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In P. schultei 20 metaphase plates contained 44 chromosomes (44,XX) and two of them contained 43 chromosomes (43,X0). The female karyotype of P. schultei consisted of two pairs of large metacentrics, one pair of medium metacentrics and one pair of large submetacentrics. Remaining chromosomes were medium and small submetacentrics and acrocentrics. In contrast to the female, the male karyotype contained only three large metacentrics, suggesting that the X chromosome in this species is the large metacentric. Small pericentric and telomeric C-positive regions were found in all large metacentrics (Figure 6a). The medium sized metacentric contained large pericentric C-positive region in the short arm and small C-positive region in the terminal position of the long arm. The large submetacentric had a C-positive short arm, and in the long arm, there were a large pericentric C-band and a small C-band in the terminal position. Other chromosomes showed large pericentric C-positive regions (Figure 6a). | study | 100.0 |
Two-color FISH showed that the short arm of the large submetacentric chromosome was enriched for 18S rDNA and telomeric repeats, while ITSs were not found along the whole karyotype. 18S rDNA probe painted slightly some of the large pericentric C-bands in other chromosomes, as well (Figure 6b). | study | 99.9 |
Meiotic chromosomes were prepared from the testes of two males. They formed 21 bivalents and one univalent (X) (Figure 6c,d). C-banding technique revealed in autosome bivalents C-bands as described above. In the X chromosome, small C-bands were visible at telomeric position in both arms while in the pericentric region no C-positive region was detectable (Figure 6c). FISH with the labeled fragment of 18S rDNA and telomeric repeats intensively painted one large extended region on pachytene chromosomes. This corresponded to the short arm of a large submetacentric chromosome. Other regions were painted with labeled 18S rDNA only slightly. On pachytene chromosomes, no ITSs were found (Figure 6d). In Figure 5e, a karyotype is presented; gonosomes were identified here. | study | 100.0 |
To the best of our knowledge, this is only the second study on stick insects applying FISH techniques and here we added one more C-banding study. Five species were studied, only two of which had been karyotyped previously. The presented results provide new insights on Phasmatodea, as outlined below. | study | 99.94 |
A long series of parthenogenetic generations, as present in at least four of the studied species, could lead to an accumulation of genetic abnormalities, including chromosome mutations. Considering this, the variations in chromosome numbers observed for S. sipylus and P. khaoyaiensis may be due to laboratory linages with such chromosomic features or to technical problems. Indeed, embryos were used to obtain chromosomes, thus, selected eggs may have genomic imbalances, which would have been lethal in the egg or shortly after hatching. Thus, the questions of chromosome number variation and the probable structural rearrangement in polyploid species of stick insects in culture remain open for the moment. | study | 99.94 |
Recently, elevated levels of aneuploidy were described in laboratory lines of free-living flat worms Macrostomum lignano . During its evolutionary history this species has undergone whole genome duplication followed by chromosomal rearrangements . In this species, chromosome abnormalities might have disturbed the delicate gene balance, but instead did not lead to any abnormal development or pathological phenotype. Thus, it is at least possible that, in parthenogenetic females of polyploid species, phenotypically normal linages characterized by chromosome abnormalities can arise. These lineages can be an evolutionary dead end or can generate new diversity for further natural selection and evolution. Application of molecular in situ approaches for reliable karyotyping of individual samples of Phasmatodea is required to answer the question of comparative molecular cytogenetics of different strains of polyploid species in stick insects. | study | 99.94 |
The diversity of the C-band patterns in the studied species can be discussed concerning: (a) the location and size of C-positive regions, (b) the DNA content of C-positive regions, and (c) the large C-positive regions identified in all studied species, including bisexual Leptynia (Pantel) . | study | 100.0 |
For (a): All the studied species diverged a long time ago and went through numerous changes during their evolutionary history, involving repeat amplifications leading to C-positive regions and elimination of amplified repeats as well. In all the species we studied, C-positive regions were present in pericentric, telomeric, and interstitial positions of different chromosomes; the only exception was S. inexpectata, where no C-bands could be visualized in the termini of long chromosome arms. Also, in all the species studied here, at least one chromosome pair had a large C-banding positive region. Thus, overall, there are common features in C-band patterns in the stick insects we studied. | study | 100.0 |
For (b): Yet the DNA content of most C-positive regions in Phasmatodea is not clear. Thus, in the future, it would be very useful to estimate the DNA homology of telomeric C-bands in different Phasmatodea species. This task could be solved by chromosome microdissection of telomeric C-bands of one species followed by generation and labeling of a DNA probe by degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR) or whole-genome amplification (WGA) techniques. Other approaches using low copy repeats as probes or high-throughput approaches are also helpful in this context . The telomeric C-bands in P. khaoyaiensis chromosomes are the most promising regions for the suggested microdissection approach. They are large and present in many chromosomes and there are chromosomes with telomeric C-bands in the short or long arms, and in both. It will also be possible to compare the DNA content in such C-bands and in pericentric C-bands, and among the different chromosomes. | study | 100.0 |
For the correct functioning of a centromere, it must be flanked by clusters of repeats of 500 kb or more . We suppose that a failure in detection of C-bands in the pericentric region is due to their small sizes or may be due to technical issues with C-banding. In P. khaoyaiensis chromosomes, there are C-bands in distal regions separated by small C-negative regions (Figure 5a). The approach that has been suggested before of producing microdissection-derived probes would allow for estimating the homology of their DNA. In the case of revealed homology, it can be an argument in favor that more proximal C-bands derive from terminal ones by transposition of repeats or by a small inversion. Interestingly, the chromosomes of P. khaoyaiensis are characterized by many C-bands located close to each other. | study | 100.0 |
Also, in the future, the suggested stick insect-derived microdissection libraries could be sequenced to clarify the genetic content of C-bands, as was previously shown . Later, DNA probes homologous to the identified repeat sequences could help us to understand the distribution of these repeats in C-bands . Yet, only some of the large C-positive regions of stick insects could be shown to contain rDNA and, in some species, to be enriched with telomeric repeats . | study | 99.94 |
The presence of the rDNA-positive C-positive regions underlines two surprising points: the formation and maintenance of this region itself, and its presence in metaphases of five distantly related taxa, i.e., the five species studied here, and two species in Leptynia . Previously, large telomeric regions enriched for rDNA and telomeric repeats were discovered in voles, i.e., Sorex granarius . These regions contain more than 300 kb of discontinued telomeric repeats, localized on short arms of acrocentric chromosomes. In some telomeric regions, the sets of telomeric repeats alternate with repeats of rDNA and other DNA sequences. In the termini of other chromosomes, the sets of telomeric repeats were located a little further away from the clusters of rDNA . The possible mechanisms of formation of these terminal regions include unequal crossing-over and amplification of these repetitive DNA arrays . These very large telomeres were detected only in one vole species, Sorex granarius. In a closely related species, Sorex araneus, the telomeres were of conventional size . The large C-positive regions in stick insects showed some analogy and at the same time differences from the large Sorex granarius telomeres. Like Sorex granarius telomeres, they contain regions enriched for rDNA or both rDNA and telomeric repeats. Furthermore, in S. inexpectata this region is enriched by telomeric repeats to a smaller extent. It is unknown if the arrays of (TTAGG)n repeats in this species are shorter or their number was decreased. These regions were found both in parthenogenetic females (Figure 1, Figure 2, Figure 3, Figure 4 and Figure 5) and in bisexual species (Figure 6) . For stick insects, we can suggest mechanisms involved in the formation of these large C-positive regions, like unequal crossing over, or DNA amplification in somatic cells, as is involved in the formation of a homogeneously staining region . | study | 100.0 |
The most surprising feature of large C-positive regions containing rDNA in stick insects is the sheer size and their localization on a single chromosome pair. According to the present study, there are taxa including species with a few nucleolus organizing regions (NORs) per karyotype (most of the species studied here), while other taxa have species characterized by numerous NORs of distinct size (M. extradentata; Figure 1c). However, even in the first type of taxa, NOR locations are on different chromosomes also in related species, suggesting the transposition of rDNA followed by its amplification at the new spot and elimination of the old NORs. Also, in the three species studied here, and also in Leptynia , the large C-positive blocks are also enriched in telomeric repeats. Interestingly, in S. sipylus a large C-positive block with rDNA and telomeric repeats is present only on one chromosome; in addition, there is a smaller chromosome, with a smaller correspondingly stained region (Figure 4a–c). Either these two chromosomes are different autosomes, or this pattern is a hint of an unusual sex-chromosome system, one being the X and the other the Y chromosome. | study | 100.0 |
The large enriched regions of rDNA or rDNA and telomeric repeats suggest that there are special mechanisms for the restriction of rDNA and telomeric repeat distribution along chromosomes in stick insects. However, chromosomes of M. extradentata are different. The chromosomes of this species are characterized by two large rDNA regions, but other chromosomes also contain many small clusters of rDNA and ITSs. These additional small clusters of rDNA are located mostly near the centromeric regions, while additional clusters of telomeric repeats appear close to the end of long arms. Some clusters of telomeric repeats are located very close to each other. Also, in the FISH results they look almost like fused dots. Other clusters are separated by regions of assorted sizes, suggesting inversion-transferred telomeric repeats in more proximal positions. There are also ITSs inside the chromosomes. Two different mechanisms of ITS formation are known. One of them suggests chromosome rearrangements involving telomeres. The second suggests repair of DNA damage by telomerase . Irregular distribution of ITSs along chromosome arms with a concentration near the chromosomal ends make us hypothesize that most of them are a result of chromosome rearrangements that took place during the chromosomal evolutionary history of M. extradentata. | study | 100.0 |
In our samples, the most intense DNA amplification, leading to large C-positive regions besides the large regions enriched by rDNA or rDNA and telomeric repeats, appears to have taken place during the chromosomal evolution of P. schultei. Large C-bands are present in the pericentric regions of all chromosomes apart from a pair of large metacentric autosomes and the X chromosome. Some of them form whole chromosome arms in biarmed chromosomes; in other biarmed chromosomes, they are even present in both arms, whereas in acrocentrics, C-bands were only observed in pericentric regions. In P. schultei, the chromosome morphology after C-banding makes the identification of centromeres difficult for many chromosomes. However, in DNA amplification forming C-bands, a few copies of rDNA genes or fragments homologous to them were involved and visualized by FISH (Figure 6b). | study | 100.0 |
In stick insects, despite chromosome evolution providing a vast variety of chromosome numbers, probably involving polyploidy and whole genome duplication, all the studied species contain in their karyotypes large regions enriched by rDNA or rDNA and telomeric repeats. Besides rDNA and telomeric repeats, other DNA sequences were also amplified, providing different patterns of C-bands in the chromosomes of stick insects. | study | 99.94 |
The impact of complex humanitarian emergencies on the mental health and psychosocial well-being of the population is multi-layered and endures long after the emergency.1 Studies have demonstrated that mental health and psychosocial support responses in emergency settings are often poorly coordinated, not evidence-based and not implemented within formal national frameworks.2 Research highlights the importance of cultural understanding, training, assessment, monitoring and evaluation.3,4 The Sphere handbook: humanitarian charter and minimum standards in humanitarian response 5 and the Inter-Agency Standing Committee (IASC) Guidelines for mental health and psychosocial support in emergency settings provide standards on such implementation.1 | review | 96.7 |
In May 2014, the first Ebola virus disease case was declared in Sierra Leone; a total of 8700 people were infected and 3600 died. Sierra Leone was declared Ebola-free in November 2015 with 5100 recorded survivors6 and 3400 orphaned children.7 During the outbreak, anecdotal evidence was that increased numbers of people reported mental health and psychosocial problems.8 The outbreak affected existing health structures, halted routine activities and had a major impact on the health workforce. Mortality among health-care workers was 69% (152/219) and they were 20–30 times more likely than the general population to contract Ebola.9 Hospital staff especially faced stigmatization, blame and social exclusion and there were high levels of absenteeism from work. | other | 99.56 |
Mental health service provision in Sierra Leone is poor. In 2009 an estimated 2058 people received some form of mental health treatment, out of about 102 000 people (3% of the 3.4 million adult population) who had a severe mental disorder.10 There is one specialist psychiatric hospital in the country, located in the capital Freetown, to serve the population of 7 million. | other | 99.94 |
During the Ebola virus outbreak, the Sierra Leone psychiatric hospital was closed to admissions to prevent disease transmission. Existing government plans to create new decentralized mental health units across the country11 were brought forward as part of the emergency response. Mental health nurses who had received 12–18 months’ mental health training in 2012–2013 from a bespoke nursing curriculum12 were deployed to general hospitals in various districts. We describe here our experience of establishing one of the new units ‒ a nurse-led mental health and psychosocial support service at Connaught hospital in Freetown, the largest government hospital in the country with approximately 300 beds. | other | 94.9 |
King’s Sierra Leone Partnership, which was already supporting the government’s mental health strategic plan, assisted with the development of the unit at Connaught hospital. To equip the nurses, the World Health Organization (WHO), CBM International and local partners provided the nurses with psychological first-aid training13 focused on supporting those affected by Ebola virus disease. | other | 99.94 |
Meetings were held at Connaught hospital with the mental health focal person from the health ministry, the hospital management team, the mental health nurse allocated to the hospital and the King’s Sierra Leone Partnership team. The agreed objective was to create an inpatient liaison service and an outpatient clinic for community access. This would be a sustainable service, integrated into the existing hospital framework and providing mental health and psychosocial support for all, including those affected by Ebola. The health ministry met the human resources costs. The hospital provided office and clinical space and funding for consumables. King’s Sierra Leone Partnership provided technical expertise, staff supervision and office equipment. | other | 99.94 |
The service was launched in March 2015 and was available to those living within the Freetown city area (about 1 million people) or anyone admitted to Connaught hospital. The partnership devised a standard operating procedure. Individuals of any age with a known or suspected mental health problem or psychosocial need met the referral criteria. A service level agreement with the Sierra Leone psychiatric hospital allowed transfers for inpatient care. In keeping with hospital protocol a registration fee was levied and waived if service users were unable to pay. A single mental health nurse provided the service, with prescribing of medication carried out by a linked hospital medical physician. A range of treatments were provided. Psychological interventions were the most common, comprising basic counselling and problem-solving therapy. The WHO Mental Health Gap Action Programme (mhGAP) intervention guide,14 was the model of care used. A proforma for initial assessment of patients (including demographic information, psychiatric and risk assessment) was created. Monthly monitoring and evaluation data were collected manually from the clinic ledger and presented to the hospital and health ministry management teams. | other | 99.7 |
To strengthen the skills of Connaught hospital’s non-specialist nurses, mental health awareness training was provided by the mental health nurse and King’s Sierra Leone Partnership volunteer. A half-day session on psychological first aid,13 case identification and referral pathways was delivered to a group of 14 ward nurses. | other | 99.9 |
Mental wellbeing workshops were held for nurses, auxiliary staff and physicians who worked at Connaught hospital, including those working within the Ebola holding unit. These workshops were created and led by the mental health nurse and comprised a series of half-day sessions, for groups of 10‒15, on coping with stigma and discrimination, stress management and self-care. The mental health nurse provided one-to-one counselling to staff requiring more support. | other | 99.9 |
The human immunodeficiency virus (HIV) and epilepsy services at Connaught hospital were also offered half-day mental health awareness training by the mental health nurse, and referral pathways were created across the services. Partnerships were established with service user groups (e.g. the HIV peer network), national and international nongovernmental organizations (NGOs) providing livelihood support, child protection organizations and faith groups. | other | 99.9 |
A King’s Sierra Leone Partnership volunteer (senior mental health nurse or psychiatrist) provided regular supervision and mentoring. Weekly individual supervision of the local mental health nurse focused on clinical case review, service monitoring and continuous professional development. Monthly peer supervision including other mental health nurses in Freetown focused on clinical case review, sharing of resources (e.g. information about livelihood support programmes) and continuous professional development. The mhGAP guide was used in supervision to support case-based discussion learning and to reinforce its application within clinical practice. | other | 99.9 |
Challenges facing the service were addressed during weekly mental health team meetings (attended by the mental health nurse and King’s Sierra Leone Partnership volunteer). A timetable including times for home visits, clinics, inpatient work and supervision helped the mental health nurse to manage the workload. | other | 99.94 |
A total of 143 patients were seen within the first 12 months of the service from March 2015 to February 2016 (Table 1). Most patients (96; 67%) were referred from another department at Connaught hospital and 7 (5%) were referred from Ebola clinics; 17 (12%) were referred by themselves, or by family or other relatives. | study | 98.2 |
The most common diagnostic category was mild distress or depression, anxiety disorders and grief or social problems. Thirty patients (21%) presented with psychosis requiring medication. During the Ebola outbreak, an international NGO provided some medicines (e.g. haloperidol and amitriptyline) which were allocated to those unable to pay. Some service users reported accessing alternative treatment (including traditional and faith healing) when medication was not available. | other | 99.9 |
Seven of the patients (5%) had survived Ebola virus disease and 13 (9%) were relatives of the deceased or survivors. Survivors and bereaved relatives presented with normal grief or mild depressive or anxiety symptoms and often reported being stigmatized or discriminated against within their communities. Those who lost family income earners experienced financial difficulties. | other | 99.7 |
Fourteen non-specialist nurses were trained in mental health awareness and provided basic support on their wards and referred patients to the service. Over 100 Connaught hospital nurses, auxiliary staff and physicians participated in mental wellbeing workshops. | other | 99.94 |
Monthly updates to the hospital management encouraged service improvements. From March 2015 to February 2016, approximately 30 abandoned patients (those with no relatives to provide care or financial support) were referred to the service. Evidence of high use by abandoned patients led to a successful request for a social worker to be deployed to the hospital. | other | 99.94 |
Early engagement of participants and a partnership approach with clear roles and responsibilities for all parties was key to ensuring ownership of and commitment to the service (Box 1). The health ministry and the hospital management responded positively to mental health and psychosocial support services being incorporated into a general hospital. Shared supervision was essential for maintaining clinical standards, developing competencies and providing a support network for the mental health nurses. The mental health service at the hospital is effective, integrated and has strengthened local capacity. People are now able to access affordable mental health care at a general hospital. | other | 99.94 |
The service’s ability to adapt and respond to changing needs ensured that support for health-care workers could be provided as the impact of the Ebola disease workload became apparent. The service provided care not only for survivors, but all those affected by the outbreak who presented with psychosocial needs. | other | 99.94 |
There were challenges too. Although limited supplies of antipsychotic medications were available in local pharmacies, some patients could not afford them. The workload was high for a single nurse and the mental health nurse faced a risk of burnout and fatigue. Most referrals were from within Connaught hospital. We suspect community uptake was low because the service was new and the community had previous experience of mental health services at the hospital. Staff recruitment and training and community uptake therefore remain areas for development. Much of the focus has been on providing care for Ebola survivors, drawing attention and resources away from mental health services for the wider population. | other | 99.9 |
The Ebola virus disease outbreak weakened an already fragile health system and disrupted existing plans to develop mental health services across the country. However, the emergency response provided the opportunity, resources and focus necessary to create the new units.16 Our experience has guided the establishment of 14 other mental health units countrywide so far. The service is inclusive and accessible to the entire population. There are plans to further develop the service, with integration into primary-care structures, increased community utilization and greater staff recruitment. A service evaluation ‒ measuring outcomes, follow-up rates, barriers to access and service coverage ‒ is underway. We believe our approach is a suitable framework for delivering mental health services and developing more resilient systems during an emergency response. | other | 99.9 |
In sub-Saharan Africa, heterosexual HIV-1 serodiscordant couples account for a substantial proportion of new HIV-1 infections [1–3]. Randomized clinical trials have provided definitive evidence that antiretroviral treatment (ART) for HIV-1 infected persons and pre-exposure prophylaxis (PrEP) for HIV-1 uninfected persons are highly efficacious in decreasing HIV-1 transmission risk within HIV-1 serodiscordant partnerships . Mathematical modeling studies have found that providing HIV-1 serodiscordant couples with antiretroviral prevention interventions may have a significant impact on the HIV-1 epidemic . Delivery of antiretroviral based HIV-1 prevention interventions, particularly in resource-constrained settings, must target those at highest risk for HIV-1, which would achieve maximal public health benefit in a cost-effective manner [7–9]. | review | 99.8 |
We previously developed and validated an empiric risk scoring tool to identify highest-risk HIV-1 serodiscordant African heterosexual couples using data from 8500 stable HIV-1 serodiscordant African couples enrolled in three prospective studies . The score is composed of variables that are easily measurable in clinical settings including whether the couple had any unprotected sex in the prior month, the number of children in the partnership, marital status, age of the HIV-1 uninfected partner, circumcision status of HIV-1 uninfected male partners, and plasma HIV-1 RNA concentrations in the HIV-1 infected partner (Fig. 1). Additional variables such as gender, duration of partnership, hormonal contraception use and CD4 count were considered for the scoring tool but these were less predictive of HIV-1 transmission risk than the included factors. The maximum score is 12 and a score of 0–2 has an anticipated HIV-1 incidence of <1 % per year, 3–4 has an anticipated incidence of approximately 2 % per year, and a score ≥5 has an anticipated HIV-1 incidence of >3 % per year . In the present analysis, we assessed the ability of the HIV-1 risk score to identify higher-risk HIV-1 serodiscordant couples for recruitment into a prospective study delivering ART and PrEP for HIV-1 prevention in Kenya and Uganda.Fig. 1HIV-1 risk score worksheet | study | 100.0 |
The Partners Demonstration Project is a prospective, open-label cohort study of the delivery of antiretroviral-based HIV-1 prevention to high-risk HIV-1 serodiscordant couples in four sites in Kenya and Uganda. HIV-1 infected partners are offered ART according to the national ART initiation guidelines which, as of 2014, recommend ART for all HIV-1 infected partners in serodiscordant couples, regardless of CD4 count . PrEP is offered to the HIV-1 uninfected partner prior to and for the first 6 months after ART initiation by the infected partner, at which time viral suppression is expected. | study | 98.4 |
Between November 2012 and August 2014, HIV-1 serodiscordant couples were recruited for the Partners Demonstration Project from HIV-1 voluntary counseling and testing (VCT) centers, HIV-1 care providers, programs for prevention of mother-to-child HIV-1 transmission (PMTCT) services, and community promotion activities for couples’ VCT. Enrollment was completed in August 2014. At the screening visit, demographic and behavioral information were collected via interviewer-administered standardized questionnaires. Screening laboratory tests included repeat HIV-1 testing for both partners following the national HIV-1 testing algorithms, serum creatinine and hepatitis B surface antigen (HBsAg) for HIV-1 uninfected partners, and CD4 count and plasma HIV-1 RNA concentrations for HIV-1 infected partners. | study | 100.0 |
Based on data collected during screening, we computed the HIV-1 risk score for all HIV-1 serodiscordant couples; couples with a risk score ≥5 met the study eligibility criteria. Couples who had a HIV-1 risk score below the “high risk” cutoff (<5) were counseled about the prevalence and significance of HIV-1 serodiscordant results, behavioral risk reduction, the importance of condom use to reduce the risk of HIV-1 transmission, and their transmission risk. They were also referred to local public health clinics for ART provision according to national guidelines, male circumcision, and condoms. For couples who had a risk score ≥5, additional eligibility requirements included having adequate renal function and not having hepatitis B infection for HIV-1 uninfected partners. We excluded couples in whom the HIV-1 infected partner was already using of ART or had any WHO stage III or IV condition so that the research process would not distract from the urgent need for these individuals to initiate ART. HIV-1 uninfected women were excluded if they were pregnant or breastfeeding. Eligibility criteria were reviewed in totality to determine which couples met all criteria and were offered enrollment. | study | 100.0 |
To understand the ability of the HIV-1 risk score to identify high risk couples for antiretroviral-based prevention in the setting of an implementation project, we used descriptive statistics to summarize the proportion of screened couples that had an HIV-1 risk score ≥5 and the proportion of higher-risk couples that enrolled in the Partners Demonstration Project. Analyses were done using STATA version 13.1 (StataCorp, College Station, TX). | study | 100.0 |
Among screened couples, 43 (2.5 %) had an HIV-1 risk score of 0–2, 319 (18.8 %) scored 3–4, and 1331 (78.6 %) scored ≥5 (the higher-risk population, Fig. 2). One couple that did not complete screening was not scored. There were 681 HIV-1 serodiscordant couples that were screened for the study but did not enroll: 613 (90.0 %) were not eligible, 66 (9.7 %) were eligible but did not enroll and 2 (0.3 %) did not complete screening. Of the ineligible HIV-1 serodiscordant couples, 252 (41.1 %) had a HIV-1 risk score ≥5 and the main reasons for their ineligibility were advanced clinical HIV-1 disease (41.7 %), infection with hepatitis B (21.8 %) or use of ART (13.9 %). Three-quarters (76 %) of HIV-1 serodiscordant couples scoring ≥5 enrolled into the study. Of the enrolled couples, 479 (47.3 %) scored >7, a level of risk with HIV-1 incidence >7 % per year in prior cohorts .Fig. 2Flow chart of HIV-1 serodiscordant couples screened for eligibility to the Partners Demonstration Project | study | 100.0 |
The median age of the HIV-1 uninfected partner was 29 years [interquartile range (IQR) 26–36], and 20 % were <25 years of age (Table 1). The HIV-1 uninfected partner was male in 67 % of the partnerships. Most couples (97.8 %) were married or cohabitating and had been living together for a median of 2.5 years [IQR 0.8–7.0] but had only learned of their HIV-1 serodiscordant status a median of 1 month [IQR 1–3] prior to the screening date. Over half of the couples (56.5 %) had no children and 64.8 % reported sex unprotected by condoms in the month prior to enrollment. A third of HIV-1 uninfected males were not circumcised. The median age of HIV-1 infected partners was 28 years [IQR 23–35] and 41.8 % had plasma HIV-1 RNA levels ≥50,000 copies/mL (median 4.6 log10 copies/mL, IQR 3.8–5.0). The median CD4 count was 436 cells/uL [IQR 272–638] and 41 % had a CD4 count >500 cells/μL. More than a third (34.7 %) of HIV-1 infected partners with CD4 counts >500 cells/μL were in partnerships that had a HIV-1 risk score ≥7 (Fig. 3). For twelve of the enrolled participants baseline plasma HIV-1 RNA levels were detectable even though the HIV-1 antibody test was negative, suggesting early HIV infection. Eligible couples who did not enroll had similar characteristics to enrolled couples.Table 1Baseline characteristics of enrolled HIV-1 serodiscordant couples in the Partners Demonstration Project (N = 1013)Median [IQR] or N (%)Age of HIV-1 uninfected partner29 (26–36) 18–2038 (3.8) 21–30534 (52.7) ≥ 31441 (43.5)Number of children within partnershipa 0 (0–1) 0572 (56.5) 1–2334 (33.0) ≥ 3107 (10.6)Not circumcised (male HIV-1 uninfected only)225 (33.1)Married/ cohabitating with study partnera 991 (97.8)Unprotected sex in month prior to enrollmenta 656 (64.8)Viral load of HIV-1 infected partner4.6 (3.8–5.0) < 10,000280 (28.1) 10,000–49,999301 (30.2) ≥ 50,000417 (41.8) aData obtained from HIV-1 uninfected partners Fig. 3Proportion of enrolled couples in each CD4 category, by risk score | study | 99.94 |
In the Partners Demonstration Project, the use of a validated HIV-1 risk score identified heterosexual HIV-1 serodiscordant couples with characteristics consistent with high-risk of HIV-1 transmission. The score is comprised of easy to measure behavioral and biologic risk factors for HIV-1 [10, 12] and those with high scores are a natural priority population for coordinated delivery of early ART and time-limited PrEP prior to ART initiation and viral suppression. Three-quarters of the couples with a high score (≥5) were motivated to join the study and initiate PrEP and/or ART for HIV-1 prevention. | study | 99.94 |
The risk score is a composite variable that facilitates the assessment of the distribution of risk within a HIV-1 serodiscordant partnership. A couple may have high risk on some factors and low on others, but the risk score tool enables computation of a level of overall risk for the partnership. Of note, we used a scoring tool that incorporates HIV-1 plasma viral load but a tool without viral load was also validated for use in places where such testing is not routinely available [10, 12]. Upon exclusion of viral load from the scoring tool a cut off of ≥4 would distinguish couples with an expected incidence >3 % per year and if applied to this cohort, 92 % of the couples would remain eligible and 66 % of the ineligible couples would still screen out. | study | 100.0 |
In our prior randomized clinical trial of PrEP efficacy and safety (the Partners PrEP Study), eligibility criteria were similar minus the use of a risk scoring tool, study sites included the 4 that were part of the current study, and similar strategies were employed to recruit HIV serodiscordant couples . Qualitatively, participants recruited into the Partners Demonstration Project were younger (median age 29 years in the Partners Demonstration Project versus 33 years in the Partners PrEP Study), had fewer children (median of 0 in the Partners Demonstration Project versus 2 in the Partners PrEP Study), had a higher proportion of unreported sex prior to enrollment (65 % in Partners Demonstration Project versus 27 % in the Partners PrEP Study), and had higher plasma HIV-1 RNA concentrations (4.6 log copies/ml in Partners Demonstration Project versus 3.9 log copies/ml in Partners PrEP Study). These characteristics all indicate higher HIV-1 risk in the cohort that was recruited using the scoring tool. | study | 99.94 |
The risk score identifies HIV-1 serodiscordant couples with high risk of transmission for whom extra effort should be taken to overcome barriers to using HIV-1 prevention methods, including delays in ART initiation. Many HIV-1 infected partners in this study had high CD4 counts and by current guidelines, their indication for ART initiation was for the prevention benefit of their uninfected partner [12, 13]. Counseling of HIV-1 serodiscordant couples should emphasize the clinical and prevention benefits of ART, including for HIV-1 infected persons with higher CD4 and who are asymptomatic. In one review of ART initiation among HIV-1 infected partners in HIV-1 serodiscordant partnerships in East Africa, half of those found to be eligible delayed ART initiation by more than six months, with the delay more pronounced for those with higher CD4 counts . Importantly, for maximal public health impact, PrEP may be reserved for couples during periods when they are at high risk of HIV-1 transmission. Thus, for the Partners Demonstration Project, where the goal was to demonstrate that higher-risk couples could be recruited and retained, couples who did not meet the risk score criteria were counseled about their ongoing HIV-1 risk and referred to public health clinics where they could access ART, as well as counseling services, STI screening and treatment, and medical male circumcision. PrEP is an effective strategy for HIV-1 serodiscordant couples when the infected partner delays ART initiation or for a time-limited period (e.g., 6 months) after ART initiation by the infected partner prior to becoming virally suppressed . Future PrEP programs may use a similar scoring criterion to prioritize subsets of couples for PrEP; local context, including resource availability, would likely also shape prioritization decisions. | review | 99.25 |
One limitation of our findings is that the majority of couples were recruited from voluntary counseling and testing centers, demonstrating motivation and health-seeking behavior, thus potentially impacting the generalizability to settings with provider-initiated counseling and testing and other testing strategies [16, 17]. Furthermore, we assessed feasibility of using the HIV-1 risk score within the Partners Demonstration Project at research clinics. Thus, the use of this score within a public health setting has not been evaluated. However, the Partners Demonstration Project was designed to reflect operations of public health clinics in Kenya and Uganda as much as possible. | study | 100.0 |
Antiretroviral-based HIV-1 prevention interventions will achieve the greatest impact among HIV-1 serodiscordant couples if they are implemented with strategic and cost-effective provision to motivated couples at highest risk of HIV-1 transmission . The HIV-1 risk score, an easy-to-use tool that utilizes information routinely collected in HIV prevention counseling sessions, identified this high-risk sub-population and prioritized them for antiretroviral based HIV-1 prevention interventions. The risk score is a pragmatic and inexpensive method that public health clinics could employ to help identify couples that would benefit most from an antiretroviral-based HIV-1 prevention intervention. | study | 99.94 |
Worsening renal function (WRF) during hospitalization for acute heart failure (AHF) is associated with poorer outcome. However, some studies suggest that transient WRF during treatment for AHF may not be harmful, and may even reflect a better therapeutic response . We recently showed that patients with AHF and a good diuretic response had a higher incidence of WRF but better outcomes . The cause of WRF appears to be an important factor for determining risk related to WRF. Early identification of patients at risk of WRF, as well as a robust definition and better understanding of its cause and consequences, may improve risk stratification. Novel biomarkers may play a role in achieving this goal. | study | 99.9 |
Neutrophil Gelatinase Associated Lipocalin (NGAL), a 25 kDa member of the Lipocalin family expressed by the renal tubular epithelium, is released into both urine and blood in response to tubular injury. Higher plasma NGAL has been associated with poorer clinical outcomes in AHF . A number of small studies showed conflicting findings on the potential value of plasma NGAL as an early marker of WRF . For instance, in 207 patients with AHF, neither serum creatinine nor NGAL was able to accurately predict WRF . In sharp contrast, in another study in 119 AHF patients, NGAL (below a certain cutoff value) had a 100% negative predictive value for the prediction of WRF . A recent study evaluating NGAL as a predictor of acute kidney injury (AKI) showed similar results for NGAL, compared with serum creatinine, in the ability to predict AKI . In the present study, we aimed to establish the value of plasma NGAL as an early predictor of WRF, and as a discriminator between WRF with a good and a poor prognosis. | study | 99.94 |
Patient characteristics for patients with and without WRF, stratified by survival, are presented in Table 1. Patients who developed WRF during the first four days (n = 325; 22%) had a higher Left Ventricular Ejection Fraction (LVEF), higher systolic blood pressure, less edema, worse baseline renal function, higher NGAL levels, lower hemoglobin, and more anemia (all p < 0.05). Profiles for survivors at 180 days versus patients who died were similar, regardless of whether WRF developed; patients who died had a lower ejection fraction, lower blood pressure, worse renal function, reflected by higher Blood Urea Nitrogen (BUN), and plasma concentrations of creatinine and NGAL (all p < 0.05). Tables S1 and S2 present baseline characteristics, by tertiles, of baseline serum creatinine and plasma NGAL. Higher levels were associated with more advanced age and more co-morbidity. Plasma concentrations of NGAL, correlated with serum creatinine (Spearman’s rho 0.58 at baseline and 0.60 at day 4, p < 0.001), estimated GFR (Spearman’s rho −0.60 at baseline and −0.62 at day 4, p < 0.001) and BUN (Spearman’s rho 0.52 at baseline and 0.54 at day 4, p < 0.001), and modestly with CRP (Spearman’s rho 0.12 at day 1, 0.13 at day 4, p < 0.001). | study | 99.94 |
Figure 1 displays changes in serum creatinine and NGAL during the first week of admission in patients with and without WRF, adjusted for study treatment. Biomarker changes for alternative WRF definitions are presented as supplementary Figures S1 and S2, and display similar patterns. Serum creatinine and plasma NGAL trajectories differed significantly between patients with and without WRF for all definitions (p for interaction with time <0.001), and rolofylline treatment had no effect (p = n.s.). Figure 2 shows the relative creatinine and plasma NGAL changes over the first 7 days in patients with and without WRF. In patients who developed WRF, NGAL levels did not rise significantly sooner than creatinine levels; both markers increased in parallel over the first 2 days (p for difference n.s.), with NGAL rising further than creatinine over the course of 7 days, while displaying greater variability (p < 0.05). Patterns were similar for alternative definitions of WRF (Figures S3 and S4). | study | 100.0 |
In ROC curve analyses, WRF proved difficult to predict well, with modest AUC values. Baseline and day 2 NGAL and creatinine were similarly predictive of WRF, while a non-diagnostic creatinine change on day 2 was a much stronger predictor of WRF than NGAL change on day 2 (Table 2). | study | 100.0 |
In sensitivity analyses, predictive value for other WRF definitions/cut-offs showed similar patterns (Tables S3 and S4). Baseline plasma NGAL was independently predictive of WRF in a multivariable model (Table 3), while serum creatinine was not. NGAL contributed significantly to improving WRF prediction (AUC 0.648 vs. 0.635 for model with vs. without NGAL, p = 0.002). In sensitivity analyses, multivariable models for other WRF cut-offs consistently included NGAL, which significantly improved model discrimination in all models (p < 0.05), but not creatinine. However, these small improvements are likely not clinically relevant. | study | 100.0 |
To investigate the value of NGAL for distinguishing between WRF with good and poor outcomes, we examined NGAL and creatinine trajectories (Figure 3) in patients who experienced WRF (or not) who had died, or were alive, after 180 days. Baseline plasma NGAL was higher and rose further in patients who died compared to survivors, and was higher in patients with WRF, irrespective of outcome. The pattern was similar when the 60-day endpoint was examined. In mutually adjusted models, including NGAL and Creatinine, NGAL was a stronger predictor of WRF with a poor outcome, and improved the model when added to creatinine, showing consistently higher Goodness of Fit (Table 4). | study | 100.0 |
In Cox models, baseline serum creatinine and plasma NGAL were invariably associated with both 180-day mortality and the 60-day composite (all p < 0.001), although this did not persist following multivariable adjustment (all p = n.s.). WRF was independently associated with both endpoints (multivariable HR for 180-day mortality: 1.45, 95% CI 1.12–1.88, p = 0.004; multivariable HR for the 60-day composite: 1.27, 95% CI 1.01–1.59, p = 0.04); sensitivity analyses with absolute creatinine change and other definitions for WRF showed similar performance (data not shown). | study | 100.0 |
In patients with a rise in serum creatinine, higher baseline plasma NGAL (p for interaction 0.024)—but not higher baseline serum creatinine (p for interaction = 0.464)—posed a significant, relatively greater risk of reaching the 60-day composite endpoint. Supplementary Figure S5 displays the multivariable hazard ratios for the 60-day composite endpoint for the continuous interactions between creatinine change, and baseline values of creatinine or NGAL. The continuous hazard functions for creatinine change, stratified by either baseline creatinine levels (first panel) or baseline NGAL levels (second panel), illustrate the interaction between creatinine change and baseline biomarker levels. Patterns were similar for the 180-day mortality endpoint, but no interactions reached significance. | study | 100.0 |
The clinical value of changes in NGAL, combined with WRF, was examined by comparing clinical outcomes between patients with and without WRF, and with a similar rise in NGAL on day 4. This was defined as an increase of ≥1 SD (≥88 ng/mL) in NGAL (n = 83), as the SD for creatinine change by day 4 was about 0.3 mg/dL, resembling the definition of WRF. The Kaplan-Meier curve is displayed in Figure 4, showing a significantly increased risk of mortality, only if both markers rose significantly (p-value for WRF with NGAL increase ≥88 ng/mL versus the other three groups = 0.007). Patients with ≥1 SD rise in NGAL had significantly higher creatinine at baseline than those who did not (p < 0.05), but similar levels, irrespective of whether WRF developed (1.8 vs. 1.7 mg/dL with vs. without WRF, p = 0.59). Baseline characteristics in this small subgroup did not differ significantly based on WRF status. | study | 100.0 |
We examined the value of NGAL for predicting clinically relevant WRF and outcomes in 1447 patients admitted with AHF (to our knowledge, the largest cohort of AHF patients with available serial plasma NGAL measurements). WRF was common, occurring in 22% of patients during the first four days of admission. Patients who developed WRF were more likely to have poor renal function at baseline, although only NGAL levels—but not creatinine—were independently associated with the development of WRF. We found no indication that plasma NGAL rises earlier than creatinine in AHF patients who develop WRF; both markers rose in tandem over the first two days of admission. Although NGAL showed statistically significant incremental value for predicting WRF, no combination of markers performed particularly well, with AUCs below 0.60. While high levels of both NGAL and creatinine at baseline were associated with mortality and rehospitalization, neither was independently predictive after adjustment for clinical covariates. | study | 99.94 |
NGAL has been identified as a powerful early predictor of WRF in a number of different clinical settings , although the data in AHF are conflicting . Similarly to Breidthardt et al. , we found modest predictive ability for plasma NGAL, which provided minimal improvement on top of creatinine for predicting WRF. Our data further confirm findings by the prospective biomarker study Acute Kidney Injury Neutrophil Gelatinase-Associated Lipocalin Evaluation of Symptomatic Heart Failure Study (AKINESIS) that recently showed similar results—NGAL was not a more sensitive predictor of AKI in patients admitted with acute HF . Whereas AKINESIS only assessed severe and sustained increases in creatinine, more closely resembling acute kidney injury, we evaluated the much more common used definitions of WRF. Furthermore, our study not only provides data on inhospital changes in plasma NGAL, but also long term outcomes, whereas in AKINESIS only inhospital events were evaluated. In the end, considering the poor performance of both markers for AKI/WRF prediction in both AKINESIS and the present study, the clinical relevance of the associations is debatable at best. | study | 99.94 |
One potential issue is the self-fulfilling nature of predicting a rise in creatinine, using creatinine. Interestingly, we found that baseline NGAL values—but not baseline creatinine values—predicted WRF in multivariable models. Regardless, the hypothesis that NGAL rises earlier than creatinine does not hold true in this AHF cohort, as illustrated by the estimated trajectories corrected for study treatment. There are several potential explanations for the lack of an early rise in plasma NGAL, and thus the poor prognostic accuracy for WRF in AHF. First, plasma NGAL—in contrast with urinary NGAL—may not be a particularly appropriate tubular marker; it is strongly related to glomerular filtration rate, as reflected by its correlation with GFR and creatinine, and also involved in iron scavenging and immune response, as indicated by the correlation with markers such as CRP and markers of anemia . Shrestha et al noted strong correlations between urinary NGAL and measures for natriuresis and response to diuretics, while plasma NGAL only correlated well with GFR, though both predicted WRF . Second, there are multiple mechanisms for WRF in AHF patients. For example, true AKI (resulting in tubular damage), with substantial and rapid loss of function and decreased urine output is probably not comparable to the kind of WRF studied extensively in AHF. In the clinical context of AHF, changes in renal function may be driven more by hemodynamic and neurohormonal (mal) adaptation and drug effects than the (hypoxic) kidney injury common in intensive care or post-surgical settings; Dupont et al. showed that despite a relatively high incidence of AKI, defined based on creatinine increases, tubular injury was relatively uncommon in a small, prospective study of 141 AHF patients . Third, in contrast with studies in post-surgical or post-intervention patients , the timing of renal injury is often unclear in AHF, and its pre-hospital course may vary significantly, and may include undetected WRF. Pre-admission worsening congestion and intensification of diuretic therapy may have already triggered progressive renal impairment in the patients in our study—all of whom had at least a brief history of heart failure. Fourth, there is ongoing debate regarding the best measure for renal function and injury; a definition of WRF, based on a more “pure” marker, such as cystatin C or measured GFR, may have yielded very different results. | study | 99.7 |
Impaired and worsening renal function are established risk markers in heart failure . Data on the prognostic value of NGAL is mixed, with many —but not all —studies in both chronic and AHF reporting prognostic value, though correction for potential confounders varies greatly. Givertz et al. previously reported on the prognostic value of various renal markers in PROTECT, concluding that creatinine change and baseline BUN were strong predictors of outcome . Additionally, our analyses show that NGAL modulates the risk of outcomes associated with creatinine change, conferring a greater relative risk to patients with higher NGAL levels with a creatinine increase, but not to patients without. This effect is independent of baseline creatinine. Furthermore, a large increase in NGAL during admission conferred an additional risk of death (only in patients with WRF). Thus, while plasma NGAL levels appear to largely reflect GFR (and thus creatinine), they do have some incremental value for assessing the risk associated with WRF, and could help discriminate between higher and lower risk WRF. | study | 99.9 |
Identifying patients at high risk of developing renal dysfunction and poor outcomes remains a challenge in AHF. Coupled with a lack of effective therapeutic options, this poses a problem for clinicians. Biomarkers such as NGAL can be used as diagnostic or prognostic tools, though their application requires careful and thorough evaluation. Despite the extensive but conflicting literature on plasma NGAL, our analyses in this very large group of well-characterized AHF patients, together with findings from AKINESIS, indicate fairly poor accuracy for predicting WRF. | study | 99.94 |
Plasma NGAL was not independently prognostic for death or rehospitalization. Our findings suggest elevated baseline NGAL levels, and large increases in NGAL do confer additional risk for patients who develop WRF (although the clinical relevance of these findings—given the lack of independent prognostic value for NGAL, the small numbers of patients with NGAL increases, and the post-hoc nature of our analyses—remains to be established). | study | 100.0 |
Due to the retrospective nature of this study, our results should be considered hypothesis-generating, and should therefore be interpreted cautiously. Furthermore, NGAL was measured using frozen samples, which may have affected data quality. No urine was collected, so the performance of urinary NGAL could not be compared that of plasma NGAL, and may have shown very different patterns and results. | study | 100.0 |
This is a post hoc analysis of the Placebo-controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal FuncTion (PROTECT) trial, a randomized, double-blind, placebo-controlled, multi-center study that enrolled 2033 patients admitted for acute decompensated heart failure, randomized 2:1 to rolofylline, with neutral overall results. Study design, inclusion, and exclusion criteria and results have been published previously . The trial was approved by all local Ethics Committees and conducted in accordance with the Declaration of Helsinki (NCT00328692 and NCT00354458). All patients provided written informed consent. Of the patients who remained hospitalized for at least 4 days (n = 1681), those with available NGAL and creatinine values at baseline (n = 1470), and at least one follow-up measurement for each marker during the first 4 days, were included in the analysis, resulting in a study population of 1447 patients. Patients who had already developed WRF by day 2 (n = 101) were excluded from analyses of the effects of biomarker levels and changes on day 2. | other | 98.7 |
Heart failure signs and symptoms, serum creatinine, and other hematologic and biochemical markers, were assessed daily from baseline (day 1) until discharge or day 6 and on day 7, as dictated by study protocol . Plasma NGAL levels were measured in frozen plasma samples collected on the same days and stored at −80 °C. Measurements were performed by Alere Inc. (San Diego, CA, USA) using sandwich enzyme-linked immunosorbent assays (ELISA) on a microtiter plate. The estimated glomerular filtration rate (GFR) was calculated using the simplified modification of diet in renal disease (MDRD) study equation. | study | 99.94 |
This study examined WRF occurring during the first 4 days of hospitalization, defined as a creatinine increase of ≥0.3 mg/dL (26.5 µmol/L), at any time between day 1 (baseline) and day 4, or initiation of hemofiltration as it was defined in the main study. Sensitivity analyses were performed with other definitions, including absolute creatinine, a relative creatinine increase of ≥25%, a combined increase of ≥0.3 mg/dL and ≥25%, and various cut-offs. | study | 100.0 |
The prognostic value of plasma NGAL for distinguishing between WRF and good vs. poor prognosis was examined for adjudicated endpoints of 180-day mortality and a composite of 60-day death or renal or cardiovascular rehospitalization. WRF with good vs. poor outcome was defined based on whether patients experienced either of the clinical endpoints. | study | 100.0 |
Continuous data are presented as mean ± SD if normally distributed, or median [interquartile range] if not. Group comparisons were performed using Student’s t-test, ANOVA, Wilcoxon, or Kruskall-Wallis tests, as appropriate. Differences between relative changes in biomarkers were assessed using paired Wilxocon rank sum tests. Correlations between biomarkers were evaluated using Spearman’s rank correlation. Missing data were assumed to be missing at random, and no imputations were performed. | study | 99.94 |
Changes in serial biomarker measurements were evaluated using random slope, random intercept linear mixed-effects models, adjusted for study treatment. A mixed-effects model is a hierarchical regression model that includes fixed and random (subject-specific) effects, allowing for within-subject correlation between repeated measurements. Both NGAL and creatinine were log-transformed for modeling. Model selection was based on combined assessment of likelihood ratio tests of nested models for selection of random effects, and of Bayesian and Akaike’s information criteria (measures for model fit, lower is better) for selection of fixed effects, following graphical exploration of the data. Best fit was obtained using a second order polynomial (quadratic) time transformation for creatinine and third order polynomial (cubic) time transformation for NGAL, for both fixed and random effects. | study | 100.0 |
Receiver Operator Characteristic (ROC) curve analyses and multivariable logistic regression were performed to evaluate predictors of WRF, and added value in multivariable models was assessed using likelihood ratio tests of nested models. Multivariable models were constructed via backward elimination of candidate covariates with a univariable association at p < 0.1, with a p for retention of 0.05. | study | 100.0 |
Kaplan Meier survival analyses were performed to examine group associations with the mortality and composite endpoints. Outcomes between groups were compared with log-rank tests. Cox proportional hazards regression was performed to evaluate univariable and multivariable associations with 180-day mortality and the 60-day composite, adjusting for covariates from a previously published prognostic model—age, creatinine, BUN, systolic blood pressure, edema, previous hospitalization for heart failure, serum albumin, and serum sodium . Multiple fractional polynomials were used to check for non-linearity in survival analyses. Interactions were investigated graphically. Proportionality of hazards assumptions were evaluated graphically and tested statistically. A two-tailed p-value of 0.05 was considered statistically significant. All analyses were performed using R: A Language and Environment for Statistical Computing, version 3.1.0 (R Foundation for Statistical Computing, Vienna, Austria) and Stata, version 11.2 (College Station, TX, USA). | study | 100.0 |
Plasma NGAL was not independently predictive of poor outcome, though serial plasma NGAL levels provide some additional information for the prediction of clinically significant WRF in patients with AHF. However, plasma NGAL levels did not rise earlier than creatinine in patients who developed WRF, and both NGAL and creatinine were similarly modest predictors of WRF. | study | 99.94 |
Common low back problems include disc prolapse, spinal stenosis and low back pain . Disc herniation can be categorized as protrusion (disc contained by the annulus fibrosus), extrusion (disc materials migrated out through the annulus fibrosus, but contained by the posterior longitudinal ligament) and sequestration (disc materials released into the spinal canal) . Disc prolapse commonly presents with pain and numbness radiating to the buttocks and legs due to spinal nerve or nerve root compromise; however, it may be asymptomatic in approximately 24% of all cases . Symptomatic lumbar disc disease (SLDD) is a term used to differentiate between structural abnormalities without clinical symptoms and abnormalities that induce clinical presentations . Approximately 95% of all instances of lumbar disc herniation (LDH) occur at L4-L5 and L5-S1 levels . | review | 99.9 |
Lumbar disc herniation commonly presents with low back pain, and this problem is usually associated with sacroiliac joint (SIJ) disorders. In fact, up to 30.7% of patients with LBP and sciatica also have SIJ dysfunction . A recent study reported the prevalence of SIJ dysfunction as 72.3% among patients with LDH . Researchers have claimed that depending on the type of SIJ disorder, the lumbar spine (mostly L5) can also be involved . The SIJ is part of the lumbar– pelvic–hip complex; since this complex works as a mechanical unit, the involvement of any structure can affect the position and movement of other sections . | study | 99.2 |
The use of spinal manipulative therapy (SMT) for patients with SLDD has also been suggested; however, its safety and indications have remained debatable, particularly in individuals with disc disruption or instability . In this regard, the risk of SMT causing clinically worsened disc herniation or cauda equine syndrome in patients with LDH is estimated to be less than one in 3.7 million . A systematic review in 2004 also confirmed the safety and effectiveness of SMT for patients with SLDD . | review | 99.9 |
Some studies reported significant clinical improvements in patients with SLDD after manipulation in comparison to traction , heat and sham manipulation , but no significant differences when compared to exercise therapy and medical corsets . A recent study found long-term improvement in pain and functional activity after 1 year of follow-up , and another study in 2016 reported significant improvement in leg pain after 1 month in patients with extrusion and sequestration of lumbar discs, following manipulation . | review | 99.8 |
Sacroiliac joint hypomobility has usually been overlooked in the management of patients with LDH and low back problems. However, there is no conclusive evidence for the effectiveness of SMT in the treatment of patients with LDH, and the evidence to date is contradictory. Therefore, the present study aimed to investigate the effect of SMT applied to the lumbar spine and SIJ to treat patients with SLDD who also had SIJ hypomobility. | study | 99.94 |
Twenty patients (11 males, 9 females) aged 20–50 years old with MRI-proven unilateral LDH were included IN 2010 if they had SLDD in the L4-L5 or L5-S1 segment concomitant with ipsilateral SIJ hypomobility (Table 1). Leg pain during 1 to 10 months before the study was their major complaint, and the mean level of leg pain during the previous 24 h was 30–70 out of 100 on a 0–100 numerical rating scale (NRS). The time interval allowed between the MRI diagnosis and inclusion in the study was 3 months. Exclusion criteria were sequestrated LDH with neurological signs, spinal canal stenosis, spondylolisthesis, previous lumbar surgery and gross instability. Patients a with positive well straight leg raise (SLR) test, indicating rather large disc herniation and poor prognosis for conservative treatments [15, 16], were also excluded.Table 1Participants’ demographic characteristics (N = 20)VariableValueaAge37.86 ± 9.62BMI25.10 ± 3.12Side of LDHRight11 (55)Left9 (45)Side of SIJ hypomobilityRight8 (40)Left12 (60)Segment of LDHL4 - L55 (25)L5 - S115 (75)Abbreviations: BMI body mass index, LDH lumbar disc herniation, SIJ sacroiliac jointaValues are mean ± SD for continuous variables and number (percentage) for categorical variables | study | 99.94 |
This was a pre–post test quasi-experimental study. The participants were selected among patients referred to physical therapy clinics of Shiraz, Iran. Sample size was calculated based on the NRS pain score reported in a previous related study (mean [95% CI] = 22 [15–30], α = 0.05, β = 0.02) . Written informed consent was obtained and ethical approval was granted by the Shiraz University of Medical Sciences Ethics Committee (approval number CT-88-4614). | study | 100.0 |
Demographic data, pain intensity, functional disability and clinical diagnostic tests were recorded at baseline. After that, the patients received five sessions of manipulative therapy on alternate days, and the outcomes were reassessed after the 1st and 5th sessions and at a 1-month follow-up. All patients received both lumbar and SIJ manipulations in each treatment session. | study | 47.8 |
The neutral position of the spine was used for side-posture lumbar manipulation. The patient lay on the asymptomatic side (e.g. left) in the lateral recumbent position, with his or her upper foot in the popliteal fossa of the lower leg. Standing opposite to the patient, the therapist grasped the patient’s lower shoulder and arm and applied right rotation until motion was felt in the desired segment of the lumbar spine. The patient was rolled toward the therapist, with his or her arms positioned around the therapist’s right arm. The therapist’s right forearm was in contact with the patient’s right axilla and pectoral region to maintain appropriate rotation from above. In this position, the therapist applied a high-velocity low-amplitude thrust to the pelvis in an anterior direction with his or her left forearm placed behind the patient’s right hip. The therapist pressed the spinous process of the upper vertebra downward with his or her right thumb, while pulling the spinous process of the lower vertebra upward with his or her left thumb. The procedure was done in a way that avoided exacerbating the patient’s pain at the barrier point (Fig. 1).Fig. 1Lumbar rotation manipulation | clinical case | 99.94 |
The patients lay supine on a treatment table, with their fingers interlocked behind their head. The therapist stood contralateral to the side to be manipulated and moved the patient onto his or her side, then leaned toward the dysfunction side, rotated the patient, and exerted a quick thrust to the anterior superior iliac spine in the posterior and inferior directions [18, 19] (Fig. 2).Fig. 2Sacroiliac joint manipulation | clinical case | 79.56 |
The patients’ functional disability level was determined with the Oswestry Disability Index (ODI), a 10-item questionnaire in which each item is scored from 0 to 5 . The maximum score on the ODI is 50, and higher scores indicate greater functional disability. However, in the present study the maximum score was 45, since the sex life item was omitted due to cultural issues. Therefore relative values are reported here as the total score/total possible score × 10. The MCIC for the ODI was reported as 6 points in a sample of patients with LBP who received physical therapy . | study | 100.0 |
Participants were also assessed with the SLR and slump tests to diagnose LDH, and standing flexion, sitting flexion and Gillet tests were used to diagnose SIJ hypomobility. Although the evidence is contradictory, some studies have reported acceptable reliability for the SIJ test. [25–27] The results of five clinical tests were recorded as positive or negative values at baseline, in the 5th session and 1 month after baseline. | study | 100.0 |
The data were analyzed with the Statistical Package for Social Sciences (SPSS), version 21.0 (IBM Corp., Armonk, NY, USA). The Kolmogorov–Smirnov test of normality was conducted for all quantitative variables. Repeated measure ANOVA was used to assess the trends in changes in the NRS and ODI scores. Individual time point differences were determined by the Bonferroni post hoc test, and the results of the five clinical tests were analyzed with the McNemar test. | study | 100.0 |
The NRS score for back pain showed statistically significant improvement in the 5th session (P = 0.034) and at 1-month follow-up (P = 0.047) compared to the baseline value. In addition, statistically significant improvement in the leg NRS score was seen in the 5th session (P = 0.010) and at 1-month follow-up (P = 0.006). Because the MCIC for NRS scores in the present study was 20 points, NRS score improvements in back and leg pain were not clinically significant in the 5th session or at 1-month follow-up (Figs. 3 and 4) (Table 2).Fig. 3Trend in back pain intensity during the trialFig. 4Trend in leg pain intensity during the trialTable 2Mean values of back pain, leg pain and functional disability during the trialOutcomesBaselinea1st session5th session1 monthTimes with statistically significant differences (P-value)Back NRS44.95 ± 26.1842.00 ± 25.3030.50 ± 19.3229.75 ± 16.42Baseline - 5th session (0.034)Baseline - 1 month (0.047)Leg NRS49.50 ± 23.9447.25 ± 24.3536.00 ± 16.9033.75 ± 13.75Baseline - 5th session (0.010)Baseline - 1 month (0.006)ODI14.45 ± 4.40n.d.11.35 ± 4.5410.95 ± 4.27Baseline - 5th session (0.001)Baseline - 1 month (0.001)Abbreviations: NRS numerical rating scale, ODI Oswestry Disability Index, n.d. not determinedaValues are mean ± SD | study | 99.94 |
The ODI scores indicated statistically significant improvement in the 5th session (P = 0.001) and at 1-month follow-up (P = 0.001). Because the MCIC for ODI score in the present study was 6 points, the improvements were not considered clinically significant at the 5th session or at 1-month follow-up (Fig. 5) (Table 2).Fig. 5Trend in functional disability level during the trial | study | 99.94 |
In 78.3% of our patients, the sides of SIJ hypomobility and LDH were the same. After treatment, the patients showed statistically significant improvements in Gillet, standing flexion and sitting flexion tests in the 5th session and at 1-month follow-up (P ≤ 0.001). The findings also indicated 95% improvement in the results of the SIJ hypomobility tests after SMT. We also observed a 20% improvement in the SLR test results and a 15% improvement in the slump test in the 5th session and at 1-month follow-up after SMT, although these changes were not statistically significant (Table 3).Table 3Distribution of improvements in diagnostic test results in the 5th session and after 1-month follow-upTest5th session1 month(Positive/Negative)P-value(Positive/Negative)P-valueGillet1/19< 0.001*1/19< 0.001*Standing flexion1/19< 0.001*1/19< 0.001*Sitting flexion1/19< 0.001*1/19< 0.001*SLR16/40.1217/30.25Slump17/30.2517/30.25Abbreviations: SLR straight leg raising*Significant recovery compared to baseline | study | 99.94 |
The aim of the present study was to investigate the effect of SMT on pain, functional disability and the results of clinical tests of SIJ function and LDH in patients with unilateral SLDD plus SIJ hypomobility. Our findings suggest that five sessions of lumbar and SIJ manipulation can lead to statistically significant improvement in pain and functional disability, which in turn may restore normal SIJ mobility in these patients. | study | 99.94 |
Compared to common treatments for LDH, SMT is reported to be 37,000 to 148,000 times safer than nonsteroid antiinflammatory drugs and 55,500 to 444,000 times safer than surgery . Neither worsening of symptoms nor cauda equine syndrome were observed in our participants after SMT. Epidemiologic data on the rate of injuries caused by manipulation are limited. The most common incidents are related to innocuous physiologic reactions or short-term discomfort generated at the treatment site. However, these are self-limiting events that usually resolve within 24 h after SMT . | study | 99.94 |
In rotational side-posture lumbar manipulation, the impact of the facet joints limits axial rotation of the lower lumbar vertebrae and consequently prevents annulus fibrosus tearing . In the present study, patients with sequestrated LDH who had neurological signs were excluded because these patients may have bowel and bladder disorders, and many (but not all) of them are thus candidates for surgery . In the present study manipulation was applied in the neutral flexion–extension position to reduce the risk of injury. | study | 100.0 |
The diagnosis and treatment of SIJ hypomobility in patients with SLDD are important issues that have not been adequately addressed in the literature. In 78.3% of our cases, the side of SIJ hypomobility was the same as the side of LDH. After treatment, 95% improvement was obtained in the results of SIJ hypomobility tests (Table 2). | clinical case | 77.9 |
The SIJ has been reported to be one of the main sources of low back disorders . A recent study also found that SIJ dysfunction was a prevalent concomitant pathology in patients with LDH. Therefore, SIJ dysfunction should be considered in the treatment of these patients . Pelvic asymmetry as well as hypermobility or hypomobility of the spinal or sacroiliac joints can cause low back pain [3, 30]. Any involvement of the SIJ can induce muscle spasm in the piriformis, which in turn can lead to sciatic irritation and a wide range of symptoms mimicking radiculopathy . Increased tension in the quadratus lumborum, iliopsoas or hamstring muscles may also affect the SIJ mechanism of action. Presumably, SIJ manipulation can decrease tension in these muscles and consequently correct lumbar spine dysfunction [3, 31]. | study | 99.44 |
Several mechanisms have been theorized for the mechanical and neurophysiological basis of SMT, including stimulation or modulation of the somatosensory system to evoke neuromuscular reflexes . Forceful stretching of the spinal muscles induces relaxation after SMT. Other mechanisms are induced hypoalgesia , kinematic correction [34, 35] and increased lumbar range of motion . A brief reduction in intradiscal pressure during SMT in cadavers and return to baseline within less than 1 min was reported in one earlier study . Another study showed reduced H-reflex amplitude in patients with unilateral disc herniation, which improved after SMT . The improved outcomes in our patients can be attributed to two main factors. Firstly, SIJ manipulation may improve normal functioning of the lumbar spine and related muscles . Secondly, lumbar side-posture rotational manipulation can induce spinal muscle relaxation , improve lumbar range of motion , and briefly decrease intradiscal pressure . | study | 99.94 |
The results of the SIJ hypomobility tests (including the Gillet test, standing flexion and sitting flexion tests) improved significantly in the 5th session and after 1-month follow-up compared to baseline values, whereas no statistically significant improvement was observed in the SLR and slump tests. Spinal manipulative therapy may enhance mobility of the SIJ and lumbar vertebrae, and affect the muscles in these regions, thus accounting for the improvement in pain and functional ability. However, significant changes in the slump and SLR tests may require additional interventions such as soft tissue manipulation and nerve mobilization, which were not tested in this study. | study | 100.0 |
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