Circadian phase-shifting effects of a laboratory environment: a clinical trial with bright and dim light

BACKGROUND: Our aims were to examine the influence of different bright light schedules on mood, sleep, and circadian organization in older adults (n = 60, ages 60–79 years) with insomnia and/or depression, contrasting with responses of young, healthy controls (n = 30, ages 20–40 years). METHODS: Volunteers were assessed for one week in their home environments. Urine was collected over two 24-hour periods to establish baseline acrophase of 6-sulphatoxymelatonin (aMT6s) excretion. Immediately following home recording, volunteers spent five nights and four days in the laboratory. Sleep periods were fixed at eight hours in darkness, consistent with the volunteers' usual sleep periods. Volunteers were randomly assigned to one of three light treatments (four hours per day) within the wake period: (A) two hours of 3,000 lux at 1–3 hours and 13–15 hours after arising; (B) four hours of 3,000 lux at 6–10 hours after arising; (C) four hours of dim placebo light at 6–10 hours after arising. Lighting was 50 lux during the remainder of wakefulness. The resulting aMT6s acrophase was determined during the final 30 hours in the laboratory. RESULTS: Neither mood nor total melatonin excretion differed significantly by treatment. For the three light treatments, significant and similar phase-response plots were found, indicating that the shift in aMT6s acrophase was dependent upon the circadian time of treatment. The changes in circadian timing were not significantly correlated to changes in sleep or mood. CONCLUSION: The trial failed to demonstrate photoperiodic effects. The results suggest that even low levels of illumination and/or fixed timing of behavior had significant phase-shifting effects

Circadian phase response curves to light in older and young women and men

<p>Abstract</p> <p>Background</p> <p>The phase of a circadian rhythm reflects where the peak and the trough occur, for example, the peak and trough of performance within the 24 h. Light exposure can shift this phase. More extensive knowledge of the human circadian phase response to light is needed to guide light treatment for shiftworkers, air travelers, and people with circadian rhythm phase disorders. This study tested the hypotheses that older adults have absent or weaker phase-shift responses to light (3000 lux), and that women's responses might differ from those of men.</p> <p>Methods</p> <p>After preliminary health screening and home actigraphic recording baselines, 50 young adults (ages 18–31 years) and 56 older adults (ages 59–75 years) remained in light-controlled laboratory surroundings for 4.7 to 5.6 days, while experiencing a 90-min ultra-short sleep-wake cycle. Following at least 30 h in-lab baseline, over the next 51 h, participants were given 3 treatments with 3000 lux white light, each treatment for 3 h, centered at one of 8 clock times. The circadian rhythms of urinary aMT6s (a melatonin metabolite), free cortisol, oral temperature, and wrist activity were assessed at baseline and after treatment.</p> <p>Results</p> <p>Light (3000 lux for 3 h on 3 days) induced maximal phase shifts of about 3 h. Phase shifts did not differ significantly in amplitude among older and young groups or among women and men. At home and at baseline, compared to the young, the older adults were significantly phase-advanced in sleep, cortisol, and aMT6s onset, but not advanced in aMT6s acrophase or the temperature rhythm. The inflection from delays to advances was approximately 1.8 h earlier among older compared to young participants in reference to their aMT6s rhythm peaks, and it was earlier in clock time.</p> <p>Conclusion</p> <p>In these experimental conditions, 3000 lux light could shift the phase of circadian rhythms to about the same extent among older and young adults, but the optimal light timing for phase shifting differed. For an interval near 4 PM, bright light produced only negligible phase shifts for either age group.</p

Time to Scale Up Preexposure Prophylaxis Beyond the Highest-Risk Populations? Modeling Insights From High-Risk Women in Sub-Saharan Africa

OBJECTIVES: New HIV infections remain higher in women than men in sub-Saharan Africa. Preexposure prophylaxis (PrEP) is an effective HIV prevention measure, currently prioritized for those at highest risk, such as female sex workers (FSWs), for whom it is most cost-effective. However, the greatest number of HIV infections in sub-Saharan Africa occurs in women in the general population. As countries consider wider PrEP scale-up, there is a need to weigh the population-level impact, cost, and relative cost-effectiveness to inform priority setting. METHODS: We developed mathematical models of HIV risk to women and derived tools to highlight key considerations for PrEP programming. The models were fitted to South Africa, Zimbabwe, and Kenya, spanning a range of HIV burden in sub-Saharan Africa. The impact, cost, and cost-effectiveness of PrEP scale-up for adolescent girls and young women (AGYW), women 25 to 34 years old, and women 35 to 49 years old were assessed, accounting for differences in population sizes and the low program retention levels reported in demonstration projects. RESULTS: Preexposure prophylaxis could avert substantially more infections a year among women in general population than among FSW. The greatest number of infections could be averted annually among AGYW in South Africa (24-fold that for FSW). In Zimbabwe, the greatest number of infections could be averted among women 25 to 34 years old (8-fold that for FSW); and in Kenya, similarly between AGYW and women 25 to 34 years old (3-fold that for FSW). However, the unit costs of PrEP delivery for AGYW, women 25 to 34 years old, and women 35 to 49 years old would have to reduce considerably (by 70.8%-91.0% across scenarios) for scale-up to these populations to be as cost-effective as for FSW. CONCLUSIONS: Preexposure prophylaxis has the potential to substantially reduce new HIV infections in HIV-endemic countries in sub-Saharan Africa. This will necessitate PrEP being made widely available beyond those at highest individual risk and continued integration into a range of national services and at community level to significantly bring down the costs and improve cost-effectiveness

Delayed sleep phase cases and controls

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Weak evidence of bright light effects on human LH and FSH

<p>Abstract</p> <p>Background</p> <p>Most mammals are seasonal breeders whose gonads grow to anticipate reproduction in the spring and summer. As day length increases, secretion increases for two gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH). This response is largely controlled by light. Light effects on gonadotropins are mediated through effects on the suprachiasmatic nucleus and responses of the circadian system. There is some evidence that seasonal breeding in humans is regulated by similar mechanisms, and that light stimulates LH secretion, but primate responses seem complex.</p> <p>Methods</p> <p>To gain further information on effects of bright light on LH and FSH secretion in humans, we analyzed urine samples collected in three experiments conducted for other goals. First, volunteers ages 18-30 years and 60-75 commenced an ultra-short 90-min sleep-wake cycle, during which they were exposed to 3000 lux light for 3 hours at balanced times of day, repeated for 3 days. Urine samples were assayed to explore any LH phase response curve. Second, depressed participants 60-79 years of age were treated with bright light or dim placebo light for 28 days, with measurements of urinary LH and FSH before and after treatment. Third, women of ages 20-45 years with premenstrual dysphoric disorder (PMDD) were treated to one 3-hour exposure of morning light, measuring LH and FSH in urine before and after the treatments.</p> <p>Results</p> <p>Two of the three studies showed significant increases in LH after light treatment, and FSH also tended to increase, but there were no significant contrasts with parallel placebo treatments and no significant time-of-day treatment effects.</p> <p>Conclusions</p> <p>These results gave some support for the hypothesis that bright light may augment LH secretion. Longer-duration studies may be needed to clarify the effects of light on human LH and FSH.</p

Ethnicity, sleep, mood, and illumination in postmenopausal women

BACKGROUND: This study examined how ethnic differences in sleep and depression were related to environmental illumination and circadian rhythms. METHODS: In an ancillary study to the Women's Health Initiative, 459 postmenopausal women were recorded for one week in their homes, using wrist monitors. Sleep and illumination experience were estimated. Depression was self-rated with a brief adjective check list. Affective diagnoses were made using the SCID interview. Sleep disordered breathing was monitored with home pulse oximetry. RESULTS: Hispanic and African-American women slept less than European-American women, according to both objective recordings and their own sleep logs. Non-European-American women had more blood oxygen desaturations during sleep, which accounted for 26% of sleep duration variance associated with ethnicity. Hispanic women were much more depressed. Hispanic, African-American and Native-American women experienced less daily illumination. Less daily illumination experience was associated with poorer global functioning, longer but more disturbed sleep, and more depression. CONCLUSIONS: Curtailed sleep and poor mood were related to ethnicity. Sleep disordered breathing was a factor in the curtailed sleep of minority women. Less illumination was experienced by non-European-American women, but illumination accounted for little of the contrasts between ethnic groups in sleep and mood. Social factors may be involved

Efficiency in PrEP Delivery: Estimating the Annual Costs of Oral PrEP in Zimbabwe.

Although oral PrEP is highly effective at preventing HIV acquisition, optimizing continuation among beneficiaries is challenging in many settings. We estimated the costs of delivering oral PrEP to populations at risk of HIV in seven clinics in Zimbabwe. Full annual economic costs of oral PrEP initiations and continuation visits were estimated from the providers' perspective for a six-clinic NGO network and one government SGBV clinic in Zimbabwe (January-December 2018). Disaggregating costs of full initiation and incremental follow-up visits enabled modeling of the impact of duration of continuation on the cost per person-year ($pPY) on PrEP. 4677 people initiated oral PrEP, averaging 2.7 follow-up visits per person. Average cost per person initiated was$238 ($183-$302 across the NGO clinics; $86 in the government facility). The full cost per initiation visit, including central and direct costs, was$178, and the incremental cost per follow-up visit, capturing only additional resources used directly in the follow up visits, was $22. The average duration of continuation was 3.0 months, generating an average$pPY of $943, ranging from$839 among adolescent girls and young women to $1219 in men. Oral PrEP delivery costs varied substantially by scale of initiations and by duration of continuation and type of clinic. Extending the average oral PrEP continuation from 2.7 to 5 visits (about 6 months) would greatly improve service efficiency, cutting the$pPY by more than half

Implementation and resource needs for long-acting PrEP in low- and middle-income countries: a scoping review

INTRODUCTION: Several low- and middle-income countries (LMICs) are preparing to introduce long-acting pre-exposure prophylaxis (LAP). Amid multiple pre-exposure prophylaxis (PrEP) options and constrained funding, decision-makers could benefit from systematic implementation planning and aligned costs. We reviewed national costed implementation plans (CIPs) to describe relevant implementation inputs and activities (domains) for informing the costed rollout of LAP. We assessed how primary costing evidence aligned with those domains. METHODS: We conducted a rapid review of CIPs for oral PrEP and family planning (FP) to develop a consensus of implementation domains, and a scoping review across nine electronic databases for publications on PrEP costing in LMICs between January 2010 and June 2022. We extracted cost data and assessed alignment with the implementation domains and the Global Health Costing Consortium principles. RESULTS: We identified 15 implementation domains from four national PrEP plans and FP-CIP template; only six were in all sources. We included 66 full-text manuscripts, 10 reported LAP, 13 (20%) were primary cost studies-representing seven countries, and none of the 13 included LAP. The 13 primary cost studies included PrEP commodities (n = 12), human resources (n = 11), indirect costs (n = 11), other commodities (n = 10), demand creation (n = 9) and counselling (n = 9). Few studies costed integration into non-HIV services (n = 5), above site costs (n = 3), supply chains and logistics (n = 3) or policy and planning (n = 2), and none included the costs of target setting, health information system adaptations or implementation research. Cost units and outcomes were variable (e.g. average per person-year). DISCUSSION: LAP planning will require updating HIV prevention policies, technical assistance for logistical and clinical support, expanding beyond HIV platforms, setting PrEP achievement targets overall and disaggregated by method, extensive supply chain and logistics planning and support, as well as updating health information systems to monitor multiple PrEP methods with different visit schedules. The 15 implementation domains were variable in reviewed studies. PrEP primary cost and budget data are necessary for new product introduction and should match implementation plans with financing. CONCLUSIONS: As PrEP services expand to include LAP, decision-makers need a framework, tools and a process to support countries in planning the systematic rollout and costing for LAP

Cost-effectiveness of voluntary medical male circumcision for HIV prevention across sub-Saharan Africa : results from five independent models

BACKGROUND: Voluntary medical male circumcision (VMMC) has been a recommended HIV prevention strategy in sub-Saharan Africa since 2007, particularly in countries with high HIV prevalence. However, given the scale-up of antiretroviral therapy programmes, it is not clear whether VMMC still represents a cost-effective use of scarce HIV programme resources. METHODS: Using five existing well described HIV mathematical models, we compared continuation of VMMC for 5 years in men aged 15 years and older to no further VMMC in South Africa, Malawi, and Zimbabwe and across a range of setting scenarios in sub-Saharan Africa. Outputs were based on a 50-year time horizon, VMMC cost was assumed to be US$90, and a cost-effectiveness threshold of US$500 was used. FINDINGS: In South Africa and Malawi, the continuation of VMMC for 5 years resulted in cost savings and health benefits (infections and disability-adjusted life-years averted) according to all models. Of the two models modelling Zimbabwe, the continuation of VMMC for 5 years resulted in cost savings and health benefits by one model but was not as cost-effective according to the other model. Continuation of VMMC was cost-effective in 68% of setting scenarios across sub-Saharan Africa. VMMC was more likely to be cost-effective in modelled settings with higher HIV incidence; VMMC was cost-effective in 62% of settings with HIV incidence of less than 0·1 per 100 person-years in men aged 15-49 years, increasing to 95% with HIV incidence greater than 1·0 per 100 person-years. INTERPRETATION: VMMC remains a cost-effective, often cost-saving, prevention intervention in sub-Saharan Africa for at least the next 5 years. FUNDING: Bill & Melinda Gates Foundation for the HIV Modelling Consortium