computational model accounting for motion detection in the fly was examined by comparing responses in motion-sensitive horizontal system (HS) and centrifugal horizontal (CH) cells in the fly's lobula plate with a computer simulation implemented on a motion detector of the correlation type, the Reichardt detector. First-order (linear) and second-order (quadratic nonlinear) Wiener kernels from intracellularly recorded responses to moving patterns were computed by cross correlating with the time-dependent position of the stimulus, and were used to characterize response to motion in those cells. 2. When the fly was stimulated with moving vertical stripes with a spatial wavelength of 5-40 degrees, the HS and CH cells showed basically a biphasic first-order kernel, having an initial depolarization that was followed by hyperpolarization. The linear model matched well with the actual response, with a mean square error of 27% at best, indicating that the linear component comprises a major part of responses in these cells. The second-order nonlinearity was insignificant. When stimulated at a spatial wavelength of 2.5 degrees, the first-order kernel showed a significant decrease in amplitude, and was initially hyperpolarized; the second-order kernel was, on the other hand, well defined, having two hyperpolarizing valleys on the diagonal with two off-diagonal peaks. 3. The blockage of inhibitory interactions in the visual system by application of 10-4 M picrotoxin, however, evoked a nonlinear response that could be decomposed into the sum of the first-order (linear) and second-order (quadratic nonlinear) terms with a mean square error of 30-50%. The first-order term, comprising 10-20% of the picrotoxin-evoked response, is characterized by a differentiating first-order kernel. It thus codes the velocity of motion. The second-order term, comprising 30-40% of the response, is defined by a second-order kernel with two depolarizing peaks on the diagonal and two off-diagonal hyperpolarizing valleys, suggesting that the nonlinear component represents the power of motion. 4. Responses in the Reichardt detector, consisting of two mirror-image subunits with spatiotemporal low-pass filters followed by a multiplication stage, were computer simulated and then analyzed by the Wiener kernel method. The simulated responses were linearly related to the pattern velocity (with a mean square error of 13% for the linear model) and matched well with the observed responses in the HS and CH cells. After the multiplication stage, the linear component comprised 15-25% and the quadratic nonlinear component comprised 60-70% of the simulated response, which was similar to the picrotoxin-induced response in the HS cells. The quadratic nonlinear components were balanced between the right and left sides, and could be eliminated completely by their contralateral counterpart via a subtraction process. On the other hand, the linear component on one side was the mirror image of that on the other side, as expected from the kernel configurations. 5. These results suggest that responses to motion in the HS and CH cells depend on the multiplication process in which both the velocity and power components of motion are computed, and that a putative subtraction process selectively eliminates the nonlinear components but amplifies the linear component. The nonlinear component is directionally insensitive because of its quadratic non-linearity. Therefore the subtraction process allows the subsequent cells integrating motion (such as the HS cells) to tune the direction of motion more sharply.

Dynamics of neurons controlling movements of a locust hind leg: Wiener kernel analysis of the responses of proprioceptive afferents.

1. The response properties of proprioceptive sensory neurons providing input to the local circuits controlling leg movements of the locust have been analysed by the Wiener kernel method. The proprioceptor, the femoral chordotonal organ, encodes the position and movements of the tibia about the femorotibial joint. 2. Intracellular recordings were made from sensory neurons while the apodeme of the organ was moved with a band-limited Gaussian white noise signal with a cutoff frequency of 27, 58, or 117 Hz. To define the input-output characteristics of the neurons, the first- and second-order Wiener kernels were computed by a cross-correlation between the spike response of the afferents and the white noise stimulus. 3. White noise stimulation elicited sustained spiking in 50 out of 54 afferents throughout the 20 s periods of stimulation and recording. The first-order kernels, the linear response properties, of these afferents were of six basic types that were dependent on the cutoff frequency of the white noise stimulus. These included 1) flexion-sensitive afferents that were primarily position sensitive irrespective of stimulus frequency, 2) flexion-sensitive afferents that were position sensitive at low frequencies but also coded velocity at higher frequencies, 3) flexion-sensitive afferents that coded velocity at all stimulus frequencies, 4) flexion-sensitive afferents that coded velocity at low stimulus frequencies but also acceleration at high frequencies, 5) extension-sensitive afferents that coded velocity at all stimulus frequencies, and 6) extension-sensitive afferents that coded velocity at low stimulus frequencies and acceleration at high frequencies. A seventh type contained the four remaining afferents that adapted rapidly to the stimulus within 3-5 s. These were all extension-acceleration sensitive irrespective of stimulus frequency. 4. The gain curves (produced by Fourier transform of the 1st-order kernels) and the power spectra of the linear models (produced by convolving the 1st-order kernels with the white noise) demonstrated that responses in the position-sensitive afferents are representative of a constant gain low-pass filter with a cutoff frequency of approximately 80 Hz, whereas those in the velocity- and acceleration-sensitive afferents are band passed, having peaks at 80 Hz. 5. The main nonlinearity was a signal compression in which the diagonal peak(s) of the second-order nonlinear kernels offset one or more peaks of the first-order kernels and represents a rectification or directional sensitivity of the afferents.(ABSTRACT TRUNCATED AT 400 WORDS)

Response dynamics and directional properties of nonspiking local interneurons in the cockroach cercal system.

The response properties and directional receptive fields of nonspiking local interneurons in the cercal system of the cockroach are described. Wind-evoked responses were recorded intracellularly, and then analyzed by means of the Wiener kernel method in which a Gaussian white noise signal was used as a stimulus. Cross-correlation between the response and the white noise signal produced first- (linear) and second-order (nonlinear) kernels that were used to define input-output characteristics of the interneurons. Three sets of interneurons were distinguished on the basis of kernel analysis. First, responses in interneurons 101, 107, 111, and 203 were characterized predominantly by a differentiating first-order kernel, which suggests a linear relationship to the stimulus. The amplitude and waveform of the kernel changed with the change in stimulus angle, indicating that these four cells are directionally sensitive. Second, responses in interneurons 102 and 103 were also directionally sensitive but highly nonlinear. The first-order kernel was biphasic, whereas the second-order kernel had an elongated depolarizing peak on the diagonal. The response dynamics were accounted for by a cascade of two filters, a linear band-pass filter and a static nonlinear filter, in which the nonlinearity is a signal compression (or a rectification). Third, responses in interneurons 104 and 201 consist largely of the second-order nonlinear component. The second-order kernel, which had an elongated depolarizing peak or a hyperpolarizing valley on the diagonal, did not show any directional preference. The second-order nonlinearity was dynamic, and could be modeled by a band-pass linear filter-static nonlinearity-low-pass linear filter cascade, where the static nonlinearity is a full-wave rectification. The band-pass filter would simply reflect the mechanical property of cercal hair sensilla, whereas the low-pass filter represents the transfer at synapses between the cercal afferents and the interneurons. The nonlinear response thus explains the difference in the directional sensitivity while the differentiating first-order kernel explains the velocity sensitivity of the interneurons. We show that 101 and 107 respond most preferentially to wind from the left versus right, whereas 102, 103, 111, and 203 respond to wind from the front versus rear. Thus, it is suggested that there are two subsystems responding maximally to wind displacement along two coordinate directions, one for the longitudinal direction and the other for the transverse direction. On the other hand, the full-wave-rectifier nonlinear interneurons are omnidirectional, and thus suggested to code simply the power of the wind displacement.

Filter characteristics of cercal afferents in the cockroach.

The response dynamics of cercal afferents in the cockroach. Periplaneta americana, were determined by means of a cross-correlation technique using a Gaussian white noise modulation of wind as a stimulus. The white noise stimulus could evoke sustained firing activity in most of the afferents examined (Fig. 1). The spike discharges were unitized and then cross-correlated with the stimulus to compute 1st- and 2nd-order Weiner kernels. The 1st-order kernels from a total of 28 afferents were biphasic and closely matched the time differential of a pulse (Figs. 1, 3 and 4). The amplitude and waveform of the kernels depended on the stimulus angle in such a way that the kernels were the mirror image of those on the polar opposite side (Figs. 2 and 3). The 2nd-order kernels were also differential. They had 2 diagonal peaks and 2 off-diagonal valleys in a 2-dimensional plot with 2 time axes (Figs. 1, 5 and 6). This 4-eye configuration was basically invariant irrespective of the stimulus angle, although the kernels varied in amplitude when the stimulus angle was changed. The time between the peak and a following trough of the 1st-order kernel was constant and had a mean of 4.6 +/- 0.1 ms, whereas the time between 2 diagonal peaks of the 2nd-order kernels was 4.7 +/- 0.1 ms (Figs. 4 and 6), suggesting that wind receptors (filiform sensilla) on cerci act as a band-pass filter with a peak frequency of about 106 Hz. The peak time, however, varies from 2.3 to 6.9 ms in both kernels, which may reflect the spatial distribution of the corresponding hairs on the cercus. The summation of the 1st- (linear) and 2nd-order (nonlinear) models precisely predicted the timing of the spike firing (Fig. 8). Thus, these 2 lower-order kernels can totally characterize the response dynamics of the wind receptors. The nonlinear response explains the directional sensitivity of the sensory neurons, while the differentiating 1st-order kernel explains the velocity sensitivity of the neurons. The nonlinearity is a signal compression in which one of the diagonal peaks of the 2nd-order kernel always offsets the downward phase of the 1st-order kernel (Fig. 7) and obviously represents a half-wave rectification property of the wind receptors that are excited by hair movement in only one direction and inhibited by hair movement in the polar opposite direction.

White noise analysis of graded response in a wind-sensitive, nonspiking interneuron of the cockroach.

1. A novel approach using a Gaussian white noise as stimulus is described which allowed quantitative analysis of neuronal responses in the cercal system of the cockroach, Periplaneta americana. Cerci were stimulated by air displacement which was modulated by a sinusoidal and a white noise signal. During the stimulation, intracellular recordings were made from a uniquely identifiable, nonspiking, local interneuron which locates within the terminal abdominal ganglion. The white noise stimulation was cross-correlated with the evoked response to compute first- and second-order kernels that could define the cell's response dynamics. 2. The interneuron, cell 101, has an exceptionally large transverse neurite that connects two asymmetrical dendritic arborizations located on both sides of the ganglion. 3. The first-order Wiener kernels in cell 101 were biphasic (differentiating). The waveforms of the kernels produced by the ipsilateral and contralateral stimulations were roughly mirror images of each other: the kernels produced by wind stimuli on the side ipsilateral to the cell body of the interneuron are initially depolarized and then hyperpolarized, whereas those on the other side are initially hyperpolarized. The polarity reversal occurred along the midline of the animal's body, and no well-defined kernel was produced by a stimulus directed head on or from the tail. 4. Mean square error (MSE) between the actual response and the model prediction suggests that the linear component in cell 101 comprises half of the cell's total response (MSEs for the linear models were about 50% at preferred directions), whereas the second-order, non-linear component is insignificant. The linear component of the wind-evoked response was bandpass with the preferred frequency of 70-90 Hz. 5. Accounting for a noise, we reasonably assumed that at high frequencies the graded response in cell 101 is linearly related to a modulation of the air displacement and sensitive to the rate of change of the signal (i.e., wind velocity) and the direction of its source. It is suggested that the dynamics of the first-order kernel simply reflect the dynamics of sensory receptors that respond linearly to wind stimulation.