Multiplex PCR in the empirical antibiotic treatment of patients with SARS-CoV-2 and bacterial respiratory superinfection.

Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic led to overuse of antimicrobials, which increased concerns regarding antimicrobial resistance. Objective: To measure the impact of a multiplex polymerase chain reaction (PCR) pneumonia panel on empirical antibiotic treatment for patients with critical coronavirus disease 2019 (COVID-19) with suspected bacterial respiratory superinfection. Methods: This descriptive, prospective study was undertaken in a 36-bed intensive care unit from June 2020 to July 2021. Patients with severe COVID-19 who were ventilated and under suspicion of bacterial respiratory superinfection were included in the study. The intervention was a semi-quantitative multiplex PCR alongside concurrent standard cultures. When PCR panel results were expected to be obtained within 3 h of sampling, empirical antibiotic treatment was not administered while awaiting the results. Otherwise, empirical treatment was initiated. Patients classified as 'avoided empirical treatment' avoided 48-72 h of empirical antibiotic therapy. For those patients who received empirical treatment, the PCR panel results were used to decide whether treatment should be escalated, de-escalated, maintained or stopped. Positive and negative predictive values, and 'avoided empirical treatment' were calculated. Medical conduct and panel results were analysed for patients who received empirical treatment. Results: Eighty-two patients (71% male, 29% female) were included in this study. The mean age was 57.5 years, and the mean APACHE II score was 16. Ninety PCR panels were performed, and the negative and positive predictive values were 99.9% and 66.7%, respectively. Empirical treatment was avoided in 61% of episodes. Of those patients who were receiving antibiotics when the PCR panel was performed, treatment was de-escalated in 71%, escalated in 14%, stopped in 9% and maintained in 6%. A diagnosis of bacterial respiratory superinfection was ruled out in 19% of cases. Conclusions: PCR panels prevented the initiation of empirical antibiotic treatment in two-thirds of patients, and led to de-escalation in more than two-thirds of those who had started empirical antibiotic treatment. The high negative predictive value of the PCR panel allowed the diagnosis of bacterial respiratory superinfection to be ruled out. This tool represents a significant contribution to diagnostic stewardship in order to avoid the unnecessary use of antibiotics.

Hospital environment hygiene nurse: a key player to reduce healthcare associated infections by multi-resistant organisms.

BACKGROUND: Multi-Resistant Organisms (MRO) healthcare-associated infections (HAI) are closely associated with contamination of surfaces. Outsourced companies are usually in charge of both hospital hygiene and environmental hygiene personnel (EHP) supervision, which can result in bias. METHODS: A quasi-experimental study. The intervention was to add the "Hospital Environment Hygiene Nurse" (HEHN). MRO acquired infection rate and MRO acquired colonized rate were calculated, pre and post intervention. Confounding variables: MRO carriage rate upon admission and hospitalisation days median (HDM) were calculated. RESULTS: Median length of stay: 5 days (p=0.85, interquartile range=6 days). Carriage rate upon admission: 4.3% for pre-intervention vs 5.3% post-intervention, dif. (CI 95%): 1% (-1% to 2.9%) p=0.33. MRO acquired infection rate: 4.3% for pre-intervention vs. 2% post-intervention, Standardized Infection Ratio (SIR) (CI 95%): 0.47 (0.25 to 0.87). MRO acquired colonization rate:10.4% for pre-intervention vs. 7.9% post-intervention, SIR (CI 95%): 0.75 (0.53 to 1.07). CONCLUSIONS: As a reinforcement to standard infection control (IC) measures in place, the incorporation of an exclusive, full-time HEHN was significantly useful to reduce MRO HAI.

Shifting environmental baselines in the Red Sea.

The Red Sea is among the world's top marine biodiversity hotspots. We re-examined coastal ecosystems at sites surveyed during the 1980s using the same methodology. Coral cover increased significantly towards the north, mirroring the reverse pattern for mangroves and other sedimentary ecosystems. Latitudinal patterns are broadly consistent across both surveys and with results from independent studies. Coral cover showed greatest change, declining significantly from a median score of 4 (1000-9999 m(2)) to 2 (10-99m(2)) per quadrat in 2010/11. This may partly reflect impact from coastal construction, which was evident at 40% of sites and has significantly increased in magnitude over 30 years. Beach oil has significantly declined, but shore debris has increased significantly. Although substantial, levels are lower than at some remote ocean atolls. While earlier reports have suggested that the Red Sea is generally healthy, shifting environmental baselines are evident from the current study.

Short-term clinico-radiographic response to super-selective intra-arterial cerebral infusion of Bevacizumab for the treatment of vestibular schwannomas in Neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome with a prevalence of approximately 1 in 30,000. NF 2 is characterized by bilateral vestibular schwannomas, as well as meningiomas, ependymomas and gliomas. Currently, surgical resection and radiotherapy represent the mainstay of treatment, although new studies suggest a role for certain chemotherapeutic agents. Intravenous administration of Bevacizumab (Avastin, Genetech Pharmaceuticals) has been shown to be active in the treatment of vestibular schwannomas. The IV route of administration, however, carries a risk of known systemic side-effects such as bowel perforation, wound dehiscence and pulmonary embolism. In addition, the percentage of drug that reaches the tumor site may be restricted by the blood tumor barrier. This report describes the super-selective intra-arterial infusion of Bevacizumab following blood brain barrier disruption for the treatment of vestibular schwannomas in three patients with Neurofibromatosis type 2. It represents the first time such a technique has been performed for this disease. Additionally, this method of drug delivery may have important implications in the treatment of patients with vestibular schwannomas associated with Neurofibromatosis type 2.

Intraprocedural aneurysmal rupture during coil embolization of brain aneurysms: role of balloon-assisted coiling.

BACKGROUND AND PURPOSE: Intraprocedural aneurysmal rupture is a feared complication of coil embolization of intracranial aneurysms and is associated with high rates of morbidity and mortality. We report the incidence, endovascular management, and clinical outcome of patients with IAR, with emphasis on the role of the balloon-assisted technique. MATERIALS AND METHODS: We conducted a retrospective analysis of all intracranial aneurysms treated by coil embolization between September 2001 and June 2011. All patients with IAR were studied. Comparison of immediate clinical outcomes was performed by using univariate analysis (Fisher exact test). RESULTS: Of 652 intracranial aneurysms treated with coil embolization, an IAR occurred in 22 (3.4%). Rupture occurred during placement of coils in 18 cases, microcatheters in 2 cases, and a guidewire in 1 case, and during induction of anesthesia in 1 case. Before treatment, 15 of 22 (68%) patients were in good clinical condition (WFNS grade I). There were fewer patients with worsening of the WFNS grade following an IAR when the balloon-assisted technique was used (7.7%) compared with when it was not (55.5%) (P = .023). Death occurred in 2 (9.1%) patients. CONCLUSIONS: IAR is a potentially serious complication of coil embolization. If IAR occurs, balloon-assistance is helpful in obtaining rapid hemostasis resulting in better short-term outcomes.

Endovascular treatment of spinal arteriovenous lesions: beyond the dural fistula.

During the past few decades, there have been significant advances in the understanding of spinal vascular lesions, mainly because of the evolution of imaging technology and selective spinal angiography techniques. In this article, we discuss the classification, pathophysiology, and clinical manifestations of spinal vascular lesions other than DAVFs and provide a review of the endovascular approach to treat these lesions.

Early endovascular management of oculomotor nerve palsy associated with posterior communicating artery aneurysms.

Palsy of the third cranial nerve (oculomotor nerve, CNIII) is a well-known clinical presentation of posterior communicating artery (P-com) aneurysm. We report a series of 11 patients with partial or complete third nerve palsy secondary to P-com aneurysm. All were treated with endovascular embolization within seven days of symptom onset. Third nerve palsy symptoms resolved in 7/11 (64%), improved in 2/11 (18%) and did not change in 2/11 (18%) patients.

Balloon-assisted technique for trapped microcatheter retrieval following onyx embolization. A case report.

SUMMARY: During embolization of a large frontal arteriovenous malformation (AVM), Onyx-18 (eV3) was injected into an M3 branch of the middle cerebral artery via a Marathon microcatheter (eV3). After 40 minutes of embolization, the microcatheter could not be retracted due to fixation within the Onyx cast despite prolonged, robust attempts. A balloon microcatheter (Hyperform(TM), eV3) was advanced distally and inflated to provide distal counter tension, allowing microcatheter retrieval with minimal traction on the vasculature.

Reciprocal negative regulation between S100A7/psoriasin and beta-catenin signaling plays an important role in tumor progression of squamous cell carcinoma of oral cavity.

Overexpression of S100A7 (psoriasin), a small calcium-binding protein, has been associated with the development of psoriasis and carcinomas in different types of epithelia, but its precise functions are still unknown. Using human tissue specimens, cultured cell lines, and a mouse model, we found that S100A7 is highly expressed in preinvasive, well-differentiated and early staged human squamous cell carcinoma of the oral cavity (SCCOC), but little or no expression was found in poorly differentiated, later-staged invasive tumors. Interestingly, our results showed that S100A7 inhibits both SCCOC cell proliferation in vitro and tumor growth/invasion in vivo. Furthermore, we demonstrated that S100A7 is associated with the beta-catenin complex, and inhibits beta-catenin signaling by targeting beta-catenin degradation via a noncanonical mechanism that is independent of GSK3beta-mediated phosphorylation. More importantly, our results also indicated that beta-catenin signaling negatively regulates S100A7 expression. Thus, this reciprocal negative regulation between S100A7 and beta-catenin signaling implies their important roles in tumor development and progression. Despite its high levels of expression in early stage SCCOC tumorigenesis, S100A7 actually inhibits SCCOC tumor growth/invasion as well as tumor progression. Downregulation of S100A7 in later stages of tumorigenesis increases beta-catenin signaling, leading to promotion of tumor growth and tumor progression.

Differences of chemoresistance assay between invasive micropapillary/low-grade serous ovarian carcinoma and high-grade serous ovarian carcinoma.

The objective of this study was to evaluate the pattern of chemoresistance in invasive micropapillary/low-grade serous ovarian carcinoma (invasive MPSC/LGSC) and high-grade serous ovarian carcinoma (HGSC) according to extreme drug resistance (EDR) assay testing. Surgical specimens of 44 recurrent ovarian cancer patients harvested at the time of cytoreductive surgery between August 1999 and February 2004 were identified retrospectively from the tumor registry database. Thirteen patients (29.5%) had recurrent invasive MPSC/LGSC and 31 (70.5%) patients had recurrent HGSC. Eight drugs were evaluated; EDR assay results were compared between LGSC and HGSC groups using Fisher exact tests and exact logistic regression models. Compared to HGSC, invasive MPSC/LGSC were more likely to manifest EDR to the drugs paclitaxel (69% vs 14%, P < 0.001), carboplatin (50% vs 17%, P= 0.05), cyclophosphamide (40% vs 23%, P= 0.41), gemcitabine (36% vs 19%, P= 0.40), and cisplatin (33% vs 28%, P= 0.72) and less likely to be resistant to etoposide (0% vs 44%, P= 0.007), doxorubicin (8% vs 45%, P= 0.03), and topotecan (8% vs 21%, P= 0.65). Exact logistic regression estimates revealed that invasive MPSC/LGSC patients had significantly increased probabilities of paclitaxel resistance odds ratio (OR) = 12.5 (95% CI: 2.3-100.0), P= 0.001 and carboplatin resistance OR = 4.8 (95% CI: 0.9-25.0), P= 0.07, while the HGSC cases were more likely to be resistant to etoposide OR = 12.1 (95% CI: 1.7-infinity), P=0.009 and doxorubicin OR = 8.6 (95% CI: 1.0-413.7), P= 0.05. In this retrospective analysis, patients with recurrent invasive MPSC/LGSC were more likely to manifest EDR to standard chemotherapy agents (platinum and paclitaxel). These observations may help to guide chemotherapeutic decision making in these patients if confirmed in a large-scale study.

Factores de riesgo de infección en cirugía cardiovascular / Risk factors for infection in cardiovascular surgery

Introducción: Las infecciones en cirugía cardiovascular son una importante causa de morbi mortalidad. Objetivos: conocer la incidencia de infección y los factores de riesgo relacionados con la misma. Material y Métodos:Se incluyeron todos los pacientes(p) mayores de 1 mes y menores de 18 años sometidos a cirugía cardiovascular en el período comprendido enre el 1/11/01 y el 1/1/02. Se analizaron los siguientes factores de riesgo; edad, sexo, tipo de cardiopatía, patología de base,internación,infección, uso de antibióticos y cirugía previa, score de American Society of Anesthesiology (ASA), tiempo de bomba, material protésico, requerimiento de inotrópicos,asistencia respiratoria mecánica(ARM), vías centrales, sonda vesical, drenaje de tórax, tipo de infección, germen y evolución. Resultados: Se incluyeron 350p de los cuales 184p (53 po ciento) eran de sexo masculino. La mediana de edad fue de 30 meses (r:1 menos 212m).Tenía patología de Base 75p (21 por ciento). La comunicación interventricular, la Tetralogía de Fallot y la comunicación interauricular fueron las cardiopatías más frecuentes (46 por ciento). 56p (16 por ciento) tenía cirugía previa y 30p (9 por ciento) habían tenido infección. El score de ASA fue igual o mayor de 3 en 308p (88 por ciento). La mediana de internación previa fue de un día (r:1 menos 120d). La mediana de tiempo de bomba fue de 69 minutos(13 menos 300m), 88p (25 por ciento)requirieron soporte inotrópico con una mediana de 5 días (r:1 menos 62d),147p (42 por ciento) requirieron ARM con una mediana de 4d(r:1 menos 66d). La estadía hospitalaria fue de una mediana de 5d (r:1 media 120d);38p (11 por ciento)desarrollaron infección: del sitio quirúrgico en 12p (3.5 por ciento) y 26p (7.5 por ciento)fuera del mismo. Fallecieron 11p (3 por ciento). Por análisis univariado la menor edad, la patología de base, el score de ASA mayor o igual a 3, la infección previa, el requerimiento de soporte inotrópico, el tiempo prolongado de bomba, la ARM y la estadía hospitalaria mayor de 12 días fueron factores de riesgo de infección significativos (p<0.05). Por análisis multivariado sólo fueron la patalogía de base (p<0.012).OR 4.22 (1.38 menos 12.8), el requerimiento del soporte inotrópico (p<0.027), OR 4.04(1.17 menos 13.9) y la estadía poscirugía mayor de 12 días (p<0.003), OR 1.08(1.03 menos 1.14). Conclusión: Las infecciones son una importante causa de morbimortalidad en cirugía cardiovascular

Dosis efectiva de midazolam para sedación consciente en estomatología pediátrica / Effective midazolam dosage for conscious sedation in pediatric dentistry

El estudio determinó la dosis, el efecto clínico sedativo y la seguridad del midazolam por vía oral e intranasal en 20 niños de la clínica de odontopediatría. Los datos se obtuvieron en niños clasificados como ASA 1 y con conducta de Fankl tipo II y III. La sedación fue adecuada para asegurar el éxito completo del tratamiento dental en los pacientes con sedación vía oral. La sedación se obtuvo con una dosis oral de 0.3 mg/kg de clorhidrato de midazolam. No existieron signos de depresión respiratoria o desaturación de oxígeno por abajo del 98 por ciento, determinado con el oxímetro de pulso. No se requirió suplemento de oxígeno y no se presentaron complicaciones. Se concluye que el midazolam aplicado por vía oral es una alternativa segura y efectiva en el tratamiento definitivo, reduciendo la ansiedad en niños en odontopediatría

Body mass index and asthma among Mexican adults: the effect of using self-reported vs measured weight and height.

Several recent studies have demonstrated a positive association between obesity and asthma among women but not men. The present study examines the effect of misclassification of body mass index (BMI) in the association between obesity and asthma by gender. This cross-sectional analysis included a total sample of 961 Mexican adults. Use of measured BMI revealed that obesity (BMI >30 kg/m(2)) was a risk factor for asthma diagnosis in both men (OR, 2.5; 95% CI, 1.1-5.9) and women (OR, 2.3; 95% CI, 1.5-3.8). In contrast, use of self-reported BMI showed that only women (OR, 1.7; 95% CI, 1.1-2.7) and not men (OR, 1.3; 95% CI, 0.6-2.9) were at increased risk of asthma diagnosis. Use of self-reported BMI substantially underestimated the prevalence of obesity; this bias was not related to asthma per se but was mainly due to obesity. Therefore, misclassification of BMI obscured the relationship between obesity and asthma to a greater extent among men than among women since obesity prevalence in the general population was higher among men. Measurement bias merits greater attention in future research on obesity and asthma.

Spatially extended sound equalization in rectangular rooms.

The results of a theoretical study on global sound equalization in rectangular rooms at low frequencies are presented. The zone where sound equalization can be obtained is a continuous three-dimensional region that occupies almost the complete volume of the room. It is proved that the equalization of broadband signals can be achieved by the simulation of a traveling plane wave using FIR filters. The optimal solution has been calculated following the traditional least-squares approximation, where a modeling delay has been applied to minimize reverberation. An advantage of the method is that the sound field can be estimated with sensors placed in the limits of the equalization zone. As a consequence, a free space for the listeners can be obtained.

C(5)-C(5a)-modified bicyclomycins: synthesis, structure, and biochemical and biological properties.

Bicyclomycin (1) is a novel antibiotic that targets rho transcription termination factor in Escherichia coli. We have demonstrated that retention of the C(5)-C(5a) exomethylene unit in 1 is not essential for inhibition. In a recent paper we proposed a working model for 1 and rho function and suggested that 1 binds in a cleft with the C(5)-C(5a) exomethylene unit directed toward the dimeric interface of two rho monomers. This report examines the bicyclomycin C(5)-C(5a) structural constraints necessary for retention of rho inhibitory activity. Three classes of C(5)-C(5a)-modified bicyclomycins have been prepared and their inhibitory activities evaluated in the poly C-dependent ATPase and filter disk antimicrobial assays. The first series consisted of 12 analogues (8-19) that contained a C(5a)-unsaturated substituent and possessed C(5E)-geometry. The second set were a pair of C(5a)-substituted C(5E)- and C(5Z)-geometrical isomers (21 and 23). The final group of compounds consisted of six C(5)-C(5a)-dihydrobicyclomycins (24-28, 34) where the terminal substituent was systematically varied. We find that extending the C(5)-C(5a) double bond with unsaturated substituents provides bicyclomycin derivatives with excellent inhibitory activities in the biochemical assay, and that enhanced inhibitory activity is observed for the C(5E) geometrical isomer compared with its C(5Z) counterpart. Finally, C(5a)-substituted dihydrobicyclomycin inhibitory activity appears to be tightly regulated by the nature and spatial placement of the C(5a)-terminal substituent with respect to the [4.2.2]-bicyclic ring system. The observed biochemical activities for the C(5a)-extended conjugated bicyclomycin derivatives and the (5E) and (5Z) isomers were correlated with a structural model for the 1-rho complex.

[Genetic aspects of asthma]. / Aspectos genéticos del asma.

Asthma is a complex disease associated with bronchial hyperreactivity and atopy, making asthma a disease with a phenotype that has been clinically difficult to define. Despite intense research, prevalence of asthma remain relatively high. The key reason for the high prevalence and morbility is that the fundamental mechanisms predisposing individuals to the development of asthma are not understood. Familial aggregation observed in this pathology has prompted for the search of an involved genetic component. This task is difficult due to the complex nature of asthma. A universally accepted definition for this disease is not available, clinical expression can be modulated by environmental factors, and inheritance does not follow a clear Mendelian pattern. Establishment of more precise clinical and laboratory criteria has improved the design and interpretation of genetic studies. Twin analysis and segregation studies have demonstrated an important genetic component with a probably multifactorial pattern of inheritance. "Sib pair" studies and familial segregation analyses have shown linkage between some chromosomal regions and asthma, including chromosome 5, 6, 7, 11 and 14. The search for major genes in these chromosomal segments has been focused on loci involved in the allergic process. Among these, the loci for IL-9 and IL-13 in chromosome 5 seem to play an important role in the pathogenesis of asthma. Understanding the fundamental gene-environmental interactions in the development of asthma should lead to earlier identification of susceptible individuals and more effective approaches for disease prevention.

Synthesis and evaluation of 1,2,8, 8a-Tetrahydrocyclopropa[c]pyrrolo[3,2-e]indol-4(5H)-one, the parent alkylation subunit of CC-1065 and the duocarmycins: impact of the alkylation subunit substituents and its implications for DNA alkylation catalysis.

The synthesis of 1,2,8,8a-tetrahydrocyclopropa[c]pyrrolo[3, 2-e]indol-4(5H)-one (CPI), the parent CC-1065 and duocarmycin SA alkylation subunit, is detailed. The parent CPI alkylation subunit lacks the C7 methyl substituent of the CC-1065 alkylation subunit and the C6 methoxycarbonyl group of duocarmycin SA, and their examination permitted the establishment of the impact of these natural product substituents. The studies revealed a CPI stability comparable to the CC-1065 alkylation subunit but which was 6x more reactive than the (+)-duocarmycin SA alkylation subunit, and it displayed the inherent reaction regioselectivity (4:1) of the natural products. The single-crystal X-ray structure of (+)-N-BOC-CPI depicts a near identical stereoelectronic alignment of the cyclopropane accounting for the identical reaction regioselectivity and a slightly diminished vinylogous amide conjugation relative to (+)-N-BOC-DSA suggesting that the stability distinctions stem in part from this difference in the vinylogous amide as well as alterations in the electronic nature of the fused pyrrole. Establishment of the DNA binding properties revealed that the CPI-based agents retain the identical DNA alkylation selectivities of the natural products. More importantly, the C6 methoxycarbonyl group of duocarmycin SA was found to increase the rate (12-13x) and efficiency (10x) of DNA alkylation despite its intrinsic lower reactivity while the CC-1065 C7 methyl group was found to slow the DNA alkylation rate (4x) and lower the alkylation efficiency (ca. 4x). The greater DNA alkylation rate and efficiency for duocarmycin SA and related analogues containing the C6 methoxycarbonyl is proposed to be derived from the extended length that the rigid C6 methoxycarbonyl provides and the resulting increase in the DNA binding-induced conformational change which serves to deconjugate the vinylogous amide and activate the alkylation subunit for nucleophilic attack. The diminished properties resulting from the CC-1065 C7 methyl group may be attributed to the steric impediment this substituent introduces to DNA minor groove binding and alkylation. Consistent with this behavior, the duocarmycin SA C6 methoxycarbonyl group increases biological potency while the CC-1065 C7 methyl group diminishes it.

Role of the C(6)-hydroxy group in bicyclomycin: synthesis, structure, and chemical, biochemical, and biological properties.

Bicyclomycin (1) is a commercial antibiotic whose primary site of action in Escherichia coli is the transcription termination factor rho. A recent structure-activity relationship study of 1 showed that replacing the C(6)-hydroxy group with alkoxy and thioalkoxy substituents led to dramatic losses of inhibitory activity in rho biochemical assays. The origin for this structural specificity has been explored by the synthesis and chemical, biochemical, and biological evaluation of C(6)-amino- (13), C(6)-(hydroxylamino)-(14), and C(6)-mercaptobicyclomycin (15). These compounds, like 1, are capable of entering into hydrogen bond donor interactions with rho and are capable of undergoing C(6) ring opening to generate alpha, beta-unsaturated carbonyl, imine, or thione systems. The chemical reactivity of 13-15 was compared with that of 1. We observed that 1, upon treatment with EtSH under moderate and basic conditions, readily underwent C(6) hemiaminal bond cleavage followed by conjugate addition to beta-methylene-alpha-ketoamide 2 to give Michael addition adducts whereas 13-15 reacted by initial cleavage of the C(1)-O(2) bond. Biochemical and biological assays of 13-15 and related analogues demonstrated that the C(6) hydroxy group in 1 was essential for activity. We found that replacing the C(6)-hydroxy group in 1 with weaker hydrogen bond donors led to low inhibitory activities in the rho-dependent ATPase and transcription termination assays. None of the bicyclomycin derivatives exhibited antibiotic activity against E. coli W3350 cells at a 32 mg/mL concentration. The apparent specificity for the C(6)-hydroxy group in 1 suggests that an efficient hydrogen bond donor interaction from the C(6)-hydroxy group to rho or the C(6) hemiaminal bond cleavage to 2 or both is necessary for drug function.

Periodically kicked hard oscillators.

A model of a hard oscillator with analytic solution is presented. Its behavior under periodic kicking, for which a closed form stroboscopic map can be obtained, is studied. It is shown that the general structure of such an oscillator includes four distinct regions; the outer two regions correspond to very small or very large amplitude of the external force and match the corresponding regions in soft oscillators (invertible degree one and degree zero circle maps, respectively). There are two new regions for intermediate amplitude of the forcing. Region 3 corresponds to moderate high forcing, and is intrinsic to hard oscillators; it is characterized by discontinuous circle maps with a flat segment. Region 2 (low moderate forcing) has a certain resemblance to a similar region in soft oscillators (noninvertible degree one circle maps); however, the limit set of the dynamics in this region is not a circle, but a branched manifold, obtained as the tangent union of a circle and an interval; the topological structure of this object is generated by the finite size of the repelling set, and is therefore also intrinsic to hard oscillators.