Surveillance for endemic infectious disease outbreaks: Adaptive sampling using profile likelihood estimation.

Outbreaks of an endemic infectious disease can occur when the disease is introduced into a highly susceptible subpopulation or when the disease enters a network of connected individuals. For example, significant HIV outbreaks among people who inject drugs have occurred in at least half a dozen US states in recent years. This motivates the current study: how can limited testing resources be allocated across geographic regions to rapidly detect outbreaks of an endemic infectious disease? We develop an adaptive sampling algorithm that uses profile likelihood to estimate the distribution of the number of positive tests that would occur for each location in a future time period if that location were sampled. Sampling is performed in the location with the highest estimated probability of triggering an outbreak alarm in the next time period. The alarm function is determined by a semiparametric likelihood ratio test. We compare the profile likelihood sampling (PLS) method numerically to uniform random sampling (URS) and Thompson sampling (TS). TS was worse than URS when the outbreak occurred in a location with lower initial prevalence than other locations. PLS had lower time to outbreak detection than TS in some but not all scenarios, but was always better than URS even when the outbreak occurred in a location with a lower initial prevalence than other locations. PLS provides an effective and reliable method for rapidly detecting endemic disease outbreaks that is robust to this uncertainty.

Cost-effectiveness of Treatments for Opioid Use Disorder.

Importance: Opioid use disorder (OUD) is a significant cause of morbidity and mortality in the US, yet many individuals with OUD do not receive treatment. Objective: To assess the cost-effectiveness of OUD treatments and association of these treatments with outcomes in the US. Design and Setting: This model-based cost-effectiveness analysis included a US population with OUD. Interventions: Medication-assisted treatment (MAT) with buprenorphine, methadone, or injectable extended-release naltrexone; psychotherapy (beyond standard counseling); overdose education and naloxone distribution (OEND); and contingency management (CM). Main Outcomes and Measures: Fatal and nonfatal overdoses and deaths throughout 5 years, discounted lifetime quality-adjusted life-years (QALYs), and costs. Results: In the base case, in the absence of treatment, 42 717 overdoses (4132 fatal, 38 585 nonfatal) and 12 660 deaths were estimated to occur in a cohort of 100 000 patients over 5 years, and 11.58 discounted lifetime QALYs were estimated to be experienced per person. An estimated reduction in overdoses was associated with MAT with methadone (10.7%), MAT with buprenorphine or naltrexone (22.0%), and when combined with CM and psychotherapy (range, 21.0%-31.4%). Estimated deceased deaths were associated with MAT with methadone (6%), MAT with buprenorphine or naltrexone (13.9%), and when combined with CM, OEND, and psychotherapy (16.9%). MAT yielded discounted gains of 1.02 to 1.07 QALYs per person. Including only health care sector costs, methadone cost $16 000/QALY gained compared with no treatment, followed by methadone with OEND ($22 000/QALY gained), then by buprenorphine with OEND and CM ($42 000/QALY gained), and then by buprenorphine with OEND, CM, and psychotherapy ($250 000/QALY gained). MAT with naltrexone was dominated by other treatment alternatives. When criminal justice costs were included, all forms of MAT (with buprenorphine, methadone, and naltrexone) were associated with cost savings compared with no treatment, yielding savings of $25 000 to $105 000 in lifetime costs per person. The largest cost savings were associated with methadone plus CM. Results were qualitatively unchanged over a wide range of sensitivity analyses. An analysis using demographic and cost data for Veterans Health Administration patients yielded similar findings. Conclusions and Relevance: In this cost-effectiveness analysis, expanded access to MAT, combined with OEND and CM, was associated with cost-saving reductions in morbidity and mortality from OUD. Lack of widespread MAT availability limits access to a cost-saving medical intervention that reduces morbidity and mortality from OUD. Opioid overdoses in the US likely reached a record high in 2020 because of COVID-19 increasing substance use, exacerbating stress and social isolation, and interfering with opioid treatment. It is essential to understand the cost-effectiveness of alternative forms of MAT to treat OUD.

Facile Access to Hetero-poly-functional Arenes and meta-Substituted Arenes via Two-Step Dimetalation and Mg/Halogen-Exchange Protocol.

The Grignard reagent, iPrMgCl and its lithium chloride-enhanced 'turbo' derivative iPrMgCl⋅LiCl have been employed to investigate the single iodo/magnesium exchange reactions of the trisubstituted arenes, 2,5-diiodo-N,N-diisopropylbenzamide 1, 1,4-diiodo-2-methoxybenzene 2, and 1,4-diiodo-2-(trifluoromethyl)benzene 3. These three arenes themselves were initially prepared by a double ortho-, meta'-deprotonation of N,N-diisopropylbenzamide, anisole and (trifluoromethyl)benzene, respectively, using the sodium magnesiate reagent [Na4 Mg2 (TMP)6 (nBu)2 ] (where TMP is 2,2,6,6-tetramethylpiperidide), and subsequent electrophilic quenching with iodine/THF solution. Thus, by following a combined deprotonation and magnesium/halogen exchange strategy, the simple monosubstituted arenes can be converted to trisubstituted diiodoarenes, which can ultimately be transformed into the corresponding mono-magnesiated arenes, in THF at -40 °C, within seconds in good yields. The other functional group (OMe, NiPr2 or CF3 respectively) present on the di-iodoarenes helps direct the exchange reaction to the ortho position, whereas subsequent addition of different electrophiles permits the preparation of hetero-poly-functional-arenes, with three different substituents in their structure. Intriguingly, if water is used as the electrophile, a new and facile route to prepare meta-substituted arenes, which cannot be easily obtained by conventional processes, is forthcoming. In contrast to directed ortho-metalation (DoM) chemistry, this reaction sequence can be thought of as InDirect meta-Metalation (IDmM). The scope of the chemistry has been tested further by exposing the initial unreacted iodo-functionality at the meta-position to a second Mg/I-exchange reaction and subsequent functionalization.

Optimizing Interventions Across the HIV Care Continuum: A Case Study Using Process Improvement Analysis.

UNAIDS' 90-90-90 goal for 2020 is for 90% of HIV-infected people to know their status, 90% of infected individuals to receive antiretroviral therapy (ART), and 90% of those on ART to achieve viral suppression. To achieve these ambitious goals, effective care delivery programs are needed. In this paper we present a case study showing how HIV care can be improved by viewing the patient care process as a production process and applying methods of process improvement analysis. We examine the continuum of HIV care at a hospital-based HIV clinic in Kingston, Jamaica. We perform qualitative analysis to identify key programmatic, personnel, and clinical areas for process improvement. We then perform quantitative analysis. We develop a stochastic model of the care process which we use to evaluate the effects of potential process improvements on the number of patients who receive ART and the number who achieve viral suppression. We also develop a model for optimal investment of a fixed budget among interventions aimed at improving the care cascade and we use the model to determine the optimal investment among three interventions that the clinic could invest in. By viewing the patient care process as a production process and applying qualitative and quantitative process improvement analysis, our case study illustrates how clinics can identify the best ways to maximize clinical outcomes. Our methods are generalizable to other HIV care clinics as well as to clinics that provide care for other chronic conditions (e.g., diabetes, hepatitis B, or opioid use disorder).

Ultrafast amidation of esters using lithium amides under aerobic ambient temperature conditions in sustainable solvents.

Lithium amides constitute one of the most commonly used classes of reagents in synthetic chemistry. However, despite having many applications, their use is handicapped by the requirement of low temperatures, in order to control their reactivity, as well as the need for dry organic solvents and protective inert atmosphere protocols to prevent their fast decomposition. Advancing the development of air- and moisture-compatible polar organometallic chemistry, the chemoselective and ultrafast amidation of esters mediated by lithium amides is reported. Establishing a novel sustainable access to carboxamides, this has been accomplished via direct C-O bond cleavage of a range of esters using glycerol or 2-MeTHF as a solvent, in air. High yields and good selectivity are observed while operating at ambient temperature, without the need for transition-metal mediation, and the protocol extends to transamidation processes. Pre-coordination of the organic substrate to the reactive lithium amide as a key step in the amidation processes has been assessed, enabling the structural elucidation of the coordination adduct [{Li(NPh2)(O[double bond, length as m-dash]CPh(NMe2))}2] (8) when toluene is employed as a solvent. No evidence for formation of a complex of this type has been found when using donor THF as a solvent. Structural and spectroscopic insights into the constitution of selected lithium amides in 2-MeTHF are provided that support the involvement of small kinetically activated aggregates that can react rapidly with the organic substrates, favouring the C-O bond cleavage/C-N bond formation processes over competing hydrolysis/degradation of the lithium amides by moisture or air.

Optimal Allocation of Research Funds under a Budget Constraint.

Purpose. Health economic evaluations that include the expected value of sample information support implementation decisions as well as decisions about further research. However, just as decision makers must consider portfolios of implementation spending, they must also identify the optimal portfolio of research investments. Methods. Under a fixed research budget, a decision maker determines which studies to fund; additional budget allocated to one study to increase the study sample size implies less budget available to collect information to reduce decision uncertainty in other implementation decisions. We employ a budget-constrained portfolio optimization framework in which the decisions are whether to invest in a study and at what sample size. The objective is to maximize the sum of the studies' population expected net benefit of sampling (ENBS). We show how to determine the optimal research portfolio and study-specific levels of investment. We demonstrate our framework with a stylized example to illustrate solution features and a real-world application using 6 published cost-effectiveness analyses. Results. Among the studies selected for nonzero investment, the optimal sample size occurs at the point at which the marginal population ENBS divided by the marginal cost of additional sampling is the same for all studies. Compared with standard ENBS optimization without a research budget constraint, optimal budget-constrained sample sizes are typically smaller but allow more studies to be funded. Conclusions. The budget constraint for research studies directly implies that the optimal sample size for additional research is not the point at which the ENBS is maximized for individual studies. A portfolio optimization approach can yield higher total ENBS. Ultimately, there is a maximum willingness to pay for incremental information that determines optimal sample sizes.

Computing the Expected Value of Sample Information Efficiently: Practical Guidance and Recommendations for Four Model-Based Methods.

Value of information (VOI) analyses can help policy makers make informed decisions about whether to conduct and how to design future studies. Historically a computationally expensive method to compute the expected value of sample information (EVSI) restricted the use of VOI to simple decision models and study designs. Recently, 4 EVSI approximation methods have made such analyses more feasible and accessible. Members of the Collaborative Network for Value of Information (ConVOI) compared the inputs, the analyst's expertise and skills, and the software required for the 4 recently developed EVSI approximation methods. Our report provides practical guidance and recommendations to help inform the choice between the 4 efficient EVSI estimation methods. More specifically, this report provides: (1) a step-by-step guide to the methods' use, (2) the expertise and skills required to implement the methods, and (3) method recommendations based on the features of decision-analytic problems.

Structural and metal-halogen exchange reactivity studies of sodium magnesiate biphenolate complexes.

Bimetallic sodium magnesiates have been employed in metal-halogen exchange for the first time. Utilising the racemic phenoxide ligand 5,5',6,6'-tetramethyl-3,3'-di-tert-butyl-1,1'-biphenyl-2,2'-diol [(rac)-BIPHEN-H2], the dialkyl sodium magnesiates [(rac)-BIPHEN]Na2MgBu2(TMEDA)23 and [(rac)-BIPHEN]Na2MgBu2(PMDETA)24 have been synthesised. Both 3 and 4 can be easily prepared through co-complexation of di-n-butylmagnesium with the sodiated (rac)-BIPHEN precursor which can be prepared in situ in hydrocarbon solvent. Prior to the main investigation, synthesis of the sodiated precursor [BIPHEN]2Na4(THF)41 was explored in order to better understand the formation of sodium magnesiates utilising the dianionic (rac)-BIPHEN ligand as the parent ligand. In addition, a BIPHEN-rich sodium magnesiate [BIPHEN]2Na2Mg(THF)42 was prepared and characterised, and its formation was rationalised. Complex 1 and 4 have also been fully characterised in both solid and solution state. In terms of onward reactivity, 3 and 4 have been tested as potential exchange reagents with aryl and heteroaryl iodides to produce aryl and heteroaryl magnesium phenoxides utilising toluene as a non-polar hydrocarbon solvent. Complex 3 reacted smoothly to give a range of aryl and heteroaryl magnesium phenoxides, whilst 4's reactivity is more sluggish.

s-Block cooperative catalysis: alkali metal magnesiate-catalysed cyclisation of alkynols.

Mixed s-block metal organometallic reagents have been successfully utilised in the catalytic intramolecular hydroalkoxylation of alkynols. This success has been attributed to the unique manner in which these reagents can overcome the challenges of the reaction: namely OH activation and coordination to and then addition across a C[triple bond, length as m-dash]C bond. In order to optimise the reaction conditions and to garner vital catalytic system requirements, a series of alkali metal magnesiates were enlisted for the catalytic intramolecular hydroalkoxylation of 4-pentynol. In a prelude to the main investigation, the homometallic magnesium dialkyl reagent MgR2 (where R = CH2SiMe3) was utilised. This reagent was unsuccessful in cyclising the alcohol into 2-methylenetetrahydrofuran 2a or 5-methyl-2,3-dihydrofuran 2b, even in the presence of multidentate Lewis donor molecules such as N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDETA). Alkali metal magnesiates MIMgR3 (when MI = Li, Na or K) performed the cyclisation unsatisfactorily both in the absence/presence of N,N,N',N'-tetramethylethylenediamine (TMEDA) or PMDETA. When higher-order magnesiates (i.e., MI 2MgR4) were employed, in general a marked increase in yield was observed for MI = Na or K; however, the reactions were still sluggish with long reaction times (22-36 h). A major improvement in the catalytic activity of the magnesiates was observed when the crown ether molecule 15-crown-5 was combined with sodium magnesiate Na2MgR4(TMEDA)2 furnishing yields of 87% with 2a : 2b ratios of 95 : 5 after 5 h. Similar high yields of 88% with 2a : 2b ratios of 90 : 10 after 3 h were obtained combining 18-crown-6 with potassium magnesiate K2MgR4(PMDETA)2. Having optimised these systems, substrate scope was examined to probe the range and robustness of 18-crown-6/K2MgR4(PMDETA)2 as a catalyst. A wide series of alkynols, including terminal and internal alkynes which contain a variety of potentially reactive functional groups, were cyclised. In comparison to previously reported monometallic systems, bimetallic 18-crown-6/K2MgR4(PMDETA)2 displays enhanced reactivity towards internal alkynol-cyclisation. Kinetic studies revealed an inhibition effect of substrate on the catalysts via adduct formation and requiring dissociation prior to the rate limiting cyclisation step.

Improving the efficiency of the operating room environment with an optimization and machine learning model.

The operating room is a major cost and revenue center for most hospitals. Thus, more effective operating room management and scheduling can provide significant benefits. In many hospitals, the post-anesthesia care unit (PACU), where patients recover after their surgical procedures, is a bottleneck. If the PACU reaches capacity, patients must wait in the operating room until the PACU has available space, leading to delays and possible cancellations for subsequent operating room procedures. We develop a generalizable optimization and machine learning approach to sequence operating room procedures to minimize delays caused by PACU unavailability. Specifically, we use machine learning to estimate the required PACU time for each type of surgical procedure, we develop and solve two integer programming models to schedule procedures in the operating rooms to minimize maximum PACU occupancy, and we use discrete event simulation to compare our optimized schedule to the existing schedule. Using data from Lucile Packard Children's Hospital Stanford, we show that the scheduling system can significantly reduce operating room delays caused by PACU congestion while still keeping operating room utilization high: simulation of the second half of 2016 shows that our model could have reduced total PACU holds by 76% without decreasing operating room utilization. We are currently working on implementing the scheduling system at the hospital.

Introducing Glycerol as a Sustainable Solvent to Organolithium Chemistry: Ultrafast Chemoselective Addition of Aryllithium Reagents to Nitriles under Air and at Ambient Temperature.

Edging closer towards developing air and moisture compatible polar organometallic chemistry, the chemoselective and ultrafast addition of a range of aryllithium reagents to nitriles has been accomplished by using glycerol as a solvent, at ambient temperature in the presence of air, establishing a novel sustainable access to aromatic ketones. Addition reactions occur heterogeneously ("on glycerol conditions"), where the lack of solubility of the nitriles in glycerol and the ability of the latter to form strong intermolecular hydrogen bonds seem key to favouring nucleophilic addition over competitive hydrolysis. Remarkably, PhLi exhibits a greater resistance to hydrolysis working "on glycerol" conditions than "on water". Introducing glycerol as a new solvent in organolithium chemistry unlocks a myriad of opportunities for developing more sustainable, air and moisture tolerant main-group-metal-mediated organic synthesis.

Cost-effectiveness of Intensive Blood Pressure Management.

Importance: Among high-risk patients with hypertension, targeting a systolic blood pressure of 120 mm Hg reduces cardiovascular morbidity and mortality compared with a higher target. However, intensive blood pressure management incurs additional costs from treatment and from adverse events. Objective: To evaluate the incremental cost-effectiveness of intensive blood pressure management compared with standard management. Design, Setting, and Participants: This cost-effectiveness analysis conducted from September 2015 to August 2016 used a Markov cohort model to estimate cost-effectiveness of intensive blood pressure management among 68-year-old high-risk adults with hypertension but not diabetes. We used the Systolic Blood Pressure Intervention Trial (SPRINT) to estimate treatment effects and adverse event rates. We used Centers for Disease Control and Prevention Life Tables to project age- and cause-specific mortality, calibrated to rates reported in SPRINT. We also used population-based observational data to model development of heart failure, myocardial infarction, stroke, and subsequent mortality. Costs were based on published sources, Medicare data, and the National Inpatient Sample. Interventions: Treatment of hypertension to a systolic blood pressure goal of 120 mm Hg (intensive management) or 140 mm Hg (standard management). Main Outcomes and Measures: Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually. Results: Standard management yielded 9.6 QALYs and accrued $155 261 in lifetime costs, while intensive management yielded 10.5 QALYs and accrued $176 584 in costs. Intensive blood pressure management cost $23 777 per QALY gained. In a sensitivity analysis, serious adverse events would need to occur at 3 times the rate observed in SPRINT and be 3 times more common in the intensive management arm to prefer standard management. Conclusions and Relevance: Intensive blood pressure management is cost-effective at typical thresholds for value in health care and remains so even with substantially higher adverse event rates.

Is it trichotillomania? Hair pulling in childhood: a developmental perspective.

A cohort of children with hair pulling as the presenting symptom was followed up to enhance clinical understanding of the nature of hair-pulling behaviour in childhood. Thirty-eight children were clinically assessed for a diagnosis of trichotillomania, co-morbidity, co-existing habits and other relevant factors. Intervention consisted of a combination of behavioural strategies, self-esteem work, supportive family approaches, attachment-focused parenting models and medication. In this group of children it was difficult to define their symptoms as a clinical diagnosis of trichotillomania, using ICD-1O/DSM-IV. This article concludes that hair pulling, as a symptom in children, is a heterogeneous condition. It is useful to approach this issue from a developmental perspective. Our data warrant reappraisal of the diagnosis of trichotillomania in childhood. We explore the framework of a developmental continuum to understand and manage the problem of hair pulling in childhood.

Tropical cyclone Oscar 1983 : Psychological reactions of a Fijian population

This study provides information on the natural history of human response to disasters. In this case compensation issues or psychological intervention did not influence the outcome. This data should be of value to health service planners charged with providing medical services after a modest natural disaster. The main findings, in summary, were that in the weeks after a cyclone a significant proportion of the population was suffering from neurotic and physical symptoms. No group escaped but the elderly and those who lost the most fared the worst. Race made no difference and these results were comparable to those found in studies of caucasians. For most, the disturbance was transient and by three months morbidity levels had almost returned to control levels. A small number of individuals however remained severely disturbed and would probably require treatment