Pre- and postnatal therapy of lower urinary tract obstruction - an experience of 18 years

With prenatal detection of hydronephrosis and technological advances in surgical equipment, the management of lower urinary tract obstruction has evolved to include prenatal surgical intervention. Surgical intervention, was based upon the rationale that restoring amniotic fluid to normal levels by shunting fetal urine from the obstructed urinary system to the amniotic space would prevent lung hypoplasia and, thus, improve neonatal survival. Inaddition, relief of the obstruction would also reduce back pressure and reduce injury to the developing nephron, thus improving long-term renal function postnatally. However, this remains investigational, and the vast majority of affected infants are treated soon after birth. We have experience since 1991 with prenatal treatment of megacystis. In 23 cases of 50 detected megacystis with oligohydramnion in male and without other abnormalities a prenatal intervention by bladderpunction and in 12 cases additional vesicoamniotic shunt placement was performed. The prognosis of megacystis with oligohydramnion is stated with a survival rate of 10-30%. In our group 54% (13 children) survived. Also we want present 56 cases of urethral valves with a postnatal transurethral intervention. With a follow up time from 8.6 (3 to 15) years we attend 34 children (60%) with normal renal function, 21% (12) with mild or moderate renal insufficiency and there was a kidney transplantation in 6 cases necessary. With our multidisciplinary presentation we want to discuss the indication, interdisciplinary aspects,risks and the follow up of pre- and postnatal intervention in such cases.

[Antibiotic therapy in the outpatient setting: update 2009]

Rational outpatient therapy restricts antibiotics to infections where they are beneficial and selects substances based on local resistance patterns. Respiratory tract infections typically caused by viruses should not be treated with antibiotics (e.g., rhinitis, bronchitis, sinusitis). Many respiratory infections likely caused by bacteria can be treated with aminopenicillin, sometimes combined with a beta-lactamase inhibitor. Quinolones should be used only as exception for respiratory tract infections, since resistance is rising. For this reason uncomplicated urinary tract infections (cystitis) should be treated with trimethoprim-sulfa-methoxazole (TMP-SMX) instead of quinolones, even though approximately 20% of Escherichia coli are resistant to TMP-SMX. Skin and soft tissue infections are best treated with beta-lactam antibiotics, as long as the community acquired methicillin-resistant strains of S. aureus frequently seen in certain countries remain uncommon here.

Hierarchical modeling gave plausible estimates of associations between metabolic syndrome and components of antiretroviral therapy

OBJECTIVE: Hierarchical modeling has been proposed as a solution to the multiple exposure problem. We estimate associations between metabolic syndrome and different components of antiretroviral therapy using both conventional and hierarchical models. STUDY DESIGN AND SETTING: We use discrete time survival analysis to estimate the association between metabolic syndrome and cumulative exposure to 16 antiretrovirals from four drug classes. We fit a hierarchical model where the drug class provides a prior model of the association between metabolic syndrome and exposure to each antiretroviral. RESULTS: One thousand two hundred and eighteen patients were followed for a median of 27 months, with 242 cases of metabolic syndrome (20%) at a rate of 7.5 cases per 100 patient years. Metabolic syndrome was more likely to develop in patients exposed to stavudine, but was less likely to develop in those exposed to atazanavir. The estimate for exposure to atazanavir increased from hazard ratio of 0.06 per 6 months' use in the conventional model to 0.37 in the hierarchical model (or from 0.57 to 0.81 when using spline-based covariate adjustment). CONCLUSION: These results are consistent with trials that show the disadvantage of stavudine and advantage of atazanavir relative to other drugs in their respective classes. The hierarchical model gave more plausible results than the equivalent conventional model.

Risk factors for treatment-limiting toxicities in patients starting nevirapine-containing antiretroviral therapy

BACKGROUND: This collaboration of seven observational clinical cohorts investigated risk factors for treatment-limiting toxicities in both antiretroviral-naive and experienced patients starting nevirapine-based combination antiretroviral therapy (NVPc). METHODS: Patients starting NVPc after 1 January 1998 were included. CD4 cell count at starting NVPc was classified as high (>400/microl/>250/microl for men/women, respectively) or low. Cox models were used to investigate risk factors for discontinuations due to hypersensitivity reactions (HSR, n = 6547) and discontinuation of NVPc due to treatment-limiting toxicities and/or patient/physician choice (TOXPC, n = 10,186). Patients were classified according to prior antiretroviral treatment experience and CD4 cell count/viral load at start NVPc. Models were stratified by cohort and adjusted for age, sex, nadir CD4 cell count, calendar year of starting NVPc and mode of transmission. RESULTS: Median time from starting NVPc to TOXPC and HSR were 162 days [interquartile range (IQR) 31-737] and 30 days (IQR 17-60), respectively. In adjusted Cox analyses, compared to naive patients with a low CD4 cell count, treatment-experienced patients with high CD4 cell count and viral load more than 400 had a significantly increased risk for HSR [hazard ratio 1.45, confidence interval (CI) 1.03-2.03] and TOXPC within 18 weeks (hazard ratio 1.34, CI 1.08-1.67). In contrast, treatment-experienced patients with high CD4 cell count and viral load less than 400 had no increased risk for HSR 1.10 (0.82-1.46) or TOXPC within 18 weeks (hazard ratio 0.94, CI 0.78-1.13). CONCLUSION: Our results suggest it may be relatively well tolerated to initiate NVPc in antiretroviral-experienced patients with high CD4 cell counts provided there is no detectable viremia.

[Diabetes update: preventing type 2 diabetes. Individualized stepwise therapy (oral antidiabetic agents). Multifactorial intervention]

Preclinical disorders of glucose metabolism should be systematically included in the high-risk group for diabetes mellitus and affected individuals provided with preventive measures. Their underlying insulin resistance is determined with the help of a checklist and a method called homeostasis model assessment (HOMA). Patients with impaired fasting glucose (IFG) must change their lifestyles. If this does not lead to a response or the patient is unable to modify behavior, medication is required. In the case of manifest type 2 diabetes mellitus, a graded schedule is used for differential management, which should be based on nutritional and exercise therapy. Oral medication with metformin is probably the drug of choice in both obese and non-obese patients. It is crucial not to delay raising the level of treatment until HbA1c has fallen to within an unsatisfactory range (wait-and-see strategy). Rather, the level should be intensified when persistent exacerbation starts to become apparent (proactive therapy). In diabetes mellitus, the same guidelines for secondary prevention apply to the associated cardiovascular risk factors as with coronary heart disease. An intensified and, especially, early treatment is to be preferred over a conservative, wait-and-see approach, in this case as well.

Estimating Gesture Accuracy in Motion-Based Health Games

This manuscript details a technique for estimating gesture accuracy within the context of motion-based health video games using the MICROSOFT KINECT. We created a physical therapy game that requires players to imitate clinically significant reference gestures. Player performance is represented by the degree of similarity between the performed and reference gestures and is quantified by collecting the Euler angles of the player's gestures, converting them to a three-dimensional vector, and comparing the magnitude between the vectors. Lower difference values represent greater gestural correspondence and therefore greater player performance. A group of thirty-one subjects was tested. Subjects achieved gestural correspondence sufficient to complete the game's objectives while also improving their ability to perform reference gestures accurately.

Use of EORTC Target Definition Guidelines for Dose-Intensified Salvage Radiation Therapy for Recurrent Prostate Cancer: Results of the Quality Assurance Program of the Randomized Trial SAKK 09/10

PURPOSE Different international target volume delineation guidelines exist and different treatment techniques are available for salvage radiation therapy (RT) for recurrent prostate cancer, but less is known regarding their respective applicability in clinical practice. METHODS AND MATERIALS A randomized phase III trial testing 64 Gy vs 70 Gy salvage RT was accompanied by an intense quality assurance program including a site-specific and study-specific questionnaire and a dummy run (DR). Target volume delineation was performed according to the European Organisation for the Research and Treatment of Cancer guidelines, and a DR-based treatment plan was established for 70 Gy. Major and minor protocol deviations were noted, interobserver agreement of delineated target contours was assessed, and dose-volume histogram (DVH) parameters of different treatment techniques were compared. RESULTS Thirty European centers participated, 43% of which were using 3-dimensional conformal RT (3D-CRT), with the remaining centers using intensity modulated RT (IMRT) or volumetric modulated arc technique (VMAT). The first submitted version of the DR contained major deviations in 21 of 30 (70%) centers, mostly caused by inappropriately defined or lack of prostate bed (PB). All but 5 centers completed the DR successfully with their second submitted version. The interobserver agreement of the PB was moderate and was improved by the DR review, as indicated by an increased κ value (0.59 vs 0.55), mean sensitivity (0.64 vs 0.58), volume of total agreement (3.9 vs 3.3 cm(3)), and decrease in the union volume (79.3 vs 84.2 cm(3)). Rectal and bladder wall DVH parameters of IMRT and VMAT vs 3D-CRT plans were not significantly different. CONCLUSIONS The interobserver agreement of PB delineation was moderate but was improved by the DR. Major deviations could be identified for the majority of centers. The DR has improved the acquaintance of the participating centers with the trial protocol.

CD4 count slope and mortality in HIV-infected patients on antiretroviral therapy: multicohort analysis from South Africa

BACKGROUND In many resource-limited settings monitoring of combination antiretroviral therapy (cART) is based on the current CD4 count, with limited access to HIV RNA tests or laboratory diagnostics. We examined whether the CD4 count slope over 6 months could provide additional prognostic information. METHODS We analyzed data from a large multicohort study in South Africa, where HIV RNA is routinely monitored. Adult HIV-positive patients initiating cART between 2003 and 2010 were included. Mortality was analyzed in Cox models; CD4 count slope by HIV RNA level was assessed using linear mixed models. RESULTS About 44,829 patients (median age: 35 years, 58% female, median CD4 count at cART initiation: 116 cells/mm) were followed up for a median of 1.9 years, with 3706 deaths. Mean CD4 count slopes per week ranged from 1.4 [95% confidence interval (CI): 1.2 to 1.6] cells per cubic millimeter when HIV RNA was <400 copies per milliliter to -0.32 (95% CI: -0.47 to -0.18) cells per cubic millimeter with >100,000 copies per milliliter. The association of CD4 slope with mortality depended on current CD4 count: the adjusted hazard ratio (aHRs) comparing a >25% increase over 6 months with a >25% decrease was 0.68 (95% CI: 0.58 to 0.79) at <100 cells per cubic millimeter but 1.11 (95% CI: 0.78 to 1.58) at 201-350 cells per cubic millimeter. In contrast, the aHR for current CD4 count, comparing >350 with <100 cells per cubic millimeter, was 0.10 (95% CI: 0.05 to 0.20). CONCLUSIONS Absolute CD4 count remains a strong risk for mortality with a stable effect size over the first 4 years of cART. However, CD4 count slope and HIV RNA provide independently added to the model.

Are They Really Lost? "True" Status and Reasons for Treatment Discontinuation among HIV Infected Patients on Antiretroviral Therapy Considered Lost to Follow Up in Urban Malawi

INTRODUCTION Patients who are lost to follow-up (LTFU) while on antiretroviral therapy (ART) pose challenges to the long-term success of ART programs. We describe the extent to which patients considered LTFU are misclassified as true disengagement from care when they are still alive on ART and explain reasons for ART discontinuation using our active tracing program to further improve ART retention programs and policies. METHODS We identified adult ART patients who missed clinic appointment by more than 3 weeks between January 2006 and December 2010, assuming that such patients would miss their doses of antiretroviral drugs. Patients considered LTFU who consented during ART registration were traced by phone or home visits; true ART status after tracing was documented. Reasons for ART discontinuation were also recorded for those who stopped ART. RESULTS Of the 4,560 suspected LTFU cases, 1,384 (30%) could not be traced. Of the 3,176 successfully traced patients, 952 (30%) were dead and 2,224 (70%) were alive, of which 2,183 (99.5%) started ART according to phone-based self-reports or physical verification during in-person interviews. Of those who started ART, 957 (44%) stopped ART and 1,226 (56%) reported still taking ART at the time of interview by sourcing drugs from another clinic, using alternative ART sources or making brief ART interruptions. Among 940 cases with reasons for ART discontinuations, failure to remember (17%), too weak/sick (12%), travel (46%), and lack of transport to the clinic (16%) were frequently cited; reasons differed by gender. CONCLUSION The LTFU category comprises sizeable proportions of patients still taking ART that may potentially bias retention estimates and misdirect resources at the clinic and national levels if not properly accounted for. Clinics should consider further decentralization efforts, increasing drug allocations for frequent travels, and improving communication on patient transfers between clinics to increase retention and adherence.

Tracing of patients lost to follow-up and HIV transmission: Mathematical modelling study based on two large ART programmes in Malawi

OBJECTIVES: Treatment as prevention depends on retaining HIV-infected patients in care. We investigated the effect on HIV transmission of bringing patients lost to follow up (LTFU) back into care. DESIGN: Mathematical model. METHODS: Stochastic mathematical model of cohorts of 1000 HIV-infected patients on antiretroviral therapy (ART), based on data from two clinics in Lilongwe, Malawi. We calculated cohort viral load (CVL; sum of individual mean viral loads each year) and used a mathematical relationship between viral load and transmission probability to estimate the number of new HIV infections. We simulated four scenarios: 'no LTFU' (all patients stay in care); 'no tracing' (patients LTFU are not traced); 'immediate tracing' (after missed clinic appointment); and, 'delayed tracing' (after six months). RESULTS: About 440 of 1000 patients were LTFU over five years. CVL (million copies/ml per 1000 patients) were 3.7 (95% prediction interval [PrI] 2.9-4.9) for no LTFU, 8.6 (95% PrI 7.3-10.0) for no tracing, 7.7 (95% PrI 6.2-9.1) for immediate, and 8.0 (95% PrI 6.7-9.5) for delayed tracing. Comparing no LTFU with no tracing the number of new infections increased from 33 (95% PrI 29-38) to 54 (95% PrI 47-60) per 1000 patients. Immediate tracing prevented 3.6 (95% PrI -3.3-12.8) and delayed tracing 2.5 (95% PrI -5.8-11.1) new infections per 1000. Immediate tracing was more efficient than delayed tracing: 116 and to 142 tracing efforts, respectively, were needed to prevent one new infection. CONCLUSION: Tracing of patients LTFU enhances the preventive effect of ART, but the number of transmissions prevented is small.

Monitoring of antiretroviral therapy and mortality in HIV programmes in Malawi, South Africa and Zambia: mathematical modelling study

OBJECTIVES Mortality in patients starting antiretroviral therapy (ART) is higher in Malawi and Zambia than in South Africa. We examined whether different monitoring of ART (viral load [VL] in South Africa and CD4 count in Malawi and Zambia) could explain this mortality difference. DESIGN Mathematical modelling study based on data from ART programmes. METHODS We used a stochastic simulation model to study the effect of VL monitoring on mortality over 5 years. In baseline scenario A all parameters were identical between strategies except for more timely and complete detection of treatment failure with VL monitoring. Additional scenarios introduced delays in switching to second-line ART (scenario B) or higher virologic failure rates (due to worse adherence) when monitoring was based on CD4 counts only (scenario C). Results are presented as relative risks (RR) with 95% prediction intervals and percent of observed mortality difference explained. RESULTS RRs comparing VL with CD4 cell count monitoring were 0.94 (0.74-1.03) in scenario A, 0.94 (0.77-1.02) with delayed switching (scenario B) and 0.80 (0.44-1.07) when assuming a 3-times higher rate of failure (scenario C). The observed mortality at 3 years was 10.9% in Malawi and Zambia and 8.6% in South Africa (absolute difference 2.3%). The percentage of the mortality difference explained by VL monitoring ranged from 4% (scenario A) to 32% (scenarios B and C combined, assuming a 3-times higher failure rate). Eleven percent was explained by non-HIV related mortality. CONCLUSIONS VL monitoring reduces mortality moderately when assuming improved adherence and decreased failure rates.

Cost-effectiveness of point-of-care viral load monitoring of antiretroviral therapy in resource-limited settings: mathematical modelling study

BACKGROUND Monitoring of HIV viral load in patients on combination antiretroviral therapy (ART) is not generally available in resource-limited settings. We examined the cost-effectiveness of qualitative point-of-care viral load tests (POC-VL) in sub-Saharan Africa. DESIGN Mathematical model based on longitudinal data from the Gugulethu and Khayelitsha township ART programmes in Cape Town, South Africa. METHODS Cohorts of patients on ART monitored by POC-VL, CD4 cell count or clinically were simulated. Scenario A considered the more accurate detection of treatment failure with POC-VL only, and scenario B also considered the effect on HIV transmission. Scenario C further assumed that the risk of virologic failure is halved with POC-VL due to improved adherence. We estimated the change in costs per quality-adjusted life-year gained (incremental cost-effectiveness ratios, ICERs) of POC-VL compared with CD4 and clinical monitoring. RESULTS POC-VL tests with detection limits less than 1000 copies/ml increased costs due to unnecessary switches to second-line ART, without improving survival. Assuming POC-VL unit costs between US$5 and US$20 and detection limits between 1000 and 10,000 copies/ml, the ICER of POC-VL was US$4010-US$9230 compared with clinical and US$5960-US$25540 compared with CD4 cell count monitoring. In Scenario B, the corresponding ICERs were US$2450-US$5830 and US$2230-US$10380. In Scenario C, the ICER ranged between US$960 and US$2500 compared with clinical monitoring and between cost-saving and US$2460 compared with CD4 monitoring. CONCLUSION The cost-effectiveness of POC-VL for monitoring ART is improved by a higher detection limit, by taking the reduction in new HIV infections into account and assuming that failure of first-line ART is reduced due to targeted adherence counselling.

Anti-infective therapy of peri-implantitis with adjunctive local drug delivery or photodynamic therapy: 12-month outcomes of a randomized controlled clinical trial

OBJECTIVE: The objective of the study is to compare the clinical, microbiological and host-derived effects in the non-surgical treatment of initial peri-implantitis with either adjunctive local drug delivery (LDD) or adjunctive photodynamic therapy (PDT) after 12 months. MATERIALS AND METHODS: Forty subjects with initial peri-implantitis, that is, pocket probing depths (PPD) 4-6 mm with bleeding on probing (BoP) and radiographic bone loss ≤2 mm, were randomly assigned to two treatment groups. All implants were mechanically debrided with titanium curettes and with a glycine-based powder airpolishing system. Implants in the test group (N = 20) received adjunctive PDT, whereas minocycline microspheres were locally delivered into the peri-implant pockets of control implants (N = 20). At sites with residual BoP, treatment was repeated after 3, 6, 9 and 12 months. The primary outcome variable was the change in the number of peri-implant sites with BoP. Secondary outcome variables included changes in PPD, clinical attachment level (CAL), mucosal recession (REC) and in bacterial counts and crevicular fluid (CF) levels of host-derived biomarkers. RESULTS: After 12 months, the number of BoP-positive sites decreased statistically significantly (P < 0.05) from baseline in both groups (PDT: 4.03 ± 1.66-1.74 ± 1.37, LDD: 4.41 ± 1.47-1.55 ± 1.26). A statistically significant (P < 0.05) decrease in PPD from baseline was observed at PDT-treated sites up to 9 months (4.19 ± 0.55 mm to 3.89 ± 0.68 mm) and up to 12 months at LDD-treated sites (4.39 ± 0.77 mm to 3.83 ± 0.85 mm). Counts of Porphyromonas gingivalis and Tannerella forsythia decreased statistically significantly (P < 0.05) from baseline to 6 months in the PDT and to 12 months in the LDD group, respectively. CF levels of IL-1β decreased statistically significantly (P < 0.05) from baseline to 12 months in both groups. No statistically significant differences (P > 0.05) were observed between groups after 12 months with respect to clinical, microbiological and host-derived parameters. CONCLUSIONS: Non-surgical mechanical debridement with adjunctive PDT was equally effective in the reduction of mucosal inflammation as with adjunctive delivery of minocycline microspheres up to 12 months. Adjunctive PDT may represent an alternative approach to LDD in the non-surgical treatment of initial peri-implantitis.

Optimal time for initiating antiretroviral therapy (ART) in HIV-infected, treatment-naive children aged 2 to 5 years old

BACKGROUND The use of combination antiretroviral therapy (cART) comprising three antiretroviral medications from at least two classes of drugs is the current standard treatment for HIV infection in adults and children. Current World Health Organization (WHO) guidelines for antiretroviral therapy recommend early treatment regardless of immunologic thresholds or the clinical condition for all infants (less than one years of age) and children under the age of two years. For children aged two to five years current WHO guidelines recommend (based on low quality evidence) that clinical and immunological thresholds be used to identify those who need to start cART (advanced clinical stage or CD4 counts ≤ 750 cells/mm(3) or per cent CD4 ≤ 25%). This Cochrane review will inform the current available evidence regarding the optimal time for treatment initiation in children aged two to five years with the goal of informing the revision of WHO 2013 recommendations on when to initiate cART in children. OBJECTIVES To assess the evidence for the optimal time to initiate cART in treatment-naive, HIV-infected children aged 2 to 5 years. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the AEGIS conference database, specific relevant conferences, www.clinicaltrials.gov, the World Health Organization International Clinical Trials Registry platform and reference lists of articles. The date of the most recent search was 30 September 2012. SELECTION CRITERIA Randomised controlled trials (RCTs) that compared immediate with deferred initiation of cART, and prospective cohort studies which followed children from enrolment to start of cART and on cART. DATA COLLECTION AND ANALYSIS Two review authors considered studies for inclusion in the review, assessed the risk of bias, and extracted data on the primary outcome of death from all causes and several secondary outcomes, including incidence of CDC category C and B clinical events and per cent CD4 cells (CD4%) at study end. For RCTs we calculated relative risks (RR) or mean differences with 95% confidence intervals (95% CI). For cohort data, we extracted relative risks with 95% CI from adjusted analyses. We combined results from RCTs using a random effects model and examined statistical heterogeneity. MAIN RESULTS Two RCTs in HIV-positive children aged 1 to 12 years were identified. One trial was the pilot study for the larger second trial and both compared initiation of cART regardless of clinical-immunological conditions with deferred initiation until per cent CD4 dropped to <15%. The two trials were conducted in Thailand, and Thailand and Cambodia, respectively. Unpublished analyses of the 122 children enrolled at ages 2 to 5 years were included in this review. There was one death in the immediate cART group and no deaths in the deferred group (RR 2.9; 95% CI 0.12 to 68.9). In the subgroup analysis of children aged 24 to 59 months, there was one CDC C event in each group (RR 0.96; 95% CI 0.06 to 14.87) and 8 and 11 CDC B events in the immediate and deferred groups respectively (RR 0.95; 95% CI 0.24 to 3.73). In this subgroup, the mean difference in CD4 per cent at study end was 5.9% (95% CI 2.7 to 9.1). One cohort study from South Africa, which compared the effect of delaying cART for up to 60 days in 573 HIV-positive children starting tuberculosis treatment (median age 3.5 years), was also included. The adjusted hazard ratios for the effect on mortality of delaying ART for more than 60 days was 1.32 (95% CI 0.55 to 3.16). AUTHORS' CONCLUSIONS This systematic review shows that there is insufficient evidence from clinical trials in support of either early or CD4-guided initiation of ART in HIV-infected children aged 2 to 5 years. Programmatic issues such as the retention in care of children in ART programmes in resource-limited settings will need to be considered when formulating WHO 2013 recommendations.

Retention in care under universal antiretroviral therapy for HIV-infected pregnant and breastfeeding women ('Option B+') in Malawi

OBJECTIVE To explore the levels and determinants of loss to follow-up (LTF) under universal lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women ('Option B+') in Malawi. DESIGN, SETTING, AND PARTICIPANTS We examined retention in care, from the date of ART initiation up to 6 months, for women in the Option B+ program. We analysed nationwide facility-level data on women who started ART at 540 facilities (n = 21 939), as well as individual-level data on patients who started ART at 19 large facilities (n = 11 534). RESULTS Of the women who started ART under Option B+ (n = 21 939), 17% appeared to be lost to follow-up 6 months after ART initiation. Most losses occurred in the first 3 months of therapy. Option B+ patients who started therapy during pregnancy were five times more likely than women who started ART in WHO stage 3/4 or with a CD4 cell count 350 cells/μl or less, to never return after their initial clinic visit [odds ratio (OR) 5.0, 95% confidence interval (CI) 4.2-6.1]. Option B+ patients who started therapy while breastfeeding were twice as likely to miss their first follow-up visit (OR 2.2, 95% CI 1.8-2.8). LTF was highest in pregnant Option B+ patients who began ART at large clinics on the day they were diagnosed with HIV. LTF varied considerably between facilities, ranging from 0 to 58%. CONCLUSION Decreasing LTF will improve the effectiveness of the Option B+ approach. Tailored interventions, like community or family-based models of care could improve its effectiveness.