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Abstract Background Birds chronically infected with avian malaria parasites often show relapses of parasitaemia after latent stages marked by absence of parasites in the peripheral circulation. These relapses are assumed to result from the activation of dormant exo-erythrocytic stages produced during secondary (post-erythrocytic) merogony of avian Plasmodium spp. Yet, there is no morphological proof of persistent or dormant tissue stages in the avian host during latent infections. This study investigated persistence of Plasmodium relictum pSGS1 in birds with latent infections during winter, with the goal to detect presumed persisting tissue stages using a highly sensitive RNAscope® in situ hybridization technology. Methods Fourteen domestic canaries were infected with P. relictum pSGS1 by blood-inoculation in spring, and blood films examined during the first 4 months post infection, and during winter and spring of the following year. After parasitaemia was no longer detectable, half of the birds were dissected, and tissue samples investigated for persisting tissue stages using RNAscope ISH and histology. The remaining birds were blood-checked and dissected after re-appearance of parasitaemia, and their tissues equally examined. Results Systematic examination of tissues showed no exo-erythrocytic stages in birds exhibiting latent infections by blood-film microscopy, indicating absence of dormant tissue stages in P. relictum pSGS1-infected canaries. Instead, RNAscope ISH revealed rare P. relictum blood stages in capillaries of various tissues and organs, demonstrating persistence of the parasites in the microvasculature. Birds examined after re-appearance of parasitemia showed higher numbers of P. relictum blood stages in both capillaries and larger blood vessels, indicating replication during early spring and re-appearance in the peripheral circulation. Conclusions The findings suggest that persistence of P. relictum pSGS1 during latent infection is mediated by continuous low-level erythrocytic merogony and possibly tissue sequestration of infected blood cells. Re-appearance of parasitaemia in spring seems to result from increased erythrocytic merogony, therefore representing recrudescence and not relapse in blood-inoculated canaries. Further, the study highlights strengths and limitations of the RNAscope ISH technology for the detection of rare parasite stages in tissues, providing directions for future research on persistence and tissue sequestration of avian malaria and related haemosporidian parasites.

Background: Birds chronically infected with avian malaria parasites often show relapses of parasitaemia after latent stages marked by absence of parasites in the peripheral circulation. These relapses are assumed to result from the activation of dormant exo-erythrocytic stages produced during secondary (post-erythrocytic) merogony of avian Plasmodium spp. Yet, there is no morphological proof of persistent or dormant tissue stages in the avian host during latent infections. This study investigated persistence of Plasmodium relictum pSGS1 in birds with latent infections during winter, with the goal to detect presumed persisting tissue stages using a highly sensitive RNAscope® in situ hybridization technology. Methods: Fourteen domestic canaries were infected with P. relictum pSGS1 by blood-inoculation in spring, and blood films examined during the first 4 months post infection, and during winter and spring of the following year. After parasitaemia was no longer detectable, half of the birds were dissected, and tissue samples investigated for persisting tissue stages using RNAscope ISH and histology. The remaining birds were blood-checked and dissected after re-appearance of parasitaemia, and their tissues equally examined. Results: Systematic examination of tissues showed no exo-erythrocytic stages in birds exhibiting latent infections by blood-film microscopy, indicating absence of dormant tissue stages in P. relictum pSGS1-infected canaries. Instead, RNAscope ISH revealed rare P. relictum blood stages in capillaries of various tissues and organs, demonstrating persistence of the parasites in the microvasculature. Birds examined after re-appearance of parasitemia showed higher numbers of P. relictum blood stages in both capillaries and larger blood vessels, indicating replication during early spring and re-appearance in the peripheral circulation. Conclusions: The findings suggest that persistence of P. relictum pSGS1 during latent infection is mediated by continuous low-level erythrocytic merogony and possibly tissue sequestration of infected blood cells. Re-appearance of parasitaemia in spring seems to result from increased erythrocytic merogony, therefore representing recrudescence and not relapse in blood-inoculated canaries. Further, the study highlights strengths and limitations of the RNAscope ISH technology for the detection of rare parasite stages in tissues, providing directions for future research on persistence and tissue sequestration of avian malaria and related haemosporidian parasites. [ABSTRACT FROM AUTHOR]

Abstract Background Sri Lanka after eliminating malaria in 2012, is in the prevention of re-establishment (POR) phase. Being a tropical country with high malariogenic potential, maintaining vigilance is important. All malaria cases are investigated epidemiologically and followed up by integrated drug efficacy surveillance (iDES). Occasionally, that alone is not adequate to differentiate Plasmodium falciparum reinfections from recrudescences. This study evaluated the World Health Organization and Medicines for Malaria Venture (MMV) recommended genotyping protocol for the merozoite surface proteins (msp1, msp2) and the glutamate-rich protein (glurp) to discriminate P. falciparum recrudescence from reinfection in POR phase. Methods All P. falciparum patients detected from April 2014 to December 2019 were included in this study. Patients were treated and followed up by iDES up to 28 days and were advised to get tested if they develop fever at any time over the following year. Basic socio-demographic information including history of travel was obtained. Details of the malariogenic potential and reactive entomological and parasitological surveillance carried out by the Anti Malaria Campaign to exclude the possibility of local transmission were also collected. The msp1, msp2, and glurp genotyping was performed for initial and any recurrent infections. Classification of recurrent infections as recrudescence or reinfection was done based on epidemiological findings and was compared with the genotyping outcome. Results Among 106 P. falciparum patients, six had recurrent infections. All the initial infections were imported, with a history of travel to malaria endemic countries. In all instances, the reactive entomological and parasitological surveillance had no evidence for local transmission. Five recurrences occurred within 28 days of follow-up and were classified as recrudescence. They have not travelled to malaria endemic countries between the initial and recurrent infections. The other had a recurrent infection after 105 days. It was assumed a reinfection, as he had travelled to the same malaria endemic country in between the two malaria attacks. Genotyping confirmed the recrudescence and the reinfection. Conclusions The msp1, msp2 and glurp genotyping method accurately differentiated reinfections from recrudescence. Since reinfection without a history of travel to a malaria endemic country would mean local transmission, combining genotyping outcome with epidemiological findings will assist classifying malaria cases without any ambiguity.

Proton pump inhibitors (PPIs) are currently routinely used for the treatment of reflux esophagitis (RE); however, with frequent symptom recurrence after discontinuation and limited clinical improvement in accompanying gastrointestinal symptoms. This study aims to explore the adjuvant therapeutic effect of Bifidobacterium supplement for RE patients. A total of 110 eligible RE patients were recruited and randomly assigned to the placebo and probiotic groups. All patients were treated with rabeprazole tablets and simultaneously received either Bifidobacterium animalis subsp. lactis MH-02 or placebo for 8 weeks. Patients who achieved clinical remission then entered the next 12 weeks of follow-up. RDQ, GSRS scores, and endoscopy were performed to assess clinical improvement, and changes in intestinal microbiota were analyzed with high-throughput sequencing. Our results revealed that MH-02 combined therapy demonstrated an earlier time to symptom resolution (50.98% vs. 30.61%, p = 0.044), a significant reduction in the GSRS score (p = 0.0007), and a longer mean time to relapse (p = 0.0013). In addition, high-throughput analyses showed that MH-02 combined therapy increased the α (p = 0.001) diversity of gut microbiota and altered microbial composition by beta diversity analysis, accompanied with significantly altered gut microbiota taxa at the genus level, where the abundance of some microbial genera including Bifidobacterium, Clostridium, and Blautia were increased, while the relative abundance of Streptococcus and Rothia were decreased (p < 0.05). Collectively, these results support the beneficial effects of MH-02 as a novel complementary strategy in RE routine treatment. [ABSTRACT FROM AUTHOR]

Background: Sri Lanka after eliminating malaria in 2012, is in the prevention of re-establishment (POR) phase. Being a tropical country with high malariogenic potential, maintaining vigilance is important. All malaria cases are investigated epidemiologically and followed up by integrated drug efficacy surveillance (iDES). Occasionally, that alone is not adequate to differentiate Plasmodium falciparum reinfections from recrudescences. This study evaluated the World Health Organization and Medicines for Malaria Venture (MMV) recommended genotyping protocol for the merozoite surface proteins (msp1, msp2) and the glutamate-rich protein (glurp) to discriminate P. falciparum recrudescence from reinfection in POR phase. Methods: All P. falciparum patients detected from April 2014 to December 2019 were included in this study. Patients were treated and followed up by iDES up to 28 days and were advised to get tested if they develop fever at any time over the following year. Basic socio-demographic information including history of travel was obtained. Details of the malariogenic potential and reactive entomological and parasitological surveillance carried out by the Anti Malaria Campaign to exclude the possibility of local transmission were also collected. The msp1, msp2, and glurp genotyping was performed for initial and any recurrent infections. Classification of recurrent infections as recrudescence or reinfection was done based on epidemiological findings and was compared with the genotyping outcome. Results: Among 106 P. falciparum patients, six had recurrent infections. All the initial infections were imported, with a history of travel to malaria endemic countries. In all instances, the reactive entomological and parasitological surveillance had no evidence for local transmission. Five recurrences occurred within 28 days of follow-up and were classified as recrudescence. They have not travelled to malaria endemic countries between the initial and recurrent infections. The other had a recurrent infection after 105 days. It was assumed a reinfection, as he had travelled to the same malaria endemic country in between the two malaria attacks. Genotyping confirmed the recrudescence and the reinfection. Conclusions: The msp1, msp2 and glurp genotyping method accurately differentiated reinfections from recrudescence. Since reinfection without a history of travel to a malaria endemic country would mean local transmission, combining genotyping outcome with epidemiological findings will assist classifying malaria cases without any ambiguity. [ABSTRACT FROM AUTHOR]

Background Artemisinin-based combination therapies (ACTs) are recommended as first-line treatment against uncomplicated Plasmodium falciparum infection. Mutations in the PfKelch13 (PF3D7_1343700) gene led to resistance to artemisinin in Southeast Asia. Mutations in the Pfcoronin (PF3D7_1251200) gene confer reduced artemisinin susceptibility in vitro to an African Plasmodium strain, but their role in clinical resistance has not been established. Methods We conducted a retrospective observational study of Israeli travellers returning from sub-Saharan Africa with P. falciparum malaria, including patients with artemether–lumefantrine (AL) failure. Blood samples from all malaria-positive patients are delivered to the national Parasitology Reference Laboratory along with personal information. Confirmation of malaria, species identification and comparative parasite load analysis were performed using real-time PCR. DNA extractions from stored leftover samples were analysed for the presence of mutations in Pfkelch13 and Pfcoronin. Age, weight, initial parasitaemia level and Pfcoronin status were compared in patients who failed treatment vs responders. Results During 2009–2020, 338 patients had P. falciparum malaria acquired in Africa. Of those, 15 (24–69 years old, 14 males) failed treatment with AL. Four were still parasitemic at the end of treatment, and 11 had malaria recrudescence. Treatment failure rates were 0% during 2009–2012, 9.1% during 2013–2016 and 17.4% during 2017–2020. In all patients, the Pfkelch13 propeller domain had a wild-type sequence. We did find the P76S mutation in the propeller domain of Pfcoronin in 4/15 (28.6%) of the treatment-failure cases compared to only 3/56 (5.5%) in the successfully treated patients (P  = 0.027). Conclusion AL treatment failure emergence was not associated with mutations in Pfkelch13. However, P76S mutation in the Pfcoronin gene was more frequently present in the treatment-failure group and merits further investigation. The increase of malaria incidence in sub-Saharan-Africa partly attributed to the COVID-19 pandemic might also reflect a wider spread of ACT resistance. [ABSTRACT FROM AUTHOR]

Interventions to reduce the prevalence of trachoma and transmission of ocular Chlamydia trachomatis have been implemented in Oromia Region, Ethiopia. Following an impact survey in which the trachomatous inflammation—follicular (TF) prevalence in 1–9-year-olds is <5%, a surveillance survey is recommended 2 years later, without additional antibiotic treatment. We report results of surveillance surveys in 11 evaluation units (EUs) covering 12 districts in Oromia Region, to plan whether future interventions are needed. We use a two-stage cluster-sampling cross-sectional survey design. In each EU, 26 clusters (villages) were systematically selected with probability proportional to size; from each cluster, 30 households were selected using compact segment sampling. Water, sanitation and hygiene (WASH) access was assessed in all selected households. All residents of selected households aged ≥1 year were examined for TF and trachomatous trichiasis (TT) by certified graders. Of 31,991 individuals enumerated, 29,230 (91% of) individuals were examined. Eight EUs had an age-adjusted TF prevalence in 1−9-year-olds of ≥5% and seven had a TT prevalence unknown to the health system among adults aged ≥15 years of ≥0.2%. About one-third of visited households had access to an improved water source for drinking, and 5% had access to an improved latrine. Despite TF reductions to <5% at impact survey, prevalence recrudesced to ≥5% in all but three of the 11 EUs. Operational research is needed to understand transmission dynamics and epidemiology, in order to optimise elimination strategies in high-transmission settings like these. [ABSTRACT FROM AUTHOR]

Dis-moi quelle jeunesse tu as, je te dirais quelle nation tu auras, dit-on. Le fondement de notre objet d’étude repose sur les méfaits ou les conséquences de la délinquance juvénile dans la ville de Kindu. Ce phénomène implique une mise en relief de multiples causes qui entrent en compte dans la destruction de son avenir ; et pourtant, nous sommes tous sans ignorer que, la jeunesse d’aujourd’hui constitue l’avenir de demain. A Kindu, la montée de la délinquance juvénile constitue un vif sujet d’inquiétude au quotidien et la forme la plus courante de cette délinquance est connue sous le « BASE ». En effet, étant jeunes, il nous a été incontournable de passer outre ce climat qui entache la moralité publique dans la ville. Cette étude s’est donnée l’obligation de déterminer les causes de cette délinquance dans la ville de Kindu y ressortir les conséquences. Dans la recherche des explications, nous avons fait usage de la méthode stratégique, associée à l’approche juridique.

Objective To investigate the efficacy and safety of transanal local resection combined with radiotherapy and chemotherapy with linear cutting stapler in the treatment of stage T2N0M0 low rectal cancer. Methods The clinical data of 57 patients with stage T2N0M0 low rectal cancer treated in the First Affiliated Hospital of Hebei North University from February 2017 to February 2019 were retrospectively analyzed, and they were divided into two groups according to different surgical methods: transanal local resection combined with radiotherapy and chemotherapy group (TAE group, 27 cases) and traditional radical surgery group (RS group, 30 cases). The general data, operation related indexes, Wexner score and QLQ-C30 score, postoperative complications and follow-up outcomes were compared between two groups. Results The operation time, postoperative hospitalization days and intraoperative bleeding volume in TAE group were significantly lower than those in RS group (P＜0.05). The postoperative Wexner score of TAE group was significantly lower than that in RS group (2.10±1.40 vs 6.60±2.10, t =9.041, P＜0.01). QLQ-C30 score in TAE group was significantly higher than that in RS group (90.31±3.32 vs 71.59±6.35, t =13.716, P＜0.01). The incidence of complications in TAE group decreased compared to RS group without significant difference (3.70% vs 23.33%, P＞0.05). Both groups were followed up for 3 years or more, with only 1 recurrence in TAE group and no recurrence in RS group. Conclusion The use of linear cutting stapler for transanal local resection combined with radiotherapy and chemotherapy for low rectal cancer can shorten the operation time and postoperative hospital stay, reduce intraoperative bleeding, improve the postoperative defecation and the quality of life of patients, and it does not increase the long-term recurrence rate.

Urban birds' stress response frequently differs in magnitude from non-urban conspecifics. This urban phenotype may reflect response to selection, sorting during colonization of urban environments, developmental plasticity, or phenotypic flexibility in response to urban environments. We investigated whether exposure to one characteristic of an urban environment, chronic disturbance, could induce an attenuated acute glucocorticoid response over a short time in adult non-urban dark-eyed juncos (Junco hyemalis), which, if true, would support the phenotypic flexibility hypothesis. We tested this during the period of spring gonadal recrudescence. We simulated a high-disturbance urban-like environment by exposing non-urban experimental birds to chronic disturbance (30-min psychological stressors 4x/day for 3 weeks); controls were minimally disturbed. We found that chronically disturbed birds had a lower acute corticosterone response after 3 weeks of treatment. Baseline corticosterone was not affected. Chronically disturbed birds had less body fat and lower body condition than controls at the end of the experiment, although on average all birds gained weight over the course of the experiment. Feathers grown during the experiment did not show an effect of the disturbance treatment on feather corticosterone or fault bars, although captive-grown feathers had lower corticosterone and more fault bars than wild-grown feathers. We conclude that adult male juncos have the capacity to attenuate their acute corticosterone response in an environment with high frequency of disturbance, potentially facilitating colonization of urban habitats. Future research may show whether successful urban colonists differ from unsuccessful species in this regard. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of different methods of complete mesocolectomy (CME) on the platelet activation, complication rate and tumor recurrence in patients with colon cancer. Methods 80 patients with colon cancer in The 2nd People's Hospital of Kunming from January 2020 to January 2022 were selected and divided into 2 groups according to the treatment plan, with 40 cases in each group. The control group underwent open CME, and the observation group underwent laparoscopic CME to compare the perioperative situation, number of lymph node dissection, incidence of postoperative complications, as well as serum inflammatory [interleukin-6 ( IL-6), C-reactive protein ( CRP) ] and platelet activation indicators [platelet neutrophil aggregates ( PNA), platelet lymphocytic aggregation ( PlyA), platelet leukocyte aggregation (PMA), platelet leukocyte aggregates (PLA)] before and after surgery and the tumor recurrence rate between the two groups. Results　The intraoperative blood loss and postoperative drainage volume in the observation group were less than those in the control group, and the anal defecation time, anal exhaust time and hospitalization days were shorter than those in the control group (P < 0.05). The number of stage III, positive and left and right hemicolic lymph nodes dissection in the observation group was higher than that in the control group, and the incidence of postoperative complications was lower than that in the control group (P < 0.05). Serum IL-6 and CRP in the observation group were lower than those in the control group 1 day after the operation (P < 0.05). PLA, PlyA, PMA and PNA in the observation group were lower than those in the control group 1 day after the operation (P < 0.05). The one-year recurrence rate of the observation group was lower than that of the control group, and the survival time without recurrence was longer than that of the control group (P < 0.05). Conclusion　The operative time of laparoscopic CME for colon cancer is similar to that of open CME, but it can reduce the intraoperative bleeding, reduce the inflammatory response, improve the platelet activation, promote the disease recovery, improve the lymph node clearance, reduce the recurrence risk, prolong survival, and reduce complications. [ABSTRACT FROM AUTHOR]

Imported malaria and recurrent infections are becoming an emerging issue in many malaria non-endemic countries. This study aimed to determine the molecular patterns of the imported malaria infections and recurrence. Blood samples were collected from patients with imported malaria infections during 2016-2018 in Guangxi Zhuang Autonomous Region, China. Next-generation amplicon deep-sequencing approaches were used to assess parasite genetic diversity, multiplexity of infection, relapse, recrudescence, and antimalarial drug resistance. A total of 44 imported malaria cases were examined during the study, of which 35 (79.5%) had recurrent malaria infections within 1 year. The majority (91.4%) had one recurrent malaria episode, whereas two patients had two recurrences and one patient had three recurrences. A total of 19 recurrence patterns (the species responsible for primary and successive clinical episodes) were found in patients returning from malaria epidemic countries. Four parasite species were detected with a higher than usual proportion (46.2%) of non-falciparum infections or mixed-species infections. An increasing trend of recurrence infections and reduced drug treatment efficacy were observed among the cases of imported malaria. The high recurrence rate and complex patterns of imported malaria from Africa to non-endemic countries have the potential to initiate local transmission, thereby undermining efforts to eliminate locally acquired malaria. Our findings highlight the power of amplicon deep-sequencing applications in molecular epidemiological studies of the imported malaria recurrences.

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Babesia microti is an obligate intra-erythrocytic parasite transmitted by infected ticks. B. microti is a eukaryote much larger than prokaryotic microbes and more similar to human hosts in their biochemistry and metabolism. Moreover, Babesia spp. possess various immune evasion mechanisms leading to persistent and sometimes life-threatening diseases in immunocompromised hosts. Chronic lymphocytic leukemia (CLL) is the most prevalent adult B-cell malignancy, and a small percentage of CLL transforms into aggressive lymphomas. CLL also causes immune dysfunction due to the over-expansion of immature and ineffective B-cells. When our patient with indolent CLL presented with anemia, pancytopenia, and splenomegaly, all his healthcare providers presumptively assumed a malignant transformation of CLL. However, these are also the signs and symptoms of babesiosis. Herein, we report a case where B. microti infection was presumed as a malignant transformation of CLL and narrowly avoided a devastating outcome. Although the patient developed fulminant sepsis, he finally received the correct diagnosis and treatment. Unfortunately, the disease recrudesced twice. Each time, it became more difficult to control the infection. We describe the clinical course of the case and discuss the case-specific literature review. This report highlights the importance of differential diagnoses ruling out infections which include babesiosis, prior to initiating the treatment of B-cell malignancy.

Malaria is widespread throughout the world and affects many animal species. Although the origin of this vector-borne disease was discovered more than a century ago, several aspects of the within-host infection dynamic are still poorly understood. Among them, the factors triggering parasite recurrences – episodes of brief increase in parasite number following a period when the parasite was either absent or present at very low levels in the blood – have still not been clearly identified. Yet, recurrences may contribute significantly to overall infection prevalence in vertebrate host populations. Here, we investigated whether artificial or natural increases in stress hormone levels in chronically infected birds influence the replication rate of Plasmodium relictum and transmission to its natural vector, the mosquito Culex pipiens. Our results provide evidence that increased levels of corticosterone, either induced by oral ingestion or caused by handling stress, can trigger malaria recurrences. However, we did not observe any effect on the transmission rate of the parasite to the mosquito vector. Our study is a first fundamental step in understanding the mechanisms underlying malaria recurrences. It remains to be ascertained whether this feature extends to other malaria system and in particular to human malaria.

Proton pump inhibitors (PPIs) are currently routinely used for the treatment of reflux esophagitis (RE); however, with frequent symptom recurrence after discontinuation and limited clinical improvement in accompanying gastrointestinal symptoms. This study aims to explore the adjuvant therapeutic effect of Bifidobacterium supplement for RE patients. A total of 110 eligible RE patients were recruited and randomly assigned to the placebo and probiotic groups. All patients were treated with rabeprazole tablets and simultaneously received either Bifidobacterium animalis subsp. lactis MH-02 or placebo for 8 weeks. Patients who achieved clinical remission then entered the next 12 weeks of follow-up. RDQ, GSRS scores, and endoscopy were performed to assess clinical improvement, and changes in intestinal microbiota were analyzed with high-throughput sequencing. Our results revealed that MH-02 combined therapy demonstrated an earlier time to symptom resolution (50.98% vs. 30.61%, p = 0.044), a significant reduction in the GSRS score (p = 0.0007), and a longer mean time to relapse (p = 0.0013). In addition, high-throughput analyses showed that MH-02 combined therapy increased the α (p = 0.001) diversity of gut microbiota and altered microbial composition by beta diversity analysis, accompanied with significantly altered gut microbiota taxa at the genus level, where the abundance of some microbial genera including Bifidobacterium, Clostridium, and Blautia were increased, while the relative abundance of Streptococcus and Rothia were decreased (p < 0.05). Collectively, these results support the beneficial effects of MH-02 as a novel complementary strategy in RE routine treatment.

Weiling Zhou,1 Weijing Li,2 Cuiying He,2 Ruijuan Ma,2 Qian Gao,1 Yuan Wang,1 Lei Feng,1 Lihong Liu2 1Department of Endocrine and Metabolic Diseases, The Fourth Hospital of Hebei Medical University (Hebei Tumor Hospital), Shijiazhuang, People’s Republic of China; 2Department of Hematology, The Fourth Hospital of Hebei Medical University (Hebei Tumor Hospital), Shijiazhuang, People’s Republic of ChinaCorrespondence: Lihong Liu, Department of Hematology, The Fourth Hospital of Hebei Medical University (Hebei Tumor Hospital), Shijiazhuang, People’s Republic of China, Tel +86 13831177920, Email liulihong111222@163.comPurpose: To explore the effects of primary and secondary hyperglycemia and the application of the hypoglycemic drug metformin on the prognosis of patients with diffuse large B-cell lymphoma (DLBCL).Methods: We performed a retrospective analysis of 1767 DLBCL patients.Cox regression method was used for analysis to evaluate the prognostic factors, and the Kaplan-Meier method was used to draw a survival curve to analyze the effect of hyperglycemia and the hypoglycemic drug metformin on the progression-free survival (PFS) and overall survival (OS) of DLBCL patients.Results: Our study showed that patients with hyperglycemia tend to have higher age (age> 60 years), high body mass index (BMI)(≥ 24kg/m2), late Ann Arbor stage (III–IV), high international prognostic index (IPI) (3– 5 score), high lactic dehydrogenase (LDH) level (> 250U/L), bulky disease and comorbidity. Hyperglycemia affects the survival time of the DLBCL population (PFS: adjusted HR 1.41, 95% CI: 1.16– 1.70, P < 0.001, OS: adjusted HR 1.33, 95% CI:1.09– 1.61, P=0.004).Compared with the non-hyperglycemia group, the secondary hyperglycemia increase affects the prognosis of the DLBCL population (P< 0.001). Compared with the secondary hyperglycemia group, the primary hyperglycemia group has a poor prognosis (P< 0.05). For patients with DLBCL and hyperglycemia (732 patients in total), the use of metformin can improve their PFS and OS (PFS: adjusted HR 0.69, 95% CI: 0.49– 0.96, P=0.028, OS: adjusted HR 0.68, 95% CI: 0.49– 0.95, P=0.024).Conclusion: Hyperglycemia and secondary hyperglycemia are related to the poor prognosis of DLBCL population.For patients with DLBCL combined with hyperglycemia, the application of metformin can improve survival rate.Keywords: hyperglycemia, diffuse large B-cell lymphoma, metformin, recrudescence, death, prognosis

Androgenetic alopecia (AGA) is a transracial and cross‐gender disease worldwide with a youth‐oriented tendency, but it lacks effective treatment. The binding of androgen receptor (AR) and androgen plays an essential role in the occurrence and progression of AGA. Herein, novel proteolysis targeting chimera degrader of AR (AR‐PROTAC) is synthesized and integrated with dissolving microneedles (PROTAC‐MNs) to achieve AR destruction in hair follicles for AGA treatment. The PROTAC‐MNs possess adequate mechanical capabilities for precise AR‐PROTAC delivery into the hair follicle‐residing regions for AR degradation. After applying only once topically, the PROTAC‐MNs achieve an accelerated onset of hair regeneration as compared to the daily application of the first‐line topical drug minoxidil. Intriguingly, PROTAC‐MNs via single administration still realize superior hair regeneration in AGA recrudescence, which is the major drawback of minoxidil in clinical practice. With the degradation of AR, the PROTAC‐MNs successfully regulate the signaling cascade related to hair growth and activate hair follicle stem cells. Furthermore, the PROTAC‐MNs do not cause systemic toxicity or androgen deficiency‐related chaos in vivo. Collectively, these AR‐degrading dissolving microneedles with long‐lasting efficacy, one‐step administration, and high biocompatibility provide a great therapeutic potential for AGA treatment. [ABSTRACT FROM AUTHOR]

Reproductive abnormalities, that could lead to possible effects at the population level, have been observed in wild fish throughout the United States, with high prevalence in largemouth bass (LMB; Micropterus salmoides) and smallmouth bass (Micropterus dolomieu). Estrone (E1) and atrazine (ATR) are common environmental contaminants often associated with agricultural land use. 17alpha-ethinylestradiol (EE2) is a contaminant associated with wastewater treatment effluent, and a representative, well-studied estrogen commonly used for fish toxicity testing. Our objective was to assess whether early gonad recrudescence in adult fish was a period of sensitivity for alterations in reproductive condition and function. Adult male LMB were exposed from post-spawning to early gonad recrudescence to either a mixture of E1 (47.9 ng/L) + ATR (5.4 µg/L), or EE2 (2.4 ng/L) in outdoor experimental ponds. Gonad samples were collected from fish just prior to the start of exposure (July), at the end of the exposure period (December), the following spring just prior to spawning (April), and post spawning (May). Gonadosomatic index (GSI) was significantly reduced in E1 + ATR-exposed and EE2-exposed males compared to control at every post-exposure time point. Reduced sperm count and sperm motility were observed in the mixture treatment (E1 + ATR) compared to the control. Sperm motility was also reduced in the EE2 treatment. These data together indicate that estrogenic endocrine-disrupting compounds can lessen the reproductive condition of adult male LMB, and that effects of exposure during early gonad recrudescence can persist at least through the subsequent spawning cycle. [ABSTRACT FROM AUTHOR]

Abstract Background The duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria. Methods Individual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up. Results Overall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0–22%] in those treated with ≤ 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up following AL underestimated the risk of recrudescence by a median of 2.8 percentage points compared to day 63 estimates and those limited to 42 days following DP underestimated the risk of recrudescence by a median of 2.0 percentage points compared to day 42 estimates. The analysis was limited by few clinical trials following patients for longer than 42 days (9 out of 83 trials) and the imprecision of PCR genotyping which overcalls recrudescence in areas of higher transmission biasing the later distribution. Conclusions Restricting follow-up of clinical efficacy trials to day 28 for AL and day 42 for DP will miss a proportion of late recrudescent treatment failures but will have a modest impact in derived efficacy. The results highlight that as genotyping methods improve consideration should be given for trials with longer duration of follow-up to detect early indications of emerging drug resistance.

Many standard-textbook population-genetic results apply to a wide range of species. Sometimes, however, population-genetic models and principles need to be tailored to a particular species. This is particularly true for malaria, which next to tuberculosis and HIV/AIDS ranks among the economically most relevant infectious diseases. Importantly, malaria is not one disease--five human-pathogenic species of Plasmodium exist. P. falciparum is not only the most severe form of human malaria, but it also causes the majority of infections. The second most relevant species, P. vivax, is already considered a neglected disease in several endemic areas. All human-pathogenic species have distinct characteristics that are not only crucial for control and eradication efforts, but also for the population-genetics of the disease. This is particularly true in the context of selection. Namely, fitness is determined by so-called fitness components, which are determined by the parasites live-history, which differs between malaria species. The presence of hypnozoites, i.e., dormant liver-stage parasites, which can cause disease relapses, is a distinct feature of P. vivax and P. ovale sp. In P. malariae inactivated blood-stage parasites can cause a recrudescence years after the infection was clinically cured. To properly describe population-genetic processes, such as the spread of anti-malarial drug resistance, these features must be accounted for appropriately. Here, we introduce and extend a population-genetic framework for the evolutionary dynamics of malaria, which applies to all human-pathogenic malaria species. The model focuses on, but is not limited to, the spread of drug resistance. The framework elucidates how the presence of dormant liver stage or inactivated blood stage parasites that act like seed banks delay evolutionary processes. It is shown that, contrary to standard population-genetic theory, the process of selection and recombination cannot be decoupled in malaria. Furthermore, we discuss the connection between haplotype frequencies, haplotype prevalence, transmission dynamics, and relapses or recrudescence in malaria. [ABSTRACT FROM AUTHOR]

Simple Summary: Although widely used in clinical practice as an alternative to surgical castration, the recovery of testicular endocrine and germinative function subsequent to treatment with a 4.7 mg deslorelin implant has not been well characterized until now. It is, however, relevant for the veterinary practitioner to advise the pet owner about the expected return to "normal" testosterone concentrations, prostatic volume, and pre-treatment semen quality. Our study showed that testosterone was no longer different from untreated controls on D14 after implant removal, whereas normospermia was reached on D84-133. All of the effects induced were fully reversible, albeit after individually varying time periods. Although deslorelin slow-release implants are widely used in the clinic, detailed published information about the recovery of testosterone concentrations (T), semen quality, and testicular and prostatic volume (TV, PV) after treatment is still missing. This article aims to characterize changes during restart after a five-months treatment and subsequent implant removal. Seven male Beagle dogs were treated with deslorelin (treatment group, TG), and three saline-treated dogs served as controls (CG). Deslorelin implants were removed after five months (D ex), followed by detailed andrological examinations for TV, PV, semen collection, and blood sampling for T-analysis with/without GnRH/hCG stimulation tests. TV, PV, and T increased rapidly after D ex in TG, not differing from CG from D91 (TV), D49 (PV), and D14 (T). The first sperm-containing ejaculates were collected between D49 and 70, whereas the samples were normospermic between D84 and 133. A T increase (>0.1 ng/mL) subsequent to the GnRH/hCG stimulation test was observed from D28/29 onwards, respectively. Histological assessment of testicular tissue at the end of the observational period (D149 after implant removal) revealed normal spermatogenesis. Our data confirm that the restart of endocrine and germinative testicular function is highly variable, but nevertheless, all of the effects induced were reversible. [ABSTRACT FROM AUTHOR]

Morphological modifications and shifts in organelle relationships are hallmarks of dormancy in eukaryotic cells. Communications between altered mitochondria and nuclei are associated with metabolic quiescence of cancer cells that can survive chemotherapy. In plants, changes in the pathways between nuclei, mitochondria, and chloroplasts are associated with cold stress and bud dormancy. Plasmodium falciparum parasites, the deadliest agent of malaria in humans, contain a chloroplast-like organelle (apicoplast) derived from an ancient photosynthetic symbiont. Antimalarial treatments can fail because a fraction of the blood-stage parasites enter dormancy and recrudesce after drug exposure. Altered mitochondrial-nuclear interactions in these persisters have been described for P. falciparum , but interactions of the apicoplast remained to be characterized. In the present study, we examined the apicoplasts of persisters obtained after exposure to dihydroartemisinin (a first-line antimalarial drug) followed by sorbitol treatment, or after exposure to sorbitol treatment alone. As previously observed, the mitochondrion of persisters was consistently enlarged and in close association with the nucleus. In contrast, the apicoplast varied from compact and oblate, like those of active ring-stage parasites, to enlarged and irregularly shaped. Enlarged apicoplasts became more prevalent later in dormancy, but regular size apicoplasts subsequently predominated in actively replicating recrudescent parasites. All three organelles, nucleus, mitochondrion, and apicoplast, became closer during dormancy. Understanding their relationships in erythrocytic-stage persisters may lead to new strategies to prevent recrudescences and protect the future of malaria chemotherapy., (Published by Oxford University Press on behalf of National Academy of Sciences 2024.)

Many standard-textbook population-genetic results apply to a wide range of species. Sometimes, however, population-genetic models and principles need to be tailored to a particular species. This is particularly true for malaria, which next to tuberculosis and HIV/AIDS ranks among the economically most relevant infectious diseases. Importantly, malaria is not one disease—five human-pathogenic species of Plasmodium exist. P. falciparum is not only the most severe form of human malaria, but it also causes the majority of infections. The second most relevant species, P. vivax, is already considered a neglected disease in several endemic areas. All human-pathogenic species have distinct characteristics that are not only crucial for control and eradication efforts, but also for the population-genetics of the disease. This is particularly true in the context of selection. Namely, fitness is determined by so-called fitness components, which are determined by the parasites live-history, which differs between malaria species. The presence of hypnozoites, i.e., dormant liver-stage parasites, which can cause disease relapses, is a distinct feature of P. vivax and P. ovale sp. In P. malariae inactivated blood-stage parasites can cause a recrudescence years after the infection was clinically cured. To properly describe population-genetic processes, such as the spread of anti-malarial drug resistance, these features must be accounted for appropriately. Here, we introduce and extend a population-genetic framework for the evolutionary dynamics of malaria, which applies to all human-pathogenic malaria species. The model focuses on, but is not limited to, the spread of drug resistance. The framework elucidates how the presence of dormant liver stage or inactivated blood stage parasites that act like seed banks delay evolutionary processes. It is shown that, contrary to standard population-genetic theory, the process of selection and recombination cannot be decoupled in malaria. Furthermore, we discuss the connection between haplotype frequencies, haplotype prevalence, transmission dynamics, and relapses or recrudescence in malaria.

This article discusses two cases of recurrent malaria in non-endemic areas, challenging the conventional understanding of malaria recurrence patterns. In the first case, a genetic polymorphism in cytochrome P450 enzymes was found, which may have affected the patient's response to treatment. In the second case, the biological mechanism underlying the persistence of P. malariae remains unknown. The article emphasizes the need for further research and monitoring to adapt treatment protocols in the face of evolving challenges posed by the malaria parasite. [Extracted from the article]

Background: Extragonadal yolk sac tumor (YST) of peritoneum is a rare malignancy. Case Description: A 37-year-old Chinese woman was admitted to hospital with a 3-month abdominal pain 4 years ago. Alpha-fetoprotein was 228,499.0 ng/mL. Computed tomography scan revealed a massive mass in the left lower abdomen. Exploratory laparotomy exposed a huge mesenteric mass. Then, mesenteric tumor resection, partial sigmoidectomy, and single-lumen fistula of sigmoid colon were performed. Postoperative pathologic diagnosis reported a stage IV mesenteric YST. After surgery, the patient received 6 courses of BEP (bleomycin, etoposide, and cisplatin) chemotherapy. Seven months later, the patient underwent stoma reversion of sigmoid colon and received another 2 courses of BEP chemotherapy. Three months after the last chemotherapy, liver metastases were diagnosed. She subsequently underwent 3 surgeries, radiotherapy for liver metastases, and multiple tiers of palliative chemotherapies, including TP (docetaxel and carboplatin), VIP (ifosfamide, cisplatin, and etoposide), TIP (paclitaxel, ifosfamide, and cisplatin), and so on. After the third surgery (left hepatic lesion resection and right iliac lymph node resection), she received 4 cyclic chemotherapies of BEP' (boanmycin, etoposide, and cisplatin) without pulmonary toxic side effects. Conclusion: Postoperative histopathology and immunohistochemistry are gold standards for the diagnosis of peritoneal YST. The standard first-line treatment is surgery plus BEP chemotherapy. Second-line therapy regimens and above, including VIP and TIP, improve the prognosis of recurrent germ cell tumors. This relapsed and refractory patient with peritoneal YST benefits from the secondary BEP' chemotherapy. [ABSTRACT FROM AUTHOR]

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BackgroundEpidemics of infectious diseases have a great negative impact on people's daily life. How it changes over time and what kind of laws it obeys are important questions that researchers are always interested in. Among the characteristics of infectious diseases, the phenomenon of recrudescence is undoubtedly of great concern. Understanding the mechanisms of the outbreak cycle of infectious diseases could be conducive for public health policies to the government.MethodIn this study, we collected time-series data for nine class C notifiable infectious diseases from 2009 to 2021 using public datasets from the National Health Commission of China. Oscillatory power of each infectious disease was captured using the method of the power spectrum analysis.ResultsWe found that all the nine class C diseases have strong oscillations, which could be divided into three categories according to their oscillatory frequencies each year. Then, we calculated the oscillation power and the average number of infected cases of all nine diseases in the first 6 years (2009–2015) and the next 6 years (2015–2021) since the update of the surveillance system. The change of oscillation power is positively correlated to the change in the number of infected cases. Moreover, the diseases that break out in summer are more selective than those in winter.ConclusionOur results enable us to better understand the oscillation characteristics of class C infectious diseases and provide guidance and suggestions for the government's prevention and control policies.

Abstract Background Malaria control in sub-Saharan Africa relies upon prompt case management with artemisinin-based combination therapy (ACT). Ring-stage parasite mRNA, measured by sbp1 quantitative reverse-transcriptase PCR (qRT-PCR), was previously reported to persist after ACT treatment and hypothesized to reflect temporary arrest of the growth of ring-stage parasites (dormancy) following exposure to artemisinins. Here, the persistence of ring-stage parasitaemia following ACT and non-ACT treatment was examined. Methods Samples were used from naturally infected Malian gametocyte carriers who received dihydroartemisinin–piperaquine (DP) or sulfadoxine–pyrimethamine (SP–AQ) with or without gametocytocidal drugs. Gametocytes and ring-stage parasites were quantified by qRT-PCR during 42 days of follow-up. Results At baseline, 89% (64/73) of participants had measurable ring-stage parasite mRNA. Following treatment, the proportion of ring-stage parasite-positive individuals and estimated densities declined for all four treatment groups. Ring-stage parasite prevalence and density was generally lower in arms that received DP compared to SP–AQ. This finding was most apparent days 1, 2, and 42 of follow-up (p

Abstract Background Dynamics of infection by Bartonella and Rickettsia species, which are epidemiologically associated in dogs, have not been explored in a controlled setting. Objectives Describe an outbreak investigation of occult Bartonella spp. infection among a group of dogs, discovered after experimentally induced Rickettsia rickettsii (Rr) infection. Animals Six apparently healthy purpose‐bred Beagles obtained from a commercial vendor. Methods Retrospective and prospective study. Dogs were serially tested for Bartonella spp. and Rr using serology, culture, and PCR, over 3 study phases: 3 months before inoculation with Rr (retrospective), 6 weeks after inoculation with Rr (retrospective), and 8 months of follow‐up (prospective). Results Before Rr infection, 1 dog was Bartonella henselae (Bh) immunofluorescent antibody assay (IFA) seroreactive and 1 was Rickettsia spp. IFA seroreactive. After inoculation with Rr, all dogs developed mild Rocky Mountain spotted fever compatible with low‐dose Rr infection, seroconverted to Rickettsia spp. within 4‐11 days, and recovered within 1 week. When 1 dog developed ear tip vasculitis with intra‐lesional Bh, an investigation of Bartonella spp. infection was undertaken. All dogs had seroconverted to 1‐3 Bartonella spp. between 7 and 18 days after Rr inoculation. Between 4 and 8 months after Rr inoculation, Bh DNA was amplified from multiple tissues from 2 dogs, and Bartonella vinsonii subsp. berkhoffii (Bvb) DNA was amplified from 4 of 5 dogs' oral swabs. Conclusions and Clinical Importance Vector‐borne disease exposure was demonstrated in research dogs from a commercial vendor. Despite limitations, our results support the possibilities of recrudescence of chronic subclinical Bartonella spp. infection after Rr infection and horizontal direct‐contact transmission between dogs.

In malaria, anti-parasite immune response of the host may lead to dysregulated inflammation causing severe neuropathology arising from extensive damage to the Blood Brain Barrier (BBB). Use of anti-malarial drugs alone can control parasitemia and reduce inflammation but it cannot reduce pathology if chronic inflammation has already set in. In the present study, we have tested the efficacy of a new oral artemsinin based combination therapy (ACT) regimen using a combination of anti-malarial compounds like nanoartemisinin and nanoallylated-chalcone9 [{1-(4-Chlorophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy) phenyl]-prop-2-en-1-one}]given together with anti-inflammatory-cum- anti-malarial compounds like nanoandrographolide and nanocurcumin to C57BL/6 mice infected with P. berghei ANKA. Untreated infected mice developed Experimental Cerebral Malaria (ECM) and died between 10 to 12 days after infection from severe BBB damage. We observed that oral treatments with nanoartemisinin or nano allylated chalcone 9 or nanoandrographolide alone, for 4 days after the onset of ECM, delayed the development of severe neurolopathology but could not prevent it. Nanocurcumin treatment for 4 days on the other hand, prevented damage to the BBB but the mice died because of hyperparasitemia. A single time oral administration of our ACT controlled blood parasitemia and prevented damage to the BBB, but recrudescence occurred due to persistence of parasites in the spleen. However the recrudescent parasites failed to induce ECM and BBB damage, leading to prolonged survival of the animals. A second time treatment at the start of recrudescence led to complete parasite clearance and survival of mice without pathology or parasitemia for 90 days. FACS analysis of spleen cells and gene expression profile in brain and spleen as well as quantitation of serum cytokine by ELISA showed that P. berghei ANKA infection in C57Bl/6 mice leads to a Th1-skewed immune response that result in severe inflammation and early death from ECM. Oral treatment with our ACT prevented a heightened pro-inflammatory response by modulating the Th1, Th2 and Treg immune responses and prevented ECM and death.

Reproductive abnormalities, that could lead to possible effects at the population level, have been observed in wild fish throughout the United States, with high prevalence in largemouth bass (LMB; Micropterus salmoides) and smallmouth bass (Micropterus dolomieu). Estrone (E1) and atrazine (ATR) are common environmental contaminants often associated with agricultural land use. 17alpha-ethinylestradiol (EE2) is a contaminant associated with wastewater treatment effluent, and a representative, well-studied estrogen commonly used for fish toxicity testing. Our objective was to assess whether early gonad recrudescence in adult fish was a period of sensitivity for alterations in reproductive condition and function. Adult male LMB were exposed from post-spawning to early gonad recrudescence to either a mixture of E1 (47.9 ng/L) + ATR (5.4 µg/L), or EE2 (2.4 ng/L) in outdoor experimental ponds. Gonad samples were collected from fish just prior to the start of exposure (July), at the end of the exposure period (December), the following spring just prior to spawning (April), and post spawning (May). Gonadosomatic index (GSI) was significantly reduced in E1 + ATR-exposed and EE2-exposed males compared to control at every post-exposure time point. Reduced sperm count and sperm motility were observed in the mixture treatment (E1 + ATR) compared to the control. Sperm motility was also reduced in the EE2 treatment. These data together indicate that estrogenic endocrine-disrupting compounds can lessen the reproductive condition of adult male LMB, and that effects of exposure during early gonad recrudescence can persist at least through the subsequent spawning cycle.

Imported malaria and recurrent infections are becoming an emerging issue in many malaria non-endemic countries. This study aimed to determine the molecular patterns of the imported malaria infections and recurrence. Blood samples were collected from patients with imported malaria infections during 2016–2018 in Guangxi Zhuang Autonomous Region, China. Next-generation amplicon deep-sequencing approaches were used to assess parasite genetic diversity, multiplexity of infection, relapse, recrudescence, and antimalarial drug resistance. A total of 44 imported malaria cases were examined during the study, of which 35 (79.5%) had recurrent malaria infections within 1 year. The majority (91.4%) had one recurrent malaria episode, whereas two patients had two recurrences and one patient had three recurrences. A total of 19 recurrence patterns (the species responsible for primary and successive clinical episodes) were found in patients returning from malaria epidemic countries. Four parasite species were detected with a higher than usual proportion (46.2%) of non-falciparum infections or mixed-species infections. An increasing trend of recurrence infections and reduced drug treatment efficacy were observed among the cases of imported malaria. The high recurrence rate and complex patterns of imported malaria from Africa to non-endemic countries have the potential to initiate local transmission, thereby undermining efforts to eliminate locally acquired malaria. Our findings highlight the power of amplicon deep-sequencing applications in molecular epidemiological studies of the imported malaria recurrences.

In the present study, we propose and analyze an epidemic mathematical model for malaria dynamics, considering multiple recurrent phenomena: relapse, reinfection, and recrudescence. A limitation in hospital bed capacity, which can affect the treatment rate, is modeled using a saturated treatment function. The qualitative behavior of the model, covering the existence and stability criteria of the endemic equilibrium, is investigated rigorously. The concept of the basic reproduction number of the proposed model is obtained using the concept of the next-generation matrix. We find that the malaria-free equilibrium point is locally asymptotically stable if the basic reproduction number is less than one and unstable if it is larger than one. Our observation on the malaria-endemic equilibrium of the proposed model shows possible multiple endemic equilibria when the basic reproduction number is larger or smaller than one. Hence, we conclude that a condition of a basic reproduction number less than one is not sufficient to guarantee the extinction of malaria from the population. To test our model in a real-life situation, we fit our model parameters using the monthly incidence data from districts in Central Sumba, Indonesia called Wee Luri, which were collected from the Wee Luri Health Center. Using the first twenty months’ data from Wee Luri district, we show that our model can fit the data with a confidence interval of 95%. Both analytical and numerical experiments show that a limitation in hospital bed capacity and reinfection can trigger a more substantial possibility of the appearance of backward bifurcation. On the other hand, we find that an increase in relapse can reduce the chance of the appearance of backward bifurcation. A non-trivial result appears in that a higher probability of recrudescence (treatment failure) does not always result in the appearance of backward bifurcation. From the global sensitivity analysis using a combination of Latin hypercube sampling and partial rank correlation coefficient, we found that the initial infection rate in humans and the mosquito infection rate are the most influential parameters in determining the increase in total new human infections. We expand our model as an optimal control problem by including three types of malaria interventions, namely the use of bed net, hospitalization, and fumigation as a time-dependent variable. Using the Pontryagin maximum principle, we characterize our optimal control problem. Results from our cost-effectiveness analysis suggest that hospitalization only is the most cost-effective strategy required to control malaria disease.

Although deslorelin slow-release implants are widely used in the clinic, detailed published information about the recovery of testosterone concentrations (T), semen quality, and testicular and prostatic volume (TV, PV) after treatment is still missing. This article aims to characterize changes during restart after a five-months treatment and subsequent implant removal. Seven male Beagle dogs were treated with deslorelin (treatment group, TG), and three saline-treated dogs served as controls (CG). Deslorelin implants were removed after five months (D ex), followed by detailed andrological examinations for TV, PV, semen collection, and blood sampling for T-analysis with/without GnRH/hCG stimulation tests. TV, PV, and T increased rapidly after D ex in TG, not differing from CG from D91 (TV), D49 (PV), and D14 (T). The first sperm-containing ejaculates were collected between D49 and 70, whereas the samples were normospermic between D84 and 133. A T increase (>0.1 ng/mL) subsequent to the GnRH/hCG stimulation test was observed from D28/29 onwards, respectively. Histological assessment of testicular tissue at the end of the observational period (D149 after implant removal) revealed normal spermatogenesis. Our data confirm that the restart of endocrine and germinative testicular function is highly variable, but nevertheless, all of the effects induced were reversible.

Abstract Recurrences of COVID‐19 infection may occur in immunocompromised patients. Reinfection or reactivation of COVID‐19 virus is a challenging issue in these patients.

Recurrences of COVID-19 infection may occur in immunocompromised patients. Reinfection or reactivation of COVID-19 virus is a challenging issue in these patients. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) can infect developing fetuses in utero and cause severe congenital defects independent of route of maternal infection. Infected men can shed ZIKV RNA in semen for over six months. Whether prolonged viral RNA shedding in semen indicates a persistent infection in the male reproductive tract is unknown. We hypothesized that if ZIKV establishes a persistent infection in the male reproductive tract (MRT), then immunosuppressant treatment should stimulate ZIKV replication and seminal shedding. Male mice were infected with ZIKV and immunosuppressed when they shed viral RNA but not infectious virus in ejaculates. Following immunosuppression, we did not detect infectious virus in ejaculates. However, we did detect ZIKV positive and negative sense RNA in the epididymal lumens of mice treated with cyclophosphamide, suggesting that ZIKV persists in the epididymis. This study provides insight into the mechanisms behind ZIKV sexual transmission, which may inform public health decisions regarding ZIKV risks. • Zika virus persists in the epididymal lumen after virus is no longer shed in ejaculates. • Infectious Zika virus does not recrudesce following acute infection and immunosuppression. • Immunosuppression resulted in higher levels of ZIKV RNA in the epidiymides. [ABSTRACT FROM AUTHOR]

Abstract Background Plasmodium malariae is the most neglected of the six human malaria species and it is still unknown which is the mechanism underlying the long latency of this Plasmodium. Case presentation A case of PCR-confirmed P. malariae recurrence in a 52-year old Italian man was observed 5 months after a primary attack. In the interval between the two observed episodes of malaria the patient denied any further stay in endemic areas except for a visit to Libya, a country considered malaria-free. Genomic DNA of the P. malariae strain using five microsatellites (PM2, PM9, PM11, PM25, PM34) and the antigen marker of circumsporozoite (csp) was amplified and sequenced. Analysis of polymorphisms of the P. malariae csp central repeat region showed differences between the strains responsible of the first and second episode of malaria. A difference in the allele size was also observed for the sequence analysis of PM2 microsatellites. Conclusions Plasmodium malariae is a challenging human malaria parasite and even with the use of molecular techniques the pathogenesis of recurrent episodes cannot be precisely explained.

Abstract Background Current World Health Organization guidelines for conducting anti-malarial drug efficacy clinical trials recommend genotyping Plasmodium falciparum genes msp1 and msp2 to distinguish recrudescence from reinfection. A more recently developed potential alternative to this method is a molecular genotyping assay based on a panel of 24 single nucleotide polymorphism (SNP) markers. Methods Performance parameters of these two genotyping methods were compared using data from two recently completed drug efficacy trials. Blood samples from two anti-malarial therapeutic trials were analysed by both msp genotyping and the 24 SNP assay. Additionally, to conserve time and resources, the statistical program R was used to select the most informative SNPs for a set of unrelated Malawian samples to develop a truncated SNP-based assay for the region surrounding Blantyre, Malawi. The ability of this truncated assay to distinguish reinfection from recrudescence when compared to the full 24 SNP assay was then analysed using data from the therapeutic trials. Results A total of 360 samples were analysed; 66 for concordance of msp and SNP barcoding methodologies, and 294 for assessing the most informative of the 24 SNP markers. SNP genotyping performed comparably to msp genotyping, with only one case of disagreement among the 50 interpretable results, where the SNP assay identified the sample as reinfection and the msp typing as recrudescence. Furthermore, SNP typing was more robust; only 6% of samples were uninterpretable by SNP typing, compared to 19.7% when msp genotyping was used. For discriminating reinfection from recrudescence, a truncated 6 SNP assay was found to perform at 95.1% the accuracy of the full 24 SNP bar code. Conclusions The use of SNP analysis has similar sensitivity to the standard msp genotyping in determining recrudescence from reinfection. Although more expensive, SNP typing is faster and less work intensive. Limiting the assay to those SNPs most informative in the geographical region of interest may further decrease the workload and the cost, making this technique a feasible and affordable alternative in drug efficacy trials.

Objective: To analyze the prescription patterns of general practitioners for the treatment of typhoid fever, identifying the gaps in treatment and recommendations for change of practice by general practitioners (GP’s). Study Design: Descriptive cross sectional study. Place and Duration of Study: Different regions of Rawalpindi & Islamabad, from Sep to Nov 2011. Methodology: Convenient Sampling was done and one hundred GP’s (n=100) were selected. We visited their clinics for private practise and gotconsent to fill questionnaires. Those who answered questionnaire and fulfilled the eligibility criteria were finally selected as study participants. Practitioners were selected irrespective of age, sex, ethnicity and locations within twin cities of Rawalpindi and Islamabad. Results: The prescription patterns revealed 55% GP’s recommend quinolone’s, 40% GP’s 3rd generation cephalosporins, 2% GP’s chloramphenicol, 1% GP’s ampicillin / cotrimoxazole and 2% GP’s prescribe other than these drugs. Forty one percent GP’s recommended antibiotics for 14 days, 36% GP’s advise for 10 days, 15% GP’s recommend for 7 days, 7% GP’s for 5 days and only 1% GP’sprescribed antibiotics for 3 days. Sixty two percent GP’s were of opinion that effective order of drugs in the treatment of typhoid fever is quinolones, 3rd generation cephalosporin and ampicillin while 3rd generation cephalosporins, quinolones, azithromycin, ampicillin and chloramphenicol is effective orderin view of 32% GP’s. For relapse / recrudescence of typhoid fever, 50% GP’s prefer 3rd generation cephalosporins, 29% prescribed quinolones, 8% advise azithromycin / nalidixic acid, 6% recommended chloramphenicol and 3% prescribed ampicillin / cotrimoxazole. Conclusion: Inappropriate prescription pattern.........

Abstract Background Onchocerciasis, or river blindness, is a dermal filariasis caused by infection with the nematode parasite Onchocerca volvulus, transmitted to humans through the bites of blackflies of the genus Simulium. Despite the decade-long West African Regional Programme for the Elimination of Onchocerciasis, involving the mass administration of ivermectin to populations in endemic areas, recrudescence has occurred. An example is in the Cascades Region of south-west Burkina Faso where the resumption of transmission had resulted in infection prevalences of up to 70% in some villages. In 2011, a strategy for community-directed distribution of ivermectin (CDTI) was set up to respond to this worrying re-emergence. Here, we report on a study of Onchocerca spp. transmission in the affected area carried out from January to December 2012. Every month, host-seeking adult females of the S. damnosum complex were collected at sites on the River Comoé near the four villages (Bodadiougou, Bolibana, Badara Karaboro and Badara Dogossè) that had recorded the highest prevalences in 2010. Collected blackflies were dissected and infective larvae were identified using the O-150 PCR method. Results A total of 9114 S. damnosum (s.l.) adult females were collected, of which 5142 were parous (56.4%) and 78 (1.51%) were infective carrying a total of 137 infective larvae. The annual transmission potential (ATP) was calculated as 0, 30, 255 and 771 infective larvae/man/year in Badara Dogossè, Bolibana, Badara Karaboro and Bodadiougou, respectively. Transmission levels in the latter two are of particular concern as they were higher than 100 infective larvae/person/year, the designated minimum threshold required for elimination of severe pathology, including damage to vision. Conclusions These results confirm that recrudescence of onchocerciasis has occurred, and that transmission of O. volvulus was active at sites on the Comoé River in the Cascades region in 2012. In accordance with WHO recommendations, CDTI should be continued and the situation in the Cascades region should be closely monitored if further spread of this outbreak is to be avoided.

La fièvre jaune (FJ) est une fièvre hémorragique virale, causée par le virus de la fièvre jaune, transmise par les moustiques du genre Aedes. Au Tchad depuis 2013, 04 cas de fièvre jaune ont été identifiés et confirmés dans le cadre du programme national de surveillance de la fièvre. Nous rapportons ici l´observation clinique du dernier cas confirmé dans le district sanitaire de Lai. Il s´agit d´un homme de 57 ans sans antécédents médicaux et chirurgicaux significatifs et un statut vaccinal inconnu. Il a consulté le 21 avril 2020 pour fièvre, ictère d´épistaxis d´abondance modérée à faible et hépatomégalie douloureuse. Dont les explorations para-cliniques ont permis de mettre en évidence le virus de la fièvre jaune en post mortem par RT-PCR. Ainsi la confirmation de la fièvre jaune dans ce district, le faible niveau de couverture vaccinale, la réalité de la circulation du virus et la présence du vecteur dans le pays devraient avertir d´une réelle menace de réémergence de la fièvre jaune au Tchad.

Background: Malaria control in sub-Saharan Africa relies upon prompt case management with artemisinin-based combination therapy (ACT). Ring-stage parasite mRNA, measured by sbp1 quantitative reverse-transcriptase PCR (qRT-PCR), was previously reported to persist after ACT treatment and hypothesized to reflect temporary arrest of the growth of ring-stage parasites (dormancy) following exposure to artemisinins. Here, the persistence of ring-stage parasitaemia following ACT and non-ACT treatment was examined. Methods: Samples were used from naturally infected Malian gametocyte carriers who received dihydroartemisinin–piperaquine (DP) or sulfadoxine–pyrimethamine (SP–AQ) with or without gametocytocidal drugs. Gametocytes and ring-stage parasites were quantified by qRT-PCR during 42 days of follow-up. Results: At baseline, 89% (64/73) of participants had measurable ring-stage parasite mRNA. Following treatment, the proportion of ring-stage parasite-positive individuals and estimated densities declined for all four treatment groups. Ring-stage parasite prevalence and density was generally lower in arms that received DP compared to SP–AQ. This finding was most apparent days 1, 2, and 42 of follow-up (p < 0.01). Gametocytocidal drugs did not influence ring-stage parasite persistence. Ring-stage parasite density estimates on days 14 and 28 after initiation of treatment were higher among individuals who subsequently experienced recurrent parasitaemia compared to those who remained free of parasites until day 42 after initiation of treatment (pday 14 = 0.011 and pday 28 = 0.068). No association of ring-stage persistence with gametocyte carriage was observed. Conclusions: The current findings of lower ring-stage persistence after ACT without an effect of gametocytocidal partner drugs affirms the use of sbp1 as ring-stage marker. Lower persistence of ring-stage mRNA after ACT treatment suggests the marker may not reflect dormant parasites whilst it was predictive of re-appearance of parasitaemia. [ABSTRACT FROM AUTHOR]

La fièvre jaune (FJ) est une fièvre hémorragique virale, causée par le virus de la fièvre jaune, transmise par les moustiques du genre Aedes. Au Tchad depuis 2013, 04 cas de fièvre jaune ont été identifiés et confirmés dans le cadre du programme national de surveillance de la fièvre. Nous rapportons ici l'observation clinique du dernier cas confirmé dans le district sanitaire de Lai. Il s'agit d'un homme de 57 ans sans antécédents médicaux et chirurgicaux significatifs et un statut vaccinal inconnu. Il a consulté le 21 avril 2020 pour fièvre, ictère d'épistaxis d'abondance modérée à faible et hépatomégalie douloureuse. Dont les explorations para-cliniques ont permis de mettre en évidence le virus de la fièvre jaune en post mortem par RT-PCR. Ainsi la confirmation de la fièvre jaune dans ce district, le faible niveau de couverture vaccinale, la réalité de la circulation du virus et la présence du vecteur dans le pays devraient avertir d'une réelle menace de ré-émergence de la fièvre jaune au Tchad. English abstract Yellow fever (YF) is a viral haemorrhagic fever caused by yellow fever virus transmitted by Aedes mosquitoes. Since 2013, in Chad, four cases of yellow fever have been detected and confirmed as part of the national fever surveillance program. We here report the last clinical case confirmed in the health district of Lai. The patient was a 57-year-old man with no significant medical and surgical history and unknown immunisation status. He consulted on April 21st, 2020 for fever, moderate to low abundance jaundice and epistaxis (nosebleed) and painful hepatomegaly. Paraclinical examinations, such as RT-PCR, objectified yellow fever virus in post-mortem tissue sample. Thus, confirmed yellow fever cases in this district, the low level of vaccination coverage, the circulation of the virus and the presence of vector in the country should warn of a real threat of reemergence of yellow fever in Chad. [ABSTRACT FROM AUTHOR]