Heat-shock responses: systemic and essential ways of malaria parasite survival.

Fever is a part of the human innate immune response that contributes to limiting microbial growth and development in many infectious diseases. For the parasite Plasmodium falciparum, survival of febrile temperatures is crucial for its successful propagation in human populations as well as a fundamental aspect of malaria pathogenesis. This review discusses recent insights into the biological complexity of the malaria parasite's heat-shock response, which involves many cellular compartments and essential metabolic processes to alleviate oxidative stress and accumulation of damaged and unfolded proteins. We highlight the overlap between heat-shock and artemisinin resistance responses, while also explaining how the malaria parasite adapts its fever response to fight artemisinin treatment. Additionally, we discuss how this systemic and essential fight for survival can also contribute to parasite transmission to mosquitoes.

A novel Modulator of Ring Stage Translation (MRST) gene alters artemisinin sensitivity in Plasmodium falciparum.

The implementation of artemisinin (ART) combination therapies (ACTs) has greatly decreased deaths caused by Plasmodium falciparum malaria, but increasing ACT resistance in Southeast Asia and Africa could reverse this progress. Parasite population genetic studies have identified numerous genes, single-nucleotide polymorphisms (SNPs), and transcriptional signatures associated with altered artemisinin activity with SNPs in the Kelch13 (K13) gene being the most well-characterized artemisinin resistance marker. However, there is an increasing evidence that resistance to artemisinin in P. falciparum is not related only to K13 SNPs, prompting the need to characterize other novel genes that can alter ART responses in P. falciparum. In our previous analyses of P. falciparum piggyBac mutants, several genes of unknown function exhibited increased sensitivity to artemisinin that was similar to a mutant of K13. Further analysis of these genes and their gene co-expression networks indicated that the ART sensitivity cluster was functionally linked to DNA replication and repair, stress responses, and maintenance of homeostatic nuclear activity. In this study, we have characterized PF3D7_1136600, another member of the ART sensitivity cluster. Previously annotated as a conserved Plasmodium gene of unknown function, we now provide putative annotation of this gene as a Modulator of Ring Stage Translation (MRST). Our findings reveal that the mutagenesis of MRST affects gene expression of multiple translation-associated pathways during the early ring stage of asexual development via putative ribosome assembly and maturation activity, suggesting an essential role of MRST in protein biosynthesis and another novel mechanism of altering the parasite's ART drug response.IMPORTANCEPlasmodium falciparum malaria killed more than 600,000 people in 2021, though ACTs have been critical in reducing malaria mortality as a first-line treatment for infection. However, ACT resistance in Southeast Asia and emerging resistance in Africa are detrimental to this progress. Mutations to Kelch13 (K13) have been identified to confer increased artemisinin tolerance in field isolates, however, genes other than K13 are implicated in altering how the parasite responds to artemisinin prompts additional analysis. Therefore, in this study we have characterized a P. falciparum mutant clone with altered sensitivity to artemisinin and identified a novel gene (PF3D7_1136600) that is associated with alterations to parasite translational metabolism during critical timepoints for artemisinin drug response. Many genes of the P. falciparum genome remain unannotated, posing a challenge for drug-gene characterizations in the parasite. Therefore, through this study, we have putatively annotated PF3D7_1136600 as a novel MRST gene and have identified a potential link between MRST and parasite stress response mechanisms.

Protein KIC5 is a novel regulator of artemisinin stress response in the malaria parasite Plasmodium falciparum.

Artemisinin combination therapies (ACTs) have led to a significant decrease in Plasmodium falciparum malaria mortality. This progress is now threatened by emerging artemisinin resistance (ART-R) linked originally in SE Asia to polymorphisms in the Kelch propeller protein (K13) and more recently to several other seemingly unrelated genetic mutations. To better understand the parasite response to ART, we are characterizing a P. falciparum mutant with altered sensitivity to ART that was created via piggyBac transposon mutagenesis. The transposon inserted near the putative transcription start site of a gene defined as a "Plasmodium-conserved gene of unknown function," now functionally linked to K13 as the Kelch13 Interacting Candidate 5 protein (KIC5). Phenotype analysis of the KIC5 mutant during intraerythrocytic asexual development identified transcriptional changes associated with DNA stress response and altered mitochondrial metabolism, linking dysregulation of the KIC5 gene to the parasite's ability to respond to ART exposure. Through characterization of the KIC5 transcriptome, we hypothesize that this gene may be essential under ART exposure to manage gene expression of the wild-type stress response at early ring stage, thereby providing a better understanding of the parasite's processes that can alter ART sensitivity.

A meta-analysis of dropout from evidence-based psychological treatment for post-traumatic stress disorder (PTSD) in children and young people.

Background: Despite the established evidence base of psychological interventions in treating PTSD in children and young people, concern that these trauma-focused treatments may 'retraumatise' patients or exacerbate symptoms and cause dropout has been identified as a barrier to their implementation. Dropout from treatment is indicative of its relative acceptability in this population. Objective: Estimate the prevalence of dropout in children and young people receiving a psychological therapy for PTSD as part of a randomized controlled trial (RCT). Methods: A systematic search of the literature was conducted to identify RCTs of evidence-based treatment of PTSD in children and young people. Proportion meta-analyses estimated the prevalence of dropout. Odds ratios compared the relative likelihood of dropout between different treatments and controls. Subgroup analysis assessed the impact of potential moderating variables. Results: Forty RCTs were identified. Dropout from all treatment or active control arms was estimated to be 11.7%, 95% CI [9.0, 14.6]. Dropout from evidence-based treatment (TFCBTs and EMDR) was 11.2%, 95% CI [8.2, 14.6]. Dropout from non-trauma focused treatments or controls was 12.8%, 95% CI [7.6, 19.1]. There was no significant difference in the odds of dropout when comparing different modalities. Group rather than individual delivery, and lay versus professional delivery, were associated with less dropout. Conclusions: Evidence-based treatments for children and young people with PTSD do not result in higher prevalence of dropout than non-trauma focused treatment or waiting list conditions. Trauma-focused therapies appear to be well tolerated in children and young people.

Antecedentes: A pesar de la base de evidencia establecida de intervenciones psicológicas en el tratamiento del TEPT en niños y gente joven, la preocupación por el que estos tratamientos focalizados en el trauma puedan 'retraumatizar' a los pacientes o exacerbar sus síntomas y causar abandono, ha sido identificada como una barrera para su implementación. El abandono del tratamiento es indicador de su aceptabilidad relativa en esta población.Objetivo: Estimar la prevalencia de abandono en niños y gente joven que reciben una terapia psicológica para el TEPT como parte de un ensayo aleatorizado controlado (RCT en su sigla en inglés).Métodos: Se realizó una búsqueda sistemática de la literatura para identificar RCTs de tratamientos basados en evidencia para el TEPT en niños y gente joven. Mediante metaanálisis de proporción se estimó la prevalencia de abandono. Los Odds Ratio compararon la probabilidad relativa de abandono entre diferentes tratamientos y controles. Mediante análisis de subgrupo se evaluó el impacto de potenciales variables moderadoras.Resultados: Se identificaron cuarenta RCTs. El abandono de todas las ramas de tratamiento o control activo se estimó en 11.7%, IC de 95% [9.0, 14.6]. El abandono de tratamientos basados en la evidencia (TF-CBTs y EMDR) fue de 11.2%, IC de 95% [8.2, 14.6]. El abandono de tratamientos sin foco en trauma o controles fue de 12.8%, IC de 95% [7.6, 19.1]. No hubo diferencia significativa en la probabilidad de abandono al comparar las diferentes modalidades. La entrega en grupos Individual y por legos versus profesionales, se asociaron a menor abandono.Conclusiones: Los tratamientos basados en evidencia para niños y gente joven con tept no resultan en una mayor prevalencia de abandono que los tratamientos sin foco en trauma o condiciones de lista de espera. las terapias focalizadas en el trauma parecen ser bien toleradas en niños y gente joven.

Autism Spectrum Disorder in Early Intervention in Psychosis Services: Implementation and Findings of a 3-step Screening and Diagnostic Protocol.

Evidence indicates that autism spectrum disorder (ASD) is underidentified in populations with psychosis, but that clinical presentations of comorbid ASD and psychosis (ASD-P) and specific treatment needs that may relate to this group are not well understood. In fact, recent studies of ASD in first-episode psychosis suggest that there may be a specific clinical presentation of ASD-P. In response, the Cambridgeshire and Peterborough Early Intervention in Psychosis (EIP) service in the UK implemented and evaluated a 3-step ASD screening and diagnostic protocol, using the Autism Spectrum Disorder in Adults Screening Questionnaire (ASDASQ), case note review, and the Autism Diagnostic Observation Schedule (ADOS-2) and the Childhood Autism Spectrum Test (CAST). As a quality improvement project, the evaluation aimed to (1) establish the prevalence of patients with ASD-P, (2) describe characteristics of the clinical presentation of ASD-P and compare them to those of patients suffering from psychosis but no ASD, and (3) determine any differences in treatment between psychosis patients with and without ASD. Notably, at least 9% of the EIP service caseload met the criteria for a diagnosis of ASD-P, with half identified via the implementation of this protocol. The patients with ASD-P had specific clinical presentations and treatment needs that differed from those of patients with psychosis but no ASD. Thus, the findings from this study supported existing evidence concerning the underdetection of ASD in EIP populations. Our findings also added to emerging evidence for a clinical presentation of ASD-P with specific treatment needs. Our protocol has now been established as routine practice, and its implementation has improved the detection and treatment of patients with ASD-P within our EIP service.

A multicenter study on the perineal versus penoscrotal approach for implantation of an artificial urinary sphincter: cuff size and control of male stress urinary incontinence.

PURPOSE: In a single center retrospective study we previously reported superior dry rates and fewer artificial urinary sphincter revisions when the sphincter cuff was placed via the traditional perineal approach compared with a penoscrotal approach. A multicenter study was performed to compare the approaches further and explain the disparity in outcomes. MATERIALS AND METHODS: We performed a retrospective review of 158 patients who underwent these procedures from April 1987 to October 2007 at 4 centers. RESULTS: During 184 surgeries in 158 patients 201 artificial urinary sphincter cuffs were placed (90 penoscrotal and 111 perineal). Among patients with known followup the completely dry rate for single cuff artificial urinary sphincters was 17 of 62 (27.4%) in the penoscrotal group and 41 of 93 (44.1%) in the perineal group (p = 0.04). Continued incontinence necessitated subsequent tandem cuff in 7 of the 62 (11.3%) penoscrotal cases compared to only 5 of the 93 (5.4%) perineal cases. Cuff size in the penoscrotal group was 5.0 cm in 1 patient (1.1%), 4.5 cm in 11 (12.2%) and 4.0 cm in 78 (86.7%). Cuff size in the perineal group was 5.5 cm in 1 patient (0.9%), 5.0 cm in 8 (7.2%), 4.5 cm in 30 (27.0%) and 4.0 cm in 72 (64.9%). CONCLUSIONS: There appears to be a higher completely dry rate with fewer subsequent tandem cuff additions with the perineal approach compared to the penoscrotal approach. This disparity may be explained by a more proximal artificial urinary sphincter cuff placement in the perineal group as evidenced by a larger cuff size.

Centers of excellence concept and penile prostheses: an outcome analysis.

PURPOSE: Outcome analysis has shown that the center of excellence concept, in which all of a specific type of surgery is done by 1 surgeon rather than by multiple surgeons in a group, provides superior outcomes for total joint replacement, radical cancer and heart valve surgery. We compared penile prosthesis implantation outcomes between the center of excellence and multiple surgeon approaches in a large, single specialty urological surgical practice. MATERIALS AND METHODS: Between February 2001 and August 2004 a total of 57 penile prostheses were implanted by 10 surgeons at a large urology practice (multiple surgeon group). Between July 2004 and April 2005 a total of 57 penile prostheses were placed by a single surgeon (center of excellence group). Chart review of the 2 patient groups was performed. RESULTS: The patient groups showed no statistical differences in age, race, cause of impotence or percent with diabetes. The median cylinder length of prostheses placed by the center of excellence surgeon was 2 cm greater than the length of the cylinders placed by the multiple surgeon team (p <0.0001). Excluding cases requiring additional procedures the median placement time was considerably shorter for the center of excellence surgeon than for the multiple surgeon team (34 vs 94 minutes, p <0.0001). There were 8 iatrogenic failures (infection, erosion and poor positioning) requiring surgical removal in the multiple surgeon group but none in the COE group (p <0.05). Although followup for the multiple surgeon team was longer, Kaplan-Meier revision-free survival curves showed significantly longer survival for the center of excellence group (log rank test p = 0.0283). CONCLUSIONS: The center of excellence concept in penile prosthesis surgery appears to deliver superior surgical outcomes in terms of shorter operative time, longer cylinders and fewer iatrogenic complications.

Perineal approach for artificial urinary sphincter implantation appears to control male stress incontinence better than the transscrotal approach.

PURPOSE: Traditionally cuff placement of an artificial urinary sphincter is done through a perineal approach. A new approach through a penoscrotal incision or transscrotal approach is reportedly more rapid and easier than the traditional incision. These 2 approaches were evaluated to determine which one controlled male stress urinary incontinence better. MATERIALS AND METHODS: We performed a retrospective chart review of 94 patients who underwent artificial urinary sphincter placement procedures from April 1987 to March 2004. RESULTS: A total of 126 artificial urinary sphincter cuffs (120 procedures, including double cuff placement in 6) were placed in 94 patients with 63 placed penoscrotally and 63 placed perineally. Of the double cuff placements 1 was perineal and 5 were transscrotal. In patients with a single initial or revision cuff the self-reported completely dry rate was 28.6% with the penoscrotal approach and 56.5% with the perineal approach (p = 0.01), while for initial cuffs only the dry rate was 28.0% and 56.7% for the penoscrotal and perineal approach, respectively (p = 0.03). Five of 28 patients (17.9%) with initial penoscrotal placement later underwent tandem cuff placement for continued incontinence, whereas only 1 of 32 (3.1%) with initial perineal placement later had a tandem cuff added (p = 0.06). There was no difference in the estimated failure-free survival (failure for any reason) of the device. CONCLUSIONS: When the artificial urinary sphincter cuff is placed through a perineal approach, there appears to be a higher completely dry rate and fewer subsequent tandem cuff additions than when the artificial urinary sphincter cuff is placed through a penoscrotal incision.

Revision washout decreases implant capsule tissue culture positivity: a multicenter study.

PURPOSE: Positive cultures, visible biofilm and confocal micrography confirm bacterial presence on clinically uninfected inflatable penile prostheses at revision surgery. Salvage irrigation has been proved to rescue patients with clinically infected inflatable penile prostheses. Similar washout at revision for noninfectious reasons significantly lowers subsequent infection rates. We investigated a larger series of patients for positive culture rates and evaluated implant capsule tissue culture rates before and after revision washout. MATERIALS AND METHODS: At 4 institutions a total of 148 patients with inflatable penile prostheses underwent revision surgery for noninfectious reasons between June 2001 and September 2005. Swab cultures of the fluid around the pump and visible biofilm were obtained. Also, in 65 patients a wedge of tissue from the capsule that forms around the pump was cultured. After implant removal revision washout of the implant spaces was performed and a second wedge of tissue was cultured. RESULTS: Of the 148 patients 97 (66%) had positive bacterial swab cultures of the fluid around the pump or biofilm. A total of 124 isolates were cultured. Of the 65 implant capsule tissue cultures obtained before washout 28 (43%) were positive for bacteria, while 16 (25%) obtained after revision washout were positive. CONCLUSIONS: Positive cultures and visible bacterial biofilm are present on clinically uninfected inflatable penile prostheses at revision surgery in most patients. Revision washout appears to decrease the bacterial load on implant capsule tissue at revision surgery of inflatable penile prostheses for noninfectious reasons.

Biofilm formation on clinically noninfected penile prostheses.

PURPOSE: Biofilms are matrix enclosed bacterial populations that adhere to each other and/or to surfaces of implanted medical devices. Biofilm formation has consistently been demonstrated in association with infected penile prosthetic material. Clinically noninfected patients undergoing revision for mechanical malfunction have a surprisingly high rate of positive intraoperative cultures. After revision replacement prostheses have a higher rate of postoperative infection than first time implants. We characterized biofilm formation on penile prostheses in clinically noninfected patients undergoing revision surgery. MATERIALS AND METHODS: Ten patients undergoing revision or removal of inflatable penile prosthetic devices due to mechanical malfunction were included. Specimens from the corporeal cylinders, scrotal pump and reservoir were analyzed. Bacterial biofilm coverage was detected and characterized using confocal scanning laser microscopy. RESULTS: Bacterial biofilm formation associated with multiple microorganisms was demonstrated on 8 of 10 prostheses. Biofilms consisted of gram-positive rods, cocci and fungal elements. CONCLUSIONS: The degree of biofilm formation on these prosthetic devices suggests that most patients have bacterial coverage on the implant. Host mechanisms to control infection may lead to a homeostatic balance that enables biofilms to exist on the surface of the prosthesis without generating clinical infection. A critical threshold of biofilm extent may exist beyond which clinical infection may occur. These results justify further evaluation of biofilms and penile prosthesis infections. Furthermore, the findings help to explain why strategies such as mini salvage procedures to eliminate subclinical biofilms may decrease the postoperative infection risk in patients undergoing repair or replacement of penile prostheses.

Birth defects in Arkansas: is folic acid fortification making a difference?

BACKGROUND: Since 1998, fortification of grain products with folic acid has been mandated in the United States, in an effort to reduce the prevalence of neural tube defects (NTDs). Published reports have shown a reduction in the prevalence of spina bifida since fortification was mandated, but no published studies have reported a reduction in birth defects, other than NTDs, that are postulated to be associated with folic acid deficiency. This study was performed to determine if fortification has reduced the prevalence of NTDs and other birth defects in Arkansas. METHODS: Using data from the Arkansas Reproductive Health Monitoring System, prevalences were computed for thirteen specific birth defects with prior evidence supporting a protective effect of folic acid or multivitamins. Prevalences were calculated using data for live births to Arkansas residents for 1993-2000. Exposure to folic acid fortification was classified by birth year as "pre-fortification" (1993-1995), "transition" (1996-1998) or "post-fortification" (1999-2000). Logistic regression analysis was used to compute crude and adjusted prevalence odds ratios comparing the identified time periods. RESULTS: Prevalences decreased between the pre- and post-fortification periods for spina bifida, orofacial clefts, limb reduction defects, omphalocele, and Down syndrome, but only the decrease in spina bifida was statistically significant (prevalence odds ratio 0.56; 95% confidence interval, 0.37, 0.83). CONCLUSION: In Arkansas, the prevalence of spina bifida has decreased since folic acid fortification of foods was implemented. Similar studies by other birth defects surveillance systems are needed to confirm a preventive effect of fortification for malformations other than spina bifida.

Regional bias in birth defect prevalence rates for Arkansas: influence of incomplete ascertainment along surveillance system borders.

BACKGROUND: As part of the continuing evaluation of the Arkansas Reproductive Health Monitoring System (ARHMS), we assessed the effects on birth defect prevalence rates introduced by incomplete case ascertainment along surveillance boundaries. METHODS: Using data from ARHMS and Arkansas Vital Statistics for 1993-1998, we determined birth defect prevalence rates (per 10,000 live births), stratified by race, among three geographic comparison groups of counties. These included: (1) the Northeast Group, near the state border at Memphis, Tennessee; (2) the Central Group, surrounding Little Rock, Arkansas; and (3) the Southwest Group, near Texarkana, Texas. These counties have similar socioeconomic measures and proximity to health care facilities, but are differentiated by limitations imposed by ARHMS' surveillance borders. Maternal age-standardized rates from the control groups were used to impute expected rates, for the Northeast Group and statewide, which were compared with reported rates. RESULTS: We found that there were 620 fewer reported birth defect cases than expected for the Northeast Group. The Northeast Group's prevalence rates were approximately half of the control groups' rates (310.6 vs. 529.8, respectively, for Whites, and 240.8 vs. 550.1, respectively, for African-Americans). Incorporating the missed cases into statewide prevalence calculations could increase prevalence rates from 502.6 to 523.2 for Whites and from 527.4 to 590.7 for African-Americans. CONCLUSIONS: This study identified significant regional differences in reported birth defect rates in Arkansas. Case ascertainment might be incomplete in other surveillance systems lacking the means to share data with neighboring systems. Regional inaccuracy can hinder evaluation of localized birth defect trends or targeted prevention efforts.