MDCT of hand and wrist infections: emphasis on compartmental anatomy.

Hand and wrist infections can present with a spectrum of manifestations ranging from cellulitis to deep-space collections. The various infectious processes can be categorised as superficial or deep infections based on their respective locations relative to the tendons. Superficial hand infections are located superficial to the tendons and are comprised of cellulitis, lymphangitis, paronychia, pulp-space infections, herpetic whitlow, and include volar as well as dorsal subcutaneous abscesses. Deep hand infections are located deep to the tendon sheaths and include synovial space infections, such as infectious tenosynovitis, deep fascial space infections, septic arthritis, necrotising fasciitis, and osteomyelitis. Knowledge of hand and wrist compartmental anatomy is essential for the accurate diagnosis and management of hand infections. Although early and superficial infections of the hand may respond to non-surgical management, most hand infections are surgical emergencies. Multidetector computed tomography (MDCT), with its muliplanar reformation (MPR) and three-dimensional (3D) capabilities, is a powerful tool in the emergency setting for the evaluation of acute hand and wrist pathology. The clinical and imaging features of hand and wrist infections as evident on MDCT will be reviewed with emphasis on contiguous and closed synovial and deep fascial spaces. Knowledge of hand compartmental anatomy enables accurate characterisation of the infectious process and localise the extent of disease in the acute setting.

The association between area-level factors and mortality in severe mental illnesses: A systematic review.

BACKGROUND: Premature mortality is a well-documented adverse outcome for people living with severe mental illnesses (SMI). Emerging evidence suggests that area-level factors play a role that are experienced disproportionately by this population. This review assesses the potential association between area-level factors and mortality in people with SMI. METHOD: We searched Medline, EMBASE, PsychINFO, Social Policy and Practice, Web of Science and OpenGrey databases. Literature searches were conducted in May 2020 and updated in June 2023. Reference lists were hand-searched and authors of included studies contacted to identify additional studies and minimise publication biases. Narrative synthesis was used to appraise the included studies. The review protocol was registered on PROSPERO (CRD42019155447). RESULTS: Our searches identified 7 studies (8 papers), which were included in the review, and indicated evidence of an association between deprivation and mortality. One study suggested an association between mortality in SMI and urbanicity in low to middle income settings which was not observed in studies from high income settings. One study suggested a protective association of area-level ethnic density with mortality within urbanised settings. CONCLUSION: Consistent associations were reported between residence in areas of higher deprivation and increased risk of mortality in SMI. Two studies suggested an association between area-level ethnic density and urbanicity and mortality in SMI. Most studies were conducted across high income countries and therefore future research could benefit from similar investigations being conducted in low- and middle-income countries. These methods would inform health and social policies, including interventions to reduce premature mortality in SMI.

Viking: Mars atmospheric water vapor mapping experiment--preliminary report of results.

Observations made from the Viking I orbiter show very little water vapor in the Mars atmosphere in the southern hemisphere (0 to 3 precipitable micrometers) with a gradual increase across the equator to northern latitudes. Maximum amounts between 20 and 30 micrometers have been observed in the short period covered by the observations to date. The season, northern midsummer, corresponds to the beginning of the water vapor cycle in that hemisphere. A strong repetitive diurnal cycling between the solid and vapor phases is observed at a site to the east of the Tharsis Ridge at 10 degrees north latitude; the vapor lies close to the martian surface and is most probably in saturation equilibrium with a surface haze or fog throughout much of the day.

Mars: northern summer ice cap--water vapor observations from viking 2.

Observations of the latitude dependence of water vapor made from the Viking 2 orbiter show peak abundances in the latitude band 70 degrees to 80 degrees north in the northern midsummer season (planetocentric longitude approximately 108 degrees ). Total column abundances in the polar regions require near-surface atmospheric temperatures in excess of 200 degrees K, and are incompatible with the survival of a frozen carbon dioxide cap at martian pressures. The remnant (or residual) north polar cap, and the outlying patches of ice at lower latitudes, are thus predominantly water ice, whose thickness can be estimated to be between 1 meter and 1 kilometer.

The use of a Type-I lyophilisate collagen as an osteoinductive factor in pseudarthroses of the forearm.

The purpose of this study was to assess the use of a novel bone void filler consisting of Type I collagen and various growth factors (VEGF, TGFß-1, TGFß-2, IGF-1, BMP-2, BMP-3, and BMP-7) and surgical fixation to treat diaphyseal forearm pseudarthroses. Eleven patients underwent an osteosynthesis procedure for isolated pseudarthrosis fractures of the forearm (six radial and five ulnar diaphysis). The mean duration between the initial failed surgical fixation and re-operation was 38 weeks. Radiographic signs of fracture healing after the application of the bone void filler were noted at a mean of 5 weeks, and complete fracture consolidation was achieved at a mean of 6 weeks. All patients demonstrated improved range of motion and grip strength. Additionally, all patients were pain-free by 6 weeks. The combination of a novel bovine bone-derived bone void filler and stable internal fixation led to union and rapid healing of forearm pseudarthroses.

GLC3 and GHA1 of Saccharomyces cerevisiae are allelic and encode the glycogen branching enzyme.

In the yeast Saccharomyces cerevisiae, glycogen serves as a major storage carbohydrate. In a previous study, mutants with altered glycogen metabolism were isolated on the basis of the altered iodine-staining properties of colonies. We found that when glycogen produced by strains carrying the glc-1p (previously called gha1-1) mutation is stained with iodine, the absorption spectrum resembles that of starch rather than that of glycogen, suggesting that this mutation might reduce the level of branching in the glycogen particles. Indeed, glycogen branching activity was undetectable in extracts from a glc3-1p strain but was elevated in strains which expressed GLC3 from a high-copy-number plasmid. These observations suggest that GLC3 encodes the glycogen branching enzyme. In contrast to glc3-1p, the glc3-4 mutation greatly reduces the ability of yeast to accumulate glycogen. These mutations appear to be allelic despite the striking difference in the phenotypes which they produce. The GLC3 clone complemented both glc3-1p and glc3-4. Deletions and transposon insertions in this clone had parallel effects on its ability to complement glc3-1p and glc3-4. Finally, a fragment of the cloned gene was able to direct the repair of both glc3-1p and glc3-4. Disruption of GLC3 yielded the glycogen-deficient phenotype, indicating that glycogen deficiency is the null phenotype. The glc3-1p allele appears to encode a partially functional product, since it is dominant over glc3-4 but recessive to GLC3. These observations suggest that the ability to introduce branches into glycogen greatly increases the ability of the cell to accumulate that polysaccharide. Northern (RNA) blot analysis identified a single mRNA of 2,300 nucleotides that increased in abundance ca. 20-fold as the culture approached stationary phase. It thus appears that the expression of GLC3 is regulated, probably at the level of transcription.

Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype.

Glucokinase (GK) is expressed in the pancreatic beta-cells and liver, and plays a key role in the regulation of glucose homeostasis. The enzymatic activity and thermal stability of wild-type (WT) GK and several mutant forms associated with maturity-onset diabetes of the young type 2 (MODY-2) were determined by a steady-state kinetic analysis of the purified expressed proteins. The eight MODY-2 mutations studied were Ala53Ser, Val367Met, Gly80Ala, Thr168Pro, Arg36Trp, Thr209Met, Cys213Arg, and Val226Met. These missense mutations were shown to have variable effects on GK kinetic activity. The Gly80Ala and Thr168Pro mutations resulted in a large decrease in Vmax and a complete loss of the cooperative behavior associated with glucose binding. In addition, the Gly80Ala mutation resulted in a sixfold increase in the half-saturating substrate concentration (S0.5) for ATP, and Thr168Pro resulted in eight- and sixfold increases in the S0.5 values for ATP and glucose, respectively. The Thr209Met and Val226Met mutations exhibited three- and fivefold increases, respectively, in the S0.5 for ATP, whereas the Cys213Arg mutation resulted in a fivefold increase in the S0.5 for glucose. These mutations also led to a small yet significant reduction in Vmax. Of all the mutations studied, only the Cys213Arg mutation had reduced enzymatic activity and decreased thermal stability. Two mutants, Ala53Ser and Val367Met, showed kinetic and thermal stability properties similar to those of WT. These mutants had increased sensitivities to the known negative effectors of GK activity, palmitoyl-CoA, and GK regulatory protein. Taken together, these results illustrate that the MODY-2 phenotype may be linked not only to kinetic alterations but also to the regulation of GK activity.

Calf lens alpha-crystallin quaternary structure. A three-layer tetrahedral model.

Calf lens alpha-crystallins are polydisperse globular particles made of a large number of two types of subunits, A and B, both of molecular weight congruent to 20,000. alpha-Crystallin populations consisting on average of 40 subunits or more were subjected to various changes in pH, ionic strength, temperature and urea concentration. Modifications in quaternary structure induced by variation of these physicochemical parameters were followed by means of X-ray and quasi-elastic light-scattering and quantified in terms of weight average molecular weight (M), radius of gyration (Rg) and hydrodynamic radius (Rh). High-pressure liquid chromatography was used as a control of polydispersity. Increasing the pH, decreasing the ionic strength and incubating at temperatures from 20 degrees C to 45 degrees C all resulted in the formation of particles of decreasing M, Rg and Rh values. These effects are cumulative. All monomodal alpha-crystallin populations encountered in this study, which covers a wide range of sizes and molecular weights, may be accounted for by a three-layer model with partial filling up of the layers. Applying basic principles of symmetry and postulating specific contacts between protein subunits to construct this three-layer model leads to tetrahedral symmetry, with 12, 24 and 24 sites in the first, second and third layers, respectively. Variations in probabilities of site occupancy account for both the observed quaternary structure modifications and the intrinsic polydispersity of alpha-crystallins

Smooth pursuit eye movements to extraretinal motion signals: deficits in relatives of patients with schizophrenia.

BACKGROUND: Although mounting evidence supports the idea that smooth pursuit abnormality marks the genetic liability to schizophrenia, the precise ocular motor mechanism underlying the abnormality remains unknown. Based on recent findings in schizophrenia, we hypothesize that subtle deficits in the ability to hold online and/or use extraretinal motion information underlie the pursuit abnormality in vulnerable individuals. METHODS: The hypothesis was tested in 69 first-degree, biological relatives of probands with schizophrenia; 26 relatives had schizophrenia spectrum personalities (SSP). Subjects recruited from the community (n=71; 29 with SSP), without a known family history of psychosis, constituted the comparison groups. The traditional smooth pursuit gain measure, which is a ratio of smooth pursuit eye velocity in response to both retinal and extraretinal motion signals and the target velocity, was obtained. In addition, newly developed measures of predictive smooth pursuit (ie, in the presence of only extraretinal motion signals) were obtained. The latter measures were evaluated after the current retinal motion signals were made unavailable by briefly making the target invisible. RESULTS: Relatives, particularly those with SSP, showed significantly poorer predictive pursuit response to extraretinal motion signals (F(2,136)=6.51, P<.005), compared with the community subjects. However, the traditional smooth pursuit gain in response to both retinal and extraretinal motion signals was not different between groups. CONCLUSIONS: These results suggest that relatives of patients with schizophrenia, particularly those with SSP, have specific deficits in predictive pursuit based on only extraretinal motion signals. Normal smooth pursuit gain in response to both retinal and extraretinal motion signals is likely due to compensation based on retinal motion information. The latter suggests normal retinal motion processing and smooth pursuit motor output.

Introduction of single-copy sequences into the chromosome of Escherichia coli: application to gene and operon fusions.

We have developed a general method for the introduction of any cloned sequence into the chromosome of Escherichia coli. This method employs an Hfr strain which carries a fragment of bla (the pBR322 gene imparting ampicillin resistance) between lacI and lacZ. Plasmid-borne inserts which are flanked by sequences from bla and lacZ can be introduced at this locus by homologous recombination. The isolation of recombinants is enhanced by selection for transfer of an integrated copy of the plasmid during conjugation. Once introduced into the chromosome, the inserted sequences can be transferred to other strains by conventional methods such as P1 transduction or conjugation. This method is suitable for the transfer of any cloned sequence to the chromosome and is particularly well suited to the construction of chromosomal gene and operon fusions with lacZ.

Isocitrate dehydrogenase kinase/phosphatase.

In Escherichia coli, isocitrate dehydrogenase (IDH) is regulated by phosphorylation. This phosphorylation cycle is catalyzed by an unusual, bifunctional protein:IDH kinase/phosphatase. IDH kinase/phosphatase is expressed from a single gene, aceK, and both activities are catalyzed by the same polypeptide. The amino acid sequence of IDH kinase/phosphatase does not exhibit the characteristics which are typical of other protein kinases, although it does contain a consensus ATP binding site. The available evidence suggests that the IDH kinase and IDH phosphatase reactions occur at the same active site and that the IDH phosphatase reaction results from the back reaction of IDH kinase tightly coupled to ATP hydrolysis. The function of the IDH phosphorylation cycle is to control the flux of isocitrate through the glyoxylate bypass. This pathway is essential for growth on acetate because it prevents the quantitative loss of the acetate carbons as CO2 in the Krebs' cycle. IDH kinase/phosphatase monitors general metabolism by responding to the levels of a wide variety of metabolites, many of which activate IDH phosphatase and inhibit IDH kinase. The ability of IDH kinase/phosphatase to monitor general metabolism allows. the IDH phosphorylation cycle to compensate for substantial perturbations of the system, such as a 15-fold overproduction of IDH. The significance of the cellular level of IDH kinase/phosphatase has also been evaluated. The level of this protein is in great excess of that required for steady-state growth on acetate. In contrast, IDH kinase/phosphatase is, in some cases, rate-limiting for the dephosphorylation of IDH which results when preferred carbon sources are added to cultures growing on acetate.

Subanesthetic doses of ketamine stimulate psychosis in schizophrenia.

We administered ketamine to schizophrenic individuals in a double-blind, placebo-controlled design using a range of subanesthetic doses (0.1, 0.3, and 0.5 mg/kg) to evaluate the nature, dose characteristics, time course, and neuroleptic modulation of N-methyl-D-aspartate (NMDA) antagonist action on mental status in schizophrenia. Ketamine induced a dose-related, short (< 30 minutes) worsening in mental status in the haloperidol-treated condition, reflected by a significant increase in BPRS total score for the 0.3 mg/kg (p = .005) and 0.5 mg/kg (p = .01) challenges. Positive symptoms (hallucinations, delusions, thought disorder), not negative symptoms accounted for these changes. These ketamine-induced psychotic symptoms were strikingly reminiscent of the subject's symptoms during active episodes of their illness. Results from six patients who were retested in the same design after being neuroleptic-free for 4 weeks failed to indicate that haloperidol blocks ketamine-induced psychosis. Several subjects evidenced delayed or prolonged (8-24 hours) psychotomimetic effects such as worsening of psychosis with visual hallucinations. These data suggest that antagonism of NMDA-sensitive glutamatergic transmission in brain exacerbates symptoms of schizophrenia.

Psychosis-proneness and verbal memory in a college student population.

Previous research has revealed numerous neuropsychological deficits in schizophrenics. Research on individuals with schizotypal personality features has also demonstrated similar neuropsychological deficits. However, the latter literature is limited in scope. This study examined verbal memory function in psychometrically identified (Chapman Scales) psychosis-prone college students (n = 409). Subjects were administered a standard verbal memory procedure (Logical Memory; Wechsler Memory Scale-Revised) as well as measures of verbal intelligence (Shipley Scale) and depression (Beck Depression Inventory). Results reveal no relationship between degree of schizotypic features and recall measures (immediate recall, delayed recall, and retention rate). Moreover, comparisons between low schizotypic subjects and those scoring at the extreme (greater than 2 standard deviations above the mean) also failed to reveal significant differences in recall. These results raise the possibility that memory deficits may be specific to schizophrenia and not the schizophrenia spectrum or that they are restricted to only those with the familial form of the disorder (i.e., those with family histories of schizophrenia).

Absence of ketamine effects on memory and other cognitive functions in schizophrenia patients.

Glutamatergic dysfunction may play an important role in both the pathophysiology of schizophrenia, and impaired memory commonly observed in that disorder. NMDA receptor antagonists impair learning/memory in animal models, putatively based on its ability to block long-term potentiation (LTP) in the hippocampus. Although well studied in animal models, research in humans is limited and confounded by administration of NMDA antagonists before the learning experience. Based on presumed glutamatergic dysfunction, it was predicted that the NMDA antagonist ketamine would not effect memory in schizophrenic subjects. Bolus injections of ketamine (0.5 mg/kg) or placebo were given to seven patients with schizophrenia in this double-blind cross-over study. Immediately prior to injection, subjects were administered verbal and figural memory tests. Delayed recalls were obtained 30-45 min postinjection. In order to rule out drug-induced generalized cognitive impairments, other cognitive tasks were administered pre- and postinjection. The results indicate no differences between the drug and placebo conditions for either memory task, and no changes on the other cognitive tasks observed.

Sexual abuse and bulimia: response to inpatient treatment and preliminary outcome.

The purpose of this study was to explore the clinical impact of child sex abuse on bulimic patients. Specifically, differences in treatment response and preliminary treatment outcome between hospitalized bulimic patients with and without a reported history of sexual abuse were examined. The patients were evaluated for past history of alleged sexual abuse by investigator-based interview and ratings of severity of sexual abuse were made. Assessments of mood, eating disordered-related attitudes, and eating behaviors were conducted at the start of treatment, weekly during treatment, and three months post discharge. Sixty-one per cent (45) of the 74 patients enrolled in the study reported a history of child sexual abuse. The majority of such events constituted serious and very serious abuse by this study's criteria. The abused subjects exhibited higher levels of depression, anxiety, and eating disordered attitudes at each assessment point relative to nonabused subjects. In addition, abused subjects were more likely to be re-hospitalized in the 3 month post-discharge period. Significant differences in the extent of actual bulimic behaviors were not detected. Both the abused and nonabused bulimic patients demonstrated significant reductions in psychiatric symptomatology from pretreatment to posttreatment, and from posttreatment to follow-up. Contrary to prediction, differences in symptomatology between the very serious, serious, and least serious abused groups were not detected. Results suggest that bulimic patients with reported histories of sexual abuse can be effectively engaged in a conventional eating disorder treatment program, but that such abuse may place patients at a disadvantage owing to higher levels of pretreatment symptom severity. Findings suggest that extended and/or more specific intervention may be warranted for the abused bulimic patient.

Covert visual attention in schizophrenia spectrum personality disordered subjects: visuospatial cuing and alerting effects.

A recent study observed lateralized deficit in the disengagement of covert visual attention in schizophrenic patients. Subsequent attempts to replicate this finding have had mixed results. Differences in the neuroleptic treatment or other secondary factors associated with schizophrenia are some of the possible reasons for these inconsistent findings. In this study, we examined the ability to shift covert visual attention in neuroleptic-naive, schizophrenia spectrum personality disordered (SSPD; n = 35) subjects and normal controls (n = 34) under a variety of spatial cuing and alerting conditions. We hypothesized that SSPD subjects would have difficulty with disengagement of covert visual attention from an invalidly cued left visual field when the target appeared in the right visual field in comparison to the normal subjects. As predicted, schizophrenia spectrum personality disordered subjects had significantly longer latencies for the right visual field invalid targets than normals (p = .014). Under the remaining cue conditions, spectrum subjects performed normally. Consequently, the cost of left visual field invalid cueing for the right visual field target was significantly higher in spectrum personality subjects than in normals. The cost for the invalid right visual field cue and the benefits of valid cue in both fields were very similar in the two groups. The findings of an asymmetrical deficit in the disengagement and shift of covert visual attention in schizophrenia spectrum subjects are similar to the one's observed in patients with unilateral left hemisphere lesions.

Deep wound infections after neuromuscular scoliosis surgery: a multicenter study of risk factors and treatment outcomes.

STUDY DESIGN: A retrospective case-control study evaluating risk factors for infection, causative organisms, and results of treatment in patients with cerebral palsy or myelomeningocele who underwent fusion for scoliosis was performed. OBJECTIVES: To identify risk factors for infection, and to characterize the infections in terms of infecting organisms and response to treatment. SUMMARY OF BACKGROUND DATA: No previous studies have analyzed risk factors or causative organisms, nor have they indicated results of treatment for infections in this group of patients. METHODS: After a 10-year retrospective review of 210 surgically treated patients, deep wound infections developed in 16 patients with myelomeningocele and 9 patients with cerebral palsy. These patients were studied extensively for possible risk factors, along with 50 uninfected patients matched for age, diagnosis, and year of surgery. Statistical testing was performed to identify risk factors. The courses of the infections were characterized in terms of organisms isolated and response to treatment. Treatment was performed in a stepwise fashion and classified in terms of the most successful step: debridement and closure, granulation over rods, or instrumentation removal. RESULTS: Of the 10 risk factors tested, 2 were found to be significant: degree of cognitive impairment and use of allograft. Findings showed that 52% of the infections were polymicrobial. Gram-negative organisms were isolated as commonly as gram-positive organisms. The most common organisms were coagulase-negative Staphylococcus, Enterobacter, Enterococcus, and Escherichia coli.- Debridement and closure were successful in 11 of 25 patients with deep wound infection. Of the 14 patients with infection not resolved by serial debridements and closure, 2 were managed successfully by allowing the wound to granulate over rods, and 7 required rod removal for persistent wound drainage. There were three symptomatic pseudarthroses. Infections resulting from gram-positive organisms were most often managed successfully with debridement and closure (P = 0.012). CONCLUSIONS: Patients with cerebral palsy or myelomeningocele who have severe cognitive impairment, and those who received allograft may be at increased risk for infection. Infections are more often polymicrobial and caused by gram-negative organisms than is typical for elective orthopedic procedures. This suggests an enteric source. Treatment with debridement and closure was not always successful. Patients in whom infection develops are then at increased risk for pseudarthrosis.

Tennis after total hip arthroplasty.

The purpose of this study was to characterize patients who play tennis after undergoing hip arthroplasty in terms of their functional abilities and degree of satisfaction. A questionnaire was sent to all United States Tennis Association member associations in a tri-state area to identify players who had undergone a hip arthroplasty. The study group had 50 men and 8 women with a mean age of 70 years (range, 47 to 89). Only 14% of the patients' surgeons approved this tennis activity, with 34% of the surgeons recommending only doubles. Three patients required revision surgery after a mean of 8 years. One year after arthroplasty, players played both singles and doubles approximately three times per week. All tennis players were extremely satisfied with their hip arthroplasties and their increased ability to participate in their favorite sport. Because this study was confined to association members, further studies are needed to assess the general effect of tennis on total hip arthroplasty. Until future studies are performed, the authors would recommend that physicians advise caution in tennis activities and to carefully follow their patients yearly to see if osteolysis is occurring prematurely.

Infections associated with dental procedures in total hip arthroplasty.

Dental procedures may lead to a transient bacteraemia lasting for up to 30 minutes. Of the numerous cases of total hip arthroplasty (THA) reported which have been infected from haematogenous sources, dental procedures have been involved only infrequently. We reviewed the records of 2973 patients after THA. Of the late infections identified in 52 patients, three (6%) were strongly associated with a dental procedure. Infection was diagnosed by culture from the affected joint; Streptococcus viridans was identified in two cases and Peptostreptococcus in one. One patient had diabetes mellitus and another rheumatoid arthritis, both conditions predisposing to infection. The dental operations all lasted for more than 45 minutes and no patient received perioperative antibiotics. Infection of a THA after dental procedures is more common than has been previously suspected. Patients with systemic disease, or who are undergoing extensive procedures, should be considered for prophylactic antibiotic treatment.

Treatment response in obese binge eaters: preliminary results using a very low calorie diet (VLCD) and behavior therapy.

The present study compared the treatment response of male and female obese binge eaters and nonbinge eaters attending a university-based weight reduction program employing a very low calorie diet (VLCD) and concurrent behavior therapy. Twenty-nine percent of female patients (n = 19) and 22% of male patients (n = 6) were characterized as binge eaters based on their scores on the Binge Eating Scale. No significant differences were found between binge and nonbinge groups on measures of weight loss, adherence to the diet, or drop-out rate, although a trend towards greater attrition in the binge group (32%) relative to the nonbinge group (17%) was noted. However, binge eaters had significantly higher pretreatment levels of trait anxiety, state anxiety, and depression as well as higher within treatment levels of anxiety and depression despite significant reductions in depression over the course of treatment. Further examination revealed a binge status X sex interaction effect on state anxiety. Binge-eating females had significantly higher anxiety levels pretreatment and throughout the 10 weeks of the study. No differences between binge and nonbinge males on levels of anxiety were found. These preliminary results tentatively suggest that a VLCD in conjunction with behavior therapy may be an effective method of weight loss for this segment of the obese population, but that elevated levels of anxiety persist in female patients. Future studies must address the long-term maintenance of weight loss in this population as well as other treatment strategies.